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Environmental Contaminants, Iron Deficiency, and Iron-Deficiency Anemia: A Review of the Literature.
Abstract
Iron deficiency (ID) and ID anemia (IDA) are global health concerns that tend to affect vulnerable populations, including women, children, and those living in areas disproportionately affected by environmental health hazards. A review of the literature was conducted using the top ten chemicals of public health concern as identified by the World Health Organization (WHO) in 2020, in combination with the terms “iron deficiency” and “anemia.” Both epidemiological and controlled experimental studies were considered. Eight contaminants or exposure classifications were ultimately considered to be within the scope of this review: lead, cadmium, arsenic, mercury, indoor and ambient air pollution, asbestos, dioxin and dioxin-like polychlorinated biphenyls (PCBs), and fluoride. Lead, cadmium, indoor and ambient air pollution, and fluoride are reliably linked to higher IDA prevalence and lower hematological parameters, including hemoglobin, hematocrit, and red blood cell count, all indicators of anemia. Direct measures of ID are less frequently reported. Further research studies, particularly controlled exposure studies, are needed to determine the importance of arsenic and mercury in contributing to the global ID and IDA burden. There is limited evidence that supplemental or dietary iron fortification can ameliorate the effects of lead, but not fluoride, and the efficacy of fortification has not been widely studied in the context of the remaining contaminants. Asbestos, dioxin, and dioxin-like PCBs are linked to anemia; however, the role of iron homeostasis is more complex and tends to include iron bioaccumulation. The narrative review has identified a need for renewed effort to address environmental factors beyond diet and nutrition when implementing ID and IDA interventions.
1. Introduction
In 2020, the World Health Organization (WHO) released a list of the top ten contaminants or contaminant groups of public health concern, including air pollution, arsenic, asbestos, benzene, cadmium, dioxin and dioxin-like substances, fluoride, lead, mercury, and pesticides [1]. Of these, eight have been linked to iron deficiency (ID) or anemia. Anemia is classified as one of the top WHO global health targets [2]. A quarter of the global population is anemic, and anemia is responsible for 660 years lived with disability per 100,000 people [3]. Providing additional nutritive iron is not always an effective treatment, so mitigating exposure to key chemicals will be necessary to tackle the global disease burden [3].
The scope of this review is a summary of the current understanding of the effects of exposure to key chemicals of global health concern on ID and ID anemia (IDA) (ID/IDA) using the last twenty years of research. Toxic metals (lead, cadmium, mercury, and arsenic), air pollution (indoor and ambient), asbestos, dioxin and dioxin-like compounds (DLCs), and fluoride will be discussed. Though there is robust evidence that benzene causes aplastic anemia, the condition is caused by damage to the bone marrow and is unrelated to iron homeostasis, so this topic is outside the scope of this review. Pesticides are similarly not implicated in iron-related anemias.
We developed the following literature search strategy, using PubMed and Google Scholar as our databases, to conduct a rigorous nonsystematic narrative review. The following search terms were entered using a strategy of pairing each exposure term (lead/Pb, cadmium/Cd, mercury/Hg, arsenic/As, air pollution, PM2.5, PM10, dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), DLCs, polychlorinated biphenyls (PCBs), and fluoride) with the terms “anemia” and “iron deficiency.” Observational studies of human populations or wildlife were selected using the following inclusion criteria: a reported anemia diagnosis, systemic hemoglobin levels, systemic iron levels, systemic ferritin levels, and/or red blood cell counts, and documented exposure to the toxicant or toxicant group of interest, either by self-reported use, investigator-reported use, ecological probability, or quantification in biofluids. Experimental in vivo and in vitro studies were included based on the criteria that the study was designed to deliver a controlled quantity of the chemical of interest to an animal model or mammalian cell line and reported elemental iron, ferritin and/or hemoglobin quantitation, and/or expression of genes or proteins with key roles in iron absorption and transport. In order to provide a contemporary perspective, only articles published since 2003 have been considered. The aim of this review is to determine which of the global priority pollutants have sufficient evidence to be implicated in ID/IDA, identify gaps in understanding, and discuss a role for iron supplementation intervention.
2. Toxic Heavy Metals and Metalloids
The relationship between toxic metal and metalloid exposure and ID/IDA can be difficult to study in populations because of the complicated interplay between the two factors. ID is both induced by and increases the absorption of certain heavy metals, and disentangling the direction of influence is a challenge, especially from cross-sectional epidemiological studies. The perinatal period appears to engender special vulnerability to these phenomena because maternal and child health can be significantly impacted by the interaction between metal burden and ID.
2.1. Lead
2.1.1. Observational Studies
Epidemiological studies have determined associations between blood lead levels and parameters associated with ID/IDA (Table 1). Interpretation of these findings differs among researchers, and it remains unclear if the primary directionality of the relationship is that lead exposure causes ID or ID increases lead absorption. Among pregnant women, higher blood lead levels have frequently been linked to ID/IDA with poor birth outcomes; however, one study of mothers found no association between lead in breast milk or infant hair with maternal anemia status? [4–6, 29]. Higher blood lead levels in infants and children are associated with lower hemoglobin and blood iron levels and higher anemia prevalence. A cross-sectional study of infants found an association between lead levels and ID [7]. Exposure to lead from e-waste processing inhibited hemoglobin synthesis in children, and those living in a region with especially high lead exposure leading to blood lead levels over 100 ug/L have higher rates of anemia [8, 9]. In addition to those in lead hotspots, children living in cities with higher blood lead were more likely to have lower hemoglobin levels, suggesting urban lead exposure is also linked to iron status [10, 11]. This association may also exacerbate the effects of other illnesses, which has been found in children with malaria [12]. In contrast, several studies of otherwise healthy children found no association with iron status or anemia, and one found a positive correlation between blood lead and iron [13–17].
| Study details | Exposure assessment | Relevant findings | Reference |
|---|---|---|---|
|
|
|
[4] |
|
|
Anemia prevalence, postpartum hemoglobin, postpartum iron supplementation use ? | [5] |
|
|
|
[6] |
|
|
|
[7] |
|
|
|
[8] |
|
|
IDA prevalence ? | [9] |
|
|
IDA, low transferrin saturation prevalence ? | [10] |
|
|
Hemoglobin ? | [11] |
|
|
Hemoglobin ? | [12] |
|
|
Anemia prevalence ? | [13] |
|
Lead, arsenic; blood | Hemoglobin ? | [14] |
|
Lead; blood, mine proximity | ID, IDA prevalence ? | [15] |
|
Lead, cadmium; blood |
|
[16] |
|
Lead, cadmium; blood | Elemental iron ? | [17] |
|
|
|
[18] |
|
|
|
[19] |
|
|
Elemental iron ? | [20] |
|
Lead, cadmium; blood, urine |
|
[21] |
|
Lead, cadmium; blood |
|
[22] |
|
Lead; community water | Hemoglobin ? | [23] |
|
Cadmium; blood and urine |
|
[24] |
|
Cadmium; blood | Ferritin ? | [25] |
|
Cadmium; food, urine, and feces, |
|
[26] |
|
Mercury; hair | Hemoglobin ? | [27] |
|
Arsenic; hair | Hemoglobin ? | [28] |
- Note: Arrows (?, ?, ?) indicate directional change of outcomes in relation to increasing levels of the exposure of interest.
Although there is a sensible emphasis on studying the health impacts of lead on mothers and children, adult lead exposure, both in industrial and everyday settings, also contributes to disease development. Lead exposure or biomarkers of lead toxicity in factory workers have been linked to higher anemia prevalence among otherwise healthy men and women [18–20]. Like children, adults living in areas with a history of smelting activity are at risk for lead toxicity, including anemia [21]. Adult lead-associated anemia was also found among those who ingested ayurvedic medicines, unregulated herbal supplements traditionally used in India [30]. In contrast, one study of adults found no such association between blood lead and iron status [22]. Although interpretation of causality from cross-sectional studies is typically limited, the U.S. Environmental Protection Agency (EPA) attempted to determine the directionality of the relationship between lead exposure and anemia. Researchers compared the geolocation of measurable lead levels in drinking water with hemoglobin levels in patients with chronic kidney disease and found that patients with lead-contaminated drinking water had reduced hemoglobin [23]. Because this study methodology involved testing lead levels at the exposure source, researchers interpreted these findings as evidence that lead exposure may have caused the lower hemoglobin in this population. Interestingly, an environmental study of Nile crocodiles also found that animals with higher lead burden exhibited signs of anemia, suggesting the effect is not specific to mammalian hematology [31]. Environmental sampling has not always yielded an association between lead levels and blood parameters, including a study of wood mice in a polluted region with historical industrial activity [32].
