Roles of biomarkers in evaluating interactions among mixtures of lead, cadmium and arsenic

Human exposure to environmental chemicals is most correctly characterized as exposure to mixtures of these agents. The metals/metalloids, lead (Pb), cadmium (Cd), and arsenic (As), are among the leading toxic agents detected in the environment. Exposure to these elements, particularly at chronic low dose levels, is still a major public health concern. Concurrent exposure to Pb, Cd, or As may produce additive or synergistic interactions or even new effects that are not seen in single component exposures. Evaluating these interactions on a mechanistic basis is essential for risk assessment and management of metal/metalloid mixtures. This paper will review a number of individual studies that addressed interactions of these metals/metalloids in both experimental and human exposure studies with particular emphasis on biomarkers. In general, co-exposure to metal/metalloid mixtures produced more severe effects at both relatively high dose and low dose levels in a biomarker-specific manner. These effects were found to be mediated by dose, duration of exposure and genetic factors. While traditional endpoints, such as morphological changes and biochemical parameters for target organ toxicity, were effective measures for evaluating the toxicity of high dose metal/metalloid mixtures, biomarkers for oxidative stress, altered heme biosynthesis parameters, and stress proteins showed clear responses in evaluating toxicity of low dose metal/metalloid mixtures. Metallothionein, heat shock proteins, and glutathione are involved in regulating interactive effects of metal/metalloid mixtures at low dose levels. These findings suggest that further studies on interactions of these metal/metalloid mixtures utilizing biomarker endpoints are highly warranted.     

Cadmium, mercury and lead in medicinal herbs in Brazil.

Samples of herbal medicine used in Brazil were analyzed, after nitric digestion, for the content of cadmium, mercury and lead, by atomic absorption spectrophotometry. Fifteen samples of ginkgo biloba (Ginkgo biloba), 13 of celastraceae (Maytenus ilicifolia), 14 of cascara buckthorn (Rhamnus purshiana), 13 of eggplant (Solanum melongena), 15 of horse chestnut (Aesculus hippocastanum), 13 of Brazilian ginseng (Pffafia glomerata), 17 of centella asiatic (Hydrocotyle asiatica), 13 of guarana (Paullinia cupana), 12 of artichoke (Cynara scolymus) and five samples of chlorella (Chlorella pyrenoidosa) were analyzed. Cadmium, mercury and lead were not detected (limit of quantifications of 0.20, 0.01 and 2.0 mg/kg, respectively) in any sample of artichoke, eggplant and guarana. Cadmium was found in samples of the other medicinal herbs at levels up to 0.74 microg/g and mercury up to 0.087 microg/g. Three samples of horse chestnut contained 153, 156 and 1480 microg Pb/g, while the highest concentration found in the other samples analyzed was 22 microg Pb/g. The estimated lead intake through the consumption of horse chestnut reached 440% of Provisional Tolerable Weekly Intake (PTWI), and might be of concern to consumers if the medicine was taken on a long-term basis. Cadmium and mercury exposure through the herbal medicines does not appear to be of health concern.     

Dyslipdemia induced by chronic low dose co-exposure to lead,cadmium and manganese in rats: the role of oxidative stress

Lead (Pb), cadmium (Cd) and manganese (Mn) have many potential adverse health effects in vitro and in animal models of clinical toxicity. The current study investigated the dyslipidaemic and oxidative stress effects of chronic low-dose oral exposure to Pb, Cd and Mn and the combination (Pb + Cd + Mn) in rats for 15 weeks. Chronic exposure to the metals did not significantly (P > 0.05) alter serum lipid profiles. However, the atherogenic index decreased by 32.2% in the Pb + Cd + Mn group, relative to the control. The triglyceride/high-density lipoprotein cholesterol ratio decreased by 39.4% in the Pb + Cd + Mn group, relative to the control, and elevated by 81.8, 94.8 and 20.8%, relative to the Pb, Cd and Mn groups, respectively. While the serum concentrations of malondialdehyde significantly increased in the Mn and Pb + Cd + Mn groups, that of glutathione peroxidase-1 decreased in the Pb + Cd + Mn group, and metallothionein-1 and zinc concentrations markedly decreased in all the metal treatment groups.The results suggest that long-term exposure of rats to Pb + Cd + Mn may result in hypolipidaemia, mediated via oxidative stress and metal interactions. Individuals who are constantly exposed to environmentally relevant levels of the metals may be at risk of hypolipidaemia.     

