Special Issue "Toxic Metals, Chronic Diseases and Related Cancers"

A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Toxicology and Public Health".

Deadline for manuscript submissions: 31 July 2020.

Special Issue Editor

Prof. Dr. Soisungwan Satarug

Guest Editor
UQ Diamantina Institute and Centre for Health Services Research, Centre for Kidney Disease Research and Translational Research Institute, Woolloongabba, Brisbane, Australia
Interests: epidemiology of cadmium toxicity; genetic and nutritional influence of cadmium toxicity outcomes; cadmium toxicity in at-risk subpopulations; novel methods of measuring cadmium in tissues; reverse dosimetry
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

It is estimated that 70–90% of the risk of acquiring chronic diseases such as kidney disease, type-2 diabetes, and cancers can be attributed to environmental exposures. The toxic heavy metals, cadmium (Cd), lead (Pb), and mercury (Hg) are of particular public health concern and this is reflected by the World Health Organization (WHO) and the Agency for Toxic Substances and Disease Registry (ATSDR) listing them as priority substances.

Years of production and industrial use have led to the widespread presence of these metals in the environment. Being non-biodegradable, they persist in the environment and readily enter food chains. The continued use of contaminated fertilizers by the agricultural sector has further increased their levels in the food we eat. Total diet studies have shown that Cd and Pb are present in virtually all foodstuffs, while mercury is present in seafood in the form of methylmercury. Foods that are frequently consumed in large quantities such as rice, potatoes, wheat, leafy salad vegetables, and other cereal crops are the most significant dietary sources, while shellfish, crustaceans, mollusks, offal, and spinach are additional dietary sources.

Given the globally rising incidence of chronic kidney disease, Alzheimer’s disease, type-2 diabetes, and cancer of various sites, this Toxics Special Issue calls for reports on epidemiologic and laboratory investigations that may help prioritize efforts to assess toxicities and the impact of these environmental toxicants on public health. Topics may include intestinal absorption, transport, cellular uptake, metabolic effects, novel toxicity targets, toxic threshold levels, toxic mechanisms, detoxification, speciation, mitigation of soil-to-plant transference, and environmental exposure minimization strategies. Authors are invited and welcome to submit original research papers, reviews, and short communications.

Prof. Soisungwan Satarug
Guest Editor

Manuscript Submission Information

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Keywords

  • Cadmium
  • Lead
  • Mercury
  • Cancer
  • Chronic diseases
  • Diabetes
  • Metal transporters
  • Metabolic syndrome
  • Soil-to-plant transfer
  • Tolerable intake levels
  • Total diet studies

Published Papers (10 papers)