2.1.2. Experimental Studies
Controlled experimental studies of lead exposure have the potential to provide clarity on the precise nature of the relationship between lead and anemia (Table 2). After nearly a month of lead acetate administration, male rabbits and male rats both exhibited signs of anemia [33, 34]. Nine weeks of lead acetate exposure in rats led to decreased iron levels in blood and kidneys, but increased iron (and other micronutrient metals) in the urine, suggesting targeted metal excretion is partially responsible for these deficiencies [35]. Despite the prevalent focus on developmental outcomes of lead exposure in the public consciousness, few experimental studies have investigated the impact of early life exposure to lead on anemia, though one study did find that aging mice accumulated iron in brain tissue after developmental lead exposure, though systemic iron levels were not reported [36]. In addition to the evidence from environmental sampling of crocodiles mentioned above, one group looked at cockerel chicks and found that administration of lead acetate induces anemia, further supporting conservation of this association in nonmammalian species [37]. However, one study in mice found no impact of lead exposure on hemoglobin [38]. Providing iron supplementation to schoolchildren in Mexico with high blood lead levels did reduce lead burden over time but did not improve measures of cognitive ability [46]. These findings indicate preexisting ID worsened lead absorption in this population, and that iron supplementation can reverse lead accumulation but not the cognitive effects.
| Exposure | Model | Relevant findings | Reference |
|---|---|---|---|
| Lead | Male Wistar rat |
|
[33] |
| Lead | Male rabbits | Hemoglobin ? | [34] |
| Lead, cadmium | Female Sprague-Dawley rats |
|
[35] |
| Lead | Sprague-Dawley rats | Cerebral iron ?, blood iron ?? ?time dependent | [36] |
| Lead | Cockerel chickens | Red blood cell count, hemoglobin ? | [37] |
| Lead | C57BL/6J mice |
|
[38] |
| Cadmium | C57BL/6J mice |
|
[39] |
| Cadmium | Male Sprague-Dawley rats, rPT cells |
|
[40] |
| Cadmium | Male Sprague-Dawley rats |
|
[41] |
| Cadmium | C57BL/6J x Cast/EiJ mice, female adults, offspring |
|
[42] |
| Cadmium | Female C57BL/6 mice, HeLa cells |
|
[43] |
| Cadmium | Ovariectomized female Sprague-Dawley rats | Osseous iron ? | [44] |
| Arsenic | Male Wistar rats |
|
[45] |
- Note:?Arrows (?, ?, ?) indicate directional change of outcomes in response to the exposure of interest.
2.2. Cadmium
2.2.1. Observational Studies
Cadmium burden typically correlates with markers of ID/IDA such as serum hemoglobin, total body iron, and serum ferritin in adults, including mothers in Turkey, Ohioan adults, participants in the 2003–2008 National Health and Nutrition Examination Survey (NHANES), and Iranian adults [5, 22, 24, 25] (Table 1). However, a few studies have found that blood cadmium did not correlate with ID/IDA although the researchers noted overall cadmium levels were low in one of the studied populations [16, 17, 21]. Samples collected from wood mice indigenous to an area with a history of smelting revealed higher cadmium burden was associated with lower hematocrit, suggesting higher anemia risk extends to wild mammalian populations [32]. In a rare example of longitudinal observation, preexisting ID was not found to stimulate female farmers to absorb more cadmium [26].
2.2.2. Experimental Studies
The impact of cadmium exposure on various parameters related to ID/IDA has been widely studied in rodent models (Table 2). Short-term (3?weeks), high-dose (100–200 ppm cadmium chloride) exposure in drinking water did not induce iron imbalance in mice [43]. In contrast, long-term oral cadmium exposure consistently leads to deficient iron status. Exposure for up to nearly two years via high dose (300 ppm) dietary augmentation induced marked hepatic hypoferremia, which appeared to be caused by reduced intestinal iron uptake [39]. Renal hypoferremia also occurred after one to six months of exposure to 50–75 ppm cadmium chloride in drinking water and was linked to renal oxidative stress and chronic kidney injury [40]. Iron metabolism and import-related genes were dysregulated in the kidneys, including upregulation of Lrp2, Slc39a14, and Slc39a8 after 1 month and downregulation of Cubn, Lrp2, Slc39a14, and Slc39a8 at 6 months, suggesting duration of exposure impacts the nature of iron metabolism dysregulation [40]. Interestingly, coadministering apocynin, an antioxidant, improved anemia-related blood parameters, suggesting cadmium-induced IDA is related to oxidative stress [41]. Cadmium-induced ID also occurs with developmental exposure and impacts the developing offspring. Two months of maternal cadmium exposure through drinking water (1–50 ppm) before and during gestation led to maternal and newborn ID and hepatic hypoferremia [42]. Offspring exhibited reduced birthweight and cardiovascular abnormalities, two features associated with ID in humans [42, 47].
Although few in vitro studies examine the relationship between cadmium and iron, iron content was reduced in primary renal proximal tubule (rPT) cells treated with 1.25–10 uM cadmium [40]. In HeLa cells, cadmium exposure downregulated the expression of transferrin receptor genes and iron regulatory proteins, suggesting a lack of available machinery for iron transport and storage [43]. However, interpretation of in vitro studies is limited because cadmium bypasses intestinal or respiratory absorption in cultured cell platforms, and systemic ID/IDA cannot be evaluated.
Similar to the findings from lead exposure studies, iron and other micronutrient metals were more abundant in the urine of cadmium exposed rats, again suggesting that upregulation of metal excretion is partially responsible for decreased physiological iron availability seen with toxic metal exposure [35]. Additionally, long-term cadmium exposure led to iron deposition in the bones of rats which may contribute to iron depletion seen in other organs and blood [44].
2.3. Mercury and Arsenic
Compared to lead and cadmium, very few controlled experimental studies have been conducted to investigate the impacts of mercury or arsenic on ID/IDA (Table 2). Unlike cadmium, mercury levels in breast milk or infant hair were not implicated in maternal anemia status or hemoglobin levels [5] (Table 1). Globally, children and adults are at high risk of mercury exposure when they live near or work in the unregulated gold mining industry. In areas of the Peruvian Amazon where gold mining is an important income source, exposure to methylmercury via contaminated fish led to an inverse association between hair mercury and hemoglobin in children under twelve [27]. In this population, it is unclear if preexisting anemia rendered children more vulnerable to mercury absorption, or mercury exposure caused the low hemoglobin levels [27]. In support of the conclusion that methylmercury exposure can lead to anemia, Nile tilapia exposed to doses of methylmercury chloride ranging from 0.5 to 2 mg/kg-diet for 60 days exhibited lower hemoglobin levels, reduced red blood cell count, and upregulation of hepatic metallothionein, suggesting heavy metal toxicity and anemia [48]. Unlike lead, cadmium, and mercury, all of which are predominantly released into the environment through anthropogenic activities, arsenic is naturally found in soil and groundwater hotspots throughout the world in a manner that is difficult to remediate. In contrast to mercury, arsenic burden was not associated with anemia incidence in people or sheep [14, 28] (Table 1). However, rats given 100 ppm arsenic for 10 weeks developed low hemoglobin, a phenotype that was successfully rescued by the administration of chelators [45] (Table 2).
2.4. Summary
It is clear that body burden of heavy metals and metalloids is frequently associated with hematological biomarkers of ID and anemia in adults, children, and both wild and experimental animals. Exposure to cadmium, and to some extent lead, tends to both decrease intestinal iron uptake and encourage the transport of iron from blood, liver, and kidney compartments into the bones and urine, reducing its bioavailability. The hypothesis that ID/IDA itself increases the absorption of metals due to compensatory upregulation of divalent cation uptake was supported in the context of lead but remains unsupported in cadmium. Although mercury and arsenic have been linked to anemia at the population levels, there is insufficient experimental evidence to determine a causal relationship.
3. Particulate Matter (PM) and Other Nonmetal Air Pollutants
Poor air quality is one of the most common toxic exposures, with 99% of the global population living in areas where at least one pollutant exceeds WHO recommendations [49]. Key health concerns associated with air pollution include asthma, cardiovascular diseases, and cancer [50]. Despite evidence that air pollution is also linked to anemia, it is not currently emphasized by WHO as a significant risk [49]. While outdoor air quality has been vastly improved in the last few decades, the risks of indoor air pollution are often overlooked and unregulated despite most people spending the majority of their day inside [50].
