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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., Competing Interests: Conflicts of Competing Interest None., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

The Christmas Island flying-fox (Pteropus natalis) is the last native mammal on Christmas Island and its population is in decline. Phosphate mining occurs across much of the eastern side of Christmas Island. The phosphate deposits are naturally rich in cadmium, and potentially other metals, which may be threatening the Christmas Island flying-fox population. To test this, concentrations of metals (cadmium, copper, iron, mercury, lead, and zinc) were measured in fur and urine collected from Christmas Island flying-foxes and interpreted concurrently with urinalysis and serum biochemistry data. In addition, metal concentrations in liver and kidney samples from two Christmas Island flying-foxes and associated histological findings from one of these individuals are reported. Fur cadmium concentrations were significantly higher in the Christmas Island flying-fox compared to concentrations found in flying-foxes in mainland Australia. Additionally, 30% of Christmas Island flying-foxes had urine cadmium concentrations exceeding maximum concentrations previously reported in flying-foxes in mainland Australia. Glucosuria and proteinuria were identified in two Christmas Island flying-foxes, suggestive of renal dysfunction. In one aged flying-fox, kidney cadmium concentrations were four-fold higher than toxic thresholds reported for domestic mammals. Microscopic evaluation of this individual identified bone lesions consistent with those described in laboratory animals with chronic cadmium poisoning. These results suggest that Christmas Island flying-foxes are being exposed to cadmium and identification of these sources is recommended as a focus of future research. Unexpectedly, urine iron concentrations in Christmas Island flying-foxes were higher compared to previous studies of Australian mainland flying-foxes, which suggests that urinary excretion of iron may be an important aspect of iron homeostasis in this species whose diet is iron rich., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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 β 2 Microglobulin (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.

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., (Copyright © 2018 John Wiley & Sons, Ltd.)

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.

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 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.

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.

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, β2-microglobulin (β2-MG) and N-acetyl-β-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 (β2-MG) and 4.1 (NAG) μg/g creatinine in men and 1.5 (urinary protein), 1.4 (β2-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., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

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.

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.

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.

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.

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.

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.

Objectives: A clinical case regarding a cadmium-exposed worker is described., Clinical Case: The subject during the work as welder (male, 42-years-old at the time of the first investigation) developed a Fanconi-like syndrome due to high exposure to cadmium fumes. Ten years after exposure removal, the subject showed clinical and laboratory evidence of nephrolithiasis (calcium phosphate stones)., Conclusions: The clinical case confirms the possibility of nephrolithiasis in cadmium-exposed workers and suggests that susceptible subjects may develop kidney stones after lesion of the tubular cells.

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.

Objective: To examine whether environmental exposure to cadmium has been inducing kidney dysfunction among middle-aged women in the general population in Japan., Methods: This study was conducted in 2000 and 2001. Morning spot urine samples were collected from 10,753 women (mostly aged 35 to 60 years) in ten prefectures all over Japan (thus about 1,000 women per site). Urine samples were analyzed for cadmium (Cd-U), calcium (Ca-U), magnesium (Mg-U), zinc (Zn-U), alpha(1)- and beta(2)-microglobulins (alpha(1)- and beta(2)-MG-U). The urinary analyte concentrations were corrected for creatinine (cr) concentration (i.e., Ucr). The data thus obtained were subjected to statistical evaluation by chi-square test, ANOVA, multiple comparison test, and simple regression analysis (SRA) as well as multiple regression analysis (MRA) including logistic regression analysis (LRA). Log-normal distribution was assumed for Cd-Ucr, alpha(1)-MG-Ucr and beta(2)-MG-Ucr, whereas normal distribution was considered for age, Ca-Ucr, Mg-Ucr and Zn-Ucr., Results: Geometric mean values (GM) of Cd-Ucr were distributed unevenly, depending on the sampling areas, with a grand GM of 1.3 microg/g cr, the highest (3.2 microg/g cr) and lowest GM values(0.8 microg/g cr) being significantly different from GMs of other areas. Correlation matrix analysis with subjects of all ages showed that log alpha(1)-MG-Ucr and log beta(2)-MG-Ucr correlated significantly (r=0.272 and 0.202, respectively) with log Cd-Ucr, but they correlated also with age (r=0.280 and 0.213, respectively). The same analysis with the two selected age groups (41-50 and 51-60 years), however, failed to show close correlation of alpha(1)-MG-Ucr and log beta(2)-MG-Ucr with Cd-Ucr. Both MRA and LRA indicated that age was a confounding factor in the evaluation of the effect of Cd-U on the two MG levels. Whereas the LRA with the all-age group showed a positive influence of log Cd-Ucr on log alpha(1)-MG-Ucr and log beta(2)-MG-Ucr, such effect disappeared in parallel with the disappearance of age effects when LRA was conducted with the two selected age groups. An exceptional observation was the influence of log Cd-Ucr on log alpha(1)-MG-Ucr (but not on log beta(2)-MG-Ucr) in LRA when a cut-off value of 5.00 mg for alpha(1)-MG-U/g cr was applied. Comparison between the low and high Cd-U groups showed that both alpha(1)-MG-Ucr and beta(2)-MG-Ucr were higher in the high Cd-U groups, but prevalence of cases with alpha(1)-MG-Ucr and beta(2)-MG-Ucr in excess of the cut-off values did not differ between the two groups except when a cut-off value of 5.00 mg/g cr was employed for alpha(1)-MG-U., Conclusions: In over-all evaluation, no clear-cut evidence was obtained in the present study to show that environmental exposure to Cd has induced tubule dysfunction among middle-aged women in the general population in Japan. It might be the case, however, that an increase in alpha(1)-MG-U was associated with Cd exposure. In this sense, it is apparently desirable from public health viewpoints to make further efforts to reduce the intensity of the general population's exposure to environmental Cd.

