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The Benefits of Pre- and Post-challenge Urine Heavy Metal Testing: Part 1
Abstract
Measuring urine heavy metals is an accepted method for assessing the presence of these toxins in an individual. A random sample (without a flushing agent) is excellent for showing current exposures because it reflects the level of heavy metals in the bloodstream during the hours immediately before bladder voiding. A sample taken after using a heavy-metal-mobilizing agent provides a reflection of total body burden. By utilizing both pre- and post-flush testing, the clinician gains information that cannot be acquired by other means, including identification of current exposures to lead and mercury - critical for proper treatment. Conducting pre-flush testing is also currently the clinician's only means of identifying cadmium toxicity. In addition, pre- and post-challenge testing allows the clinician to identify which chelating agent is the most effective for the patient; and if oral agents are employed, possible absorption problems can be identified. Since these benefits are not realized with only post-flush testing, it is recommended that clinicians test both before and after a chelation challenge.
... Different heavy metals, once reached in the human body, can be tested by several ways, such as Hair Tissue Mineral Analysis (HTMA) [5] complementary diagnosis method with urine and blood tests, or "chelation challenge test," also called a "provoked urine test" [6]. ...
... Generally, HTMA, which basically is a spectrometric method, is very useful in evaluating a person's nutritional status and health. The second way, which uses chelators isn't always a happy choice because these chelators can bind besides heavy metal, some important minerals in human body, such as calcium and iron [6,7]. Testing for heavy metals at part per billion (ppb) levels in drinking water is essential to meet national and international established limits. ...
The analysis of drinking-water for metal contamination is an important step in en-suring human and environmental health. During the investigation, physicochemical properties and contents of several metals including Pb, Cd, Cr, Ni, Cu, Mn, Al, Zn, Fe and Ba were analyzed in order to determine the water quality in 75 wells from Dambovita County, Romania during the year of 2015. The concentrations of these metals (µg/L) in drinking-water samples collected from different wells used by people from rural area, mainly for own consumption, were determined by ICP-MS and compared with levels reported by Romanian regulation and World Health Organization, in order to establish if these metals could be responsible for some health problems in rural area. The data set obtained was subjected to the PCA analysis to identify water quality variables. The correlation analysis showed a high degree of metal association in the order: Ba/Sr > Mg/Ca > Sr/Ca > Ba/Ca > Fe/Ca > Ba/Fe > Ni/Cr > > Fe/Sr > Fe/Ba > Fe/Ni > Cu/Cr > Cu/Pb > Zn/Pb.
... In the current cohort composed of a young Taiwanese population, we found higher geometric means of urine lead levels (1.50 µg/g creatinine) than the levels in other countries [30,31]. Additionally, the geometric means of urine cadmium levels (0.63 µg/g creatinine) were also higher than the levels reported in other countries [32,33] and exceeded 0.5 µg/g creatinine, a threshold value thought to start causing kidney damage [19,34]. A previous study reported that Taiwanese people may have higher heavy metal exposure than people from the Western world [35]. ...
Background:
Exposure to lead and cadmium has been linked to changes in lipid metabolism and the development of arteriosclerosis, but the role of lipoprotein profiles in this relationship is not well understood, including the potential role of novel lipid biomarkers.
Methods:
In this study, we enrolled 736 young Taiwanese subjects aged 12 to 30 years to assess the correlation between urine levels of lead and cadmium, lipoprotein profiles, and carotid intima-media thickness (CIMT).
Results:
Higher levels of lead and cadmium were significantly associated with higher levels of low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), LDL-triglyceride (LDL-TG), and CIMT. Participants with higher levels of lead and cadmium had the highest mean values of CIMT, LDL-C, sdLDL-C, and LDL-TG. In a structural equation model, lead had a direct and indirect association with CIMT through LDL-C and sdLDL-C, whereas cadmium had a direct association with CIMT and an indirect association through LDL-C.
Conclusion:
Our results suggest higher levels of lead and cadmium are associated with abnormal lipid profiles and increased CIMT. These heavy metals could have additive effects on lipids and CIMT, and the relationship between them may be mediated by lipoprotein levels. Further research is needed to determine the causal relationship.
... Nevertheless, some of those widely used substances are known to be harmful at some concentration, e.g. cadmium concentration greater than 0.5 µg g −1 creatinine in urine can lead to kidney damage (Crinnion, 2009), copper concentration higher than 250 mg kg −1 of a pigs' fodder can cause the hemolysis of a blood cells (Espinosa and Stein, 2021). For zinc, consuming 200-800 mg day −1 can lead to vomiting and diarrhea (Plum et al., 2010). ...
Threats connected with contamination of environment with heavy metals include negative influence on human and animal health and also negatively influence the biodiversity of ecosystems. While applying various techniques of heavy metal remediation from soils, an important problem is the adsorption of ions on solid particles. In this respect, the composition and properties of soil strongly affect the efficiency of the process. Therefore, the aim of this study was to determine the efficiency of copper(II) and zinc(II) ions leaching from soils of different types (luvisols, podzols, chernozem) by means of natural surfactants: Quillaja saponaria extract containing saponins and biosurfactant produced by P. aeruginosa belonging to rhamnolipids. The studies included both heavy metal removal tests from soils and the evaluation of ecotoxicity of applied surfactants towards soil microorganisms. The results obtained allow to conclude that especially the saponins from Q. saponaria constitute an effective and environmentally safe remediation agent, allowing to achieve elimination from luvisols over 80% for zinc(II) ions and 70% for copper(II) ions.
... Urine: Kidneys are the main organ to be affected by cadmium in long term exposure (49). Crinnion suggested; urinary cadmium concentration equal or greater than 0.5 µg/g creatinine is associated with renal damage, also the concentrations more than 2.0 µg/g of creatinine may be translated into extensive damage (50). Tubular dysfunction followed by cadmium nephrotoxicity increases urinary excretion of low molecular weight proteins such as ß 2 -microglobulin, α 1 microglobulin, retinol binding protein, enzymes such as N -acetyl -ßglucosaminidase, and calcium (51). ...