3.1. Indoor Air Pollution
Globally, solid fuels like coal, wood, and animal dung provide energy for indoor cookstoves and are often used in small unventilated homes. Women and children are particularly vulnerable as the household members that traditionally spend more time indoors than men [51]. Based on survey responses, women who report using biomass fuels, defined as plant or animal waste material, for indoor cooking were at greater risk for anemia during pregnancy than those who used so-called clean fuels like electricity or gas [52–54] (Table 3). However, one survey conducted among nonpregnant women did not suggest any correlation between cooking fuel type and anemia or blood hemoglobin [55]. In addition to survey data, direct measurement of indoor air PM in the homes of women along with blood sampling found that household PM2.5 and PM10 levels negatively correlated with hemoglobin levels [51]. Commercially available air purifiers, a feasible household-level intervention, were effective at improving both household PM concentrations and hemoglobin levels in women [78]. Women in one rural community exhibited no association overall between the use of indoor cooking fires and hemoglobin, but surprisingly, among a subset of iron-deficient women, indoor fire use was linked to higher hemoglobin, suggesting that measuring hemoglobin alone is not sufficient to evaluate the health status of those exposed to indoor air pollution [56].
| Study details | Exposure assessment | Relevant findings | Reference |
|---|---|---|---|
|
|
Anemia prevalence ? | [53] |
|
|
|
[54] |
|
|
|
[52] |
|
|
Anemia prevalence ? | [55] |
|
|
Hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin ? | [51] |
|
|
Hemoglobin ? | [56] |
|
|
|
[57] |
|
|
Anemia prevalence ? | [58] |
|
|
Anemia prevalence ? | [59] |
|
|
Anemia prevalence ? | [60] |
|
|
|
[61] |
|
|
Anemia prevalence ? | [62] |
|
|
Hemoglobin ? | [63] |
|
|
Anemia prevalence ? | [64] |
|
|
|
[65] |
|
|
|
[66] |
|
|
|
[67] |
|
|
|
[68] |
|
|
Anemia prevalence ? | [69] |
|
|
Hemoglobin ? | [70] |
|
PM2.5, | ||
, ,
| , organic matter, mineral dust, black carbon; satellite and field monitoring |
|
, ,
- , organic matter, black carbon
- Anemia prevalence ?
- Multiparous:
- Black carbon,
- , PM2.5, organic matter
- Hemoglobin ?
,
- , mineral dust
- Hemoglobin ?
- PM2.5,
, ,
|
[71] | ||
|
|
||
|
|
|
[72] | ||
|
|
|
[73] |
|
|
|
[74] |
|
|
Moderate-severe anemia prevalence ? hemoglobin ? | [75] |
|
|
||
,
|
Anemia prevalence ? | [76] | |
|
|
|
[77] |
- Note:?Arrows (?, ?, ?) indicate directional change of outcomes in relation to increasing levels of the exposure of interest.
Children living in homes in rural areas where unclean cooking fuels, including kerosene, coal, charcoal, wood, and plant and animal matter, were predominantly used were more likely to have anemia, though there was a joint effect of fuel type with rurality [57, 58]. Exposure to smoke from biomass fuels at both the country level and the household level correlated with higher anemia prevalence [60, 61]. The use of biomass fuel tends to correlate with several potential factors with joint or confounding effects, including household socioeconomic status and rural or urban setting [57, 60, 61]. Another source of indoor PM and other contaminants is secondhand, or passive, tobacco smoke. Children who live in households where one or more adult resident smokes are also more likely to be anemic [62].
Radon gas is another type of indoor air pollutant, that, unlike indoor cookfires, is not anthropogenic. Released from the radioactive decay of underground uranium and thorium deposits, radon contamination of household air occurs in hotspots worldwide, including Mexico, Sweden, and Czechia. Found in households of all levels of socioeconomic status, even small quantities of radon gas can cause health effects like lung cancer, but the impact on anemia is not well studied [79, 80]. Beta particles, a highly penetrative type of radiation emitted by radon gas, in conjunction with PM and black carbon have been associated with decreased hemoglobin in elderly men [63]. The researchers suggest that because ionizing radiation can damage bone marrow, the process of erythropoiesis is impaired [63]. It is not yet known if radon exposure leads to ID/IDA.
3.2. Ambient Air Pollution
Regulation of ambient, or outdoor, air pollution is a top priority of global public health organizations. Epidemiological studies that compare regional levels of ambient air contaminants like PM, nitrogen dioxide (NO2), carbon monoxide (CO), and sulfur dioxide (SO2) to the individual prevalence of anemia, either through medical histories or direct measurement of biomarkers like hemoglobin and serum ferritin, have consistently found that people of all ages that live in more polluted air are more likely to be anemic and iron deficient [64] (Table 3).
In two studies of older adults, those exposed to PM2.5, NO2, ultrafine PM, engine combustion vapor, and black carbon were more likely to exhibit features of anemia, including lower hemoglobin and hematocrit [65, 66]. PM10, PM2.5, and PM1 levels in the community of residence were all associated with a greater risk of anemia diagnosis and with lower individual hemoglobin levels among adults [67]. PM2.5 was also associated with anemia among adults admitted to the hospital with another major illness [68]. Both mothers and children were more likely to have low hemoglobin levels if ambient PM2.5, PM10, SO2, or CO levels had been high during the third trimester of pregnancy [69–71].
Several studies conducted with young children also reveal a strong relationship between ambient PM and childhood anemia. Living in an area with high levels of ambient PM2.5 is a particularly strong risk factor for childhood anemia [72, 74, 75]. More in-depth analysis suggested the cumulative effect of exposure to constituent components of PM2.5 contributed to a 50% increased likelihood of anemia while the standard measurement of PM2.5 exposure, total PM2.5 mass, increased anemia odds by only 10%, suggesting that there is an additive effect of exposure to different types and sources of PM2.5 [76]. Secondary analysis of data from 36 countries confirmed this association is a global phenomenon [77].
3.3. Summary
Despite the robust and consistent evidence in humans, very few studies have been conducted to explain the causal factors that link both ambient and indoor air pollution with iron homeostasis and hematopoietic function. Suspensions of environmental PM2.5 samples were shown to induce hemolysis in vitro, and fulvic acid, a component of both tobacco and wood smoke, was shown to disturb iron trafficking in cultured respiratory epithelial cells, both of which result in ID and inflammation [81, 82]. In fact, several researchers postulate that chronic exposure to polluted air leads to sustained systemic inflammation [66, 74, 76]. Anemia of inflammation, also called anemia of chronic disease, occurs when physiologically available iron is low, despite adequate intake and storage, and is often linked to long-term illnesses like autoimmune disease or infection, but has not been examined in the context of environmental exposures [83].
4. Asbestos
Occupational asbestos exposure is commonly associated with pulmonary diseases and cancers, and there is developing interest in the role of iron in these pathologies [84] (Table 4). Workers with documented long-term asbestos inhalation exhibit elevated levels of extracellular iron and upregulated iron import machinery, and these finding are recapitulated in mice [85, 90]. Extracellular iron overload itself is linked to mesothelioma initiation [91, 92]. However, experimental evidence suggests asbestos-induced disruption of iron homeostasis is more complex because silicate fibers, the predominate component of industrial asbestos, bind and sequester iron with high affinity and extracellular iron accumulation may result in functional intracellular ID [86, 93] (Table 5). Exposing both rodents and primary human bronchial epithelial cells to silica particles results in rapid chelation of intracellular iron by the fibrous particles, along with the generation of reactive oxidants and activation of apoptosis pathways [94, 95]. Providing additional sources of available iron ameliorates the sequestration effect [94, 95].
| Subject | Exposure assessment | Relevant findings | Reference |
|---|---|---|---|
|
|
Bronchoalveolar lavage fluid iron ? | [85] |
|
|
Iron content in lungs near asbestos fibers ? | [86] |
|
Fluoride; drinking water, serum, urine |
|
[87] |
|
Fluoride; drinking water, urine | Anemia prevalence ? | [88] |
|
Fluoride; drinking water, cooking water, urine, serum |
|
[89] |
- Note: Arrows (?, ?, ?) indicate directional change of outcomes in relation to increasing levels of the exposure of interest.
| Exposure | Model | Relevant findings | Reference |
|---|---|---|---|
| Asbestos | C57BL/6 mice | Lung iron, abundance of iron transport/absorption/binding proteins (DMT1, Dcytb, ferritin) ? | [90] |
| Asbestos | Rat tissue in vitro | Asbestos-bound hemoglobin, hemolysis ? | [93] |
| Asbestos | BEAS-2B cells |
|
[94] |
| Asbestos | Primary human bronchial epithelial cells |
|
[95] |
| TCDD | C57BL/6J mice |
|
[96] |
| TCDD, PCB126 | C57BL/6 mice |
|
[97] |
| TCDD | Female Baladi goats |
|
[98] |
| TCDD | Rainbow trout | HBA, HBB1 ? | [99] |
| PCB77 | Salmon larvae | Anemia incidence ? | [100] |
| PCB77 | Female Balb/c mice, HepG2 cells, L-02?cells |
|
[101] |
| PCB126 | American mink | Red blood cell count, hemoglobin, hematocrit ? | [102] |
| PCB126 | Female C57BL/6 mice, HepG2 cells |
|
[103] |
| Fluoride | European rabbits |
|
[104] |
| Fluoride | Goats |
|
[105] |
| Fluoride | Male Sprague-Dawley rats |
|
[106] |
| Fluoride | Broiler chickens | Red blood cell count, hemoglobin, hematocrit ? | [107] |
| Fluoride | Wistar-albino rats | Red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin ? | [108] |
- Note:?Arrows (?, ?, ?) indicate directional change of outcomes in response to the exposure of interest.
4.1. Summary
The high affinity of asbestos for binding iron interferes with normal iron trafficking. Asbestos exposure leads to an imbalance between the iron levels of the extracellular and cellular spaces. While the extracellular iron overload is linked to asbestos-induced cancers, cellular ID impairs lipid metabolism, detoxification, and mitochondrial function [109]. Increasing the bioavailability of iron, however, can overcome this process [84].
