Relationship between mortality and rice cadmium concentration in inhabitants of the polluted Jinzu River basin, Toyama, Japan: A 26 year follow-up.

The aim of this study was to investigate the relationship between mortality and rice cadmium (Cd) concentration in inhabitants of a polluted area in Japan. The target subjects were inhabitants of the Jinzu River basin who participated in health examinations for screening of renal dysfunction from 1979 to 1984. The mean rice Cd concentration in each hamlet was used as an index of the Cd exposure. We conducted a 26 year follow-up survey in 3281 inhabitants (1544 men and 1737 women) whose data regarding the rice Cd concentration were available. Mortality risk ratios for all and specific causes were estimated after adjustments for age at baseline, smoking status and history of hypertension using a Cox hazard model or Fine and Gray competing risks regression model. The mortality risk ratios of rice Cd concentration (+0.1 ppm) for all causes in women were significantly increased (risk ratio: 1.04). Furthermore, the relative risks of rice Cd concentration for kidney and urinary tract disease, renal diseases, renal failure and toxic effects of cadmium were significantly increased in both sexes. These findings indicated that increased rice Cd concentration decreased the prognosis for life over a long-term observation in women. This result provides important information for determining the worldwide standard for allowable rice Cd concentration.

The liver in itai-itai disease (chronic cadmium poisoning): pathological features and metallothionein expression.

Cadmium (Cd) is a highly hepatotoxic heavy metal, which is widely dispersed in the environment. Acute Cd hepatotoxicity has been well studied in experimental animals; however, effects of prolonged exposure to Cd doses on the liver remain unclear. In the present study, to evaluate chronic Cd hepatotoxicity, we examined specimens from cases of itai-itai disease, the most severe form of chronic Cd poisoning. We compared 89 cases of itai-itai disease with 27 control cases to assess Cd concentration in organs. We also examined 80 cases of itai-itai disease and 70 control cases for histopathological evaluation. In addition, we performed immunohistochemistry for metallothionein, which binds and detoxifies Cd. Hepatic Cd concentration was higher than Cd concentration in all other organs measured in the itai-itai disease group, whereas it was second highest following renal concentration in the control group. In the liver in the itai-itai disease group, fibrosis was observed at a significantly higher rate than that in the control group. Metallothionein expression was significantly higher in the itai-itai disease group than that in the control group. Prolonged exposure to low doses of Cd leads to high hepatic accumulation, which can then cause fibrosis; however, it also causes high expression of metallothionein, which is thought to reduce Cd hepatotoxicity.

[Comparative characteristics of lead and cadmium intoxication in the Khanty-Mansi autonomous district].

The Khanty-Mansi Autonomous District (KMAD) occupies a prominent place in the economy of Russia in oil and gas production and energy generation. The development of hydrocarbon raw material extraction in the district does great damage to the environment and nature. This results in the accumulation of toxic chemical elements in man. The levels of lead, cadmium, calcium, and zinc were measured in the hair of indigenous and non-indigenous populations of the district. High lead and cadmium and low calcium and zinc concentration were found in indigenous adults and children in the KMAD.

The Case For Cadmium and Lead Heavy Metal Screening.

Exposure to cadmium and lead is widespread, and is related to environmental contamination, occupational sources, food, tobacco and other consumer products. Lower socioeconomic status increases the risk of heavy metal exposure and the diseases associated with cadmium and lead toxicity. Concurrent toxicity with both cadmium and lead is likely but has not often been assessed. There is now substantial evidence linking cadmium and lead to many diseases including hypertension, diabetes mellitus, obesity, cancer, coronary artery disease, chronic kidney disease (CKD) and lung disease. Both chronic renal failure and ischemic heart disease patients have been treated separately in recent studies with calcium disodium ethylenediaminetetraacetic acid (Ca EDTA) chelation therapy. In patients with CKD, serum creatinine 1.5-4.0 mg/dL, and increased body lead burden, weekly low dose chelation with Ca EDTA slowed the rate of decline in renal function in diabetics and non-diabetics. In patients with a history of myocardial infarction, the Trial to Assess Chelation Therapy (TACT) study showed that Ca EDTA chelation decreased the likelihood of cardiovascular events, particularly in diabetics. Ca EDTA chelation administered carefully at lower dosage (<50 mg/kg per week) is generally safe. In the past, acute renal failure associated with much higher dosage was reported. We suggest that the preponderance of the evidence favors a more activist approach towards diagnosis and possible intervention in heavy metal toxicity.

[Clinical and biochemical syndromes of cadmium-induced acute porphyrinopathy].

