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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.

Human exposures to metals, metalloids, and their compounds frequently occur as mixtures, and hence it is important to consider the joint action of these elements in terms of both mechanisms of acti ...

Recommendations aimed at protecting the public from toxicity of essential elements have usually been developed separately from those recommendations aimed at protection from deficiency. Because of ...

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 and10.63 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 intake10.63 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 intake10.63 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 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-β-d-glucosaminidase [NAG] and its isoform B [NAGB], β2 -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 (

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 β2Microglobulin (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

The kinetics and metabolism of cadmium include uptake, absorption, transport, distribution within the body, excretion, and accumulation, as well as binding to proteins in tissues and biological fluids. The data have been derived from experimental studies on animals and human beings, and from studies of populations exposed to different levels of cadmium. The fate of the cadmium absorbed into the body is largely determined by the transport and metabolism of the protein. The distribution of cadmium varies depending on length of exposure, route, and dose. The liver and the kidneys have attracted most interest as storage tissue for cadmium. Cadmium accumulates in a number of organs of humans with “normal” exposure via food. The apparent half-time in a tissue as measured from accumulation curves in normally exposed people will be longer than the “true” half-times, because of the influx of cadmium via blood from the other tissues.

This book contains the following chapters: Introduction. Principles and Problems of Cadmium Analysis. Uses, Occurrence, and Intake. Metallothionein. Normal Values for Cadmium in Human Tissue, Blood, and Urine in Different Countries. Kinetics and Metabolism. Kinetic Model of Cadmium Metabolism.

Metallic elements constitute a large proportion of all existing elements. They are intrinsic components of the earth's crust and the environment, thus causing variable exposures of humans. Metallic macroelements occurring in high concentrations in human tissues play a key role in the practice of clinical medicine and are not included in the present book, which focuses in trace metals/metalloids, i.e., those metallic elements that occur in trace concentrations in human tissues. These metals are also those that have widespread use in various industrial processes and consumer products and such anthropogenic processes have increased human exposures. Many metallic chemical species such as inorganic and organic compounds of lead and mercury as well as inorganic compounds of arsenic and cadmium are recognized as toxic agents causing acute and chronic poisoning at high exposures. Epidemiological studies in recent decades have demonstrated that relatively low exposures in the general environment increase the occurrence of several diseases. The total worldwide exposure to metallic species makes an important contribution to the global burden of disease. This book deals with the risk and hazard assessment of human exposures to these metallic species. Such assessments are crucial in order to estimate the likelihood that existing exposures cause human disease or other adverse effects and for judging the need for societal action to reduce exposures. Some trace metals are essential for human life and well-being, and a minimum daily intake from food is required. For population groups with lower intakes, deficiency will result in disease states, also contributing to the global burden of disease. There is an obvious need to define exposures leading to toxicity or deficiency and to recommend preventive action. This chapter discusses, in an introductory way, historical developments in the field as well as current methods and exposure situations of importance for estimation of hazards and risks related to human metal exposures. It further draws attention to issues of current concern for hazard assessment, risk assessment, and prevention. The subsequent chapters of this book further develop these considerations.

Dose–effect and dose–response assessments are important to the overall risk assessment process by providing a quantitative estimation of the relationship between dose/exposure and the occurrence of adverse effects from human exposure to metallic species. This chapter defines the concepts of dose–effect and dose–response relationships, discusses the importance of identifying the critical effect and estimates the critical concentration for toxicity in the critical organ. It further describes how to use these concepts in quantitation of the overall relationship between external exposure, internal exposure/dose, and the likelihood of occurrence of adverse effects in groups or populations. This chapter gives definitions of the no-observed-adverse-effect level, benchmark dose, and its lower confidence limit, which are important concepts in risk assessment. It further describes various approaches to estimate a low (acceptable) risk to humans, based on experimental and epidemiological data. The chapter gives special emphasis on quantitative estimation of dose–response relationships based on the mechanism of action and toxicokinetic and toxicodynamic modeling and describes results of such modeling in terms of dose–response curves. It includes discussions of the use of adverse outcome pathways.