5. Dioxin and Dioxin-Like Substances
TCDD (or “dioxin”) and DLCs, including 12 congeners of PCBs, are of particular concern because they do not break down and have become ubiquitous in the environment. Because of their environmental persistence, dioxin and DLCs have been detected in most life forms. Accumulation in humans and wildlife is linked to toxicity of the immune, reproductive, and hepatobiliary systems, and dioxin is a long-established iron chelator [110, 111]. Despite this knowledge, very few observational studies have been conducted to determine the association between dioxin or DLCs and ID and anemia. Two ecological studies found no association between hemoglobin and hematocrit levels in loggerhead sea turtles and their dioxin-like PCB burden, although the dioxin-like congeners were not universally detected in these populations [112, 113].
5.1. Experimental Studies
Anemia is a frequently reported consequence of dioxin exposure in rodents (Table 5). Rats treated orally with heptachlorodibenzo-p-dioxin (HpCDD) exhibited severe and sometimes lethal anemia, and mice treated with TCDD also displayed anemia and disrupted expression of genes related to heme metabolism and iron homeostasis [96, 114]. However, unlike what is observed in the context of heavy metal exposure, increasing available iron exacerbates the effects of dioxin, as iron accumulation and hepcidin repression have also been found [97, 115]. Dioxin-induced anemia is similarly documented in nonrodent models. Rainbow trout and goats fed TCDD-contaminated food developed anemia and reduced expression of the hemoglobin gene HBB1, and goats orally treated with TCDD also developed anemia [98, 99]. Dioxin-like PCBs, including PCB-77 and PCB-126, similarly induce anemia, but not ID. PCB-77 leads to anemia characterized by hepcidin suppression, increased serum iron, and reduced hemoglobin in mice and salmon larvae [100, 101]. PCD-126 induces a similar profile in mice and the American mink [102, 103].
5.2. Summary
Although dioxin and DLCs consistently lead to anemia in experimental settings, iron levels are generally increased in these models, not decreased. Dioxins and DLCs are also known to cause inflammation, and anemia of inflammation is often characterized by low levels of hemoglobin in the context of adequate iron stores [116]. Dioxins and DLCs do not generate ID/IDA, but these findings prompt further research into the potential link between dioxin-induced inflammation and inadequate hemoglobin levels.
6. Fluoride
Fluoridated water is considered one of the greatest public health advancements in the dental field and is effective at preventing tooth decay and dental caries [117, 118]. However, there are hotspots throughout the globe, particularly in Southern Asia, with high levels of naturally existing fluoride in ground water and mineral deposits. Excess fluoride, or fluorosis, is most commonly linked to bone malformations and dental staining, but development or exacerbation of anemia has also been documented in humans and experimental animals [119, 120]. Fluorosis can cause ID/IDA by reducing intestinal iron absorption but is also known to directly damage red blood cells [89].
6.1. Observational Studies
Those who live in areas where drinking water contains high levels of fluoride (> 1.0 mg/L) are at risk for developing fluorosis, which can include ID/IDA (Table 4). Adults in fluoride endemic regions display both ID, characterized by low corpuscular hemoglobin, and IDA, characterized by low hemoglobin and hematocrit [87]. Children only exhibited ID, suggesting they had not had fluorosis for long enough to progress into anemia [87]. Women in fluoride endemic regions are more likely to have IDA in pregnancy and give birth to low-birth-weight babies [88]. Diagnosed ID combined with fluorosis leads to lower hematological values than either condition alone [89]. However, since most studies in the field are not longitudinal, it is often unclear whether fluorosis or ID/IDA tends to precede the other. Iron supplementation is not sufficient to ameliorate fluorosis-induced ID/IDA. Despite dietary iron fortification, children who live in areas where popular food seasonings contain calcium fluorite maintain ID/IDA status unless these sources of fluoride are removed from their diets [121, 122].
6.2. Experimental Studies
A variety of animals exposed to fluoride in laboratory settings also develop ID/IDA (Table 5). Rabbits treated with 10–50 mg/kg sodium fluoride develop anemia characterized by reduced red blood cell count [104], and goats respond likewise to similar treatment regimens [105]; ID parameters were not measured in these studies. Broiler chicken exposed to very high doses of sodium fluoride (800–1200 mg/kg) also develop anemia [107]. However, conflicting findings have been reported in similarly exposed rats: one study reported reduced hemoglobin and red blood cell count, while the other reported no effect of fluoride treatment [106, 108].
6.3. Summary
While low-level water fluoridation and periodic fluoride treatment is important for sustaining dental health, excessive amounts have been consistently linked to the development of ID/IDA. Unfortunately, iron supplementation does not improve outcomes. Removal of environmental sources of fluoride, like drinking water and certain seasonings, is required to treat and prevent fluorosis-induced anemia.
7. Discussion and Conclusion
There is sufficient evidence that two of the priority toxic metals, lead and cadmium, can cause ID/IDA. Twelve cross-sectional studies of global populations detected an association between lead exposure and ID/IDA [4, 6–12, 19–21, 23]. Six cross-sectional studies found no association between lead exposure and ID/IDA [5, 13–16, 22]. Two studies conducted among adults and children living or working in proximity with industrial contamination sites found a positive correlation between circulating lead and iron, so these findings likely represent coabsorption of anthropogenically released metals [17, 18]. Experimental findings further strengthen this assertion. Five controlled experimental studies in mammalian and avian models found that one to three months of lead exposure produced reduced systemic iron and/or at least one feature of anemia [33–35, 37, 38]. Only one rodent study reported increased cerebral and circulating iron in aged offspring after prenatal lead exposure, which may represent developmental programming of iron homeostasis dysregulation [36]. Iron fortification has been shown to be effective in reducing lead burden but did not reverse the lead-induced cognitive delays in children [46]. There is an urgent need for more and earlier intervention programs that provide iron fortification to children in lead-endemic areas. Fewer cross-sectional studies have measured cadmium exposure and parameters related to ID/IDA than those that have examined lead exposure. In total, seven studies investigated this association cross-sectionally, five of which found evidence of increased odds of anemia diagnosis, or at least one biomarker of ID/IDA [7, 16, 22, 24, 25]. One longitudinal study found that preexisting ID did not change the way women absorbed cadmium from their occupational exposure as farmers [26]. These findings provide context to cross-sectional studies, suggesting that when ID and higher cadmium burden coincide, the causal mechanism is not that ID causes increased cadmium absorption. Cadmium and ID/IDA have been experimentally investigated more often than lead; ten in vivo and in vitro studies fit the inclusion criteria. In four rodent and two mammalian cell models, iron levels were reduced after cadmium exposure, or at least one biomarker of anemia was detected [39–43]. Only one rodent study found no effect [43]. A possible mechanism of both lead- and cadmium-induced ID/IDA arises from evidence that iron accumulates in the urine and bones of exposed animals, while it is depleted from the blood, liver, and kidneys [35, 44, 36]. Evidence for mercury- and arsenic-induced ID/IDA is limited. Only one epidemiological study noted a decline in hemoglobin with mercury exposure [27]. Several biomarkers of IDA were detected in rats exposed to arsenic [45]. Overall, more research is required to determine the relationship of both mercury and arsenic to ID/IDA. Established cohorts should be leveraged to quantify mercury and arsenic levels in existing samples to enable reporting of associations with anemia prevalence and hematological parameters and provide sufficient data to support the design of in vivo experimental studies that interrogate the underlying mechanisms.
Overall, there is also sufficient evidence that air pollution causes ID/IDA. In total, 26 observational studies that examined indoor or ambient air pollution fit the inclusion criteria, and 24 found a significant impact on ID/IDA. One found no association, and one found that hemoglobin was elevated [55, 56]. Indoor cookstove and solid fuel use accounts for ten of these studies, eight of which found evidence that women and children living in homes with indoor cookstoves are more likely to have ID/IDA [52–54, 57–61]. Ambient air pollution, typically measured at the ecological level, accounts for 15 of the included articles, all of which found an increased ID/IDA prevalence or at least one biomarker of ID/IDA related to at least component of ambient air pollution [65–73, 76, 77]. Overall, air pollution of any kind is the priority chemical with the most consistent epidemiological correlation to ID/IDA. Unfortunately, there is a dearth of experimental studies that interrogate the directionality or mechanisms behind this association, though there is some evidence that in vitro exposure to components of air pollution exposure induces hemolysis and inflammation and can perturb iron trafficking [81, 82].
Asbestos displays a well-defined mechanism of interfering with the physiological availability of iron. Asbestos fibers sequester iron into the extracellular space and cells become deficient. Four experimental studies examined the effects of asbestos in lung tissue or cells on iron trafficking, two of which specifically studied the intracellular space. Cellular iron was found to be depleted, which could be rescued by administration of additional bioavailable iron [94, 95]. Treatment with iron supplementation may prevent asbestos-induced ID/IDA; however, this was gleaned from cell culture models, and no intervention should be implemented without first considering the impact on asbestos-related cancer development and progression. Dioxin is similarly an iron chelator, reducing iron’s bioavailability. Dioxin has been known for decades to induce anemia because of its role in iron sequestration. Since 2003, experimental studies have linked dioxins or DLCs to anemia and/or iron dysregulation. Dioxin does not cause ID and in fact tends to increase iron levels, making these chemicals poor candidates for remediation by iron supplementation [97, 101, 103]. It is not clear if this iron is bioavailable or bound to PCBs. There is evidence that fluoride does induce ID/IDA, but it is not able to be relieved by supplementation [121, 122]. Three additional epidemiological studies all found that living in areas with very high levels of fluoride in ground water is a strong risk factor for ID/IDA [87–89]. Of five experimental studies, four exhibited the same trend as the observational studies, further strengthening the conclusion that fluorosis symptoms may include ID/IDA [104–106].
