Toxics, Volume 6, Issue 2 (June 2018) – 15 articles

The effect of toxic concentrations of La³⁺ on the Ca, K, Na, Mg, and Cl channels of planaria was investigated through the use of various agonists and antagonists to those channels. It was demonstrated that La exerts its toxic effects through L-type, but not T-type, Ca channels. La also demonstrated activity at Na, K, Mg, and Cl channels, but, these effects were most likely mediated by other effects of La on Ca activity. However, these interactions appear to be very complex and confounded by oxidative stresses. The study also introduces a planaria stress scale which allows the effects of toxic substances to be examined on a continuum. Full article

Cadmium (Cd) is an environmental contaminant that damages the kidney, the liver, and bones. Some epidemiological studies showed associations between Cd exposure and periodontal disease. The purpose of this study was to examine the relationship between Cd exposure and periodontal disease in experimental animals. Male Sprague/Dawley rats were given daily subcutaneous injections of Cd (0.6 mg/kg/day) for up to 12 weeks. The animals were euthanized, and their mandibles and maxillae were evaluated for levels of periodontal bone by measuring the distance from the cementoenamel junction (CEJ) to the alveolar bone crest (ABC) of the molar roots. After 12 weeks of Cd exposure in animals, there was a significantly greater distance between the CEJ and ABC in the palatal aspect of the maxillary molars and the lingual aspect of the mandibular molars when compared with controls (p < 0.0001). This study shows that Cd has significant, time-dependent effects on periodontal bone in an animal model of Cd exposure. These findings support the possibility of Cd being a contributing factor to the development of periodontal disease in humans. Full article

Fruits and vegetables are considered a beneficial contribution to the human diet. Especially, berries contain a great deal of bioactive compounds, such as anthocyanins, organic acids, tannins, phenols, and antioxidants. Apart from organic substances, inorganic nutrients are also present in fruits. Some metals and metalloids are essential for humans, whilst others may exhibit harmful effects. Wild grown berries, collected in so-called unpolluted areas, are considered to be free of any potentially toxic ingredients. However, due to transmission processes pollutants can also reach remote areas and, furthermore, metal uptake from the soil via roots has to be taken into account. Thus, the presented study focused on the determination of Al, Cd, Cr, Ni, and Pb in lingonberries, blueberries, and rose hips collected in a non-polluted area in Croatia. Neither Cd nor Cr could be found in any sample. Ni levels were mainly up to 25 mg/kg, in a comparable range to the literature data. No health threat is to be expected by eating these fruits and berries regarding Cd, Cr, and Ni. Rose hips, however, contain Pb beyond the stipulated limit in fruits, and also Al is present at a high level (8 mg/g). Full article

The measurement of DNA adducts provides important information about human exposure to genotoxic chemicals and can be employed to elucidate mechanisms of DNA damage and repair. DNA adducts can serve as biomarkers for interspecies comparisons of the biologically effective dose of procarcinogens and permit extrapolation of genotoxicity data from animal studies for human risk assessment. One major challenge in DNA adduct biomarker research is the paucity of fresh frozen biopsy samples available for study. However, archived formalin-fixed paraffin-embedded (FFPE) tissues with clinical diagnosis of disease are often available. We have established robust methods to recover DNA free of crosslinks from FFPE tissues under mild conditions which permit quantitative measurements of DNA adducts by liquid chromatography-mass spectrometry. The technology is versatile and can be employed to screen for DNA adducts formed with a wide range of environmental and dietary carcinogens, some of which were retrieved from section-cuts of FFPE blocks stored at ambient temperature for up to nine years. The ability to retrospectively analyze FFPE tissues for DNA adducts for which there is clinical diagnosis of disease opens a previously untapped source of biospecimens for molecular epidemiology studies that seek to assess the causal role of environmental chemicals in cancer etiology. Full article