Cadmium poisoning has been reported from many parts of the world. It is one of the global health problems that affect many organs and in some cases it can cause deaths annually. Long-term exposure to cadmium through air, water, soil, and food leads to cancer and organ system toxicity such as skeletal, urinary, reproductive, cardiovascular, central and peripheral nervous, and respiratory systems. Cadmium levels can be measured in the blood, urine, hair, nail and saliva samples. Patients with cadmium toxicity need gastrointestinal tract irrigation, supportive care, and chemical decontamination traditional-based chelation therapy with appropriate new chelating agents and nanoparticle-based antidotes. Furthermore it has been likewise recommended to determine the level of food contamination and suspicious areas, consider public education and awareness programs for the exposed people to prevent cadmium poisoning.
... 6,7 Heavy metals such as mercury, lead, chromium and arsenic are acutely toxic to humans, but can only be detected in the body through physically invasive blood 8,9 or privacy invading urine testing. 10 Saliva is an alternative, non-invasive testing base from both the physical and privacy viewpoints, 11 making it an excellent candidate for measurement of heavy metal uptake in the body. On the other hand, silver-mercury amalgams are widely used as dental fillings. ...
A surface-enhanced Raman scattering (SERS) biosensor has been developed by incorporating a gold nanohole array with a SERS probe (gold nanostar@Raman-reporter@silica sandwich structure) into a single detection platform via DNA hybridization, which circumvents the nanoparticle aggregation and the inefficient Raman scattering issues. Strong plasmonic coupling between the Au nanostar and the Au nanohole array results in large enhancement of electromagnetic field, leading to amplification of the SERS signal. The SERS sensor has been used to detect Ag(I) and Hg(II) ions in human saliva because both the metal ions could be released from dental amalgam fillings. The developed SERS sensor can be adapted as a general detection platform for non-invasive measurement of a wide range of analytes such as metal ions, small molecules, DNA and proteins in bodily fluids.
... To determine the degree of a long term, low grade exposure, environmental physicians developed provocation tests [6]. Such a provocation test involves the use of a metal-binding chelating agent to provoke a response. ...
The intravenous application of DMPS is most useful for the diagnosis of multiple metal overexposure. It is also the treatment of choice for Sb, As and Hg and has the strongest Cu binding ability of the chelators tested.
... • Available testing methods may underestimate total body burden of environmental pollutants; however, provoked urinary excretion challenge for toxic metals and serum persistent organic pollutants are clinically useful. 176,177 Gastrointestinal function ...
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a relatively common illness, yet despite considerable investigation, current treatments have modest benefits, and the prognosis remains poor. Because CFS/ME is a heterogeneous disorder with diverse etiological factors and pathological features, a patient-centered integrative framework based on modifiable physiological and environmental factors may offer hope for more effective management and better clinical outcomes. An individualized approach may also help target interventions for subgroups most likely to respond to specific treatments. This review summarizes a number of avenues for integrative management, including dietary modification, functional nutritional deficiencies, physical fitness, psychological and physical stress, environmental toxicity, gastrointestinal disturbances, immunological aberrations, inflammation, oxidative stress, and mitochondrial dysfunction. A personalized, integrative approach to CFS/ME deserves further consideration as a template for patient management and future research.
... Thus testing of whole blood or serum generally does not adequately detect toxicants that are being stored primarily in organs, bone, muscle or adipose tissues [26,87]. As well, levels of toxicant compounds in blood and urine can also fluctuate rapidly as a result of nutrient or pharmaceutical use, caloric restriction, hydration, underlying nutrient status, thermal changes, or exercise [106][107][108][109][110]. ...
The World Health Organization warns that chronic, noncommunicable diseases are rapidly becoming epidemic worldwide.
Escalating rates of neurocognitive, metabolic, autoimmune and cardiovascular diseases cannot be ascribed only to genetics, lifestyle, and nutrition; early life and ongoing exposures, and bioaccumulated toxicants may also cause chronic disease. Contributors to ill health are summarized from
multiple perspectives—biological effects of classes of toxicants, mechanisms of toxicity, and a synthesis of toxic contributors to major diseases.
Healthcare practitioners have wide-ranging roles in addressing environmental factors in policy and public health and clinical practice.
Public health initiatives include risk recognition and chemical assessment then exposure reduction, remediation, monitoring, and avoidance.
The complex web of disease and environmental contributors is amenable to some straightforward clinical approaches addressing multiple toxicants.
Widely applicable strategies include nutrition and supplements to counter toxic effects and to support metabolism; as well as exercise and sweating,
and possibly medication to enhance excretion. Addressing environmental health and contributors to chronic disease has broad implications for society,
with large potential benefits from improved health and productivity.
... For more details on pre-and post-challenge urine heavy metal testing, see articles in previous volumes of this journal. 25,26 Table 6 provides blood levels of mercury, lead, and cadmium for clinicians utilizing blood testing. 1 These levels are much lower than established lab reference ranges for these three heavy metals, as the reference ranges are based on acute toxicity data (and are typically derived from industrial exposure data). ...
