Reducing disease and death from Artisanal and Small-Scale Mining (ASM) - the urgent need for responsible mining in the context of growing global demand for minerals and metals for climate change mitigation.

Artisanal and small-scale mining (ASM) takes place under extreme conditions with a lack of occupational health and safety. As the demand for metals is increasing due in part to their extensive use in 'green technologies' for climate change mitigation, the negative environmental and occupational consequences of mining practices are disproportionately felt in low- and middle-income countries. The Collegium Ramazzini statement on ASM presents updated information on its neglected health hazards that include multiple toxic hazards, most notably mercury, lead, cyanide, arsenic, cadmium, and cobalt, as well as physical hazards, most notably airborne dust and noise, and the high risk of infectious diseases. These hazards affect both miners and mining communities as working and living spaces are rarely separated. The impact on children and women is often severe, including hazardous exposures during the child-bearing age and pregnancies, and the risk of child labor. We suggest strategies for the mitigation of these hazards and classify those according to primordial, primary, secondary, and tertiary prevention. Further, we identify knowledge gaps and issue recommendations for international, national, and local governments, metal purchasers, and employers are given. With this statement, the Collegium Ramazzini calls for the extension of efforts to minimize all hazards that confront ASM miners and their families.

Gadolinium in Medical Imaging-Usefulness, Toxic Reactions and Possible Countermeasures-A Review.

Gadolinium (Gd) is one of the rare-earth elements. The properties of its trivalent cation (Gd3+) make it suitable to serve as the central ion in chelates administered intravenously to patients as a contrast agent in magnetic resonance imaging. Such Gd-chelates have been used for more than thirty years. During the past decades, knowledge has increased about potential harmful effects of Gd-chelates in patients with severe renal dysfunction. In such patients, there is a risk for a potentially disabling and lethal disease, nephrogenic systemic fibrosis. Restricting the use of Gd-chelates in persons with severely impaired renal function has decreased the occurrence of this toxic effect in the last decade. There has also been an increasing awareness of Gd-retention in the body, even in patients without renal dysfunction. The cumulative number of doses given, and the chemical structure of the chelate given, are factors of importance for retention in tissues. This review describes the chemical properties of Gd and its medically used chelates, as well as its toxicity and potential side effects related to injection of Gd-chelates.

Metallothionein and Cadmium Toxicology-Historical Review and Commentary.

More than one and a half centuries ago, adverse human health effects were reported after use of a cadmium-containing silver polishing agent. Long-term cadmium exposure gives rise to kidney or bone disease, reproductive toxicity and cancer in animals and humans. At present, high human exposures to cadmium occur in small-scale mining, underlining the need for preventive measures. This is particularly urgent in view of the growing demand for minerals and metals in global climate change mitigation. This review deals with a specific part of cadmium toxicology that is important for understanding when toxic effects appear and, thus, is crucial for risk assessment. The discovery of the low-molecular-weight protein metallothionein (MT) in 1957 was an important milestone because, when this protein binds cadmium, it modifies cellular cadmium toxicity. The present authors contributed evidence in the 1970s concerning cadmium binding to MT and synthesis of the protein in tissues. We showed that binding of cadmium to metallothionein in tissues prevented some toxic effects, but that metallothionein can increase the transport of cadmium to the kidneys. Special studies showed the importance of the Cd/Zn ratio in MT for expression of toxicity in the kidneys. We also developed models of cadmium toxicokinetics based on our MT-related findings. This model combined with estimates of tissue levels giving rise to toxicity, made it possible to calculate expected risks in relation to exposure. Other scientists developed these models further and international organizations have successfully used these amended models in recent publications. Our contributions in recent decades included studies in humans of MT-related biomarkers showing the importance of MT gene expression in lymphocytes and MT autoantibodies for risks of Cd-related adverse effects in cadmium-exposed population groups. In a study of the impact of zinc status on the risk of kidney dysfunction in a cadmium-exposed group, the risks were low when zinc status was good and high when zinc status was poor. The present review summarizes this evidence in a risk assessment context and calls for its application in order to improve preventive measures against adverse effects of cadmium exposures in humans and animals.

The association between cumulative cadmium intake and osteoporosis and risk of fracture in a Chinese population.