AIM: To study the specific features of porphyrin metabolic disturbances in cadmium poisoning. MATERIAL AND METHODS: The paper describes a patient who has developed clinical and biochemical syndromes of acute porphyrinopathy after exposure to cadmium-containing paint the vapors. The levels of delta-aminolevulinic acid, porphobilinogen, coproporphyrin, and uroporphyrin in urine and those of coproporphyrin and protoporphyrin in feces were measured. The concentrations of lead, cadmium, and copper were determined in whole blood and urine; selective screening of amino acids for hereditary metabolic diseases was made. RESULTS: The clinical signs of acute porphyrinopathy developed in the patient mimicked those of acute porphyries known by the current classification. The biochemical syndrome more corresponded to lead poisoning. However, the blood and urinary lead levels were not greater than the normal values, but the blood showed a 4-fold increase in cadmium, which seemed to induce porphyrin dysmetabolism.

Monitoring of human populations for early markers of cadmium toxicity: a review.

Exposure of human populations to cadmium (Cd) from air, food and water may produce effects in organs such as the kidneys, liver, lungs, cardiovascular, immune and reproductive systems. Since Cd has been identified as a human carcinogen, biomarkers for early detection of susceptibility to cancer are of an importance to public health. The ability to document Cd exposure and uptake of this element through biological monitoring is a first step towards understanding its health effects. Interpretation and application of biological monitoring data for predicting human health outcomes require correlation with biological measures of organ system responses to the documented exposure. Essential to this understanding is the detection and linkage of early biological responses toxic effects in target cell populations. Fortunately, advances in cell biology have resulted in the development of pre-clinical biological markers (biomarkers) that demonstrate measurable and characteristic molecular changes in organ systems following chemical exposures that occur prior to the onset of overt clinical disease or development of cancer. Technical advances have rendered a number of these biomarkers practical for monitoring Cd-exposed human populations. Biomarkers will be increasingly important in relation to monitoring effects from the exposure to new Cd-based high technology materials. For example, cadmium-selenium (CdSe), nano-materials made from combinations of these elements have greatly altered cellular uptake characteristics due to particle size. These differences may greatly alter effects at the target cell level and hence risks for organ toxicities from such exposures. The value of validated biomarkers for early detection of systemic Cd-induced effects in humans cannot be underestimated due to the rapid expansion of nano-material technologies. This review will attempt to briefly summarize the applications, to date, of biomarker endpoints for assessing target organ system effects in humans and experimental systems from Cd exposure. Further, it will attempt to provide a prospective look at the possible future of biomarkers. The emphasis will be on the detection of early toxic effects from exposure to Cd in new products such as nano-materials and identification of populations at special risk for Cd toxicity.

The benefit of pre- and post-challenge urine heavy metal testing: part 2.

Measuring heavy metal levels in the urine is an accepted method for assessing the presence of a heavy metal burden in an individual. Random samples (without a flushing agent) are excellent for showing current exposures, as they reflect the level of heavy metals in the bloodstream during the hours immediately before bladder voiding. Samples taken after using a heavy metal mobilizing agent are a reflection of total body burden. Part 1 reviewed the benefits of doing pre-flush (baseline) testing utilizing the published Centers for Disease Control (CDC) heavy metal normal ranges for interpretation that allow the clinician to identify current exposures to lead and mercury and to identify cadmium toxicity. In part 2 the benefits of doing both pre- and post-challenge testing are reviewed. Information gleaned from performing both tests is unparalleled in allowing the clinician to identify which chelating agent will be most effective for the patient. If oral agents are employed, then possible absorption problems can be identified. Since none of these benefits are realized with only post-flush testing, it is recommended that clinicians do heavy metal testing both before and after a challenge with an effective and proven heavy metal mobilizing agent. The pitfalls of oral chelation in the case of malabsorption syndromes, such as gluten intolerance, are also discussed.

The benefits of pre- and post-challenge urine heavy metal testing: Part 1.

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.

Diagnostic significance of metallothionein members in recognizing cadmium exposure in various organs under low-dose exposure.

Metallothioneins (MTs) are known to protect cells against oxidative stress, especially providing protection against cadmium (Cd) toxicity. To date, besides liver and kidney, the expression profiles of MT members have not been thoroughly determined in a full-spectrum of organs, especially under low-dose exposure settings. Furthermore, their diagnostic value has not been evaluated in reflecting the Cd exposure in diverse organs. In the present study, we unearthed the expression profiles of five MT members in diverse organs from mice upon low-dose Cd exposure. Compared to most organs, the deposition of Cd in cartilage has been overlooked in the past, implying the potential Cd toxicity to the joint. In contrast to MT1 and MT2 (MT1/2), the expression levels of MT3, MTL5 and MT4 were minimal with or without Cd treatment. Distinct from Cd mass, the levels of MT1/2 were similar in heart and lung to that of kidney. Our study signified the rationale of MT1/2 induction in recognizing Cd exposure extent in diverse organs including liver, kidney, heart and lung. Importantly, MT1/2 expression was induced in liver and lung cells even upon low-dose Cd exposure. Thus, our combined data unraveled the expression of MT members across various organs in Cd-exposed mice, and pinpointed their diagnostic value in characterizing Cd poisoning.