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Research

Open AccessArticle
Mercury Exposure and Associations with Hyperlipidemia and Elevated Liver Enzymes: A Nationwide Cross-Sectional Survey
Toxics 2020, 8(3), 47; https://doi.org/10.3390/toxics8030047 (registering DOI) - 01 Jul 2020
Abstract
Mercury (Hg) has obesogenic properties. However, the associated health outcomes of population-level mercury exposure were unclear. This study investigated the relationships between blood mercury levels and obesity-related outcomes such as hyperlipidemia and elevated liver enzymes. Using the second cycle of the Korean National [...] Read more.
Mercury (Hg) has obesogenic properties. However, the associated health outcomes of population-level mercury exposure were unclear. This study investigated the relationships between blood mercury levels and obesity-related outcomes such as hyperlipidemia and elevated liver enzymes. Using the second cycle of the Korean National Environmental Health Survey (n = 6454), we performed logistic regression to examine the effects of Hg on hyperlipidemia and elevated liver enzymes. The blood mercury levels were significantly higher in the hyperlipidemia group (n = 3699, male: 4.03 μg/L, female: 2.83 μg/L) compared to the non-hyperlipidemia group (n = 2755, male: 3.48 μg/L, female: 2.69 μg/L), and high blood mercury levels were associated with an 11% higher risk of hyperlipidemia. The elevated liver enzymes group had higher mean blood mercury levels (n = 1189, male: 4.38 μg/L, female: 3.25 μg/L) than the normal group (n = 5265, male: 3.64 μg/L, female: 2.70 μg/L), and elevated blood mercury was associated with a 35% higher risk of elevated liver enzymes. Moreover, the effect was constant after adjusting for personal medications. These results indicate that mercury exposure is significantly associated with hyperlipidemia and elevated liver enzymes. Full article
(This article belongs to the Special Issue Toxic Metals, Chronic Diseases and Related Cancers)
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Open AccessArticle
Exposure Assessment of Cadmium in Female Farmers in Cadmium-Polluted Areas in Northern Japan
Toxics 2020, 8(2), 44; https://doi.org/10.3390/toxics8020044 - 17 Jun 2020
Abstract
Akita prefecture is located in the northern part of Japan and has many cadmium-polluted areas. We herein performed an exposure assessment of cadmium in 712 and 432 female farmers in two adjacent cadmium-polluted areas (A and B, respectively), who underwent local health examinations [...] Read more.
Akita prefecture is located in the northern part of Japan and has many cadmium-polluted areas. We herein performed an exposure assessment of cadmium in 712 and 432 female farmers in two adjacent cadmium-polluted areas (A and B, respectively), who underwent local health examinations from 2001–2004. We measured cadmium concentrations in 100 food items collected from local markets in 2003. We then multiplied the intake of each food item by its cadmium concentration in each subject to assess cadmium intake from food and summed cadmium intake from all food items to obtain the total cadmium intake. Median cadmium intake levels in areas A and B were 55.7 and 47.8 µg/day, respectively, which were both higher than that of the general population and were attributed to local agricultural products, particularly rice. We also calculated weekly cadmium intake per body weight and compared it to the previous provisional tolerable weekly intake reported by the Joint FAO (Food and Agriculture Organization)/WHO (World Health Organization) expert committee on food additives or current tolerable weekly intake in Japan of 7 µg/kg BW/week. Medians in areas A and B were 7.2 and 6.0 µg/kg BW/week, respectively. Similar estimated values were also obtained by the Monte Carlo simulation. These results demonstrated that the cadmium exposure levels among the farmers were high enough to be approximately the tolerable weekly intake. Full article
(This article belongs to the Special Issue Toxic Metals, Chronic Diseases and Related Cancers)
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Open AccessArticle
Genotoxic Effects of Aluminum Chloride and Their Relationship with N-Nitroso-N-Methylurea (NMU)-Induced Breast Cancer in Sprague Dawley Rats
Toxics 2020, 8(2), 31; https://doi.org/10.3390/toxics8020031 - 20 Apr 2020
Abstract
Recently, soluble forms of aluminum for human use or consumption have been determined to be potentially toxic due to their association with hepatic, neurological, hematological, neoplastic, and bone conditions. This study aims to assess the genotoxic effect of aluminum chloride on genomic instability [...] Read more.