ENT and olfactometric examinations were carried out on 73 workers at an electrochemical plant involved in the production of cadmium-nickel batteries, where cadmium fumes were emitted into the workplace. Exposure levels exceeded the maximum allowable concentrations by about 1-2 times. The controls included 43 non-exposed, age- and cigarette-smoking-matched people. The olfactometric tests were carried out by the blast injection method, using natural coffee, aniseed, lemon and mint oils; two threshold measurements were assessed: maximum perceptible odour (MPO) and minimum identifiable odour (MIO). In addition, blood chemistries and urinalysis were carried out. The study revealed the smell lesion in 45.2% of the exposed group vs 4.6% of the controls. A statistically significant correlation between olfactory dysfunction and cadmium concentrations in the blood and urine was found; however, no correlation with the duration of employment was observed. It seems most likely that cigarette smoking, which is a considerable source of cadmium, may intensify this dysfunction, hence heavy smokers should not work in conditions of cadmium exposure.

Objective: The present study was initiated to investigate the validity of cadmium (Cd) and lead (Pb) in urine in comparison with the metals in blood as a biological marker of nonoccupational exposure of general populations to these metals as environmental pollutants., Design: Peripheral blood samples, morning spot-urine samples, and 24-h total food duplicate samples were collected from 107 nonsmoking women (aged 30-59 years) in four urban and rural survey sites in Korea., Methods: Portions of the samples were digested by heating in the presence of mineral acids, and the digests were analyzed for Cd and Pb by graphite furnace atomic absorption spectrophotometry. The metal concentrations in urine were adjusted for creatinine concentration and a specific gravity of 1.016. The analyte levels were evaluated on an individual basis (n = 107) and also on a group basis, i.e., in terms of geometric means for the survey sites (n = 4)., Results: Cd in urine correlated with Cd in blood on an individual as well as survey-site basis and tended to correlate with Cd in food duplicates on a group basis. The correlation of Pb in urine with Pb in blood was weaker than that of Cd in urine with Cd in blood when evaluated on an individual and survey-site basis. Pb in urine correlated with Pb in food duplicates either weakly or even negatively when examined on a survey-site basis., Conclusions: Cd in urine proved to be valid as a biological marker of environmental exposure of general populations, whereas less support was obtained for Pb in urine as an exposure marker.

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.

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.