The references level of cadmium intake for renal dysfunction in a Chinese population.

Recent several studies indicated that a more restrictive dietary intake guideline for cadmium should be made for sufficient health protection. In the present study, we showed the references level of food cadmium intake (FCd) and total cadmium intake (TCd) for renal dysfunction by using benchmark dose (BMD) approach. 342 subjects living in a control and a cadmium polluted area were included in this study. The FCd, TCd and cadmium in urine (UCd) and blood (BCd) were calculated or determined. Urinary ß2Microglobulin (UBMG) was determined as indicator of renal function. The median FCd, TCd, UCd and BCd were 1.4 g, 1.4 g, 3.1 µg/g creatinine(cr) and 1.3 µg/L in control and 3.3 g, 3.6 g, 13.5 µg/g cr and 12.1 µg/L in polluted area. The 95% lower confidence bounds of BMD (BMDLs) of FCd for renal dysfunction were 1.36-1.55 g (BMR = 10%) and 0.88-1.11 g (BMR = 5%). The BMDLs of TCd were 1.29-1.46 g (BMR = 10%) and 0.73-0.95 g (BMR = 5%). FCd and TCd are valuable markers for the predication of renal dysfunction induced by cadmium. The BMDLs of FCd were close to previous report in Japan and the BMDLs of TCd were lower than the critical standard previously reported, in particular at BMR of 5% which can be interpreted as representing the influence of smoking.

Hair analyses: worthless for vitamins, limited for minerals.

Despite many major and minor problems with interpretation of analytical data, chemical analyses of human hair have some potential value. Extensive research will be necessary to define this value, including correlation of hair concentrations of specific elements with those in other tissues and metabolic pools and definition of normal physiological concentration ranges. Many factors that may compromise the correct interpretation of analytical data require detailed evaluation for each specific element. Meanwhile, hair analyses are of some value in the comparison of different populations and, for example, in public health community surveys of environmental exposure to heavy metals. On an individual basis, their established usefulness is much more restricted and the limitations are especially notable for evaluation of mineral nutritional status. There is a wide gulf between the limited and mainly tentative scientific justification for their use on an individual basis and the current exploitation of multielement chemical analyses of human hair.

New approaches for detecting thresholds of human nephrotoxicity using cadmium as an example.

Damage to the kidneys is one of the primary toxic actions of metals. Nephrotoxic substances not only cause renal disease directly, but they can also destroy renal reserve capacity, potentially placing those people with additional risk factors, such as diabetes, hypertension, cardiovascular disease, and genetic predispositions, at greater risk. To detect nephrotoxicity in people at a stage where intervention can be effective, sensitive methods are needed. One of the major advantages of using sensitive biomarkers of renal damage is that people who may be particularly susceptible to renal damage can be identified early, at a reversible stage of damage, and the progression to end-stage renal disease may be halted or delayed. Various categories of tests can be used to detect effects of nephrotoxic substances on the kidney. Through the use of biomarkers of damage to various parts of the nephron, U.S. and European studies have both shown a similar pattern of damage among men occupationally exposed to cadmium. These studies indicate various thresholds of renal effects, which researchers suggest represent a cascade of progressively severe damage to the kidney. Research into new biomarkers of damage caused by exposure to nephrotoxic substances centers around mechanisms of cell death, including necrosis and apoptosis; mechanisms of cell growth, regeneration, and proliferation, including factors that control cell cycle, influence gene expression, and modulate nucleic acid synthesis; and genetic factors that increase susceptibility to renal disease. Examples of types of candidate biomarkers include cytokines, lipid mediators, growth factors, transcription factors and protooncogenes, extracellular matrix components (collagen, glycoproteins, and proteoglycans), and cell adhesion molecules. Research into new categories of biomarkers may provide additional insights into the mechanisms of damage caused by nephrotoxins.

Public health consequences of heavy metals in dump sites.

Metals differ from most synthetic organic chemicals in that their clinical manifestations are well known and methods for their measurement in the body are generally well established. Since metals are ubiquitous, special care should be taken to identify the source, whether dump site or not. Isotopic ratios may be used for lead. Time of exposure may be highly variable so estimates will be necessary of integrated "dose-commitment." Transmission to man will follow many pathways. The contamination of children's hands and clothing by dust may be an important route. Because effects are so different, the chemical species (e.g., organic versus inorganic forms) of each metal must be identified. Exposure assessment requires identification of suitable indicator media, usually blood in the case of lead, urine with cadmium and inorganic mercury, and blood or hair with regard to methylmercury. Human head hair may have considerable potential, as it may provide a recapitulation of past exposures. The first health complaints associated with most metals are usually nonspecific. The complex social, political, and legal issues strongly indicate the need for objective tests for health effects. Most important is the identification and measurement of the critical effect, i.e., an effect that alerts the public health authorities that further exposure should cease. For example, in the case of lead, the critical effect is hematologic; with cadmium it is the presence in urine of abnormally high concentration of small molecular weight protein; and with mercury no early objective test has yet been devised.