Growing evidences demonstrated that zinc oxide nanoparticles (ZnONPs) could reach the brain after oral ingestion; however, the “neurotoxicity of” ZnONPs after oral exposure has not been fully investigated. This study aimed to explore the “neurotoxicity of” ZnONPs (<100 nm) after oral exposure to two doses; 40 and 100 mg/kg for 24 h and 7 days. The exposure to 40 and 100 mg/kg of ZnONPs for 24 h did not elicit “neurotoxicity” compared to normal control. However, the daily exposure to both doses for 7 days caused oxidative stress in brain tissue as detected by the elevation of the levels of malondialdehyde, the main product of lipid peroxidation and nitrite as an index of nitric oxide with concomitant decline in the concentrations of antioxidants. In addition, both doses resulted in DNA fragmentation which was confirmed by increased percentage of tailed DNA, DNA tail intensity and length and tail moment particularly with the dose 100 mg/kg. Moreover, both doses led to the elevation of the inflammatory cytokines along with increased apoptotic markers including caspase-3 and Fas. Heat shock protein-70 levels were also elevated possibly as a compensatory mechanism to counteract the ZnONPs-induced oxidative stress and apoptosis. The present results indicate the “neurotoxicity of” ZnONPs after recurrent oral exposure via oxidative stress, genotoxicity, inflammatory response and apoptosis. Full article

Twelve applications of poultry litter were made to a 2.1-ha field located in the Shenandoah Valley of Virginia, United States (USA), between March 1999 and August 2014. The field was planted with bermudagrass (Cynodon dactylon) and used as a pasture on an active farm. Copper, iron, manganese, zinc, and arsenic concentrations in the poultry litter were measured, and the application rates of these metals were calculated. The median application rates were: Cu, 1.32 kg/ha, Fe, 5.57 kg/ha, Mn, 1.80 kg/ha, Zn, 1.39 kg/ha, and As, 0.011 kg/ha. Twelve surface and subsurface soil samples were taken from the treated field in February 2016. Twelve samples were also taken from a comparison site. The comparison site was directly adjacent to the study site, consisted of the same soil type, and had been maintained as an undisturbed forest. Extractable Cu, Fe, Mn, Zn, and As concentrations in the soil samples were determined by atomic absorption spectroscopy, and the results of the chemical analysis were analyzed by ANOVA. Fe and Mn were depleted from the soil in the treated field, while Cu and Zn levels increased over the 12 years of treatment and grazing, and arsenic levels were unchanged in both the surface and subsurface soils between the comparison and the study site. The changes observed for Cu, Fe, Mn, and Zn are within the critical deficiency level and critical toxicity level for these metals, and no arsenic remains in the soil from roxarsone feed supplements, which were added to the poultry feed when the litter was applied to the study site. Full article

It is essential to understand contaminant exposure and to compare levels of contaminants in organisms at different ages to determine if there is bioaccumulation, and to compare levels encountered in different geographical areas. In this paper, we report levels of mercury, lead, cadmium, cobalt, arsenic and selenium in the blood of semipalmated sandpipers (Calidris pusilla) wintering in Suriname as a function of age, and compare them to blood levels in northbound migrants at a stopover in Delaware Bay, New Jersey. We found (1) young birds had higher levels of cadmium, cobalt, and lead than adults (after second year birds); (2) there were no age-related differences for arsenic, mercury and selenium; (3) only four of the possible 16 inter-metal correlations were significant, at the 0.05 level; (4) the highest correlation was between cadmium and lead (Kendall tau = 0.37); and (5) the adult sandpipers had significantly higher levels of cadmium, mercury and selenium in Suriname than in New Jersey, while the New Jersey birds had significantly higher levels of arsenic. Suriname samples were obtained in April, after both age classes had spent the winter in Suriname, which suggests that sandpipers are accumulating higher levels of trace elements in Suriname than in Delaware Bay. The levels of selenium may be within a range of concern for adverse effects, but little is known about adverse effect levels of trace elements in the blood of wild birds. Full article

The frequently observed association between kidney toxicity and long-term cadmium (Cd) exposure has long been dismissed and deemed not to be of clinical relevance. However, Cd exposure has now been associated with increased risk of developing chronic kidney disease (CKD). We investigated the link that may exist between kidney Cd toxicity markers and clinical kidney function measure such as estimated glomerular filtration rates (eGFR). We analyzed data from 193 men to 202 women, aged 16−87 years [mean age 48.8 years], who lived in a low- and high-Cd exposure areas in Thailand. The mean (range) urinary Cd level was 5.93 (0.05–57) μg/g creatinine. The mean (range) for estimated GFR was 86.9 (19.6−137.8) mL/min/1.73 m². Kidney pathology reflected by urinary β2-microglobulin (β2-MG) levels ≥ 300 μg/g creatinine showed an association with 5.32-fold increase in prevalence odds of CKD (p = 0.001), while urinary Cd levels showed an association with a 2.98-fold greater odds of CKD prevalence (p = 0.037). In non-smoking women, Cd in the highest urinary Cd quartile was associated with 18.3 mL/min/1.73 m² lower eGFR value, compared to the lowest quartile (p < 0.001). Evidence for Cd-induced kidney pathology could thus be linked to GFR reduction, and CKD development in Cd-exposed people. These findings may help prioritize efforts to reassess Cd exposure and its impact on population health, given the rising prevalence of CKD globally. Full article