中药天然药物活性成分的研究方法

中药天然药物活性成分研究的早期方法盲目性大，耗时、费资。较新的研究方法有两种．第一种为活性指导下的靶向追踪分离方法，用这种方法研究了中药薤白中的活血化瘀活性成分，中药粉背薯芋、总合草苔虫及黑果黄皮中的抗癌活性成分。第二种为体内代谢方法，用此法对桑白皮中的平喘成分，及穿心莲内酯的体内代谢产物进行了研究。论述了中药天然药物活性成分研究面临的困难、改进方法的思考及展望。     

Nitric oxide and superoxide anion production in monocytes from children exposed to arsenic and lead in region Lagunera, Mexico

We evaluated in Mexican children environmentally exposed to arsenic and lead monocyte nitric oxide (NO) and superoxide anion production in response to direct activation with interferon-gamma (IFN-gamma) + lipopolysaccharide (LPS). The integrity of Th1-regulated cellular immune response when monocytes were indirectly activated was also evaluated. Most children lived near a primary lead smelter. Lead and arsenic contamination in soil and dust by far exceeded background levels. As levels in water were between 10 and 30 ppb. Most children (93%) had urinary arsenic (AsU) concentrations above 50 microg/l (range 16.75-465.75) and 65% had lead blood levels (PbB) above 10 microg/dl (range 3.47-49.19). Multivariate analyses showed that NO production in monocytes activated indirectly was negatively associated with both PbB and AsU. Superoxide production in directly activated monocytes was negatively associated with AsU but positively associated with PbB. The models including the interaction term for AsU and PbB suggested the possibility of a negative interaction for NO production and a positive interaction for superoxide. There were indications of differential gender-based associations, NO production in indirectly activated monocytes obtained from girls was negatively associated with AsU but not with PbB. Superoxide production was positively associated with PbB in both directly and indirectly activated monocytes from boys but the latter was negatively associated with AsU. These effects are consistent with immune system abnormalities observed in human populations exposed to Pb or As. Further studies in larger populations are required to characterize As and Pb interactions and the mechanism(s) underlying the observed effects.     

Determination of lead,cadmium and nickel in hennas and other hair dyes sold in Turkey

The concentrations of lead, nickel and cadmium in various hennas and synthetic hair dyes were determined by high-resolution continuum source graphite furnace atomic absorption spectrometry (HR-CS GFAAS). For this purpose, 1 g of sample was digested using 4 mL of hydrogen peroxide (30%) and 8 mL of nitric acid (65%). The digests were diluted to 15 mL and the analytes were determined by HR-CS GFAAS. All determinations of Pb and Cd were performed using NH₄H₂PO₄ as a modifier. The analytes in hair certified reference materials (CRMs) were found within the uncertainty limits of the certified values. In addition, the analyte concentrations added to hair dye were recovered between 95 and 110%. The limits of detection of the method were 48.90, 3.90 and 12.15 ng g⁻¹ for Pb, Cd and Ni, respectively and the characteristic concentrations were 8.70, 1.42 and 6.30 ng g⁻¹, respectively. Finally, the concentrations of the three analytes in various synthetic hair dyes with different brands, shades and formulae as well as in two henna varieties were determined using aqueous standards for calibration. The concentrations of Pb, Cd and Ni in hair dyes were in the ranges of LOD-0.56 μg g⁻¹, LOD-0.011 ng g⁻¹ and 0.030–0.37 μg g⁻¹, respectively, whereas those in the two hennas were 0.60–0.93 μg g⁻¹, 0.033–0.065 ng g⁻¹ and 0.49–1.06 μg g⁻¹, respectively.     

石墨炉原子吸收分光光度法测定冰片中微量铅镉铜

目的:建立石墨炉原子吸收分光光度法测定冰片中微量铅、镉、铜的分析方法.方法:检查波长铅为283.3 nm,镉为228.8nm,铜为324.7 nm;灯电流为10.0 mA;狭缝宽度为0.4 nm.结果:铅在0.0～40.0 ng/mL、镉在0.0～1.0 ng/mL、铜在0～10 ng/mL范围内有较好的线性关系,平均加样回收率分别为98.3％,98.0％,97.3％.结论:石墨炉原子吸收分光光度法测定冰片中微量铅、镉、铜,方法准确、简单、灵敏,被测溶液稳定性好.     

Activity of glutathione-S-transferase in rat liver and kidneys after administration of lead or cadmium

The influence of an acute dose of lead nitrate or cadmium chloride on the activity of glutathione-S-trans-ferase (GST) was investigated in rats. CdCl₂ (10 mol/kg) did not influence the enzyme activity in either organ. In contrast Pb(NO₃)₂ (100 mol/kg) caused a significant increase of GST activity in both organs. SDS polyacrylamide gel electrophoresis (SDS-PAGE) showed that in liver the activity enhancement is due mainly to the induction of the isoenzyme GST 7-7, while in the kidneys the activity of all the isoenzymes is increased.     