The Centers for Disease Control (CDC) conducts ongoing assessments of the levels of environmental chemicals in the U.S. population. This ongoing study utilizes lab samples from the individuals who are part of the National Health and Nutrition Examination Survey (NHANES). The NHANES samples from the years 1999-2000, 2001-2002, and 2003-2004 (each representing about 2,400 individuals) were used for the CDC's national reports. In the CDC Fourth National Report on Human Exposure to Environmental Chemicals ("the fourth report") complete data from the above sample years were included. Each year additional chemicals are measured; the fourth report contains information on 75 previously untested compounds, for a total of 212 compounds measured. In the fourth report, blood and urinary levels of eight different forms of arsenic are reported. The fourth report, for the first time, also includes levels of solvents (30 different compounds) and provides adult rather than juvenile values for mercury. In the majority of individuals tested, acrylamides, cotinine, trihalomethanes, bisphenol A, phthalates, chlorinated pesticides, triclosan, organophosphate pesticides, pyrethroids, heavy metals, aromatic hydrocarbons, polybrominated diphenyl ethers, benzophenone from sunblock, perfluorocarbons from non-stick coatings, and a host of polychlorinated biphenyls and solvents were found. This review provides many of the ranges for xenobiotic toxins so a clinician can identify a patient's current exposure and toxic load compared to the national averages and monitor the effectiveness of prescribed treatments.
Exposure to retained metal fragments from war‐related injuries can result in increased systemic metal concentrations, thereby posing potential health risks to target organs far from the site of injury. Given the large number of veterans who have retained fragments and the lack of clear guidance on how to medically manage these individuals, the Department of Veterans Affairs (VA) convened a meeting of chelation experts and clinicians who care for embedded fragment patients to discuss current practices and provide medical management guidance. Based on this group's clinical expertise and review of published literature, the evidence presented suggests that, at least in the case of lead fragments, short‐term chelation therapy may be beneficial for embedded fragment patients experiencing acute symptoms associated with metal toxicity; however, in the absence of clinical symptoms or significantly elevated blood lead concentrations (greater than 80 µg/dL), chelation therapy may offer little to no benefit for individuals with retained fragments and pose greater risks due to remobilization of metals stored in bone and other soft tissues. The combination of periodic biomonitoring to assess metal body burden, longitudinal fragment imaging, and selective fragment removal when metal concentrations approach critical injury thresholds offers a more conservative management approach to caring for patients with embedded fragments.
Background: Lead is a toxic element which causes acute, subacute or chronic poisoning through environmental and occupational exposure. The aim of this study was to investigate clinical and laboratory abnormalities of chronic lead poisoning among workers of a car battery industry.
Methods: Questionnaires and forms were designed and used to record demographic data, past medical histories and clinical manifestations of lead poisoning. Blood samples were taken to determine biochemical (using Auto Analyzer; Model BT3000) and hematologic (using Cell Counter Sysmex; Model KX21N) parameters. An atomic absorption spectrometer (Perkin-Elmer, Model 3030, USA) was used to determine lead concentration in blood and urine by heated graphite atomization technique.
Results: A total of 112 men mean age 28.78±5.17 years, who worked in a car battery industry were recruited in the present study. The most common signs/symptoms of lead poisoning included increased excitability 41.9%, arthralgia 41.0%, fatigue 40.1%, dental grey discoloration 44.6%, lead line 24.1%, increased deep tendon reflexes (DTR) 22.3%, and decreased DTR (18.7%). Blood lead concentration (BLC) was 398.95 µg/L±177.40, which was significantly correlated with duration of work (P=0.044) but not with the clinical manifestations of lead poisoning. However, BLC was significantly correlated with urine lead concentration (83.67 µg/L±49.78; r2=0.711; P<0.001), mean corpuscular hemoglobin (r=-0.280; P=0.011), mean corpuscular hemoglobin concentration (r=-0.304; P=0.006) and fasting blood sugar or FBS (r=-0.258; P=0.010).
Conclusion: Neuropsychiatric and skeletal findings were common manifestations of chronic occupational lead poisoning. BLC was significantly correlated with duration of work, urine lead concentration, two hemoglobin indices and FBS.
As the risks of cadmium (Cd)-induced kidney disease have become increasingly apparent, much attention has been focused on the development and use of sensitive biomarkers of Cd nephrotoxicity. The purpose of this review is to briefly summarize the current state of Cd biomarker research. The review includes overviews of the toxicokinetics of Cd, the mechanisms of Cd-induced proximal tubule injury, and mechanistic summaries of some of the biomarkers (N-acetyl-β-D-glucosamidase; β(2)-microglubulin, metallothionein, etc.) that have been most widely used in monitoring of human populations for Cd exposure and nephrotoxicity. In addition, several novel biomarkers (kidney injury molecule-1, α-glutathione-S-transferase and insulin) that offer the potential for improved biomonitoring of Cd-exposed populations are discussed.
Background
Several epidemiologic studies have suggested an association between Parkinson’s disease (PD) and exposure to heavy metals using subjective exposure measurements.
Objectives
We investigated the association between objective chronic occupational lead exposure and the risk of PD.
Methods
We enrolled 121 PD patients and 414 age-, sex-, and race-, frequency-matched controls in a case–control study. As an indicator of chronic Pb exposure, we measured concentrations of tibial and calcaneal bone Pb stores using 109Cadmium excited K-series X-ray fluorescence. As an indicator of recent exposure, we measured blood Pb concentration. We collected occupational data on participants from 18 years of age until the age at enrollment, and an industrial hygienist determined the duration and intensity of environmental Pb exposure. We employed physiologically based pharmacokinetic modeling to combine these data, and we estimated whole-body lifetime Pb exposures for each individual. Logistic regression analysis produced estimates of PD risk by quartile of lifetime Pb exposure.
Results
Risk of PD was elevated by > 2-fold [odds ratio = 2.27 (95% confidence interval, 1.13–4.55); p = 0.021] for individuals in the highest quartile for lifetime lead exposure relative to the lowest quartile, adjusting for age, sex, race, smoking history, and coffee and alcohol consumption. The associated risk of PD for the second and third quartiles were elevated but not statistically significant at the α = 0.05 level.
Conclusions
These results provide an objective measure of chronic Pb exposure and confirm our earlier findings that occupational exposure to Pb is a risk factor for PD.