Carbon tetrachloride (CCl₄) is an efficient but highly toxic solvent, used in households and commercially in the industry under regulatory surveillance to ensure safety at the working place and to protect the workers’ health. However, acute unintentional or intentional intoxications by CCl₄ may rarely occur and are potentially life-threatening. In this review article, therapy options are discussed that are based on a literature review of traditional poisoning cases and the clinical experience with 16 patients with acute poisoning by CCl₄. Among various therapy options, the CO₂-induced hyperventilation therapy will be considered in detail as the most promising approach. This special therapy was developed because only around 1% of the intoxicating CCl₄ is responsible for the liver injury after conversion to toxic radicals via microsomal cytochrome P450 2E1 whereas 99% of the solvent will leave the body unchanged by exhalation. Therefore, to enhance CCl₄ elimination through the lungs, CO₂ is added to the inspiration air at a flow rate of 2–3 L min⁻¹ in order to achieve hyperventilation with a respiratory volume of 25–30 L min⁻¹. Under this therapy, the clinical course was favorable in 15/16 patients, corresponding to 93.8%. In essence, patients with acute CCl₄ intoxication should be treated by forced ventilation. Full article

The last few decades have seen a rise in the use of herbal supplements, natural products, and traditional medicines. However, there are growing concerns related to the safety and toxicities of these medicines. These herbal medicines are associated with complications such as liver damage with a high incidence of mortalities and morbidities. Clinical manifestations range from asymptomatic cases with abnormal liver functions tests to sudden and severe liver failure necessitating liver transplantation. This work aimed to review the etiology, risk factors, diagnosis, clinical manifestations and selected clinical case reports of herbal hepatotoxicity in developing nations. PubMed and Google Scholar searches were undertaken to identify relevant literature. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches. Little data exists on clinical cases of herb-induced liver injury in some developing countries such as Nigeria, as most incidences are either not reported to health care providers or reports from hospitals go unpublished. Studies in Nigeria have highlighted a possible correlation between use of herbs and liver disease. In Uganda, and association between the use of traditional herbal medicine with liver fibrosis in HIV-infected and non-HIV patients was demonstrated. Reports from China have revealed incidences of acute liver failure as a result of herbal medicine use. The actual incidence and prevalence of HILI in developing nations remain largely unknown due to both poor pharmacovigilance programs and non-application of emerging technologies. Improving education and public awareness of the potential risks of herbals and herbal products is desirable to ensure that suspected adverse effects are formally reported. There is need for stricter regulations and pre-clinical studies necessary for efficacy and safety. Full article

After 26 years, we followed up 7348 participants in a 1979–1984 health screening survey in the Jinzu River basin, the heaviest cadmium-polluted area in Japan. We assessed the associations of cadmium exposure levels and mortality from cancer and renal damage, indicated by records of proteinuria and glucosuria in the original survey. Mortality risks (hazard ratios) were analyzed using the Cox proportional hazards model, stratified by sex, after adjusting for age, smoking status, and hypertension, as indicated in the original survey records. In men, the adjusted hazard ratio for mortality from lung cancer was significantly lower in individuals residing in an area of historically high cadmium exposure and in subjects with a historical record of proteinuria, glucosuria, and glucoproteinuria. The risk of mortality from prostate cancer was borderline higher in cadmium-exposed men. In women, historical cadmium exposure was not associated with an increased risk of mortality from malignant neoplasms, but the adjusted hazard ratios for death from total malignant neoplasms or from renal and uterine cancers were significantly higher in exposed subjects with a historical record of proteinuria, glucosuria, and glucoproteinuria. These findings suggest that women residing in cadmium-polluted areas who exhibit markers of renal damage may be at risk of dying of cancer. Full article