DDTC-APDC-MIBK-正己烷络合萃取测定化妆品中的铅和镉

目的建立火焰原子吸收分光光度法测定化妆品中铅、镉。方法湿法消解样品后,应用DDTC-APDC络合铅、镉,经M IBK-正己烷萃取进一步浓缩,采用空气-乙炔火焰原子吸收分光光度法测定铅、镉的含量。结果化妆品中铅、镉的萃取回收率分别为99.6%~104%、91.4%~98.9%,仪器精密度(RSD)分别为1.4%、1.4%,方法精密度(RSD)分别为1.9%、1.8%。结论该方法可准确检出一些化妆品中基底干扰大、金属含量低于仪器检出限的样品。     

Fertility of rabbit sperm exposed in vitro to cadmium and lead

The heavy metals Cd²⁺ and Pb²⁺ have been associated with male reproductive toxicology, including possible inhibition of sperm undergoing hyperactivated motility, indicative of capacitation. The objective of the present study was to test fertility of rabbit sperm exposed to Cd²⁺ or Pb²⁺ in vitro, followed by insemination of superovulated does. Semen was washed to remove seminal plasma and minimize possible binding of the heavy metals by proteins. Only 400,000 treated or control sperm were inseminated as a sensitive test of treatment, and the time sperm resided in the female before possible fertilization was varied by inseminating from 0 to 12 h after ovulating the does. Only 6 of 22 males tested showed appreciable spontaneous hyperactivation and neither Cd²⁺ nor Pb²⁺ affected hyperactivation, or presumably associated capacitation. Sperm from four of these six males were used to inseminate 66 rabbits, and 1483 oocytes and embryos were collected about 27 h later. No effect of 0.1 mM Cd²⁺ on fertilizing ability of sperm was found (75% fertilization with control sperm and 78% with treated sperm). With 0.025 mM Pb²⁺ the fertilization rate in pregnant does only was 82% for controls and lower (68%) with treated sperm. These tested concentrations of Cd²⁺ and Pb²⁺ are much higher than reported concentrations in semen of exposed workers.     

Arsenic contamination and arsenicosis in China

Arsenicosis is a serious environmental chemical disease in China mainly caused by drinking water from pump wells contaminated by high levels of arsenic. Chronic exposure of humans to high concentrations of arsenic in drinking water is associated with skin lesions, peripheral vascular disease, hypertension, blackfoot disease, and high risk of cancers. Lead by the Ministry of Health of China, we carried out a research about arsenicosis in China recently. Areas contaminated with arsenic from drinking water are determined by 10% pump well water sample method while areas from burning coal are determined by existing data. Two epidemic areas of Shanxi Province and Inner Mongolia are investigated for the distribution of pump wells containing high arsenic. Well water in all the investigated villages of Shanxi Province showed polluted by high arsenic, and the average rate of unsafe pump well water is 52%. In Inner Mongolia, the high percentage of pump wells containing elevated arsenic is found only in a few villages. The average rate of unsafe pump well water is 11%. From our research, we find that new endemic areas are continuously emerging in China. Up to now, epidemic areas of arsenicosis mainly involve eight provinces and 37 counties in China. In the affected areas, the discovery of wells and coal with high levels of arsenic is continuing sporadically, and a similar scattered distribution pattern of patients is also being observed.     

Lead,mercury, and cadmium in blood and their relation to diet among Swedish adults

The aim of the present study was to examine the body burden of lead (Pb), mercury (Hg), and cadmium (Cd) in blood among Swedish adults and the association between blood levels, diet and other lifestyle factors.The study was based on a subgroup (n = 273) of the national survey Riksmaten 2010–2011 (4-day food records and questionnaire). Lead, Hg, and Cd were measured in whole blood, and Cd additionally in urine, by mass or fluorescence spectrometry methods.The median values (5–95th percentiles) of the metals in blood were as follows; Pb: 13.4 (5.8–28.6) μg/L, Hg: 1.13 (0.31–3.45) μg/L, and Cd: 0.19 (0.09–1.08) μg/L. All three metals increased with increasing age. Lead levels in blood were positively associated with intakes of game and alcohol, Hg was related to fish intake, and blood Cd related to smoking and low iron stores and to a low meat intake.Body burdens of the studied metals were generally below health based reference values, but several individuals had blood Pb levels above the reference point for possible nephrotoxic and developmental neurotoxic effects. As health effects cannot be excluded, individuals with high Pb exposure should aim at decreasing their body burden, both from food and from other exposure routes.     