Biological monitoring and exposure monitoring data for employees at a nickel-cadmium battery production facility were made available to OSHA for review. Sixteen employees were medically removed from occupational exposures to cadmium due to elevated levels of biological parameters (CdB, Cdu, B2U). While the biological monitoring parameters for most workers significantly declined during the 18 months of medical removal, the biological parameters for only one employee's values returned to the normal range. Only one worker had frank renal dysfunction, based on beta-2-microglobulin levels at the time of removal; this dysfunction remained throughout the 17 months of observation after medical removal. Significant policy implications of medical removal protection beyond the current 18-month period provided by the cadmium standards exist and require physician discretion. Mitigating issues which may make it ethically appropriate to return an employee to work despite elevated biologic monitoring parameters are also discussed.

Blood cadmium (B-Cd) and seminal fluid cadmium (Sf-Cd) were measured in 120 adult male subjects not occupationally exposed to cadmium (Cd), comprising 42 nonsmokers (including nine former smokers) and 78 smokers. The respective median and range values were: 0.46 (0.19-1.49) microgram/l of B-Cd and 0.54 (0.17-1.67) microgram/l of Sf-Cd in nonsmokers, and 4.33 (0.49-13.33) micrograms/l of B-Cd and 0.85 (0.29-3.56) microgram/l of Sf-Cd in smokers. Both indicators showed a highly significant difference in Cd exposure between the groups (P < 0.0001), although the increase in B-Cd was considerably more pronounced than that of Sf-Cd in smokers compared with nonsmokers. The results suggest a nonlinear relationship (log Sf-Cd/log B-Cd: r = 0.501, P < 0.0001), rather than linear relationship (Sf-Cd/B-Cd: r = 0.430, P < 0.0001), between the indicators. Significant correlations were found between smoking habits, i.e., the number of cigarettes per day, and an increase in B-Cd in smokers (r = 0.296, P < 0.01) and in all 120 subjects (r = 0.685, P < 0.0001), as well as between smoking habits and an increase in Sf-Cd in smokers (r = 0.378, P < 0.001) and in all 120 subjects (r = 0.488, P < 0.0001). Both indicators are necessary for evaluation of individual internal Cd dose, since they appear to differ in reflecting recent and long-term cumulative Cd exposure and/or the amount of Cd at the site(s) of its effect(s) in the body.

Background: Acute serious inhalation of cadmium fumes often causes chemical pneumonitis or metal fume fever. Because symptoms of both diseases begin several hours after exposure and closely mimic each other, one often mistakes chemical pneumonitis for metal fume fever in the early stages. It is, however, essential to differentiate between the two since chemical pneumonitis can progress to serious consequences., Case: A 43-year-old man was admitted to the hospital 2 d after exposure to cadmium fumes. The initial diagnosis was metal fume fever on the basis of his history, and he was treated accordingly. His symptoms worsened however, and transient renal impairment was identified as consistent with cadmium-induced renal toxicity. Although the possibility of drug-induced renal damage could not be excluded, abnormal urinalysis findings on admission suggested that the renal tubular damage was caused by inhaled cadmium before admission., Conclusions: Measuring the urinary cadmium concentration is an effective method for confirming acute cadmium poisoning.

An acute oral protein load causes a transient hyperfiltration that might reveal a loss of glomerular permselectivity properties. The effect of an oral protein load on the urinary excretion rate of albumin (UAE), beta-2-microglobulin (UB2MGE), and retinol-binding protein (URBPE) was thus examined in cadmium- and lead-exposed workers. The results show a transient increase in UB2MGE and URBPE without relevant changes in UAE. These changes were also observed in control groups and are due to competitive inhibition of tubular protein reabsorption by absorbed cationic amino acids. These results do not support the hypothesis that the acute protein load test is of great utility in revealing a silent glomerular filtration disturbance in lead- or cadmium-exposed workers. However, it might disclose imminent renal tubular dysfunction in cadmium workers not yet showing increased microproteinuria under baseline conditions.

Concentration-dilution of spot urine samples is a shortcoming of the biological monitoring of industrial xenobiotics. To ascertain whether the adjustment of urinary cadmium measured in spot samples is appropriate, urine samples were taken three times, once a week for 3 successive weeks, from 25 welders employed in the manufacture of jewelry (total 75 samples). Cadmium, creatinine, specific gravity, total urinary solutes, urinary volume and urinary flow rate were measured in 12-h collections and in spot samples taken immediately afterwards. Creatinine and total urinary solutes showed high inverse correlation with urinary flow rate (r = -0.858 and r = -0.768 respectively). Urinary cadmium displayed a similar trend but the correlation was not significant (r = -0.145). Creatinine adjustment of urinary cadmium values in spot samples increased the correlation with the same index in timed samples adjusted for urinary volume (r = -0.808) or urinary flow rate (r = 0.821) compared with non-adjustment (r = 0.732 and r = 0.738, respectively). Creatinine adjustment of spot sample values is also suitable for a wide range of urinary concentrations; discarding excessively diluted or concentrated urines, correlation of urine samples improved for non-adjusted or specific gravity-adjusted values, whereas no changes were observed for creatinine-adjusted values.