Bone is one of the target organs for cadmium toxicity. However, few studies have shown the association between cumulative cadmium intake and prevalence of osteoporosis and bone fracture. In the present study, we evaluated the association between cumulative cadmium intake and osteoporosis and risk of fracture in a Chinese population. A total of 790 subjects (488 women and 302 men) living in a control area and two cadmium-polluted areas were included. The cumulative cadmium intake was estimated by a food survey. The bone mineral density was determined by using single-photon absorptiometry. The cumulative cadmium intakes were 0.48, 2.14, and 11.00 g for men, and 0.42, 2.11, and 11.12 g in women in control, and moderately and heavily polluted areas, respectively. In women, the odds ratios (ORs) of subjects with a cadmium intake between 2.21 and 10.63 g and >10.63 g were 1.30 (95% CI: 0.58-2.94) and 2.36 (95% CI: 1.14-5.16), compared with those with a cadmium intake < 0.58 g after adjusting to the confounders for osteoporosis. The ORs of subjects with a cadmium intake >10.63 g were 2.34 (95% CI: 1.23-4.38) for all of the women and 2.62 (95% CI: 1.02-5.58) in women ≥ 60 years old, compared with those with a cadmium intake <10.63 g after adjusting to the confounders for bone fractures. In men, similar trends were observed, but no statistical significance was found. In addition, those subjects with renal tubular dysfunction showed high risk of bone fracture. Our results indicate that a high level of cumulative cadmium intake is associated with an increased rate of osteoporosis and fractures among women.

The association between dietary cadmium exposure and renal dysfunction - the benchmark dose estimation of reference levels: the ChinaCad study.

The tolerable dietary intake of cadmium was recommended at provisional tolerable monthly intake of 25 µg kg-1 body weight. However, several studies indicated that this tolerable level should be re-evaluated for sufficient health protection. In this study, we show the reference levels of dietary cadmium intake for renal dysfunction by using a benchmark dose (BMD) approach. A total of 790 subjects (302 men and 488 women) living in control and cadmium-polluted areas were included. The dietary cadmium intake was estimated by a food survey. Blood cadmium, urinary cadmium and renal function markers (microalbuminuria, N-acetyl-ß-d-glucosaminidase [NAG] and its isoform B [NAGB], ß2 -microglobulin and retinol binding protein) in urine were measured. We calculated the 95% lower confidence bounds of BMD (BMDLs) of cumulative cadmium intake. In control and two polluted areas, the median cumulative cadmium intake was 0.5, 2.1 and 11.1 g. The odds ratio of the intermediate (1.0-3.0 g), second highest (3.0-11.0 g) and the highest cumulative cadmium intake (>11.0 g) compared with the lowest cumulative cadmium intake (<1.0 g) were 2.8 (95% CI: 1.4-5.8), 8.1 (95% CI: 3.8-17.2) and 11.4 (95% CI: 6.5-26.4) for urinary NAG and 6.6 (95% CI: 3.2-13.8), 14.8 (95% CI: 6.8-32.2) and 22.5 (95% CI: 10.7-47.5) for urinary NAGB. The BMDLs of cumulative cadmium intake were 1.1-1.2 g (benchmark response [BMR] = 5%) for urinary NAG, and were 0.7-0.9 g (BMR = 5%) for urinary NAGB, and were 1.3-1.4 g (BMR = 5%) for urinary ß2 -microglobulin. The BMDLs of cumulative cadmium intake in a Chinese population were lower than the critical standard previously reported. Further evaluations are needed for sufficient health protection.

Early life swimming pool exposure and asthma onset in children - a case-control study.

BACKGROUND: Trichloramine exposure in indoor swimming pools has been suggested to cause asthma in children. We aimed to investigate the risk of asthma onset among children in relation to individual trichloramine exposure. METHODS: A longitudinal nested case-control study of 337 children with asthma (cases) and 633 controls aged 16-17 years was performed within a population-based cohort from The Obstructive Lung Disease in Northern Sweden studies (OLIN). Year of asthma onset and exposure time at different ages were obtained in telephone interviews. Trichloramine concentrations in the pool buildings were measured. Skin prick test results for inhalant allergens were available from previous examinations of the cohort. The risk for asthma was analyzed in relation to the cumulative trichloramine exposure before onset of asthma. RESULTS: The participation rate was high in the original cohort (88 to 96%), and in the case-control study (80%). Trichloramine concentrations ranged from 0.020 to 0.55 mg/m3 (mean 0.15 mg/m3). Swimming pool exposure in early life was associated with a significantly higher risk of pre-school asthma onset. A dose-response relationship between swimming pool exposure and asthma was indicated in children with asthma onset at 1 year of age. Children who were both sensitized and exposed had a particularly high risk. CONCLUSIONS: Early life exposure to chlorinated swimming pool environments was associated with pre-school asthma onset.