Urinary cadmium (U-Cd) has been associated with decreased peripheral bone mineral density (BMD) and osteoporosis. This association, however, has not been confirmed using femoral BMD, the international standard for diagnosing osteoporosis, at levels < 1.0 microg Cd/g creatinine.
Our goal was to investigate the statistical association between U-Cd, at levels <or= 1 microg/g creatinine, and osteoporosis, as indicated by hip BMD and self-report in a population-based sample of U.S. women >or= 50 years of age.
We drew data from the National Health and Nutrition Examination Surveys for 1988-1994 (n = 3,207) and 1999-2004 (n = 1,051). Osteoporosis was indicated by hip BMD cutoffs based on the international standard and self-report of physician diagnosis. We analyzed U-Cd levels for association with osteoporosis using multiple logistic regression.
Women >or= 50 years of age with U-Cd levels between 0.50 and 1.00 microg/g creatinine were at 43% greater risk for hip-BMD-defined osteoporosis, relative to those with levels <or= 0.50 microg/g (odds ratio = 1.43; 95% confidence interval, 1.02-2.00; p = 0.04). We observed similar effect estimates using self-report of physician-diagnosed osteoporosis. Smokers did not show a statistically increased risk.
Results suggest that U.S. women are at risk for osteoporosis at U-Cd levels below the U.S. Occupational Safety and Health Administration's 3-microg/g safety standard. Given null findings among smokers, dietary Cd, rather than tobacco, is the likely source of Cd-related osteoporosis risk for the U.S. female population >or= 50 years of age.
High chronic exposure to inorganic arsenic in drinking water has been related to diabetes development, but the effect of exposure to low to moderate levels of inorganic arsenic on diabetes risk is unknown. In contrast, arsenobetaine, an organic arsenic compound derived from seafood intake, is considered nontoxic.
To investigate the association of arsenic exposure, as measured in urine, with the prevalence of type 2 diabetes in a representative sample of US adults.
Cross-sectional study in 788 adults aged 20 years or older who participated in the 2003-2004 National Health and Nutrition Examination Survey (NHANES) and had urine arsenic determinations.
Prevalence of type 2 diabetes across intake of arsenic.
The median urine levels of total arsenic, dimethylarsinate, and arsenobetaine were 7.1, 3.0, and 0.9 mug/L, respectively. The prevalence of type 2 diabetes was 7.7%. After adjustment for diabetes risk factors and markers of seafood intake, participants with type 2 diabetes had a 26% higher level of total arsenic (95% confidence interval [CI], 2.0%-56.0%) and a nonsignificant 10% higher level of dimethylarsinate (95% CI, -8.0% to 33.0%) than participants without type 2 diabetes, and levels of arsenobetaine were similar to those of participants without type 2 diabetes. After similar adjustment, the odds ratios for type 2 diabetes comparing participants at the 80th vs the 20th percentiles were 3.58 for the level of total arsenic (95% CI, 1.18-10.83), 1.57 for dimethylarsinate (95% CI, 0.89-2.76), and 0.69 for arsenobetaine (95% CI, 0.33-1.48).
After adjustment for biomarkers of seafood intake, total urine arsenic was associated with increased prevalence of type 2 diabetes. This finding supports the hypothesis that low levels of exposure to inorganic arsenic in drinking water, a widespread exposure worldwide, may play a role in diabetes prevalence. Prospective studies in populations exposed to a range of inorganic arsenic levels are needed to establish whether this association is causal.
This report provides a review of the cadmium exposure situation in Sweden and updates the information on health risk assessment according to recent studies on the health effects of cadmium. The report focuses on the health effects of low cadmium doses and the identification of high-risk groups. The diet is the main source of cadmium exposure in the Swedish nonsmoking general population. The average daily dietary intake is about 15 micrograms/day, but there are great individual variations due to differences in energy intake and dietary habits. It has been shown that a high fiber diet and a diet rich in shellfish increase the dietary cadmium intake substantially. Cadmium concentrations in agricultural soil and wheat have increased continuously during the last century. At present, soil cadmium concentrations increase by about 0.2% per year. Cadmium accumulates in the kidneys. Human kidney concentrations of cadmium have increased several fold during the last century. Cadmium in pig kidney has been shown to have increased by about 2% per year from 1984-1992. There is no tendency towards decreasing cadmium exposure among the general nonsmoking population. The absorption of cadmium in the lungs is 10-50%, while the absorption in the gastrointestinal tract is only a few percent. Smokers have about 4-5 times higher blood cadmium concentrations (about 1.5 micrograms/l), and twice as high kidney cortex cadmium concentrations (about 20-30 micrograms/g wet weight) as nonsmokers. Similarly, the blood cadmium concentrations are substantially elevated in persons with low body iron stores, indicating increased gastrointestinal absorption. About 10-40% of Swedish women of child-bearing age are reported to have empty iron stores (S-ferritin < 12 micrograms/l). In general, women have higher concentrations of cadmium in blood, urine, and kidney than men. The population groups at highest risk are probably smokers, women with low body iron stores, and people habitually eating a diet rich in cadmium. According to current knowledge, renal tubular damage is probably the critical health effect of cadmium exposure, both in the general population and in occupationally exposed workers. Tubular damage may develop at much lower levels than previously estimated, as shown in this report. Data from several recent reports from different countries indicate that an average urinary cadmium excretion of 2.5 micrograms/g creatinine is related to an excess prevalence of renal tubular damage of 4%. An average urinary excretion of 2.5 micrograms/g creatinine corresponds to an average concentration of cadmium in renal cortex of 50 micrograms/g, which would be the result of long-term (decades) intake of 50 micrograms per day. When the critical concentrations for adverse effects due to cadmium accumulation are being evaluated, it is crucial to consider both the individual variation in kidney cadmium concentrations and the variations in sensitivity within the general population. Even if the population average kidney concentration is relatively low for the general population, a certain proportion will have values exceeding the concentration where renal tubular damage can occur. It can be estimated that, at the present average daily intake of cadmium in Sweden, about 1% of women with low body iron stores and smokers may experience adverse renal effects related to cadmium. If the average daily intake of cadmium would increase to 30 micrograms/day, about 1% of the entire population would have cadmium-induced tubular damage. In risk groups, for example, women with low iron stores, the percentage would be higher, up to 5%. Both human and animal studies indicate that skeletal damage (osteoporosis) may be a critical effect of cadmium exposure. We conclude, however, that the present evidence is not sufficient to permit such a conclusion for humans. We would like to stress, however, that osteoporosis is a very important public health problem worldwide, but especially in the Scandinav
Despite dramatic declines in children's blood lead concentrations and a lowering of the Centers for Disease Control and Prevention's level of concern to 10 microg per deciliter (0.483 micromol per liter), little is known about children's neurobehavioral functioning at lead concentrations below this level.
