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.

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.

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.

Toxicidad letal y subletal del arsénico, cadmio, mercurio y plomo sobre el pez Parachaeirodon innesi neon tetra (Characidae) / Lethal and sublethal toxicity of arsenic, cadmium, mercury and lead on fish Paracheirodon innesi neon tetra (Characidae)

La contaminación ambiental es un problema global, siendo los metales pesados los de mayor importancia; como, por ejemplo, arsénico, cadmio, mercurio y plomo. El objetivo del estudio fue evaluar la toxicidad estos cuatro metales sobre el pez Paracheirodon innesi. Para esto se realizaron bioensayos estáticos en laboratorio empleando individuos juveniles y como agentes tóxicos: arseniato de sodio, cloruro de cadmio, cloruro de mercurio y nitrato de plomo. Se determinó la concentración letal media (CL50) y la concentración efectiva media (CE50) para dos efectos subletales (nado extraño y movimiento opercular acelerado) con los programas TRAP y Excel Probit; así como la Concentración sin Efecto Pronosticada (PNEC). Los valores de CL50 y CE50 disminuyeron de manera casi continua de 24 h a 96 h para los distintos metales. El grado de toxicidad, en orden descendente, fue: mercurio > cadmio > arsénico > plomo. Los valores de CE/L50 de TRAP fueron ligeramente mayores a los de Excel Probit. La CL50-96h de estos metales fue 0,129; 23,1; 60,3 y 278 mg.L-1 para Excel Probit y 0,137; 29,4; 65,5 y 282 mg.L-1 para TRAP; respectivamente. Al comparar los valores de PNEC estimados para los cuatro metales de interés con el Estándar de Calidad Ambiental Peruano de la Categoría 4 para ríos de selva (ECA Cat 4 - E2 ríos selva), se puede indicar que la concentración límite del ECA para arsénico no es apropiada y su cumplimiento no aseguraría la conservación del medio acuático

Envinronmental pollution is a global issue, being heavy metals the most important; such as, arsenic, cadmium, mercury and lead. The study object was to evaluate these four metals on fish Paracheirodon innesi. To meet the goal static bioassays were carried out at laboratory, using juveniles and as toxic agents: sodium arsenate, cadmium chloride, mercury chloride and lead nitrate, with high purity. There were determined the median lethal concentration (LC50) and the median effective concentration (EC50) for two sublethal effects (strange swimming and accelerated opercula movement); as well as the Predicted No Effect Concentration (PNEC). LC50 and EC50 values decreased continuously from 24 to 96 h for all metals. The four evaluated metals showed the next toxicity ranking: mercury > cadmium > arsenic > lead. TRAP's L/EC50 values were slightly higher than Excel Probit's values. LC50‑96h for these metals were 0.129; 23.1; 60.3 and 278 mg.L-1 for Excel Probit and 0.137; 29.4; 65.5 y 282 mg.L-1 for TRAP, respectively. When comparing PNEC's estimated values for the four metals of interest with Peruvian Environmental Quality Standard of Category 4 for jungle rivers (EQS Cat 4 - E2 jungle rivers), it can be indicated that ECA's limit concentration to arsenic is inappropriate and its compliance would not ensure aquatic environment conservation

Histo-cytological responses of the prolactin cells of the catfish Heteropneustes fossilis to cadmium exposure / Respuesta histológica y citológica frente a la exposición a cadmio de las células prolactínicas del pez gato Heteropneustes fossilis

Cadmium is an important metal for modern industrial processes and, being biologically non-essential, poses health hazards to the organisms. In this study we aimed to evaluate the effect of cadmium exposure on the histo-cytology of prolactin cells in the freshwater catfish, Heteropneustes (H.) fossilis. Fish were subjected to 288 mg/L (0.8 of 96 h LC50) and 72 mg/L (0.2 of 96 h LC50) of cadmium chloride for short-term and long-term, respectively. After sacrificing the fish, the blood was collected on 24, 48, 72 and 96 h in short-term and after 7, 14, 21, and 28 days in long-term experiment and analyzed for plasma calcium levels. Also, pituitary glands were fixed on these intervals. The plasma calcium levels of short-term cadmium exposed fish remain unchanged after 24 h. The levels exhibit a progressive decrease from 48 h onwards. The fish exposed to cadmium for 7 days exhibit a decrease in the plasma calcium level. Thereafter, the levels progressively decrease till the end of the experiment (28 days). The prolactin cells of the control fish exhibit structural resemblance to the description given for the prolactin cells of normal H. fossilis. No change in the histological structure and nuclear volume of prolactin cells of cadmium non-exposed fish has been noticed throughout the experiment. In cadmium treated fish, the prolactin cells remain unchanged till 14 days. On day 21, the nuclear volume of these cells exhibits an increase and the cells degranulate. These changes increased profoundly on day 28. In addition, vacuolization and cytolysis were also encountered on day 28 following cadmium treatment. It is concluded that cadmium affects the prolactin cells of the fish H. fossilis thus disturbing the ionic balance.