The Association Between Renal Tubular Dysfunction and Zinc Level in a Chinese Population Environmentally Exposed to Cadmium.

Studies in vivo and in vitro have shown a protective effect of zinc against renal dysfunction caused by cadmium exposure. However, limited human data is available. In this study, we evaluated the association between renal tubular dysfunction and body zinc burden in a Chinese population exposed to cadmium. A total of 331 subjects (170 women and 161 men) living in control and cadmium-polluted area were included. Blood cadmium (BCd), urinary cadmium (UCd), serum zinc (SZn), zinc in hair (HZn), Zn/Cd ratio, and urinary ß2Microglobulin (UBMG) were measured. The median UCd, BCd, SZn, and HZn were 2.8 and 13.6 µg/g cr, 1.3 and 12.2 µg/L, 1.31 and 1.12 mg/L, and 0.14 and 0.12 mg/g in subjects living in control and polluted areas. The UBMG level of subjects living in the polluted area was significantly higher than that of the control (0.27 vs 0.11 mg/g cr, p < 0.01). SZn, HZn, and Zn/Cd ratios were negatively correlated with UBMG (p < 0.05 or 0.01). Subjects with high SZn concentrations (≥ 1.62 mg/L) had reduced risks of elevated UBMG [(odds ratio (OR) = 0.26, 95% confidence interval (CI) 0.07-0.99)] after controlling for multiple covariates compared with those with lower zinc levels. A similar result was observed in subjects with high HZn (OR = 0.09, 95% CI 0.02-0.48). The ORs of the second, third, and fourth quartiles of Zn/Cd ratio were 0.40 (95% CI 0.19-0.84), 0.14 (95% CI 0.06-0.37), and 0.01 (95% CI 0.02-0.18) for renal dysfunction compared with those of the first quartile, respectively. For those subjects with high level of UCd, high level of SZn and HZn also had reduced risks of elevated UBMG. The results of the present study show that high zinc body burden is associated with a decrease risk of renal tubular dysfunction induced by cadmium. Zinc nutritional status should be considered in evaluating cadmium-induced renal damage.

Trace element research-historical and future aspects.

During the last 30 years the International Society for Trace Element Research and the Nordic Trace Element Society has been active . During this period the importance of these elements for human diseases has been increasingly recognized, including their contribution to the global burden of disease. New analytical methods allow biomonitoring data to be related to health outcome. Future research using modern chemical methods will focus more on elemental speciation and on measuring lower concentrations leading to further identifying adverse effects and critical organs. Extensive knowledge about essentiality and toxicity of trace elements in humans has emerged during the last two decades and at present the difficulties in defining a range of acceptable oral intakes for essential elements has largely been overcome. Biological monitoring of trace element concentrations in various media such as blood or urine is of great importance and an overview is given. As an example, a more detailed description of biological monitoring of cadmium is given, explaining biokinetics including the role of metallothionein in modifying kinetics and toxicity. Finally future challenges related to risk assessment of newly developed metallic nanomaterials and metal containing medical devices are discussed.

The effects of nanoparticles on the renal system.

Through a process of translocation across biological barriers, nanoparticles can reach and deposit in secondary target organs where they may induce adverse biological reactions. Therefore, a correct assessment of nanoparticle-induced adverse effects should take into account the different aspects of toxicokinetics and tissues that may be targeted by nanoparticles. For this reason, a comprehensive evaluation of renal nanotoxicity is urgently needed as kidneys are particularly susceptible to xenobiotics and renal excretion is an expected and possible elimination route of nanoparticles in living organisms. On one hand, summarizing the findings of in vitro and in vivo studies that have investigated the adverse effects of nanoparticles on the kidney, this review intends to provide a thorough insight into the nephrotoxicity of these substances. The evaluation of the in vitro studies revealed that different types of nanoparticles (carbon, metal and/or silica nanoparticles) are able to exert significant cytotoxic effects (i.e., decreased cell viability, induction of oxidative stress, mitochondrial or cytoskeleton dysfunction and cell membrane and DNA damage). On the other hand, in vivo studies demonstrated that nanoparticles exhibited an important nephrotoxic potential both at tubular (i.e., degeneration of tubular epithelial cell, cellular fragments and proteinaceous liquid in tubule lumen, renal interstitial fibrosis) and glomerular level (i.e., swollen glomeruli, changes in Bowman's space and proliferation of mesangial cells). Although the data currently available indicate that nanoparticles may adversely impact the renal system, further studies are needed in order to clarify all the potential molecular mechanisms of nephrotoxicity induced by these xenobiotics, in particular at glomerular level.