Trace element (Hg, Pb, Cd, Zn, Cu, Ni, and Cr) occurrence was determined in the muscle tissue of swordfish collected in the Mediterranean Sea to assess whether the intakes complied with the recommended levels for essential metals and permissible levels for toxic elements. Metals were analyzed by an atomic absorption spectrophotometer (Shimadzu AA 7000). The methodology of Target Hazard Quotient (THQ) was also evaluated. The ranking order of toxic metal concentration was Hg > Cd > Pb, while for essential elements the distribution pattern followed the sequence Zn > Cu > Ni > Cr. The Estimated Weekly Intakes (EWI) as well as THQ for Cd and Pb indicated that swordfish consumption did not pose a risk to human health, whereas the major concern was for Hg. Fish size-related changes in Hg concentrations resulted in high EWI and THQ values relative to larger fish consumption, implying a potential risk to human health. For consumer protection, catches of swordfish approximately above 44 kg should be avoided as these fish have a higher risk of containing toxic levels of Hg. Full article

For the majority of lipophilic compounds, adipose tissue is traditionally considered as a storage depot and only rarely as a target organ. Meanwhile, abnormalities in adipose tissue physiology induced by chemical exposure may contribute to the current epidemic of obesity and metabolic diseases. Polybrominated diphenyl ethers (PBDEs) are a group of lipophilic flame retardants found in the majority of human samples in North America. Their ability to alter the physiology of adipose tissue is unknown. We exposed pregnant mice to 0.2 mg/kg body weight/day of BDE-47 perinatally. Transcriptomic changes in gonadal adipose tissue were analyzed in male offspring using the RNA-seq approach with subsequent bioinformatic analysis. The expression of genes of coagulation and complement cascade, de novo lipogenesis, and xenobiotic metabolism was altered in response to BDE-47 exposure. The affected molecular network included the following hubs: PPARα, HNF1A, and HNF4. These findings suggest that adipose tissue should be considered a target tissue for BDE-47, in addition to its role as a storage depot. This study also builds a background for a targeted search of sensitive phenotypic endpoints of BDE-47 exposure, including lipid profile parameters and coagulation factors in circulation. Additional studies are needed to investigate the role of PBDEs as an obesogen. Full article

The impact of chronic cadmium exposure and slow accumulation on the occurrence and development of diabetes is controversial for human populations. Islets of Langerhans play a prominent role in the etiology of the disease, including by their ability to secrete insulin. Conversion of glucose increase into insulin secretion involves mitochondria. A rat model of pancreatic β-cells was exposed to largely sub-lethal levels of cadmium cations applied for the longest possible time. Cadmium entered cells at concentrations far below those inducing cell death and accumulated by factors reaching several hundred folds the basal level. The mitochondria reorganized in response to the challenge by favoring fission as measured by increased circularity at cadmium levels already ten-fold below the median lethal dose. However, the energy charge and respiratory flux devoted to adenosine triphosphate synthesis were only affected at the onset of cellular death. The present data indicate that mitochondria participate in the adaptation of β-cells to even a moderate cadmium burden without losing functionality, but their impairment in the long run may contribute to cellular dysfunction, when viability and β-cells mass are affected as observed in diabetes. Full article

Biomarkers of environmental metal exposure in children are important for elucidating exposure and health risk. While exposure biomarkers for As, Cd, and Pb are relatively well defined, there are not yet well-validated biomarkers of Mn exposure. Here, we measured hair Mn, Pb, Cd, and As levels in children from the Mid-Ohio Valley to determine within and between-subject predictors of hair metal levels. Occipital scalp hair was collected in 2009–2010 from 222 children aged 6–12 years (169 female, 53 male) participating in a study of chemical exposure and neurodevelopment in an industrial region of the Mid-Ohio Valley. Hair samples from females were divided into three two centimeter segments, while males provided a single segment. Hair was cleaned and processed in a trace metal clean laboratory, and analyzed for As, Cd, Mn, and Pb by magnetic sector inductively coupled plasma mass spectrometry. Hair Mn and Pb levels were comparable (median 0.11 and 0.15 µg/g, respectively) and were ~10-fold higher than hair Cd and As levels (0.007 and 0.018 µg/g, respectively). Hair metal levels were higher in males compared to females, and varied by ~100–1000-fold between all subjects, and substantially less (<40–70%) between segments within female subjects. Hair Mn, Pb, and Cd, but not As levels systematically increased by ~40–70% from the proximal to distal hair segments of females. There was a significant effect of season of hair sample collection on hair Mn, Pb, and Cd, but not As levels. Finally, hair metal levels reported here are ~2 to >10-fold lower than levels reported in other studies in children, most likely because of more rigorous hair cleaning methodology used in the present study, leading to lower levels of unresolved exogenous metal contamination of hair. Full article