Synthesis and evaluations of pentahydroxylhexyl-L-cysteine and its dimer as chelating agents for cadmium or lead decorporation

N-(2,3,4,5,6-pentahydroxylhexyl)-L-cysteine (4) and N,N'-di(2,3,4,5,6-pentahydroxylhexyl)-L-cystine (5) were synthesized. As antagonists of cadmium or lead intoxication, they were found to be effective by oral administration on repeated exposure. The bioassay in vivo indicated that their cadmium-mobilizing potencies are significantly superior to those of N-acetyl-L-cysteine and their lead-mobilizing properties are equivalent to those of DL-penicillamine (DL-PA). The stability constants of the Cd-4 and Cd-5 complexes or Pb-4 and Pb-5 complexes were determined by use of pH titration. The membrane permeability of compounds 4 and 5 was evaluated by transporting across the Caco-2 cell monolayer. The effect of compounds 4 and 5 on the concentrations of essential metal ions in the renal cortex is negligible in comparison with that of the group treated with lead only. The acute toxicity of compounds 4 was tested by oral gavage and the resulting LD50 value for both mice and rats is larger than 10 g kg(-1) bw. The cytogenetic effects of compound 4 were evaluated in the Ames assay, mouse bone marrow micronucleus test, and sperms shape abnormality assay, and all of them show the negative reactions.     

Skin toxicology of lead species evaluated by their permeability and proteomic profiles: A comparison of organic and inorganic lead

Lead compounds are known to cause cytotoxicity and genotoxicity. Lead absorption by the skin is an important route through which this metal enters the body. The purpose of this work was to evaluate the skin permeability and toxicological profiles of two lead species, lead acetate and lead nitrate. This study assessed lead-induced toxicity mechanisms by focusing on the histopathology, proteomics, cell growth, and cellular ATP. In vitro skin permeation assays showed that there was no significant difference of lead accumulation within and across the skin between the two lead species. The presence of simulated sweat reduced the skin uptake of lead. The skin deposition of lead acetate was greater than that of lead nitrate with in vivo topical application. On the other hand, lead nitrate produced greater changes in the skin's histology and proteomic profiles compared to lead acetate. Four protein spots which showed significant changes were identified and are discussed in this study. These included glucose-related protein precursor (GRP) 78, K14, α-actin, and Rho GDP-dissociation inhibitor 2 (RhoGDI2). These proteins are respectively associated with oxidative stress, apoptosis, wound healing, and proliferation. Lead presented a biphasic pattern on cell growth and intracellular ATP content, with a stimulating effect at low concentrations and an inhibitory effect on cell proliferation at higher concentrations.     

Simultaneous determination of cadmium and lead in medicinal plants by anodic stripping voltammetry

A simple method for the simultaneous determination of Cd and Pb in medicinal plants by differential pulse anodic stripping voltammetry, using a hanging mercury drop electrode, was developed. The pre-concentration of the metals was performed in 0.8 mol L(-1) HCl at -0.73V for 180s. The sample preparation was carried out by dry-ashing 1.0g of finely pulverized plant samples for 2.5h at 500 degrees C. The determination limit of the method was 0.12 and 0.010 mg kg(-1) for Pb and Cd, respectively. The method was applied to the quantification of cadmium and lead in samples of Hypericum perforatum, Mikania guaco, Mikania glomerata and Peamus boldus. The voltammetric method was shown to be useful for the control of contaminants in medicinal plants.     

镉、铅、汞对苯巴比妥诱导肝微粒体药物代谢酶的影响

一次ip醋酸镉2.4mg/kg、醋酸铅100mg/kg或氯化汞 2.0 mg/kg均可抑制大鼠肝微粒体药物代谢酶。上述处理还可明显降低苯巴比妥对肝微粒’乙基吗啡N-脱甲基化酶、氨基比林N-脱甲基化酶、苯胺羟化酶和环己巴比妥羟化酶活力的诱导作用,降低苯巴比妥对细胞色素P450和细胞色素 b_5以及微粒体蛋白合成的诱导作用。结果提示镉、铅、汞可能通过降低微粒体酶的新生合成,抑制肝微粒体药物代谢酶。     

Effect of co-exposure to lead and cadmium on antioxidant status in rat ovarian granulose cells