Cadmium-its in vivo detection in man.

Neutron capture gamma-ray analysis has been applied to the in vivo detection of Cd in man. The technique was designed for the screening of industrial workers at risk. The limit of sensitivity in a liver-sized phantom is 0-5 ppm for a dose of 0-4 rad. Reproducibility and the effects of positional uncertainties have been investigated. A number of cadavers were studied to establish normal limits prior to commencement of a programme of clinical investigation. A patient with known Cd poisoning was estimated to contain 65-110 ppm of Cd in his liver. A liver dose of 0-05 rad was required.

alpha 1-Microglobulin determination in urine for the early detection of renal tubular dysfunctions caused by exposure to cadmium.

The determination of alpha 1-microglobulin (alpha 1-m) in urine was compared with that of beta 2-microglobulin (beta 2-m) for the detection of renal tubular dysfunctions caused by exposure to cadmium. alpha 1-m In urine is stable down to pH 4.5, whereas beta 2-m degrades below pH 5.5. The relationship between the urinary pH and alpha 1-m or beta 2-m in urine showed that alpha 1-m was independent of urinary pH, whereas beta 2-m-concentration decreased as urinary pH fell to a pH level below 6. Without a pH effect, alpha 1-m was highly correlated with beta 2-m in urine (N = 174, r = 0.96) from Cd-polluted subjects with renal dysfunctions. Due to the greater stability of alpha 1-m in urine, alpha 1-m seemed to be more advantageous than beta 2-m for the detection of renal tubular dysfunctions caused by Cd.

Bias induced by the use of creatinine-corrected values in evaluation of beta2-microgloblin levels.

The present study was initiated to examine if the correction for creatinine (CR or cr) is the best approach among the three methods of correction for CR, correction for a specific gravity (SG or sg) and the use of observed values in managing difference in urine density. For this purpose, a database previously developed on 10,753 adult women in 10 non-polluted areas in Japan was re-visited for information on age, urinary levels of Cd, Mg, Ca, Zn, beta(2)-MG, and creatinine, and urine specific gravity as well as smoking habits. Never-smoking women with various urine density counted 8975 cases (the various urine density group). From these cases, 7081 cases with adequate urine density (i.e. 0.5 g/l < or = CR < or = 3.0 g/l and 1.010 < or = SG < or = 1.030) were selected (the adequate urine density group). When a beta(2)-MG level of 400 microg/g CR or 400 microg/l was taken as a cut-off value for beta(2)-MG-uria, both the prevalence of beta(2)-MG(cr)-uria [i.e. cases with beta(2)-MG (as corrected for CR) in excess of 400 microg/g cr] and that of beta(2)-MG(sg)-uria increased as a function of the decrease in Cd(cr) or Cd(sg). The prevalence of beta(2)-MG(ob)-uria also varied as a function of CR and SG, especially of CR, but its range of variation was smaller than the corresponding changes in beta(2)-MG(cr)-uria prevalence. A noteworthy advantage for the use of observed values over that of SG-corrected values was the minimum effect of age. In over-all evaluation, therefore, the recommended approach appeared to be the use of non-corrected observed values (after selection of urine samples for adequate urine density if desired) or correction for SG, rather than correction for CR.

Parkinsonism after acute cadmium poisoning.

A 64-year-old man suffered from acute exposure to cadmium, followed by multiple organ failure. Three months after exposure, the patient developed parkinsonian features. The case suggests that cadmium intoxication may damage the basal ganglia, resulting in parkinsonism.

Evolution of cadmium-induced renal dysfunction in workers removed from exposure.

A retrospective examination of the medical records gathered during several surveys carried out among cadmium workers has permitted the identification of a group of 19 workers who had been examined before and after removal from cadmium exposure. All the workers had been exposed for more than 15 a (range 15.6-41.7 a). Their last examination took place from 0.3 to 7.9 a after the date of removal from cadmium exposure. At that time, all the workers exhibited sign(s) of cadmium-induced renal dysfunction. Comparison of the renal function parameters (serum creatinine, total proteinuria, aminoaciduria, albuminuria, beta 2-microglobulinuria, and the urinary excretion of retinol-binding protein) before and after the cessation of exposure indicated that cadmium-induced renal lesions, albeit of slow progression, are not reversible when exposure ceases.