Applied risk assessment is a broad category, which covers the translation of exposure and toxicological data into risk assessments and applies this information into prevention and management or regulatory action. The term risk assessment usually implies consideration of quantitative information about dose–response relationships. When there is only qualitative or semiquantitative information about dose–response, the term hazard assessment is sometimes used. Risk and hazard assessment include a number of subcategories important for public health, discussed in this chapter. Among these are various types of risks, including critical and noncritical effects, threshold and nonthreshold effects, and severity of effects such as lethal versus nonlethal effects. In addition, the issue of sensitive subpopulations at special risk for adverse health outcomes is discussed in relation to appropriate risk assessment approaches. The central importance of high-quality exposure assessments in the development of dose–response relationship calculations is considered in the development of credible risk management regulations and practices in addressing the perceived risks. One section gives a summary of hazard assessment according to the Registration, Evaluation, Authorization and Restriction of Chemicals and the management in terms of classifying chemical substances in relation to concern from identified hazard. The value of effective risk communication to the populations impacted by any risk-based intervention is considered in relation to ethical issues and prevention of adverse effects in exposed populations.

This chapter not only describes the main routes of human exposure to metals and metallic compounds in drinking water, food, and ambient and workroom air but also exposure of the skin and internal exposures from metals in medical devices. Interesting scientific developments in recent years have contributed to our understanding of uptake mechanism. The disposition of nanoparticles in the lung is now an area of considerable interest and the subject of current research efforts. This chapter gives special attention to the processes of deposition, clearance, and absorption of inhaled gases and airborne particles in the respiratory tract. Our understanding has increased in recent years of deposition and absorption mechanisms in the gastrointestinal tract, which are also included in this chapter. Specific carriers and ion channels intended for endogenous substances and essential elements play a role in the transfer also of nonessential metals and metallic compounds through cell membranes and are important for uptake in body organs. This chapter considers available knowledge on the uptake, transport, and excretion of metallic nanoparticles. Fecal excretion of several metals occurs after enterohepatic circulation, i.e., the initial uptake and excretion through the liver and bile and the partial secondary uptake in the intestine, with a proportion excreted in feces. The roles of intestinal microflora in methylating/demethylating metallic compounds are increasingly recognized. For methylmercury, such processes are important for excretion of generated inorganic mercury in feces. Accumulation of metals in the kidney and urinary excretion depends on protein binding of metals in blood plasma. The best example is the binding of cadmium to the small sulfur-rich protein metallothionein. A quantitative description of the total body turnover of metals is possible by toxicokinetic models. Such models are often helpful in developing calculations of predicted dose–response relationships. Other chapters deal with these uses of the models.

Hazard identification is a central part in the process of evaluating the safety of a metallic or any other chemical compound. Such identification evaluates the totality of information about chemical and toxicological properties. It is important to consider different metal compounds (species) separately when evaluating metabolism, toxicokinetics, and effects. The basis for classifying toxicological properties are adverse effects observed in humans, in animals, in in vitro systems, and as modeled by computational tools. Information about chemical and toxicological properties allows the classification of substances as persistent, bioaccumulative, toxic, corrosive or irritating to the skin or mucous membranes of the respiratory or gastrointestinal tract; sensitizing to the skin or respiratory tract; toxic to reproduction and development; and mutagenic or carcinogenic. The hazard identification process characterizes the weight of evidence for causation of specific adverse effects as sufficient, limited, or insufficient. Concerning induction of effects in humans, human data are of great importance and data from animals or in vitro systems are also valuable. The mechanism of action or the mode of action, when known, provides additional support. Sometimes it is possible to describe an adverse outcome pathway. Based on all available information, a systematic analysis leads to a grading of the weight of evidence supporting that the chemical compound causes the adverse effect under consideration. Human exposures known or predicted to occur form the basis for the assessments. It is important to follow applicable ethical and legal rules when performing studies involving human subjects or animals.