Swimming pool attendance is related to asthma among atopic school children: a population-based study.

BACKGROUND: By-products of water disinfectants have been suggested to cause asthma, especially in atopic children. However, studies on indoor swimming pool attendance and asthma in children have presented conflicting results. The present study examined the relationship between indoor swimming pool attendance and asthma among sensitized and non-sensitized children aged 11-12 years. METHODS: An extended ISAAC questionnaire was sent to the families of all children attending fifth or sixth grade, aged 11-12 years, in two municipalities in Northern Sweden in 2010. A total of 1866 participated (96% of those invited) in the questionnaire study and 1652 (89%) also participated in skin prick testing for 10 standard airborne allergens. Asthma was defined as physician-diagnosed asthma in combination with wheeze or use of asthma medication in the last 12 months. Current swimming pool attendance was reported as ≥ 1/week or <1/week. Logistic regression models were used for data analysis. RESULTS: The prevalence of current asthma was 8.9% (10.0% of boys; 7.9% of girls) and 14% had attended indoor pools ≥ 1/week. Children currently attending swimming pools ≥ 1/week had an increased risk of current asthma. Stratified analyses for allergic sensitization adjusted for sex, parental smoking, parental asthma, and damp housing, showed a statistically significant association for current asthma only among sensitized subjects (OR 95% CI 1.90 1.09-3.32). No association was found between current pool attendance and wheeze, sensitization, rhinitis or eczema. CONCLUSIONS: The present study supports the proposed link between indoor swimming pool attendance and asthma in sensitized children.

Non-renal effects and the risk assessment of environmental cadmium exposure.

BACKGROUND: Exposure to cadmium (Cd) has long been recognized as a health hazard, both in industry and in general populations with high exposure. Under the currently prevailing health risk assessment, the relationship between urinary Cd (U-Cd) concentrations and tubular proteinuria is used. However, doubts have recently been raised regarding the justification of basing the risk assessment on this relationship at very low exposure. OBJECTIVES: Our objective was to review available information on health effects of Cd exposure with respect to human health risk assessment. DISCUSSION: The associations between U-Cd and urinary proteins at very low exposure may not be due to Cd toxicity, and the clinical significance of slight proteinuria may also be limited. More importantly, other effects have been reported at very low Cd exposure. There is reason to challenge the basis of the existing health risk assessment for Cd. Our review of the literature found that exposure to low concentrations of Cd is associated with effects on bone, including increased risk of osteoporosis and fractures, and that this observation has implications for the health risk assessment of Cd. Other effects associated with Cd should also be considered, in particular cancer, although the information is still too limited for appropriate use in quantitative risk assessment. CONCLUSION: Non-renal effects should be considered critical effects in the health risk assessment of Cd.

Lung function in volunteers before and after exposure to trichloramine in indoor pool environments and asthma in a cohort of pool workers.

OBJECTIVES: Exposure to trichloramine (NCl(3)) in indoor swimming-pool environments is known to cause mucous membrane irritation, but if it gives rise to changes in lung function or asthma in adults is not known. (1) We determined lung function in volunteers before and after exposure to indoor pool environments. (2) We studied the occurrence of respiratory symptoms and asthma in a cohort of pool workers. DESIGN/METHODS/PARTICIPANTS: (1) We studied two groups of volunteers, 37 previously non-exposed healthy persons and 14 pool workers, who performed exercise for 2 h in an indoor pool environment. NCl(3) in air was measured during pool exposures and in 10 other pool environments. Filtered air exposures were used as controls. Lung function and biomarkers of pulmonary epithelial integrity were measured before and after exposure. (2) We mailed a questionnaire to 1741 persons who indicated in the Swedish census 1990 that they worked at indoor swimming-pools. RESULTS: (1) In previously non-exposed volunteers, statistically significant decreases in FEV(1) (forced expiratory volume) and FEV(%) (p=0.01 and 0.05, respectively) were found after exposure to pool air (0.23 mg/m(3) of NCl(3)). In pool workers, a statistically significant decrease in FEV(%) (p=0.003) was seen (but no significant change of FEV(1))(.) In the 10 other pool environments the median NCl(3) concentration was 0.18 mg/m(3). (2) Our nested case/control study in pool workers found an OR for asthma of 2.31 (95% CI 0.79 to 6.74) among those with the highest exposure. Exposure-related acute mucous membrane and respiratory symptoms were also found. CONCLUSIONS: This is the first study in adults showing statistically significant decreases in lung function after exposure to NCl(3). An increased OR for asthma among highly exposed pool workers did not reach statistical significance, but the combined evidence supports the notion that current workroom exposures may contribute to asthma development. Further research on sensitive groups is warranted.