We measured blood lead concentrations in 172 children at 6, 12, 18, 24, 36, 48, and 60 months of age and administered the Stanford-Binet Intelligence Scale at the ages of 3 and 5 years. The relation between IQ and blood lead concentration was estimated with the use of linear and nonlinear mixed models, with adjustment for maternal IQ, quality of the home environment, and other potential confounders.
The blood lead concentration was inversely and significantly associated with IQ. In the linear model, each increase of 10 microg per deciliter in the lifetime average blood lead concentration was associated with a 4.6-point decrease in IQ (P=0.004), whereas for the subsample of 101 children whose maximal lead concentrations remained below 10 microg per deciliter, the change in IQ associated with a given change in lead concentration was greater. When estimated in a nonlinear model with the full sample, IQ declined by 7.4 points as lifetime average blood lead concentrations increased from 1 to 10 microg per deciliter.
Blood lead concentrations, even those below 10 microg per deciliter, are inversely associated with children's IQ scores at three and five years of age, and associated declines in IQ are greater at these concentrations than at higher concentrations. These findings suggest that more U.S. children may be adversely affected by environmental lead than previously estimated.
It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.
Consumption of food containing mercury has been identified as a health risk. The U.S. Environmental Protection Agency (U.S. EPA) and the National Academy of Sciences recommend keeping the whole blood mercury level < 5.0 microg/L or the hair level < 1.0 microg/g. This corresponds to a reference dose (RfD) of 0.1 microg/kg body weight per day. All patients in a 1-year period (n = 720) who came for an office visit in a private internal medicine practice in San Francisco, California, were evaluated for mercury excess using the current RfD. One hundred twenty-three patients were tested (93 females, 30 males). Of these, data were statistically analyzed for 89 subjects. Mercury levels ranged from 2.0 to 89.5 microg/L for the 89 subjects. The mean for 66 women was 15 microg/L [standard deviation (SD) = 15], and for 23 men was 13 microg/L (SD = 5); 89% had levels exceeding the RfD. Subjects consumed 30 different forms or types of fish. Swordfish had the highest correlation with mercury level. Sixty-seven patients with serial blood levels over time after stopping fish showed a decline in mercury levels; reduction was significant (p < 0.0001). A substantial fraction of patients had diets high in fish consumption; of these, a high proportion had blood mercury levels exceeding the maximum level recommended by the U.S. EPA and National Academy of Sciences. The mean level for women in this survey was 10 times that of mercury levels found in a recent population survey by the U.S. Centers for Disease Control and Prevention. Some children were > 40 times the national mean.
This study investigates renal dysfunction in areas without known environmental cadmium pollution and calculates the threshold level of urinary cadmium.
Urinary total protein, beta2-microglobulin (beta2-MG), and N-acetyl-beta-D-glucosaminidase (NAG), used as indicators of renal dysfunction, and urinary cadmium concentration, used as an indicator of cadmium exposure, were measured in two sets of 24-hour urine samples from each of 828 participants (410 men, 418 women), aged 40-59 years and living in three areas without any known environmental cadmium pollution. In multiple regression and logistic regression analyses the association between indicators of cadmium exposure and indicators of renal dysfunction were studied. The lower 95% confidence limit of the dose (benchmark dose) corresponding to a 5% (BMDL5) or 10% (BMDL10) level of each indicator of renal dysfunction above the background level) was calculated as the threshold level of urinary cadmium.
With all the expressed units [g creatinine(-1) and day(-1)] in the multiple regression analysis, the partial regression coefficients showed a significant association between urinary cadmium concentration and total protein, beta2-MG, and NAG for both genders, except for total protein for women (g creatinine(-1) and day(-1). The same results were obtained for both genders in the logistic regression analysis. The BMDL10 was 0.6-1.2 microg/g creatinine and 0.8-1.6 microg/day for the men and 1.2-3.6 microg/g creatinine, and 0.5-4.7 microg/day for the women.
Cadmium exposure and the levels of the indicators of renal dysfunction were associated among the men and women aged 40-59 years in areas without any known environmental cadmium pollution. The threshold level of urinary cadmium in Japan seems to be almost the same as in Belgium and Sweden.
Cadmium is a well-known nephrotoxic agent in food and tobacco, but the exposure level that is critical for kidney effects in the general population is not defined. Within a population-based women's health survey in southern Sweden (Women's Health in the Lund Area, WHILA), we investigated cadmium exposure in relation to tubular and glomerular function, from 1999 through early 2000 in 820 women (71% participation rate) 53-64 years of age. Multiple linear regression showed cadmium in blood (median, 0.38 microg/L) and urine (0.52 microg/L; density adjusted = 0.67 microg/g creatinine) to be significantly associated with effects on renal tubules (as indicated by increased levels of human complex-forming protein and N-acetyl-beta-D-glucosaminidase in urine), after adjusting for age, body mass index, blood lead, diabetes, hypertension, and regular use of nephrotoxic drugs. The associations remained significant even at the low exposure in women who had never smoked. We also found associations with markers of glomerular effects: glomerular filtration rate and creatinine clearance. Significant effects were seen already at a mean urinary cadmium level of 0.6 microg/L (0.8 microg/g creatinine). Cadmium potentiated diabetes-induced effects on kidney. In conclusion, tubular renal effects occurred at lower cadmium levels than previously demonstrated, and more important, glomerular effects were also observed. Although the effects were small, they may represent early signs of adverse effects, affecting large segments of the population. Subjects with diabetes seem to be at increased risk.