Risk and hazard assessments are crucial in order to estimate the likelihood of human disease or other adverse health effects resulting from existing human exposures to metals and their compounds on an individual or mixture basis. External exposures produce internal doses that produce the toxic dose at the site of action, named the target dose. The target organ that suffers toxicity at the lowest external exposure level is the critical organ and the adverse effect that occurs at the lowest external exposure is the critical effect . This effect is critical because it is crucial for preventive action (for definitions of concepts, see Appendix ). It is thus important to try to estimate the target dose as accurately as possible. Unfortunately, it is seldom possible to measure this dose in living humans or animals. The concentration of the toxic metal species in the critical organ may be measured or estimated and is often a useful surrogate for the target dose. Biological monitoring (synonym: biomonitoring), for example, measurements of concentrations of metal compounds in tissues, blood, or urine, is often used as a basis for estimating target dose/concentration in critical organ. Toxicodynamics describes the mechanism or mode of action of toxicants, how they can cause tissue damage, and under what conditions in terms of tissue concentrations and time of tissue exposure/dose do adverse effects on tissue structure and function occur. When these conditions can be described in quantitative terms and when, in addition, a toxicokinetic model can be described, a quantitative toxicokinetic-toxicodynamic (TKTD) dose–response model can be set up and be used to predict relationships between exposure dose and the expected frequency of adverse health effects. A TKTD model may constitute a major part of an adverse outcome (AO) pathway describing the linking between a molecular initiating event and AO at the biological level of organization.

There is general recognition that a number of trace metals are essential for human health. For these essential trace metals (ETMs), there is a need for recommendations aimed at protection from deficiency at low dietary intakes and protection from toxicity at high intakes. Uncertainties in the evaluations forming the basis for the recommendations have in the past led to conflicting recommendations for some population subgroups. This chapter describes principles of evaluation using a balanced approach and applying methods to achieve adequate evaluations of information on adverse effects of deficiency as well as toxicity. Application of these principles intends to make it possible to define an acceptable range of oral intakes (AROIs). When intakes are in this range a great majority of the general population will suffer no adverse effects from deficiency or toxicity. The principles include the U-formed dose–response curve and the recognition that the AROI protects only approximately 95% of the general population. Persons with genetically determined special sensitivity may have needs for higher or lower intakes than those defined by the AROI. This chapter also deals with the joint action of ETMs, other metals, and some other nonmetallic food components. It summarizes a few gene–environment interactions for metal-related health effects and points out the potential importance of this relatively new research field. The chapter finally summarizes methods for evaluation of exposure to mixtures.

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 tolerable dietary intake of cadmium was recommended at provisional tolerable monthly intake of 25 μg kg

Chemistry and Human Health, Division VII of the International Union on Pure and Applied Chemistry (IUPAC), provides guidance on risk assessment methodology and, as appropriate, assessment of risks to human health from chemicals of exceptional toxicity. The aim of this document is to describe dose-response relationships for the health effects of low-level exposure to cadmium, in particular, with an emphasis on causation. The term “cadmium” in this document includes all chemical species of cadmium, as well as those in cadmium compounds. Diet is the main source of cadmium exposure in the general population. Smokers and workers in cadmium industries have additional exposure. Adverse effects have been shown in populations with high industrial or environmental exposures. Epidemiological studies in general populations have also reported statistically significant associations with a number of adverse health effects at low exposures. Cadmium is recognized as a human carcinogen, a classification mainly based on occupational studies of lung cancer. Other cancers have been reported, but dose-response relationships cannot be defined. Cardiovascular disease has been associated with cadmium exposure in recent epidemiological studies, but more evidence is needed in order to establish causality. Adequate evidence of dose-response relationships is available for kidney effects. There is a relationship between cadmium exposure and kidney effects in terms of low molecular mass (LMM) proteinuria. Long-term cadmium exposures with urine cadmium of 2 nmol mmol−1creatinine cause such effects in a susceptible part of the population. Higher exposures result in increases in the size of these effects. This assessment is supported by toxicokinetic and toxicodynamic (TKTD) modelling. Associations between urine cadmium lower than 2 nmol mmol−1creatinine and LMM proteinuria are influenced by confounding by co-excretion of cadmium with protein. A number of epidemiological studies, including some on low exposures, have reported statistically significant associations between cadmium exposure and bone demineralization and fracture risk. Exposures leading to urine cadmium of 5 nmol mmol−1creatinine and more increase the risk of bone effects. Similar associations at much lower urine cadmium levels have been reported. However, complexities in the cause and effect relationship mean that a no-effect level cannot be defined. LMM proteinuria was selected as the critical effect for cadmium, thus identifying the kidney cortex as the critical organ, although bone effects may occur at exposure levels similar to those giving rise to kidney effects. To avoid these effects, population exposures should not exceed that resulting in cadmium values in urine of more than 2 nmol mmol−1creatinine. As cadmium is carcinogenic, a ‘safe’ exposure level cannot be defined. We therefore recommend that cadmium exposures be kept as low as possible. Because the safety margin for toxic effects in kidney and bone is small, or non-existent, in many populations around the world, there is a need to reduce cadmium pollution globally.