Kidney dysfunction and cadmium exposure--factors influencing dose-response relationships.

Our early toxicological studies showed that metallothionein (MT) is a protein that carries cadmium (Cd) to the kidney, explaining why Cd exposures during long time periods may give rise to kidney dysfunction. This dysfunction is usually considered to be the critical effect, i.e. the adverse effect that occurs at the lowest exposure level. MT also provides intracellular protection against cadmium toxicity. In studies of population groups in cadmium contaminated areas in China, we investigated factors that affected the relationship between internal dose of Cd, as indicated by blood Cd (BCd) or urinary Cd (UCd), and the prevalence of kidney dysfunction. We found dose-response relationships between UCd and the prevalence of increased levels of biomarkers of renal tubular dysfunction (urinary beta-2-microglobulin, B2M, or N-acetyl-beta-d-glucosaminidase - NAG) or urinary albumin (UAlb), a biomarker of glomerular kidney dysfunction. Two years after Cd intake from contaminated rice was diminished, renal tubular dysfunction appeared unchanged or aggravated among those with higher UCd; Another 8 years later, i.e. 10 years after Cd intake was decreased, the prevalence of renal tubular dysfunction was still increased but UAlb had returned to normal. Factors that influenced the dose-response relationships were: (1) time after maximum exposure. (2) Concomitant exposure to other nephrotoxic agents such as inorganic arsenic. (3) Cd induced metallothionein mRNA levels in peripheral blood lymphocytes, used as a biomarker of the ability of each person, to synthesize MT. (4) The occurrence of increased levels in blood plasma of autoantibodies against MT. The two last points further support a role in humans of MT as a protective protein against tissue damage from cadmium and gives support to previous ideas developed partly in experimental systems.

Renal function after reduction in cadmium exposure: an 8-year follow-up of residents in cadmium-polluted areas.

BACKGROUND AND OBJECTIVE: Long-term exposure to cadmium (Cd) causes renal dysfunction, but the change in renal function with exposure is unknown. We assessed the evolution of Cd-induced renal effects after a reduction in dietary exposure to Cd in rice. METHODS: Four hundred twelve residents in previously Cd-polluted and nonpolluted areas were examined twice, in 1998 and in 2006. Changes in blood Cd, urinary Cd, and kidney function [N-acetyl-ß-d-glucosaminidase (NAG), ß2-microglobulin, and albumin in urine] were measured. RESULTS: In the most polluted area, mean blood Cd was 8.9 µg/L and 3.3 µg/L in 1998 and in 2006, respectively, and urinary Cd was 11.6 and 9.0 µg/g creatinine. Urinary albumin in 1998 increased with urinary Cd, but no such exposure-response relation appeared for 2006 albumin versus urinary Cd 1998, indicating recovery. Other biomarkers of kidney function were also elevated in 1998. Partial recovery was observed for NAG among women and was suggested for ß2-microglobulin among young individuals. The probability of having ß2-microglobulin levels above the 95th percentile in 2006 was high in those with elevated ß2-microglobulin in 1998 [odds ratio (OR) = 24.8; 95% confidence interval (CI): 11.2, 55.3] compared with albumin (OR = 3.0; 95% CI: 1.2, 7.5) and NAG (OR = 2.6; 95% CI: 1.6, 4.4). CONCLUSIONS: Results suggest that a Cd-mediated increase in urinary albumin excretion is reversible upon substantial reduction of exposure. For markers of tubular effects, we observed a tendency toward improvement but not complete recovery. Data from repeated observations suggest that ß2-microglobulin may be more informative than NAG as an indicator for an individual's future tubular function.

Biomarkers of exposure, effects and susceptibility in humans and their application in studies of interactions among metals in China.