The objective of the present study was to determine the toxic trace element status of 51 healthy Austrian women and their newborn babies. Lead, mercury and cadmium content of early breast milk, blood and urine were measured post partum by atomic absorption spectrophotometry. None of the toxic trace elements could be found in elevated concentrations; the content of mercury and cadmium in milk was below limits of detection. Mean lead concentration in breast milk was 35.8 (SD:15.0) micrograms/l. Whole blood content of lead was 37.0 (SD:12.7) micrograms/l in mothers and 26.3 (SD:11.6) in newborns. High blood concentrations of mercury were found both in mothers (4.46 micrograms/l, SD:1.95) and in umbilical cord blood (5.58 micrograms/l, SD:2.33). The corresponding values for cadmium were 0.44 (SD:0.4) micrograms/l and 0.08 (SD:0.16) micrograms/l. Urine excretion of the elements assayed was normal. Significant correlations between maternal and neonatal blood toxic mineral levels could be demonstrated in lead (p < 0.001).

Cadmium (Cd) concentrations in blood and urine were significantly higher in itai-itai disease patients, suspected patients and inhabitants in Cd-polluted areas in Japan. Urinary Cd concentrations were mainly related to the body burden of Cd and did not decrease for several years following cessation of Cd exposure. There was a close association between urinary Cd excretion and the occurrence of beta 2-microglobulinuria (beta 2-mg-uria). Probit regression analysis between urinary Cd excretion and, beta 2-mg-uria indicated that the threshold value may be set around 4 micrograms/g creatinine (cr.). Studies on inhabitants in Cd-polluted areas showed that urinary, beta 2-mg levels of more than 1000 micrograms/l or 1000 micrograms/g cr. were irreversible, while increased urinary excretion of beta 2-mg was associated with increased mortality. At present, beta 2-mg in urine is not a suitable indicator for monitoring renal tubular dysfunction in the general population since the significance of slightly increased excretion of urinary beta 2-mg has yet to be clarified.

The kidney is considered the critical organ following long term occupational or environmental exposure to cadmium. Tubular dysfunction in the form of low molecular weight proteinuria is the earliest manifestation of cadmium nephrotoxicity. The current acceptable critical concentration of cadmium in the urine is 10 ug Cd/g creatinine. The aim of this paper is to identify the presence of tubular dysfunction among workers with less than 10 ug Cd/g creatinine. The exposed group of 92 workers were from a nickel-cadmium battery factory. The control group of 122 workers were factory and sedentary office workers with no known history of exposure to nephrotoxic agents. The urinary excretion of N-acetyl-D-glucosaminidase (NAG), beta-2-microglobulin (beta 2m) and alpha-1-microglobulins (alpha 1m) were measured from morning spot urine samples. The age, sex and race adjusted NAG and alpha 1m showed increasing trend with rising urinary cadmium levels. Levels were significantly raised when the urinary cadmium was above 5 ug Cd/g creatinine. A similar trend was seen with increasing length of exposure. Renal tubular dysfunction is present among cadmium exposed workers with levels below the current critical concentration.

It has been suggested that the accumulation of tobacco-derived cadmium (Cd) in the placenta is responsible for the adverse effect of cigarette smoking on infant birthweight. We chose to test this hypothesis; therefore, we studied a population of nonsmoking pregnant women who were exposed to low levels of smelter-derived Cd and a group of nonexposed women. A higher mean placental Cd concentration (p less than .0007) was found in the exposed women (n = 106), compared with those who were not exposed (n = 55); the observed Cd concentrations were comparable to concentrations reported previously for smoking and nonsmoking women, respectively. Least squares multiple regression (controlling for potentially confounding variables) revealed no association between placental Cd and birthweight. It was, therefore, concluded that the effect of smoking on birthweight was not mediated through Cd.