In conclusion, there is very consistent evidence that air pollution exposure causes ID/IDA, but a surprising lack of reports of intervention programs targeted to regions with indoor or ambient air pollution exposure. There is also sufficient evidence to link excessive fluoride, lead, and cadmium to ID/IDA, though direct measurements of ID, like circulating iron or ferritin, are less frequently reported. There is evidentiary support for iron supplementation programs to reduce lead absorption, though only from a single study. Asbestos, dioxin, and DLCs have a more complex relationship with ID/IDA because of their affinity for iron sequestration. Despite this, increasing iron bioavailability has been shown to be effective in the context of asbestos, but not dioxins or DLCs, though only in in vitro studies. This review has ultimately identified the following imperatives: implementation of iron fortification programs to prevent childhood lead poisoning, experimental studies of the utility of iron supplementation in alleviating cadmium- and air pollution-related ID/IDA, experimental studies to confirm observational findings related to mercury and arsenic, and exposure mitigation interventions in fluorosis-endemic areas and regions with dioxin-like PCB contamination.
Conflicts of Interest
The authors declare no conflicts of interest.
Funding
This work was supported by the following grants from the U.S. National Institutes of Health: R01ES031596 and P30ES025128.
Acknowledgments
The authors thank the members of the Cowley Lab for considerate comments and feedback during the drafting of this review.
References
- 1 , 10 Chemicals of Public Health Concern, 2020, WHO.
- 2 , Anaemia, 2023, WHO.
- 3 , , et al., Prevalence, Years Lived With Disability, and Trends in Anaemia Burden by Severity and Cause, 1990–2021: Findings From the Global Burden of Disease Study 2021, The Lancet Haematology. (2023) 10, no. 9, e713–e734, https://doi.org/10.1016/s2352-3026(23)00160-6.
- 4 , , and , Response of Iron Deficiency Markers to Blood Lead Levels and Synergistic Outcomes at Prenatal Stage, Dose-Response. (2022) 20, no. 2, https://doi.org/10.1177/15593258221101744.
- 5 , , and , Lead, Mercury, and Cadmium Levels in Breast Milk and Infant Hair in the Late Period of Lactation in Ankara, Turkey, International Journal of Environmental Health Research. (2022) 32, no. 9, 1950–1961, https://doi.org/10.1080/09603123.2021.1929872.
- 6 , , et al., Blood Lead Levels in Antenatal Women and its Association With Iron Deficiency Anemia and Adverse Pregnancy Outcomes, Journal of Family Medicine and Primary Care. (2020) 9, no. 6, https://doi.org/10.4103/jfmpc.jfmpc_78_20.
- 7 , , , , , and , Low-Level Toxic Metal Exposure in Healthy Weaning-Age Infants: Association With Growth, Dietary Intake, and Iron Deficiency, International Journal of Environmental Research and Public Health. (2017) 14, no. 4, https://doi.org/10.3390/ijerph14040388, 2-s2.0-85017222026.
- 8 , , et al., Effect of Lead Exposure From Electronic Waste on Haemoglobin Synthesis in Children, International Archives of Occupational and Environmental Health. (2021) 94, no. 5, 911–918, https://doi.org/10.1007/s00420-020-01619-1.
- 9 , , et al., Effect of Lead, Calcium, Iron, Zinc, Copper and Magnesium on Anemia in Children with BLLs ? 100 ?g/L, Journal of Trace Elements in Medicine & Biology. (2023) 78, https://doi.org/10.1016/j.jtemb.2023.127192.
- 10 , , et al., Iron Deficiency in Young Lebanese Children: Association With Elevated Blood Lead Levels, Journal of Pediatric Hematology. (2008) 30, no. 5, 382–386, https://doi.org/10.1097/mph.0b013e318165b283, 2-s2.0-43149124176.
- 11 , , , and , Association of Anemia, Child and Family Characteristics With Elevated Blood Lead Concentrations in Preschool Children From Montevideo, Uruguay, Archives of Environmental & Occupational Health. (2010) 65, no. 2, 94–100, https://doi.org/10.1080/19338240903390313, 2-s2.0-77952159456.
- 12 , , , , and , Relationship Between Blood Lead Status and Anemia in Ugandan Children With Malaria Infection, BMC Pediatrics. (2020) 20, no. 1, https://doi.org/10.1186/s12887-020-02412-2.
- 13 and , Anemia and Malnutrition in Indigenous Children and Adolescents of the Peruvian Amazon in a Context of Lead Exposure: A Cross-Sectional Study, Global Health Action. (2014) 7, no. 1, https://doi.org/10.3402/gha.v7.22888, 2-s2.0-84904363530.
- 14 , , , , and , Blood’s Concentration of Lead and Arsenic Associated With Anemia in Peruvian Children, Journal of Environmental and Public Health. (2021) 2021, 1–8, https://doi.org/10.1155/2021/7283514.
- 15 , , et al., Iron Deficiency and Cognitive Impairment in Children With Low Blood Lead Levels, Toxicology Reports. (2022) 9, 1681–1690, https://doi.org/10.1016/j.toxrep.2022.08.008.
- 16 , , et al., Blood Levels of Environmental Heavy Metals are Associated With Poorer Iron Status in Ugandan Children: A Cross-Sectional Study, The Journal of Nutrition. (2023) 153, no. 10, 3023–3031, https://doi.org/10.1016/j.tjnut.2023.08.014.
- 17 , , , , and , Evaluation of Toxic and Essential Elements in Whole Blood From 0- to 6-Year-Old Children From Jinan, China, Clinical Biochemistry. (2013) 46, no. 7–8, 612–616, https://doi.org/10.1016/j.clinbiochem.2013.02.007, 2-s2.0-84884733079.
- 18 , , , , , and , Occupational Lead Toxicity in Battery Workers, Pakistan Journal of Medical Sciences. (2015) 31, no. 4, 775–780, https://doi.org/10.12669/pjms.314.7066, 2-s2.0-84937933612.
- 19 , , et al., Anemia Risk in Relation to Lead Exposure in Lead-Related Manufacturing, BMC Public Health. (2017) 17, no. 1, https://doi.org/10.1186/s12889-017-4315-7, 2-s2.0-85019036840.
- 20 , , et al., Relationship between Lead Absorption and Iron Status and its Association With Oxidative Stress Markers in Lead-Exposed Workers, Journal of Trace Elements in Medicine & Biology. (2021) 68, https://doi.org/10.1016/j.jtemb.2021.126841.
- 21 , , et al., The Association between Hemoglobin Level and Osteoporosis in a Chinese Population With Environmental Lead and Cadmium Exposure, Environmental Geochemistry and Health. (2022) 44, no. 6, 1673–1682, https://doi.org/10.1007/s10653-021-01129-0.
- 22 , , , , , and , Blood Metal Concentrations of Manganese, Lead, and Cadmium in Relation to Serum Ferritin Levels in Ohio Residents, Biological Trace Element Research. (2015) 165, no. 1, 1–9, https://doi.org/10.1007/s12011-014-0223-1, 2-s2.0-84930958635.
- 23 , , and , Associations of Community Water Lead Concentrations With Hemoglobin Concentrations and Erythropoietin-Stimulating Agent Use Among Patients With Advanced CKD, Journal of the American Society of Nephrology. (2021) 32, no. 10, 2425–2434, https://doi.org/10.1681/asn.2020091281.
- 24 , , and , The Relationship Between Body Iron Stores and Blood and Urine Cadmium Concentrations in US Never-Smoking, Non-Pregnant Women Aged 20–49 Years, Environmental Research. (2011) 111, no. 5, 702–707, https://doi.org/10.1016/j.envres.2011.03.007, 2-s2.0-79958698875.
- 25 , , et al., Association Among Sources Exposure of Cadmium in the Adult Non-Smoking General Population of Tehran, Biological Trace Element Research. (2019) 191, no. 1, 27–33, https://doi.org/10.1007/s12011-018-1590-9, 2-s2.0-85058111541.
- 26 , , et al., Comprehensive Study of the Effects of Age, Iron Deficiency, Diabetes Mellitus, and Cadmium Burden on Dietary Cadmium Absorption in Cadmium-Exposed Female Japanese Farmers, Toxicology and Applied Pharmacology. (2004) 196, no. 1, 114–123, https://doi.org/10.1016/j.taap.2003.11.024, 2-s2.0-1642302704.