Biomonitoring employs three categories of biomarkers: Biomarkers of exposure, i.e. measurements of metal concentrations in a compartment in the body reflecting external or internal exposure; Biomarkers of effects include early as well as clinical effects. Biomarkers of susceptibility indicate individuals with increased sensitivity of target molecules or metabolism causing increased target dose. The three categories of biomarkers were used in studies of health effects of metal exposures in China. Adverse effects on the kidney tubules with increased levels of the effect biomarkers beta-2-microglobulin in urine (UB2M) and urinary N-acetyl-beta-d-glucosaminidase (UNAG) were found among Cd exposed population groups in China. Among persons exposed to Cd, occupationally or in the general environment, the level of Cd-induced metallothionein mRNA (MTmRNA) in peripheral lymphocytes appeared as a useful indicator of the ability of individuals to synthesize MT. Persons with low MTmRNA levels displayed higher biomarker values of renal tubular damage than persons with high levels of MTmRNA, at comparable levels of urinary Cd. Other studies demonstrated the importance of auto-antibodies against metallothionein in plasma (MTab) in modifying the response to Cd. Persons with high levels of MTab displayed tubular proteinuria at lower levels of urinary Cd than persons with low levels of MTab. Studies in two metal contaminated areas in China demonstrated clear interactions between Cd and inorganic arsenic. Combined exposure, with increased levels of As and Cd in urine, caused considerably higher biomarker values of renal tubular damage, measured as increased urinary levels of B2M or NAG, than each of the exposures alone.

Increased hepatic and decreased urinary metallothionein in rats after cessation of oral cadmium exposure.

We investigated the role of metallothionein (MT) in tissues after cessation of cadmium (Cd) exposure. Wistar rats of both genders were given CdCl(2) in drinking water at daily doses of 0, 2.5, 5.0 or 10.0 mg Cd/kg body-weight for 12 weeks. Half of the animals were then killed; the others were given Cd-free water for the following 16 weeks, i.e. until 28 weeks after start of the experiment (28-week rats). We observed dose-dependent increases in the levels of MT in the tissues of rats 12 weeks after beginning the experiment (12-week rats). After the exposure ceased, levels of MT in the 28-week rats changed in three ways: an increase in the liver, persistence in the kidney cortex and a decrease in the medulla, relative to those levels in their 12-week counterparts. Biomarkers of kidney dysfunction were determined to be urinary MT (UMT) and urinary N-acetyl-beta-D-glucosaminidase (UNAG). After 12 weeks, we observed dose-related statistically significant increases in UMT and UNAG in all of the Cd-exposed groups. A statistically significant decrease for UNAG between the 12- and 28-week rats occurred among males at the lowest Cd dose and for UMT in all of the Cd-exposed groups. The unchanged tissue levels of MT in the kidney cortex suggest that decreased UMT is a sign either of (i) decreased transport of Cd-MT from the liver via blood plasma to the renal tubules or (ii) increased tubular reabsorption and recovery of renal tubular function.

Prevalence of kidney dysfunction in humans - relationship to cadmium dose, metallothionein, immunological and metabolic factors.

Long term cadmium (Cd) exposure in occupational and general environments may give rise to kidney dysfunction. This effect is usually considered to be the critical effect, i. e. the effect that occurs at relatively low level of exposure. The present review focused on studies of the prevalence of cadmium-related kidney dysfunction among population groups residing in cadmium contaminated areas in China. Dose-response relationships were shown between UCd and the prevalence of increased levels of biomarkers in urine of renal tubular dysfunction such as urinary beta-2-microglobulin or N-acetyl-beta-d-glucosaminidase - NAG or urinary albumin, a biomarker of glomerular kidney dysfunction. Factors that influence these dose-response relationships include: 1) Metallothionein mRNA levels in peripheral blood lymphocytes, used as a biomarker of the ability of each person, to synthesize metallothionein (a protein known to provide intracellular protection against cadmium toxicity). 2) The occurrence of increased levels in blood plasma of autoantibodies against metallothionein. 3) Concomitant changes in glucose metabolism i e Type II diabetes. 4) Concomitant exposure to other nephrotoxic agents such as inorganic arsenic. Increased susceptibility in diabetics has been shown also in population groups in Europe. In persons with type II diabetes and increased levels of autoantibodies against metallothionein in blood plasma or in persons with concomitant exposure to environmental inorganic arsenic, indications of Cd-related kidney dysfunction was observed at UCd levels around 1 microg/g creatinine, levels found among "unexposed" population groups in many countries.