The effects of combined exposure to lead and cadmium on granulose cells were studied. Adult female rats were treated i.p. with either lead acetate (LA) or cadmium acetate (CA) both, alone, or in combination at a dose of 0.05 mg/kg body weight on a daily basis for 15 days. Both metals were accumulated in the ovary after metal exposure. Metal exposure caused a decrease in reduced glutathione content along with elevated lipid peroxidation in all groups. Granulose cells of both cadmium as well as combination group demonstrated a maximum increase in lipid peroxides and catalase activity, along with decreased glutathione status and superoxide dismutase activities. Combined treated animals exhibited an intermediate effect in antioxidant status. However, "in vitro" exposure showed no significant change in antioxidant enzymes in all metal exposed cells. Data from the present study indicates that lead and cadmium in isolation and in combination cause oxidative stress. Lead and cadmium in combination do not show additive or synergistic effect indicating the competition between them due to similarity in electronic affinities. Present study highlights the effects of toxic metals that disturb membrane integrity of cells via ROS and thereby classifying mechanism for altered receptor binding, steroidogenesis, and hormone production.     

Complementary and alternative medicines use in COVID-19: A global perspective on practice,policy and research

The COVID-19 pandemic has met international health systems with a low level of preparedness and emergency response. While the emergence of effective vaccines has offered the Governments, scientific communities, and members of the public a possible way out of the pandemic, effective pharmacotherapy, including immunotherapy for COVID-19 prevention and treatment, are yet to be established. Internationally, this has led to a surge in the demand and supply of many complementary and alternative medicines (CAM) and practices. Recent studies have shown increasing CAM information requests made to pharmacists and other healthcare staff from members of public and patients aimed at prevention, symptoms relief or treatment of COVID-19.In this context, it is imperative that healthcare professionals, including pharmacists, are acquainted with current practices, policies, and research in relation to CAM use in COVID-19. This narrative commentary will provide an update on global practices, policies and research in regards to CAM use in the context of COVID-19. Healthcare professionals’ understanding of popular CAMs and those tipped for potential benefits in COVID-19, patient and consumer behaviors in relation to CAM use; and healthcare professionals' awareness of cultural, religious, and self-care practices associated with CAM use are imperative to inform effective communication and counselling practices and promote evidence based self-care when patients present for advice. This narrative provides relevant discussions specific to different continents and regions historically linked to diverse CAM practices.     

镉铅对泥鳅DNA甲基化水平的影响

目的研究镉(Cd2 )、铅(Pb2 )以及二者联合(Cd2 Pb2 )作用对泥鳅(Misgurnus anguillicaudatus)肝胰脏、肾脏及鳃DNA甲基化水平的影响。方法0.05和5.00 mg/L Cd2 、Pb2 及Cd2 Pb2 对泥鳅染毒,染毒2、7、14、212、8和35 d时取样,用高效液相色谱(HPLC)分析DNA甲基化水平。结果5.00 mg/L Cd2 、Pb2 及Cd2 Pb2 染毒2 d导致DNA异常高水平甲基化;Cd2 及Cd2 Pb2 的毒性影响大于Pb2 (P<0.05)。0.05 mg/L Cd2 与Pb2 作用下,鳃DNA甲基化水平在第7天时明显升高,而肝胰脏和肾脏则在第14天时升高(P<0.05);染毒21 d后,3种组织甲基化水平均下降,并维持异常低度甲基化。结论Cd2 、Pb2 及Cd2 Pb2 对泥鳅DNA甲基化水平的影响与离子种类、浓度及其作用的时间、靶器官等均具有相关性。     

Co-exposure to lead increases the renal response to low levels of cadmium in metallurgy workers

Purpose

Research on the effect of co-exposure to Cd and Pb on the kidney is scarce. The objective of the present study was to assess the effect of co-exposure to these metals on biomarkers of early renal effect.

Methods

Cd in blood (Cd-B), Cd in urine (Cd-U), Pb in blood (Pb-B) and urinary renal biomarkers, i.e., microalbumin (μ-Alb), beta-2-microglobulin (β₂-MG), retinol binding protein (RBP), N-acetyl-β-d-glucosaminidase (NAG), intestinal alkaline phosphatase (IAP) were measured in 122 metallurgic refinery workers examined in a cross-sectional survey.

Results and conclusions

The median Cd-B, Cd-U, Pb-B were: 0.8 μg/l (IQR = 0.5, 1.2), 0.5 μg/g creatinine (IQR = 0.3, 0.8) and 158.5 μg/l (IQR = 111.0, 219.3), respectively. The impact of Cd-B on the urinary excretion of NAG and IAP was only evident among workers with Pb-B concentrations ≥75th percentile. The association between Cd-U and the renal markers NAG and RBP was also evidenced when Pb-B ≥75th percentile. No statistically significant interaction terms were observed for the associations between Cd-B or Cd-U and the other renal markers under study (i.e., μ-Alb and β2-MG). Our findings indicate that Pb increases the impact of Cd exposure on early renal biomarkers.