High cadmium exposure is known to cause bone damage, but the association between low-level cadmium exposure and osteoporosis remains to be clarified. Using a population-based women's health survey in southern Sweden [Women's Health in the Lund Area (WHILA) ] with no known historical cadmium contamination, we investigated cadmium-related effects on bone in 820 women (53-64 years of age) . We measured cadmium in blood and urine and lead in blood, an array of markers of bone metabolism, and forearm bone mineral density (BMD) . Associations were evaluated in multiple linear regression analysis including information on the possible confounders or effect modifiers: weight, menopausal status, use of hormone replacement therapy, age at menarche, alcohol consumption, smoking history, and physical activity. Median urinary cadmium was 0.52 microg/L adjusted to density (0.67 microg/g creatinine) . After multivariate adjustment, BMD, parathyroid hormone, and urinary deoxypyridinoline (U-DPD) were adversely associated with concentrations of urinary cadmium (p < 0.05) in all subjects. These associations persisted in the group of never-smokers, which had the lowest cadmium exposure (mainly dietary) . For U-DPD, there was a significant interaction between cadmium and menopause (p = 0.022) . Our results suggest negative effects of low-level cadmium exposure on bone, possibly exerted via increased bone resorption, which seemed to be intensified after menopause. Based on the prevalence of osteoporosis and the low level of exposure, the observed effects, although slight, should be considered as early signals of potentially more adverse health effects. Key words: biochemical bone markers, bone mineral density, cadmium, lead, osteoporosis, women.
To determine if long-term exposure to high levels of lead in the environment is associated with decrements in cognitive ability in older Americans.
We completed a cross-sectional analysis using multiple linear regression to evaluate associations of recent (in blood) and cumulative (in tibia) lead dose with cognitive function in 991 sociodemographically diverse, community-dwelling adults, aged 50 to 70 years, randomly selected from 65 contiguous neighborhoods in Baltimore, MD. Tibia lead was measured with (109)Cd induced K-shell X-ray fluorescence. Seven summary measures of cognitive function were created based on standard tests in these domains: language, processing speed, eye-hand coordination, executive functioning, verbal memory and learning, visual memory, and visuoconstruction.
The mean (SD) blood lead level was 3.5 (2.2) microg/dL and tibia lead level was 18.7 (11.2) microg/g. Higher tibia lead levels were consistently associated with worse cognitive function in all seven domains after adjusting for age, sex, APOE-epsilon4, and testing technician (six domains p <or= 0.01, one domain p <or= 0.05). Blood lead was not associated with any cognitive domain. Associations with tibia lead were attenuated after adjustment for years of education, wealth, and race/ethnicity.
Independent of recent lead dose, retained cumulative dose resulting from previous environmental exposures may have persistent effects on cognitive function. A portion of age-related decrements in cognitive function in this population may be associated with earlier lead exposure.
Fish is considered protective for coronary heart disease (CHD), but mercury (Hg) intake from fish may counterbalance beneficial effects. Although neurotoxic effects of methylmercury (MeHg) are well established, cardiovascular effects are still debated. The objective of the present study was to evaluate blood pressure in relation to Hg exposure and fish consumption among a non-indigenous fish-eating population in the Brazilian Amazon.
The study was conducted among 251 persons from six communities along the Tapajós River, a major tributary of the Amazon. Data was obtained for socio-demographic information, fish consumption, height and weight to determine body mass index (BMI), systolic and diastolic blood pressure, and Hg concentration in hair samples.
Results showed that overall, systolic and diastolic blood pressure, were relatively low (mean: 113.9 mmHg +/- 14.6 and 73.7 mmHg +/- 11.0). Blood pressure was significantly associated with hair total Hg (H-Hg), age, BMI and gender. No association was observed between fish consumption and blood pressure, although there were significant inter-community differences. Logistic regression analyses showed that the Odds Ratio (OR) for elevated systolic blood pressure (> or = 130 mmHg) with H-Hg > or = 10 microg/g was 2.91 [1.26-7.28], taking into account age, BMI, smoking, gender and community.
The findings of this preliminary study add further support for Hg cardiovascular toxicity.
Neurobehavioural tests were performed by 98 dentists (mean age 32, range 24-49) exposed to elemental mercury vapour and 54 controls (mean age 34, range 23-50) with no history of occupational exposure to mercury. The dentists were exposed to an average personal air concentration time weighted average (TWA) of 0.014 (range 0.0007-0.042) mg/m3 for a mean period of 5.5 (range 0.7-24) years and had a mean blood mercury concentration of 9.8 (range 0.6-57) micrograms/l. In neurobehavioural tests measuring motor speed (finger tapping), visual scanning (trail making), visuomotor coordination and concentration (digit symbol), verbal memory (digit span, logical memory delayed recall), visual memory (visual reproduction, immediate and delayed recall), and visuomotor coordination speed (bender-gestalt time), the performance of the dentists was significantly worse than that of the controls. The dentists scored 3.9 to 38.9% (mean 13.9%) worse in these tests. In trail making, digit span, logical memory delayed recall, visual reproduction delayed recall, and bender-gestalt time test scores were more than 10% poorer. In each of the tests in which significant differences were found and in the block design time, the performance decreased as the exposed dose (product of the TWA of air mercury concentrations and the years of exposure) increased. These results raise the question as to whether the current threshold limit value of 0.050 mg/m3 (TWA) provides adequate protection against adverse effects of mercury.