Recently, soluble forms of aluminum for human use or consumption have been determined to be potentially toxic due to their association with hepatic, neurological, hematological, neoplastic, and bone conditions. This study aims to assess the genotoxic effect of aluminum chloride on genomic instability associated with the onset of N-nitroso-N-methylurea (NMU)-induced breast cancer in Sprague Dawley rats. The dietary behavior of the rats was assessed, and the concentration of aluminum in the mammary glands was determined using atomic absorption spectroscopy. Genomic instability was determined in the histological sections of mammary glands stained with hematoxylin and eosin. Moreover, micronucleus in peripheral blood and comet assays were performed. The results of dietary behavior evaluation indicated no significant differences between the experimental treatments. However, aluminum concentration in breast tissues was high in the +2000Al/−NMU treatment. This experimental treatment caused moderate intraductal cell proliferation, lymph node hyperplasia, and serous gland adenoma. Furthermore, micronucleus and comet test results revealed that +2000Al/−NMU led to a genotoxic effect after a 10-day exposure and the damage was more evident after a 15-day exposure. Therefore, in conclusion, genomic instability is present and the experimental conditions assessed are not associated with breast cancer. Full article
(This article belongs to the Special Issue Toxic Metals, Chronic Diseases and Related Cancers)
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Open AccessArticle
Theoretical Modeling of Oral Glucose Tolerance Tests Guides the Interpretation of the Impact of Perinatal Cadmium Exposure on the Offspring’s Glucose Homeostasis
Toxics 2020, 8(2), 30; https://doi.org/10.3390/toxics8020030 - 15 Apr 2020
Abstract
Oral glucose tolerance tests, in which the concentration of glucose is monitored in the circulation over 2 h after ingesting a bolus, probe diabetic or pre-diabetic conditions. The resulting glucose curves inform about glucose turnover, insulin production and sensitivity, and other parameters. However, [...] Read more.
Oral glucose tolerance tests, in which the concentration of glucose is monitored in the circulation over 2 h after ingesting a bolus, probe diabetic or pre-diabetic conditions. The resulting glucose curves inform about glucose turnover, insulin production and sensitivity, and other parameters. However, extracting the relevant parameters from a single complex curve is not straightforward. We propose a simple modeling method recapitulating the most salient features of the role of insulin-secreting pancreatic β -cells and insulin sensitive tissues. This method implements four ordinary differential equations with ten parameters describing the time-dependence of glucose concentration, its removal rate, and the circulating and stored insulin concentrations. From the initial parameter set adjusted to a reference condition, fitting is done by minimizing a weighted least-square residual. In doing so, the sensitivity of β -cells to glucose was identified as the most likely impacted function at weaning for the progeny of rats that were lightly exposed to cadmium in the perigestational period. Later in life, after young rats received non-contaminated carbohydrate enriched food, differences are more subtle, but modeling agrees with long-lasting perturbation of glucose homeostasis. Full article
(This article belongs to the Special Issue Toxic Metals, Chronic Diseases and Related Cancers)
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Open AccessArticle
In Vitro Evaluation of the Effects of Cadmium on Endocytic Uptakes of Proteins into Cultured Proximal Tubule Epithelial Cells
Toxics 2020, 8(2), 24; https://doi.org/10.3390/toxics8020024 - 01 Apr 2020
Abstract
Cadmium (Cd) is an environmental pollutant known to cause dysfunctions of the tubular reabsorption of biomolecules in the kidney. Elevated levels of urinary excretion of low-molecular-weight proteins such as β2-microglobulin (β2-MG) have been used as an indicator of Cd-induced [...] Read more.
Cadmium (Cd) is an environmental pollutant known to cause dysfunctions of the tubular reabsorption of biomolecules in the kidney. Elevated levels of urinary excretion of low-molecular-weight proteins such as β2-microglobulin (β2-MG) have been used as an indicator of Cd-induced renal tubular dysfunctions. However, very few studies have examined the direct effects of Cd on the reabsorption efficiency of proteins using cultured renal cells. Here, we developed an in vitro assay system for quantifying the endocytic uptakes of fluorescent-labeled proteins by flow cytometry in S1 and S2 cells derived from mouse kidney proximal tubules. Endocytic uptakes of fluorescent-labeled albumin, transferrin, β2-MG, and metallothionein into S1 cells were confirmed by fluorescence imaging and flow cytometry. The exposure of S1 and S2 cells to Cd at 1 and 3 µM for 3 days resulted in significant decreases in the uptakes of β2-MG and metallothionein but not in those of albumin or transferrin. These results suggest that Cd affects the tubular reabsorption of low-molecular-weight proteins even at nonlethal concentrations. The in vitro assay system developed in this study to evaluate the endocytic uptakes of proteins may serve as a useful tool for detecting toxicants that cause renal tubular dysfunctions. Full article
(This article belongs to the Special Issue Toxic Metals, Chronic Diseases and Related Cancers)
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Open AccessArticle