El cadmio es un metal importante para los procesos industriales modernos, siendo no esencial biológicamente, representa riesgos para la salud de organismos. En este estudio tratamos de evaluar el efecto de la exposición al cadmio por el aspecto histológico y citológico de células secretoras de prolactinas del pez gato de agua dulce Heteropneustes (H.) fossilis. Los peces fueron sometidos a una exposición de 288 mg/L (0,8 de 96 h CL50) and 72 mg/L (0,2 de 96 h CL50) de cloruro de cadmio por a corto y largo término respectivamente. Después del sacrificio de los peces, la sangre fue colectada, tomando muestras de 24, 48, 72 y 96 hs en el corto término y de 7, 14, 21 y 28 días en las sometidas a largo término, la cuales se analizaron para medir niveles de calcio. Además, las glándulas pituitarias fueron fijadas en esos intervalos El nivel plasmático de calcio en los experimentos de exposición a corto tiempo se mantuvo sin cambio tras 24 h. Los niveles exhibieron una caída progresiva a partir de las 48 hs. Los peces expuestos a cadmio por 7 días presentaron una disminución en el nivel plasmático de calcio. Después de esto, los niveles decayeron progresivamente hasta el fin del experimento (28 días). Las células prolactínicas de los peces controles mostraron semejanza estructural a la descripción dada para estas células normales en H. fossilis. No se observaron cambios en la estructura histológica y el volumen nuclear de las células prolactínicas de los peces no expuestos a cadmio a través de todo el experimento. En los peces tratados con cadmio las células prolactínicas se mantuvieron sin cambios hasta los 14 días. En el día 21, el volumen nuclear de esas células se incrementó y estas células presentaron desgranulación. Estos cambios aumentaron profundamente en las muestras del día 28. Adicionalmente en el día 28 posterior al tratamiento con cadmio se encontró vacuolización y citólisis. Se concluyó en que el Cadmo afecta las cñelupas prolactínicas de H fossilis, produciendo disturbios en el balance iónico.

Ailing bones and failing kidneys: a case of chronic cadmium toxicity.

Heavy metal toxicity is often caused by occupational exposure. Chronic cadmium toxicity is a significant health concern among workers engaged in zinc smelting, battery production and silver jewellery industries, particularly in developing countries. We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome. He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure. Cadmium has a long biological half-life and there is no effective treatment for people who are exposed to it. Therefore, an early diagnosis and prevention of further exposure are important.

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.

[Dosage of cadmium and lead in human blood by anodic stripping voltammetry]. / Dosage du cadmium et du plomb dans le sang humain par voltamétrie à redissolution anodique.

The objective is the determination of the conditions operating optimal to determine the concentration of the cadmium and the lead dissolved in the human blood. An electroanalytical method has been developed for the determination of lead and cadmium in whole blood by differential pulse anodic stripping voltammetry (DPASV) on a hanging mercury drop electrode (HMDE). The best conditions were found to be electrolyte support perchloric acid 0.02 M, the accumulation potential is -900 mV, and the accumulation time is 320 s. The obtained limits of detection are equal to 0.46 and 0.08 ng/mL respectively for the lead and the cadmium. The developed method was validated by the analysis of reference materials certified by total blood.

[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.

Reassessment of the threshold of urinary cadmium by using hybrid approach in a cadmium non-polluted area in Japan.

BACKGROUND AND OBJECTIVES: We applied an updated hybrid approach to estimate the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) for cadmium-induced renal effects as the threshold of urinary cadmium in humans. Using this method, the BMD and BMDL were estimated based on continuous exposure and continuous effect marker, thereby avoiding categorization of subjects, an inevitable outcome of previously used approaches. METHODS: The target subjects were 547 men and 723 women, aged 50 years or older, who lived in a cadmium non-polluted area of Japan. We measured urinary cadmium (U-Cd) as a marker of long-term exposure, and urinary protein, ß2-microglobulin (ß2-MG) and N-acetyl-ß-D-glucosaminidase (NAG) as renal effect markers. BMD and BMDL corresponding to an additional risk (BMR) of 5%, were calculated with the background risk at zero exposure set at 5%. RESULTS AND CONCLUSIONS: The BMDL of U-Cd for renal effect markers were 2.1 (urinary protein), 2.6 (ß2-MG) and 4.1 (NAG) µg/g creatinine in men and 1.5 (urinary protein), 1.4 (ß2-MG) and 3.1 (NAG) µg/g creatinine in women. The BMDLs in the present study may contribute to further discussion on health risk assessment of cadmium exposure, when compared to BMDLs obtained by previously reported methods.

[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.

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.

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 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.

Influence of drinking and/or cooking with Jinzu River water on the development of Itai-itai disease.