- 27 , , et al., Hair Mercury Level is Associated With Anemia and Micronutrient Status in Children Living Near Artisanal and Small-Scale Gold Mining in the Peruvian Amazon, The American Journal of Tropical Medicine and Hygiene. (2017) 97, no. 6, 1886–1897, https://doi.org/10.4269/ajtmh.17-0269, 2-s2.0-85037036282.
- 28 , , , , , and , High Soil and Groundwater Arsenic Levels Induce High Body Arsenic Loads, Health Risk and Potential Anemia for Inhabitants of Northeastern Iran, Environmental Geochemistry and Health. (2016) 38, no. 2, 469–482, https://doi.org/10.1007/s10653-015-9733-9, 2-s2.0-84961139672.
- 29 , , et al., A Study of Maternal and Umbilical Cord Blood Lead Levels in Pregnant Women, Indian Journal of Clinical Biochemistry. (2023) 38, no. 1, 94–101, https://doi.org/10.1007/s12291-022-01040-0.
- 30 , , and , Hematopoietic Toxicity From Lead-Containing Ayurvedic Medications, Medical Science Monitor. (2007) 13, no. 7, CR295–CR298.
- 31 , , , and , High Lead Exposure and Clinical Signs of Toxicosis in Wild Nile Crocodiles (Crocodylus niloticus) From a World Heritage Site: Lake St Lucia Estuarine System, South Africa, Chemosphere. (2022) 303, no. Pt 1, https://doi.org/10.1016/j.chemosphere.2022.134977.
- 32 , , , and , Blood Parameters as Biomarkers of Cadmium and Lead Exposure and Effects in Wild Wood Mice (Apodemus sylvaticus) Living Along a Pollution Gradient, Chemosphere. (2015) 138, 940–946, https://doi.org/10.1016/j.chemosphere.2014.12.031, 2-s2.0-84940962947.
- 33 , , et al., Cabbage Juice Supplementation Abrogates Lead Acetate-Induced Haematological and Haemorheological Imbalances in Male Wistar Rat, International Journal of Environmental Health Research. (2023) 33, no. 12, 1331–1340, https://doi.org/10.1080/09603123.2022.2086973.
- 34 , , et al., Protective Effect of Morocco Carob Honey Against Lead-Induced Anemia and Hepato-Renal Toxicity, Cellular Physiology and Biochemistry. (2016) 39, no. 1, 115–122, https://doi.org/10.1159/000445610, 2-s2.0-84976271712.
- 35 , , , and , Effects of Lead and/or Cadmium on the Distribution Patterns of Some Essential Trace Elements in Immature Female Rats, Human & Experimental Toxicology. (2011) 30, no. 12, 1914–1923, https://doi.org/10.1177/0960327111405865, 2-s2.0-84863032687.
- 36 , , et al., The Effect of Lead Exposure on Brain Iron Homeostasis and the Expression of DMT1/FP1 in the Brain in Developing and Aged Rats, Toxicology Letters. (2013) 216, no. 2–3, 108–123, https://doi.org/10.1016/j.toxlet.2012.11.024, 2-s2.0-84871583962.
- 37 , , et al., Naringin Administration Mitigates Oxidative Stress, Anemia, and Hypertension in Lead Acetate-Induced Cardio-Renal Dysfunction in Cockerel Chicks, Environmental Science and Pollution Research. (2022) 30, no. 12, 34890–34903, https://doi.org/10.1007/s11356-022-24656-4.
- 38 , , and , Heme-Regulated eIF2? Kinase Plays a Crucial Role in Protecting Erythroid Cells Against Pb-Induced Hemolytic Stress, Chemical Research in Toxicology. (2015) 28, no. 3, 460–469, https://doi.org/10.1021/tx500422q, 2-s2.0-84924854064.
- 39 , , , and , Long-Term Exposure to Cadmium Causes Hepatic Iron Deficiency Through the Suppression of Iron-Transport-Related Gene Expression in the Proximal Duodenum, Toxics. (2023) 11, no. 7, https://doi.org/10.3390/toxics11070641.
- 40 , , et al., Cadmium Induces Kidney Iron Deficiency and Chronic Kidney Injury by Interfering With the Iron Metabolism in Rats, International Journal of Molecular Sciences. (2024) 25, no. 2, https://doi.org/10.3390/ijms25020763.
- 41 , , , , , and , Apocynin Ameliorates Cadmium-Induced Hypertension Through Elevation of Endothelium Nitric Oxide Synthase, Cardiovascular Toxicology. (2013) 13, no. 4, 357–363, https://doi.org/10.1007/s12012-013-9216-0, 2-s2.0-84890568294.
- 42 , , and , Maternal Cadmium Exposure in the Mouse Leads to Increased Heart Weight at Birth and Programs Susceptibility to Hypertension in Adulthood, Scientific Reports. (2019) 9, no. 1, https://doi.org/10.1038/s41598-019-49807-5, 2-s2.0-85072393964.
- 43 and , Iron Regulatory Protein 1 is Not an Early Target of Cadmium Toxicity in Mice, but it is Sensitive to Cadmium Stress in a Human Epithelial Cell Line, Biochemistry and Cell Biology. (2008) 86, no. 5, 416–424, https://doi.org/10.1139/o08-120, 2-s2.0-54249133609.
- 44 , , , , and , Relationship Between Osteoid Formation and Iron Deposition Induced by Chronic Cadmium Exposure in Ovariectomized Rats, Journal of Applied Toxicology. (2021) 41, no. 8, 1304–1315, https://doi.org/10.1002/jat.4118.
- 45 , , , and , Arsenic Induced Blood and Brain Oxidative Stress and its Response to Some Thiol Chelators in Rats, Life Sciences. (2005) 77, no. 18, 2324–2337, https://doi.org/10.1016/j.lfs.2005.04.016, 2-s2.0-23844545645.
- 46 , , et al., Efficacy of Iron and/or Zinc Supplementation on Cognitive Performance of Lead-Exposed Mexican Schoolchildren: A Randomized, Placebo-Controlled Trial, Pediatrics (Evanston). (2006) 117, no. 3, e518–e527, https://doi.org/10.1542/peds.2005-1172, 2-s2.0-33645019697.
- 47 , , et al., Maternal Anemia and Low Birth Weight: A Systematic Review and Meta-Analysis, Nutrients. (2018) 10, no. 5, https://doi.org/10.3390/nu10050601, 2-s2.0-85047066242.
- 48 , , , , and , Dietary Exposure to Methyl Mercury Chloride Induces Alterations in Hematology, Biochemical Parameters, and mRNA Expression of Antioxidant Enzymes and Metallothionein in Nile tilapia, Environmental Science and Pollution Research. (2021) 28, no. 24, 31391–31402, https://doi.org/10.1007/s11356-021-13014-5.
- 49 , , and , WHO Ambient Air Quality Database, 2022 Update: Status Report, 2023.
- 50 , , and , Hidden Harms of Indoor Air Pollution—Five Steps to Expose Them, Nature. (2023) 614, no. 7947, 220–223, https://doi.org/10.1038/d41586-023-00287-8.
- 51 , , et al., Direct and Indirect Effects of Indoor Particulate Matter on Blood Indicators Related to Anemia, International Journal of Environmental Research and Public Health. (2021) 18, no. 24, https://doi.org/10.3390/ijerph182412890.
- 52 , , and , Does Smoke From Biomass Fuel Contribute to Anemia in Pregnant Women in Nagpur, India? A Cross-Sectional Study, PLoS One. (2015) 10, no. 5, https://doi.org/10.1371/journal.pone.0127890, 2-s2.0-84934953772.
- 53 , , , , and , Is Indoor Air Pollution From Different Fuel Types Associated With the Anemia Status of Pregnant Women in Ethiopia?, Journal of Primary Care & Community Health. (2021) 12, https://doi.org/10.1177/21501327211034374.
- 54 , , et al., The Link Between Indoor Air Pollution From Cooking Fuels and Anemia Status Among Non-Pregnant Women of Reproductive Age in Ethiopia, SAGE Open Medicine. (2022) 10, https://doi.org/10.1177/20503121221107466.
- 55 , , et al., Is Biomass Fuel Smoke Exposure Associated With Anemia in Non-Pregnant Reproductive-Aged Women?, PLoS One. (2022) 17, no. 8, https://doi.org/10.1371/journal.pone.0272641.
- 56 , , , , and , Smoky Indoor Cooking Fires are Associated With Elevated Hemoglobin Concentration in Iron-Deficient Women, Revista Panamericana de Salud Públic. (2004) 15, no. 2, 110–118, https://doi.org/10.1590/s1020-49892004000200006, 2-s2.0-1642488287.
- 57 , , , , and , Household Cooking Fuel Type and Childhood Anaemia in Sub-Saharan Africa: Analysis of Cross-Sectional Surveys of 123, 186 Children From 29 Countries, BMJ Open. (2021) 11, no. 7, https://doi.org/10.1136/bmjopen-2021-048724.
- 58 and , Does Biofuel Smoke Contribute to Anaemia and Stunting in Early Childhood?, International Journal of Epidemiology. (2007) 36, no. 1, 117–129, https://doi.org/10.1093/ije/dyl234, 2-s2.0-34447300773.