So far, the influence of lead, cadmium and mercury on human fertility has hardly been considered. First experiences by the authors with the chelating agent 2,3 dimercaptopropane-1-sulfonate (DMPS), which mobilizes heavy metals deposited in the body, seem to favour an association between the body load of heavy metals and complications during the menstrual cycle and during pregnancy. By means of an extensive survey of references, the importance of heavy metals for reproduction is demonstrated. In addition, the deficiency of particular minerals and their interaction with heavy metals are considered. Indications are given for diagnosis and therapy of the exposure to heavy metals. The practical procedure is demonstrated by means of three case studies.

Disorders of olfaction affect millions of Americans, but the extent to which occupational and environmental exposures contribute to these disorders is unknown. We examined 55 workers with chronic occupational exposure to cadmium fumes in a brazing operation. We estimated cadmium body burden using urinary cadmium levels and assessed cadmium-induced renal damage by urinary beta 2-microglobulin levels. We quantified olfactory function using a standardized test that measured two components of olfaction, butanol detection threshold and odor identification, and compared workers with a reference group. Forty-four percent of the cadmium-exposed workers were mildly hyposmic, and 13% were either moderately or severely hyposmic. In the reference group, 31% were mildly hyposmic, and the rest were normosmic. The workers with both high urinary cadmium levels and tubular proteinuria had the most significant olfactory dysfunction, with a selective defect in odor detection threshold. Our findings suggest that chronic occupational cadmium exposure sufficient to cause renal damage also is associated with impairment in olfactory function.

A new colorimetric test for kinetic determination of beta-N-acetylglucosaminidase activity in urine is evaluated according to the diagnostic usefulness in patients after kidney transplantation and in workers exposed to cadmium. The new test is suited to monitor renal parenchymal alterations.

Transferrin and protein 1, a sex linked alpha 2-microprotein, were assayed in urine from 58 workers exposed to cadmium (Cd) in a non-ferrous smelter and from 58 age matched referents. These two new markers of nephrotoxicity were compared with urinary beta 2-microglobulin (beta 2-m), retinol binding protein (RBP), albumin, and beta-N-acetyl-glucosaminidase (NAG). The response of protein 1 to Cd tubulotoxicity was similar to that of beta 2-m, RBP, and NAG. In Cd workers, protein 1 had a correlation with urinary Cd (r = 0.56) similar to beta 2-m (r = 0.48), RBP (r = 0.58), and NAG (r = 0.49). Values of these three low molecular weight proteins and of NAG were increased only in workers with urinary Cd higher than 10 micrograms/g creatinine. Urinary transferrin and albumin were similarly affected by exposure to Cd. Their response, however, was clearly more sensitive than that of low molecular weight proteins. Prevalences of positive values of these two high molecular weight proteins were not only higher but also tended to rise at lower concentrations of Cd in urine or blood. This finding suggests that in some subjects subtle defects in glomerular barrier function may precede the onset of proximal tubular impairment after chronic exposure to Cd. It remains to be assessed whether these subjects are more at risk of developing renal insufficiency.

A number of indicators of renal effect (N-acetyl-glucosaminidase, retinol binding protein, beta-2-microglobulin, albuminuria) were measured in 42 cadmium-exposed workers divided into 3 subgroups on the basis of the results of the last 10 years' biological monitoring (less than 3, 3-10, greater than 10 micrograms/l). An increase in the first three indicators was observed, particularly in the third subgroup, which, however, due to the wide dispersion of the values, was not statistically significant by the Kruskal-Wallis test. Taking the indicators singly, the marked increase in RBP and beta-2-microglobulin in the heavily exposed subjects was confirmed, along with an increasing sensitivity for NAG, while albuminuria levels were unchanged. Assessment of the "degree of association" of the altered tests demonstrated that the number and type of "association" varies between the subgroups in relation to the exposure conditions: in the first group there were no associations between the altered tests, whereas there were 2 duplicates in the second and 2 duplicates, 2 triplicates and 3 quadruplicates in the heavily exposed group. In the study of the renal effects of cadmium, it is therefore advisable to use several indicators and assess their behaviour both singly and combined, and also analyse the altered tests on the basis of the number and type of "association".