A Comparison of the Nephrotoxicity of Low Doses of Cadmium and Lead
Toxics 2020, 8(1), 18; https://doi.org/10.3390/toxics8010018 - 02 Mar 2020
Cited by 1
Abstract
Environmental exposure to moderate-to-high levels of cadmium (Cd) and lead (Pb) is associated with nephrotoxicity. In comparison, the health impacts of chronic low-level exposure to Cd and Pb remain controversial. The aim of this study was to therefore evaluate kidney dysfunction associated with [...] Read more.
Environmental exposure to moderate-to-high levels of cadmium (Cd) and lead (Pb) is associated with nephrotoxicity. In comparison, the health impacts of chronic low-level exposure to Cd and Pb remain controversial. The aim of this study was to therefore evaluate kidney dysfunction associated with chronic low-level exposure to Cd and Pb in a population of residents in Bangkok, Thailand. The mean age and the estimated glomerular filtration rate (eGFR) for 392 participants (195 men and 197 women) were 34.9 years and 104 mL/min/1.73 m2, respectively, while the geometric mean concentrations of urinary Cd and Pb were 0.25 μg/L (0.45 μg/g of creatinine) and 0.89 μg/L (1.52 μg/g of creatinine), respectively. In a multivariable regression analysis, the eGFR varied inversely with blood urea nitrogen in both men (β = −0.125, p = 0.044) and women (β = −0.170, p = 0.008), while inverse associations of the eGFR with urinary Cd (β = −0.132, p = 0.043) and urinary Pb (β = −0.130, p = 0.044) were seen only in women. An increased urinary level of Cd to the median level of 0.38 μg/L (0.44 μg/g of creatinine) was associated with a decrease in the eGFR by 4.94 mL/min/1.73 m2 (p = 0.011). The prevalence odds of a reduced eGFR rose 2.5-, 2.9- and 2.3-fold in the urinary Cd quartile 3 (p = 0.013), the urinary Cd quartile 4 (p = 0.008), and the urinary Pb quartile 4 (p = 0.039), respectively. This study suggests that chronic exposure to low-level Cd is associated with a decline in kidney function and that women may be more susceptible than men to nephrotoxicity due to an elevated intake of Cd and Pb. Full article
(This article belongs to the Special Issue Toxic Metals, Chronic Diseases and Related Cancers)
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Open AccessArticle
Biomonitoring of Trace Elements in Subjects Living Near a Hazardous Waste Incinerator: Concentrations in Autopsy Tissues
Toxics 2020, 8(1), 11; https://doi.org/10.3390/toxics8010011 - 11 Feb 2020
Cited by 1
Abstract
The only hazardous waste incinerator (HWI) in Spain started to operate in 1999. Twenty years later, the levels of 11 trace elements (As, Be, Cd, Cr, Hg, Mn, Ni, Pb, Sn, Tl and V) were analyzed in five different autopsy tissues (kidney, liver, [...] Read more.
The only hazardous waste incinerator (HWI) in Spain started to operate in 1999. Twenty years later, the levels of 11 trace elements (As, Be, Cd, Cr, Hg, Mn, Ni, Pb, Sn, Tl and V) were analyzed in five different autopsy tissues (kidney, liver, brain, bone and lung) from 20 individuals who had been living near the facility. In 2019, As, Be, Tl and V were not detected in any of the analyzed tissues, while Hg could be only quantified in very few samples. The highest levels of Cd and Pb were found in kidney and bone, respectively, while those of Mn were observed in liver and kidney. In turn, the mean concentrations of Cr and Sn were very similar in all tissues. A consistent temporal trend (1998–2019) was only found for Cr and Pb. On the one hand, the mean Cr concentrations in kidney and bone have increased progressively since 1998. In contrast, the mean levels of Pb decreased significantly over time, probably due to ban of Pb as gasoline additive. The data global analysis indicates that the emissions of trace elements by the HWI have not increased the exposure and/or accumulation of these elements in individuals living near the facility. Full article
(This article belongs to the Special Issue Toxic Metals, Chronic Diseases and Related Cancers)
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Open AccessArticle
The Source and Pathophysiologic Significance of Excreted Cadmium
Toxics 2019, 7(4), 55; https://doi.org/10.3390/toxics7040055 - 18 Oct 2019
Cited by 2
Abstract
In theory, the identification of the source of excreted cadmium (Cd) might elucidate the pathogenesis of Cd-induced chronic kidney disease (CKD). With that possibility in mind, we studied Thai subjects with low, moderate, and high Cd exposure. We measured urine concentrations of Cd, [...] Read more.