- 59 and , Solid Fuel Use is Associated With Anemia in Children, Environmental Research. (2017) 158, 431–435, https://doi.org/10.1016/j.envres.2017.06.032, 2-s2.0-85021775220.
- 60 , , and , Biomass Fuel Use for Household Cooking in Swaziland: Is There an Association With Anaemia and Stunting in Children Aged 6–36 Months?, Transactions of the Royal Society of Tropical Medicine and Hygiene. (2013) 107, no. 9, 535–544, https://doi.org/10.1093/trstmh/trt055, 2-s2.0-84889023707.
- 61 , , et al., Lower Socioeconomic Status Strengthens the Effect of Cooking Fuel Use on Anemia Risk and Anemia-Related Parameters: Findings from the Henan Rural Cohort, Science of the Total Environment. (2022) 831, https://doi.org/10.1016/j.scitotenv.2022.154958.
- 62 , , and , Passive Smoking as a Risk Factor of Anemia in Young Children Aged 0–35 Months in Jordan, BMC Pediatrics. (2007) 7, no. 1, https://doi.org/10.1186/1471-2431-7-16, 2-s2.0-34247493651.
- 63 , , et al., Association Between Ambient Beta Particle Radioactivity and Lower Hemoglobin Concentrations in a Cohort of Elderly Men, Environment International. (2020) 139, https://doi.org/10.1016/j.envint.2020.105735.
- 64 , , , , , and , Air Quality Monitoring in NIS (SERBIA) and Health Impact Assessment, Environmental Monitoring and Assessment. (2009) 158, no. 1–4, 499–506, https://doi.org/10.1007/s10661-008-0599-5, 2-s2.0-72349087192.
- 65 , , et al., Associations Between Differences in Anemia-Related Blood Cell Parameters and Short-Term Exposure to Ambient Particle Pollutants in Middle-Aged and Elderly Residents in Beijing, China, Science of the Total Environment. (2022) 816, https://doi.org/10.1016/j.scitotenv.2021.151520.
- 66 , , , and , Anemia Prevalence and Hemoglobin Levels are Associated With Long-Term Exposure to Air Pollution in an Older Population, Environment International. (2017) 101, 125–132, https://doi.org/10.1016/j.envint.2017.01.017, 2-s2.0-85011115804.
- 67 , , et al., Ambient Air Pollution Exposure Association With Anaemia Prevalence and Haemoglobin Levels in Chinese Older Adults, International Journal of Environmental Research and Public Health. (2020) 17, no. 9, https://doi.org/10.3390/ijerph17093209.
- 68 , , et al., Ambient Air Pollution and Cause-Specific Risk of Hospital Admission in China: A Nationwide Time-Series Study, PLoS Medicine. (2020) 17, no. 8, https://doi.org/10.1371/journal.pmed.1003188.
- 69 , , , , and , In-Utero Exposure to Multiple Air Pollutants and Childhood Undernutrition in India, Journal of Exposure Science and Environmental Epidemiology. (2023) 34, no. 5, 895–906, https://doi.org/10.1038/s41370-023-00591-5.
- 70 , , et al., Prenatal Exposure to Air Pollution and Pre-Labor Rupture of Membranes in a Prospective Cohort Study: The Role of Maternal Hemoglobin and Iron Supplementation, Environmental Health Perspectives. (2023) 131, no. 4, https://doi.org/10.1289/ehp11134.
- 71 , , et al., Effects of PM2.5 and its Constituents on Hemoglobin During the Third Trimester in Pregnant Women, Environmental Science and Pollution Research. (2022) 29, no. 23, 35193–35203, https://doi.org/10.1007/s11356-022-18693-2.
- 72 , Early-Life Environmental Exposures and Anaemia Among Children Under Age Five in Sub-Saharan Africa: An Insight From the Demographic & Health Surveys, Science of the Total Environment. (2022) 832, https://doi.org/10.1016/j.scitotenv.2022.154957.
- 73 , Air Pollution as a Determinant of Undernutrition Prevalence Among Under-Five Children in India: An Exploratory Study, Journal of Tropical Pediatrics. (2021) 67, no. 5, https://doi.org/10.1093/tropej/fmab089.
- 74 , , , , , and , The Association Between Ambient PM2.5 Exposure and Anemia Outcomes Among Children Under Five Years of Age in India, Environmental Epidemiology. (2021) 5, no. 1, https://doi.org/10.1097/ee9.0000000000000125.
- 75 , , , , , and , Increased Outdoor PM 2.5 Concentration is Associated With Moderate/Severe Anemia in Children Aged 6–59 Months in Lima, Peru, Journal of Environmental and Public Health. (2019) 2019, 1–8, https://doi.org/10.1155/2019/6127845, 2-s2.0-85070473398.
- 76 , , et al., Cumulative Effect of PM2.5 Components is Larger Than the Effect of PM2.5 Mass on Child Health in India, Nature Communications. (2023) 14, no. 1, https://doi.org/10.1038/s41467-023-42709-1.
- 77 , , et al., A Cross-Sectional Analysis of Ambient Fine Particulate Matter (PM2.5) Exposure and Haemoglobin Levels in Children Aged Under 5 Years Living in 36 Countries, Environmental Research. (2023) 227, https://doi.org/10.1016/j.envres.2023.115734.
- 78 , , , , , and , Effect of PM Concentration on Anemia Blood Indicators Reduced by Air Purifiers, Chemosphere. (2023) 323, https://doi.org/10.1016/j.chemosphere.2023.138131.
- 79 and , A Review on the Sources and Impacts of Radon Indoor Air Pollution, Journal of Toxicology and Environmental Health. (2018) 2, no. 1, https://doi.org/10.16966/2576-6430.112.
- 80 , , and , Health Effects of Radon Exposure, Yonsei Medical Journal. (2019) 60, no. 7, https://doi.org/10.3349/ymj.2019.60.7.597, 2-s2.0-85068981041.
- 81 , , et al., A Fulvic Acid-Like Substance Participates in the Pro-Inflammatory Effects of Cigarette Smoke and Wood Smoke Particles, Chemical Research in Toxicology. (2020) 33, no. 4, 999–1009, https://doi.org/10.1021/acs.chemrestox.0c00036.
- 82 , , et al., Hemolytic Properties of Fine Particulate Matter (PM2.5) in In Vitro Systems, Toxics. (2024) 12, no. 4, https://doi.org/10.3390/toxics12040246.
- 83 and , Anemia of Inflammation, Hematology-Oncology Clinics of North America. (2014) 28, no. 4, 671–681, https://doi.org/10.1016/j.hoc.2014.04.005, 2-s2.0-84904746883.
- 84 , , , , and , Asbestos and Iron, International Journal of Molecular Sciences. (2023) 24, no. 15, https://doi.org/10.3390/ijms241512390.
- 85 , , , and , Iron Homeostasis in the Lung Following Asbestos Exposure, Antioxidants and Redox Signaling. (2008) 10, no. 2, 371–378, https://doi.org/10.1089/ars.2007.1909, 2-s2.0-37549059887.
- 86 , , et al., The Interaction of Asbestos and Iron in Lung Tissue Revealed by Synchrotron-Based Scanning X-Ray Microscopy, Scientific Reports. (2013) 3, no. 1, https://doi.org/10.1038/srep01123, 2-s2.0-84873201448.
- 87 , , and , Haematological Changes in Fluorotic Adults and Children in Fluoride Endemic Regions of Gaya District, Bihar, India, Environmental Geochemistry and Health. (2014) 36, no. 3, 421–425, https://doi.org/10.1007/s10653-013-9570-7, 2-s2.0-84899489477.
- 88 , , et al., Study of Anaemia in Pregnancy and Low Birth Weight in Fluoride Endemic Area of Western Rajasthan: A Cohort Study, F1000Res. (2024) 12, https://doi.org/10.12688/f1000research.134720.2.
- 89 , , et al., Excessive Fluoride Consumption Increases Haematological Alteration in Subjects With Iron Deficiency, Thalassaemia, and Glucose-6-Phosphate Dehydrogenase (G-6-PD) Deficiency, Environmental Geochemistry and Health. (2017) 39, no. 4, 751–758, https://doi.org/10.1007/s10653-016-9845-x, 2-s2.0-84975141167.
- 90 , , , , and , Iron Accumulation and Expression of Iron-Related Proteins Following Murine Exposure to Crocidolite, Journal of Environmental Pathology, Toxicology and Oncology. (2009) 28, no. 2, 153–162, https://doi.org/10.1615/jenvironpatholtoxicoloncol.v28.i2.70, 2-s2.0-70350088059.
- 91 , Iron Overload as a Major Targetable Pathogenesis of Asbestos-Induced Mesothelial Carcinogenesis, Redox Report. (2014) 19, no. 1, 1–7, https://doi.org/10.1179/1351000213y.0000000075, 2-s2.0-84891872211.