This study was undertaken to estimate the amount of cadmium (Cd) exposure needed for the development of Itai-itai disease and the influence of using Jinzu River water for drinking and/or cooking on its development. The subjects comprised 38 Itai-itai disease patients admitted both for questionnaire survey and medical testing. The period when the patients started to perceive leg/back pain was defined as 'mild disease onset' and that when they experienced the most severe manifestations such as ambulatory disturbance as 'severe disease onset'. In a comparison of non-users/users of river water, mean age and lifetime Cd intake (LCd) estimated from the daily consumption of rice and other foods at the onset of mild or severe disease showed smaller values in the users than non-users. LCd in non-users/users of river water for drinking and/or cooking were estimated as 3.46-3.60 g/2.58-2.63 g at mild disease onset and 4.24-4.44 g/3.50-3.54 g at severe disease onset. A portion of the differences in LCd in non-users/users is attributable to the influence of Cd consumption from the use of river water, although it was suggested that LCd estimated from eating Cd-polluted rice exerted a greater influence on the development of Itai-itai disease than drinking and/or cooking with Cd-polluted river water.

Alterações histológicas em brânquias de tilápia nilotica Oreochromis niloticus causadas pelo cádmio / Histological alterations in gills of Nile tilapia Oreochromis niloticus caused by cadmium

Os efeitos histopatológicos do cádmio nas brânquias de tilápia Oreochromis niloticus foram estudados por microscopia óptica, usando 25mgl-1 de CdCl2 durante quatro dias, com o objetivo de identificar seus efeitos agudos na estrutura das brânquias. A morfologia geral das brânquias de O. niloticus é idêntica à de outros teleósteos, apresentando quatro pares de arcos branquiais com filamentos bem desenvolvidos. Situadas lateralmente, encontram-se as lamelas provenientes do eixo central dos filamentos. No epitélio filamentar foi possível identificar células de cloro, pavimentosas e mucosas. Os peixes expostos ao cádmio mostraram sinais de lesões epiteliais; edema intersticial, vasodilatação das lamelas, destacamento do epitélio lamelar e proliferação do epitélio filamentar. As alterações observadas também incluíram fusão nas lamelas como resultado de hiperplasia e hipertrofia epitelial, ruptura do sistema de células pilar, aneurismas e necroses.

The histopathogical effects of cadmium on the gills of tilapia Oreochromis niloticus were studied by light microscopy, using 25mgl-1 of CdCl2 during four days to identified the effects of short-term exposure on gills structure. The general morphology of O. niloticus gills is similar to the other teleostean fishes, showing four pairs of gills arches with well developed filaments. Bilaterally situated, secondary lamellae branches are found from the central axis of the filaments. The filamentar epithelium showed the chloride cells, the pavement cells and mucous cells. Fish exposed to cadmium showed signs of epithelial lesion, namely the interstitial edema, swollen of the lamellae, lifting and cellular proliferation of the filamentar epithelium. The changes of the gills also included lamellar fusion as a result of epithelial hyperplasia and hypertrophy, the breakdown of pillar cell system, and aneurisms with some ruptures and necrosis, especially in the filamentar epithelium.

Changes in tubular dysfunction marker levels in parallel with the levels of copper, rather than cadmium, in urine of middle-aged women in non-polluted areas.

OBJECTIVE: This study was initiated to investigate if and to what extent the elevations in urinary alpha(1)- and beta(2)-microglobulins (alpha(1)-MG and beta(2)-MG, respectively) are specific to Cd nephro-toxicity. METHODS: Stored urine samples, collected from 1,000 adult women in 11 prefectures all over Japan, were analysed for eight elements (Ca, Cd, Co, Cu, Mg, Mn, Ni and Zn), alpha(1)-MG, beta(2)-MG, creatinine (CR) and specific gravity (SG); the data were cited from previous publications. The levels of eight elements and two MGs were expressed as observed and after correction for CR or SG (1.016). Age, CR and SG distributed normally, whereas two MGs and eight elements distributed log-normally. The 1,000 cases were classified into quartiles (i.e., 250 cases/group) of the lowest to the highest values (Groups A to D) for each element. RESULTS: alpha(1)-MG and beta(2)-MG increased as a function of Ca, Cd and Cu when corrected for CR, and the two MGs increased in parallel only with Cd and Cu after SG correction. Prevalence of alpha(1)-MG-uria (cut-off values; 5.3 and 6.5 mg/g cr or l) and beta(2)-MG-uria (cut-off values; 300 and 400 microg/g cr or l) was elevated with increasing Ca, Cd and Cu when corrected for CR, but only with Cd and Cu when corrected for SG. Multiple regression analysis of 353 cases of 50-59 year-old women with the eight element levels as independent variables and one of the two MGs as a dependent variable showed that Cu was the most influential element, and both Cd and Zn were less influential. CONCLUSIONS: Urinary levels of alpha(1)-MG and beta(2)-MG among women with no environmental Cd exposure correlated more closely with Cu levels than Cd levels in urine. The observation suggests that sub-clinical elevation in alpha(1)-MG and beta(2)-MG is not always attributable to nephro-toxicity of Cd, and that consideration on possible effects of other elements such as Cu is necessary.