The findings presented here suggest that mercury poisoning from dental amalgam may play a role in the etiology of mental illness. Comparisons between subjects with and without amalgam showed significant differences in subjective reports of mental health. Subjects who had amalgams removed reported that symptoms of mental illness lessened or disappeared after removal. The data suggest that inorganic mercury poisoning from dental amalgam does affect the mind and emotions.
There is growing evidence that heavy metals, in general, and mercurial compounds, in particular, are immunotoxic to the human immune system. The major focus of our study is to demonstrate that methylmercuric chloride (MeHgCl) kills human lymphocytes by inducing apoptosis. T-cells exposed to 0.6-5 microM MeHgCl for 24 h were analyzed by flow cytometry. Methylmercury-treated cells exhibited increased Hoechst 33258 fluorescence while maintaining their ability to exclude the vital stain 7-aminoactinomycin. Furthermore, T-cells exposed to methylmercury exhibited changes in light scatter patterns that included decreased forward light scatter and increased side light scatter. The light scatter and fluorescent changes were consistent with morphological alterations displayed by cells during apoptosis. Cell death was further evaluated by assessing annexin V binding to the plasma membrane. Methylmercury-treated cells exhibited increased annexin V binding indicative of phosphatidylserine translocation to the outer leaflet of the plasma membrane. Using the fluorescent probe DiOC6(3), we noted that methylmercury exposure resulted in a decrease in mitochondrial transmembrane potential (Psim). Since a low Psim is associated with altered mitochondrial function, we also determined if exposure to methylmercury potentiated reactive oxygen species (ROS) generation. We noted that treated cells generated ROS, as evidenced by oxidation of hydroethidine and the generation of the fluorescent product, ethidium. Finally, we evaluated the effect of methylmercury on T-cell GSH content utilizing the fluorescent probe monochlorobimane; in the presence of MeHgCl, there is a marked loss in reduced cell thiols. The results of the study indicate that a key event in the induction of T-cell apoptosis by mercuric compounds is depletion in the thiol reserve which predisposes cells to ROS damage and at the same time activates death signaling pathways.
To estimate the equivalent cadmium levels in renal cortex and in urine, as based on autopsy analysis of subjects not exposed to cadmium occupationally.
The levels of Cd were determined in renal cortex, liver, urine and urinary bladder of 39 subjects deceased at the age 42 +/- 14 years. Flame atomic absorption spectrometry (kidneys, liver) and flameless AAS (urine, bladder) were used.
The urinary cadmium level determined post mortem is strongly correlated with the renal Cd levels. Eliminating cases with high urinary proteins and extrapolating from sets of data with elevated urinary protein concentration to its normal range yielded a value of 1.7 microg/g creatinine as equivalent to the renal level of 50 microg/g w.w.
It seems possible to use monitoring data for cadmium in urine and in renal cortex in a coherent way.
Heavy metals have been identified as factors affecting human fertility. This study was designed to investigate whether the urinary heavy metal excretion is associated with different factors of infertility. The urinary heavy metal excretion was determined in 501 infertile women after oral administration of the chelating agent 2,3-dimercaptopropane-1-sulfonic acid (DMPS). Furthermore, the influence of trace element and vitamin administration on metal excretion was investigated. Significant correlations were found between different heavy metals and clinical parameters (age, body mass index, nationality) as well as gynecological conditions (uterine fibroids, miscarriages, hormonal disorders). Diagnosis and reduction of an increased heavy metal body load improved the spontaneous conception chances of infertile women. The DMPS test was a useful and complementary diagnostic method. Adequate treatment provides successful alternatives to conventional hormonal therapy.
Long-term exposure to cadmium (Cd) causes renal damage in the general population. The maximum allowable urinary Cd concentration, which was calculated from our previous study performed in a Cd-polluted area, was almost the same as the mean urinary Cd concentration of people living in nonpolluted areas. We assessed whether environmental Cd exposure is related to renal dysfunction of people in nonpolluted areas in Japan. Blood and urine samples were collected from 2753 subjects (1105 men and 1648 women) ages over 50 years old in three nonpolluted areas. Blood was analyzed for Cd and urine was analyzed for Cd, total protein, beta(2)-microglobulin (beta(2)-mg), and N-acetyl-beta-D-glucosaminidase (NAG). Cd in blood or urine was employed as indicators of internal dose; and urinary total protein, beta(2)-mg, and NAG were used as an indicator of renal dysfunction. Multiple regression analysis and logistic regression analysis were performed to clarify the dose-effect and dose-response relationship between blood or urinary Cd concentration and indicators of renal dysfunction. Multiple regression analysis demonstrated a significant dose-effect relationship between Cd in blood and urine and indicators of renal dysfunction. Logistic regression analysis also showed that the probability that individual subjects would have abnormal values of the renal variables was significantly related to Cd in blood and urine.
Previous research suggests that environmental lead exposure correlates with age-related decreases in renal function.
Two hundred two patients with chronic renal insufficiency (indicated by a serum creatinine level between 1.5 mg per deciliter and 3.9 mg per deciliter) who had a normal total-body lead burden and no history of exposure to lead were observed for 24 months. After the observation period, 64 subjects with an elevated body lead burden were randomly assigned to the chelation control groups. For three months, the patients in the chelation group received lead-chelation therapy with calcium disodium EDTA, and the control group received placebo. During the ensuing 24 months, repeated chelation therapy was administered weekly to 32 patients with high-normal body lead burdens (at least 80 microg but less than 600 microg) unless on repeated testing the body lead burden fell below 60 microg; the other 32 patients served as controls and received weekly placebo infusions for 5 weeks every 6 months. The primary end point was an increase in the serum creatinine level to 1.5 times the base-line value during the observation period. A secondary end point was the change in renal function during the intervention period.