In theory, the identification of the source of excreted cadmium (Cd) might elucidate the pathogenesis of Cd-induced chronic kidney disease (CKD). With that possibility in mind, we studied Thai subjects with low, moderate, and high Cd exposure. We measured urine concentrations of Cd, ([Cd]u); N-acetyl-β-d-glucosaminidase, a marker of cellular damage ([NAG]u); and β2-microglobulin, an indicator of reabsorptive dysfunction ([β2MG]u). To relate excretion rates of these substances to existing nephron mass, we normalized the rates to creatinine clearance, an approximation of the glomerular filtration rate (GFR) (ECd/Ccr, ENAG/Ccr, and Eβ2MG/Ccr). To link the loss of intact nephrons to Cd-induced tubular injury, we examined linear and quadratic regressions of estimated GFR (eGFR) on ECd/Ccr, eGFR on ENAG/Ccr, and ENAG/Ccr on ECd/Ccr. Estimated GFR varied inversely with both ratios, and ENAG/Ccr varied directly with ECd/Ccr. Linear and quadratic regressions of Eβ2MG/Ccr on ECd/Ccr and ENAG/Ccr were significant in moderate and high Cd-exposure groups. The association of ENAG/Ccr with ECd/Ccr implies that both ratios depicted cellular damage per surviving nephron. Consequently, we infer that excreted Cd emanated from injured tubular cells, and we attribute the reduction of eGFR to the injury. We suggest that ECd/Ccr, ENAG/Ccr, and eGFR were associated with one another because each parameter was determined by the tubular burden of Cd. Full article
(This article belongs to the Special Issue Toxic Metals, Chronic Diseases and Related Cancers)
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Open AccessArticle
Screening for Elevated Blood Lead Levels and Related Risk Factors among Thai Children Residing in a Fishing Community
Toxics 2019, 7(4), 54; https://doi.org/10.3390/toxics7040054 - 12 Oct 2019
Abstract
The present study explored environmental and behavioral factors associated with elevated blood lead (Pb) levels in 311 children (151 girls and 160 boys), aged 3–7 years, who lived in a coastal fishing community of the Pakpoon Municipality, Nakhon Si Thammarat, Thailand. The geometric [...] Read more.
The present study explored environmental and behavioral factors associated with elevated blood lead (Pb) levels in 311 children (151 girls and 160 boys), aged 3–7 years, who lived in a coastal fishing community of the Pakpoon Municipality, Nakhon Si Thammarat, Thailand. The geometric mean for blood Pb was 2.81 µg/dL, ranging between 0.03 and 26.40 µg/dL. The percentage of high blood Pb levels, defined as blood Pb ≥ 5 µg/dL, was 10.0% in boys and 13.9% in girls. Parental occupation in producing fishing nets with lead weights was associated with a marked increase in the prevalence odds ratio (POR) for high blood Pb (POR 17.54, 95%; CI: 7.093, 43.390; p < 0.001), while milk consumption was associated with 61% reduction in the POR for high blood Pb (POR 0.393, 95%; CI: 0.166, 0.931; p = 0.034). High blood Pb was associated with an increased risk for abnormal growth (POR 2.042, 95%; CI: 0.999, 4.174; p = 0.050). In contrast, milk consumption was associated with a 43% reduction in POR for abnormal growth (POR 0.573, 95%; CI: 0.337, 0.976; p = 0.040). After adjustment for age, the mean (standard error of mean, SE) values for blood Pb were 6.22 (0.50) μg/dL in boys and 6.72 (0.49) μg/dL in girls of parents with an occupation in making fishing nets with lead weights. These mean blood Pb values were respectively 2.3 and 2.5 times higher than similarly aged boys and girls of parents with other occupations. These data are essential for setting surveillance and programmes to prevent toxic Pb exposure, especially in children of coastal fishing communities in southern Thailand. Full article
(This article belongs to the Special Issue Toxic Metals, Chronic Diseases and Related Cancers)
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Open AccessFeature PaperArticle
Biomonitoring of Trace Elements in Hair of Schoolchildren Living Near a Hazardous Waste Incinerator—A 20 Years Follow-Up
Toxics 2019, 7(4), 52; https://doi.org/10.3390/toxics7040052 - 01 Oct 2019
Cited by 4
Abstract
Since 1998, a monitoring program is periodically performed to assess the environmental and human health impact of air chemicals potentially emitted by a hazardous waste incinerator (HWI) located in Constantí (Catalonia, Spain). In 2017, samples of hair were collected from 94 schoolchildren (aged [...] Read more.
Since 1998, a monitoring program is periodically performed to assess the environmental and human health impact of air chemicals potentially emitted by a hazardous waste incinerator (HWI) located in Constantí (Catalonia, Spain). In 2017, samples of hair were collected from 94 schoolchildren (aged 10–13 years) living nearby and the levels of 11 trace elements (As, Be, Cd, Cr, Hg, Mn, Ni, Pb, Sn, Tl and V) were determined. The concentrations showed the following descending order: Pb > Hg > Ni > Sn > Mn > Cr. In turn, As, Be and Tl were not detected, while Cd and V were found only in a few samples. Some metal levels were significantly, positively correlated. Some significant differences were also noticed according to the gender and the specific zone of residence. Finally, the levels of trace elements showed fluctuations through time. Cr and Pb showed a significant decrease in comparison to the concentrations obtained in the baseline study (1998). According to the current results, metal emissions from the HWI are not relevant in terms of human health impact since their levels were similar and even lower than those reported in other contaminated areas. Full article
(This article belongs to the Special Issue Toxic Metals, Chronic Diseases and Related Cancers)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Review