- 92 , , , , , and , Dual Preventive Benefits of Iron Elimination by Desferal in Asbestos-Induced Mesothelial Carcinogenesis, Cancer Science. (2016) 107, no. 7, 908–915, https://doi.org/10.1111/cas.12947, 2-s2.0-84978897555.
- 93 , , et al., Asbestos Surface Provides a Niche for Oxidative Modification, Cancer Science. (2011) 102, no. 12, 2118–2125, https://doi.org/10.1111/j.1349-7006.2011.02087.x, 2-s2.0-81855194114.
- 94 , , , , and , The Biological Effect of Asbestos Exposure is Dependent on Changes in Iron Homeostasis, Inhalation Toxicology. (2016) 28, no. 14, 698–705, https://doi.org/10.1080/08958378.2016.1257665, 2-s2.0-84997514356.
- 95 , , et al., Sequestration of Mitochondrial Iron by Silica Particle Initiates a Biological Effect, American Journal of Physiology—Lung Cellular and Molecular Physiology. (2013) 305, no. 10, L712–L724, https://doi.org/10.1152/ajplung.00099.2013, 2-s2.0-84887588575.
- 96 , , et al., 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Induces Peripheral Blood Abnormalities and Plasma Cell Neoplasms Resembling Multiple Myeloma in Mice, Cancer Letters. (2019) 440–441, 135–144, https://doi.org/10.1016/j.canlet.2018.10.009, 2-s2.0-85055637997.
- 97 , , , , , and , Convergence of Hepcidin Deficiency, Systemic Iron Overloading, Heme Accumulation, and REV-Erb?/? Activation in Aryl Hydrocarbon Receptor-Elicited Hepatotoxicity, Toxicology and Applied Pharmacology. (2017) 321, 1–17, https://doi.org/10.1016/j.taap.2017.02.006, 2-s2.0-85013816220.
- 98 , , , and , Some Clinico and Histopathological Changes in Female Goats Experimentally Exposed to Dioxin, Pakistan Journal of Biological Sciences. (2007) 10, no. 8, 1213–1220, https://doi.org/10.3923/pjbs.2007.1213.1220, 2-s2.0-34247139365.
- 99 , , et al., Gene Expression and Pathologic Alterations in Juvenile Rainbow Trout Due to Chronic Dietary TCDD Exposure, Aquatic Toxicology. (2013) 140-141, 356–368, https://doi.org/10.1016/j.aquatox.2013.06.018, 2-s2.0-84880948479.
- 100 and , Developmental Effects Related to Angiogenesis and Osteogenic Differentiation in Salmon Larvae Continuously Exposed to Dioxin-like 3,3’,4,4’-tetrachlorobiphenyl (Congener 77), Aquatic Toxicology. (2011) 105, no. 3-4, 669–680, https://doi.org/10.1016/j.aquatox.2011.09.005, 2-s2.0-80053458529.
- 101 , , et al., PCB-77 Disturbs Iron Homeostasis Through Regulating Hepcidin Gene Expression, Gene. (2013) 532, no. 1, 146–151, https://doi.org/10.1016/j.gene.2013.09.023, 2-s2.0-84885371417.
- 102 , , et al., Enzyme Induction and Histopathology Elucidate Aryl Hydrocarbon Receptor-Mediated Versus Non-Aryl Hydrocarbon Receptor-Mediated Effects of Aroclor 1268 in American Mink (Neovison Vison), Environmental Toxicology and Chemistry. (2015) 35, no. 3, 619–634, https://doi.org/10.1002/etc.3203, 2-s2.0-84969401345.
- 103 , , et al., Polychlorinated Biphenyls (PCBs) Inhibit Hepcidin Expression Through an Estrogen-Like Effect Associated With Disordered Systemic Iron Homeostasis, Chemical Research in Toxicology. (2015) 28, no. 4, 629–640, https://doi.org/10.1021/tx500428r, 2-s2.0-84928501223.
- 104 , , , , and , Haematological Evaluation of Sodium Fluoride Toxicity in oryctolagus Cunniculus, Toxicology Reports. (2017) 4, 450–454, https://doi.org/10.1016/j.toxrep.2017.07.002, 2-s2.0-85027558101.
- 105 , , et al., Haematological Profile of Subacute Oral Toxicity of Fluoride and Ameliorative Efficacy of Aluminium Sulphate in Goats, Toxicology International. (2018) 16, no. 1, 31–35.
- 106 , , , and , Effect of Moringa Oleifera Leaves on Hematological Profile of Fluorosis Affected Rats, Bioinformation. (2022) 18, no. 1, 14–18, https://doi.org/10.6026/97320630018014.
- 107 , , et al., Effects of High Dietary Fluorine on Erythrocytes and Erythrocyte Immune Adherence Function in Broiler Chickens, Biological Trace Element Research. (2013) 155, no. 2, 247–252, https://doi.org/10.1007/s12011-013-9793-6, 2-s2.0-84885328404.
- 108 , , , and , Fluorosis and its Hematological Effects, Toxicology and Industrial Health. (2005) 21, no. 9, 255–258, https://doi.org/10.1191/0748233705th236oa, 2-s2.0-30644457813.
- 109 , , and , Why Cells Need Iron: A Compendium of Iron Utilisation, Trends in Endocrinology and Metabolism. (2024) 35, no. 12, 1026–1049, https://doi.org/10.1016/j.tem.2024.04.015.
- 110 and , An Overview of the Effects of Dioxins and Dioxin-Like Compounds on Vertebrates, as Documented in Human and Ecological Epidemiology, Journal of Environmental Science and Health, Part C. (2009) 27, no. 4, 197–211, https://doi.org/10.1080/10590500903310047, 2-s2.0-71449114195.
- 111 and , Article Commentary: Effects of Environmental Pollutants on Cellular Iron Homeostasis and Ultimate Links to Human Disease, Environmental Health Insights. (2016) 10, no. EHI, https://doi.org/10.4137/ehi.s36225.
- 112 , , , , and , Associations Between Organochlorine Contaminant Concentrations and Clinical Health Parameters in Loggerhead Sea Turtles From North Carolina, USA, Environmental Health Perspectives. (2004) 112, no. 10, 1074–1079, https://doi.org/10.1289/ehp.6923, 2-s2.0-3543151411.
- 113 , , et al., Potential Adverse Health Effects of Persistent Organic Pollutants on Sea Turtles: Evidences From a Cross-Sectional Study on Cape Verde Loggerhead Sea Turtles, Science of the Total Environment. (2013) 458–460, 283–289, https://doi.org/10.1016/j.scitotenv.2013.04.043, 2-s2.0-84877662575.
- 114 , , and , Chronic Toxicity and Carcinogenicity of 1,2,3,4,6,7,8-Heptachlorodibenzo-P-Dioxin Displays a Distinct Dose/Time Toxicity Threshold (C × t = k) and a Life-Prolonging Subthreshold Effect, Food and Chemical Toxicology. (2005) 43, no. 5, 729–740, https://doi.org/10.1016/j.fct.2005.01.013, 2-s2.0-15044341458.
- 115 , , et al., Essential Role of the AH Receptor in the Dysfunction of Heme Metabolism Induced by 2,3,7,8-Tetrachlorodibenzo-P-dioxin, Chemical Research in Toxicology. (2008) 21, no. 2, 330–340, https://doi.org/10.1021/tx700176r, 2-s2.0-41649107311.
- 116 , , et al., Dioxin-Like PCB 126 Increases Systemic Inflammation and Accelerates Atherosclerosis in Lean LDL Receptor-Deficient Mice, Toxicological Sciences. (2018) 162, no. 2, 548–558, https://doi.org/10.1093/toxsci/kfx275, 2-s2.0-85044864074.
- 117 , , , , and , Effects of Fluoridated Drinking Water on Dental Caries in Australian Adults, Journal of Dental Research. (2013) 92, no. 4, 376–382, https://doi.org/10.1177/0022034513481190, 2-s2.0-84875753748.
- 118 and , Economic Evaluation of Community Water Fluoridation, American Journal of Preventive Medicine. (2016) 50, no. 6, 790–796, https://doi.org/10.1016/j.amepre.2015.10.014, 2-s2.0-84954287032.
- 119 , , , and , Severe Magnitude of Dental and Skeletal Fluorosis and its Impact on Society and Environment in a Part of Manbhum-Singhbhum Plateau, India, BMC Public Health. (2024) 24, no. 1, https://doi.org/10.1186/s12889-024-19446-1.
- 120 , , , , and , Skeletal Fluorosis in Relation to Drinking Water in Rural Areas of West Azerbaijan, Iran, Scientific Reports. (2017) 7, no. 1, https://doi.org/10.1038/s41598-017-17328-8, 2-s2.0-85042920238.
- 121 , , and , Anaemia in Adolescent Girls: An Intervention of Diet Editing and Counselling, The National Medical Journal of India. (2016) 29, no. 4, 200–204.
- 122 , , , , and , Fluorosis is Linked to Anaemia, Current Science. (2018) 115, no. 4, 692–700, https://doi.org/10.18520/cs/v115/i4/692-700, 2-s2.0-85051860834.
Full-text study online at https://onlinelibrary.wiley.com/doi/10.1155/sci5/5007983