The primary end point occurred in 24 patients during the observation period; the serum creatinine levels and body lead burden at base line were the most important risk factors. The glomerular filtration rate improved significantly by the end of the 27-month intervention period in patients receiving chelation therapy: the mean (+/-SD) change in the glomerular filtration rate in the patients in the chelation group was 2.1+/-5.7 ml per minute per 1.73 m2 of body-surface area, as compared with -6.0+/-5.8 ml per minute per 1.73 m2 of body-surface area in the controls (P<0.001). The rate of decline in the glomerular filtration rate in the chelation group was also lower than that in the controls during the 24-month period of repeated chelation therapy or placebo.
Low-level environmental lead exposure may accelerate progressive renal insufficiency in patients without diabetes who have chronic renal disease. Repeated chelation therapy may improve renal function and slow the progression of renal insufficiency.
Increasing evidence suggests that 10 microg/dL, the current Centers for Disease Control and Prevention screening guideline for children's blood lead level, should not be interpreted as a level at which adverse effects do not occur. Using data from a prospective study conducted in Mexico City, Mexico, we evaluated the dose-effect relationship between blood lead levels and neurodevelopment at 12 and 24 months of age.
The study population consisted of 294 children whose blood lead levels at both 12 and 24 months of age were < 10 microg/dL; blood lead levels were measured by graphite furnace atomic absorption spectroscopy; Bayley Scales of Infant Development II were administered at these ages. The outcomes of interest were the Mental Development Index and the Psychomotor Development Index.
Adjusting for covariates, children's blood lead levels at 24 months were significantly associated, in an inverse direction, with both Mental Development Index and Psychomotor Development Index scores at 24 months. Blood lead level at 12 months of age was not associated with concurrent Mental Development Index or Psychomotor Development Index scores or with Mental Development Index at 24 months of age but was significantly associated with Psychomotor Development Index score at 24 months. The relationships were not altered by adjustment for cord blood lead level or, in the analyses of 24-month Mental Development Index and Psychomotor Development Index scores, for the 12-month Mental Development Index and Psychomotor Development Index scores. For both Mental Development Index and Psychomotor Development Index at 24 months of age, the coefficients that were associated with concurrent blood lead level were significantly larger among children with blood lead levels < 10 microg/dL than it was among children with levels > 10 microg/dL.
These analyses indicate that children's neurodevelopment is inversely related to their blood lead levels even in the range of < 10 microg/dL. Our findings were consistent with a supralinear relationship between blood lead levels and neurobehavioral outcomes.
Evaluation of mercury exposure in an individual patient ideally includes the presenting history, physical examination, consideration of the differential diagnosis, and mercury analysis of blood and urine specimens. Analysis of mercury in hair specimens may supply useful supplemental information about exposure to organic compounds such as methylmercury, particularly to help reconstruct the pattern of prior exposure. The most appropriate specimen is generally terminal-type hair from the occipital-neck junction, clamped to maintain strand alignment, and oriented to the scalp. Hair from the initial 0.5 cm adjacent to the scalp represents on average 1-3 wk before collection, and consideration of the time frame represented by the specimen is an important part of the evaluation. Literature reports describe hair mercury levels as high as 2400 microg/g. Hair mercury level is usually <1 microg/g in individuals who do not eat fish but may be >30 microg/g in those who frequently consume fish with high mercury content. Hair mercury level is often not correlated with blood mercury concentration or symptoms of mercury toxicity, and reports of hair contamination by exogenous mercury are not uncommon. Hair mercury level is notoriously prone to misinterpretation and should be used with an understanding of its limitations.
Runcorn, North West England, has been a site of industrial activity for over 100 years. Preliminary investigations have revealed
excess risk of renal mortality in the population living closest to several sources of pollution. Exposure to airborne mercury
has been highlighted as a possible cause, although there is also concomitant exposure to solvents and other heavy metals in
this population. The authors used validated air dispersion modeling to identify mercury-exposed populations. Standardized
mortality ratios for kidney disease were computed using the North West government region as the reference. There was a significant
exposure-response relation between modeled estimates of mercury exposure and risk of kidney disease mortality (test for trend:
p = 0.02 for men and p = 0.03 for women), and this relation was more pronounced for estimated historical exposure (test for trend: p = 0.01 for men and p < 0.001 for women). These findings suggest that exposure to mercury is a possible cause of the excess kidney disease mortality
in this population, indicating that there might still be a health legacy of the historically high levels of industrial activity
in the Runcorn area.
The grafting of human scalp hair was used as a new application of this method to explore methyl mercury incorporation into human hair and to validate this model for mercury monitoring in hair.
Human scalp grafts were transplanted to athymic BALB/c nude mice. The animals were exposed to methyl mercury either as a single dose i.p. or continuously for 4 months, using ALZET osmotic pumps. The mercury concentration in hair was determined using x-ray fluorescence (XRF) spectrometry by segmental (2 mm) analysis of a single strand, and tissue concentrations were measured by cold vapor atomic absorption analysis.
Human scalp hair grown in nude mice showed long-term persistence of human features including the expression of histocompatibility antigens (KAB 3, W 6/32, SF 1-1.1.1) and normal hair morphometry. The disposition of methyl mercury in nude mice followed a one-compartment model with a whole body elimination half-life of 6.7 days (elimination constant, k = 0.1/day). Autoradiographic studies revealed that methyl mercury was rapidly incorporated into areas of the hair follicle undergoing active keratinization. Methyl mercury concentrations in human hair transplanted onto nude mice were two orders of magnitude higher than in blood and attained a mean hair: blood ratio of 217 : 1, similar to ratios reported only in human studies.
This study demonstrated that human hair grown on nude mice can record the level of exposure to methyl mercury and can serve as a valuable research tool to study mercury incorporation into human hair.
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