Title: Chronic low-level environmental exposure to cadmium and lead: Focus on their nephrotoxicity and carcinogenicity

Authors: Soisungwan Satarug, David A. Vesey, Glenda C. Gobe, and Kenneth R. Phelps

Abstract: 

Chronic kidney disease (CKD) is the cause of significant morbidity and mortality. Its high worldwide prevalence and escalating treatment costs have made developing strategies to prevent CKD of global importance. Cadmium (Cd) and lead (Pb) are toxicants of relevance due to their widespread pollution, non-biodegradability and the known adverse health effects, including enhanced risk of CKD, diabetes and various types of cancer. Years of production and industrial use have mobilized Cd and Pb from non-bioavailable geologic matrices to where they are biologically accessible and readily enter food chains. The use of contaminated fertilizers has further increased Cd and Pb levels in food crops. Plants have the propensity to concentrate Cd and Pb from the soil and their multiple detoxification mechanisms enable them to tolerate high Cd and Pb levels that are toxic to animals and humans. The goal of this review is to provide a rational for public health policy regarding exposure limits, tolerable intake levels and the modification of the current criteria by which Cd- and Pb-induced nephrotoxicity is judged. Accordingly, dietary sources and intake levels of Cd and Pb reported by total diet studies are summarized together with urinary biomarkers, N-acetyl-β-D-glucosaminidase and β2-microglobulin (β2MG) which are often used to assess nephrotoxicity. The relationship between tubulopathy and decreased glomerular filtration rate is discussed as is the basis for urinary β2MG excretion as an indicator of nephron loss. The effects of environmental exposure to Cd and Pb on the risk of CKD and cancer reported in recent epidemiologic studies are summarized.

Keywords: cadmium; cancer; chronic kidney disease; glomerular filtration rate; lead; nephron loss; urine β2-microglobulin

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