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. Electronic supplementary material The online version of this article (10.1186/s12940-018-0383-0) contains supplementary material, which is available to authorized users.

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. Citation: Åkesson A, Barregard L, Bergdahl IA, Nordberg GF, Nordberg M, Skerfving S. 2014. Non-renal effects and the risk assessment of environmental cadmium exposure. Environ Health Perspect 122:431–438; http://dx.doi.org/10.1289/ehp.1307110

Introduction Swimming pool exposure has been suggested to cause asthma and other health effects in children by exposure to trichloramines. Aim To study the prevalence of asthma symptoms and time spent in indoor swimming pools among children. Methods A nested case-control study of 337 children with asthma and 663 controls aged 16-17 years within a longitudinal pediatric cohort from The Obstructive Lung Disease in Northern Sweden studies (OLIN). Prevalence of symptoms and exposure time at different ages were obtained by a phone interview. Skin prick testing for inhalant allergens was available from a previous examination of the cohort. Results The participation rate was high both in the original cohort (96%) and in the case-control study (80%) and the participants in the case-control study were representative. Children with asthma reported significantly more irritative eye symptoms, 22%, compared to controls (9.0%) and 5.5% of the children with asthma reported worsened asthma symptoms at indoor pools, while 1.5% had stopped attending indoor swimming pools because of asthma. All children with worsened asthma symptoms in indoor swimming pools were sensitized to at least one inhalant allergen. There was no consistent difference in the time spent in indoor swimming pools between cases and controls. Conclusion All children with worsened asthma symptoms in indoor swimming pools were sensitized to at least one inhalant allergen. There was no consistent difference in the time spent in indoor swimming pools between cases and controls.

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.

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.

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-β-d-glucosaminidase (NAG), β2-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 β2-microglobulin among young individuals. The probability of having β2-microglobulin levels above the 95th percentile in 2006 was high in those with elevated β2-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 β2-microglobulin may be more informative than NAG as an indicator for an individual’s future tubular function.

Sir,Katarzyna Byber and collaborators from the University of Zurich and the Universite Catholique de Louvain have published a systematic review paper on the association between cadmium exposure and...

The first health effects of cadmium (Cd) were reported already in 1858. Respiratory and gastrointestinal symptoms occurred among persons using Cd-containing polishing agent. The first experimental toxicological studies are from 1919. Bone effects and proteinuria in humans were reported in the 1940's. After World War II, a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan. Subsequently, the toxicokinetics and toxicodynamics of Cd were described including its binding to the protein metallothionein. International warnings of health risks from Cd-pollution were issued in the 1970's. Reproductive and carcinogenic effects were studied at an early stage, but a quantitative assessment of these effects in humans is still subject to considerable uncertainty. The World Health Organization in its International Program on Chemical Safety, WHO/IPCS (1992) (Cadmium. Environmental Health Criteria Document 134, IPCS. WHO, Geneva, 1-280.) identified renal dysfunction as the critical effect and a crude quantitative evaluation was presented. In the 1990's and 2000 several epidemiological studies have reported adverse health effects, sometimes at low environmental exposures to Cd, in population groups in Japan, China, Europe and USA (reviewed in other contributions to the present volume). The early identification of an important role of metallothionein in cadmium toxicology formed the basis for recent studies using biomarkers of susceptibility to development of Cd-related renal dysfunction such as gene expression of metallothionein in peripheral lymphocytes and autoantibodies against metallothionein in blood plasma. Findings in these studies indicate that very low exposure levels to cadmium may give rise to renal dysfunction among sensitive subgroups of human populations such as persons with diabetes.

In summary lower selenium concentrations were found in the lung cancer group compared to other smelter workers and controls. The two lowest selenium values in the total material were found in two of the lung cancer workers. This is in agreement with earlier reports of lower blood selenium levels in cancer patients (Willett et al 1983, Salonen et al 1984). An increased cancer incidence has also been found in geographical areas with low selenium contents in forage crops (Shamberger et al 1976). Numerous animal experiments have demonstrated an anticarcinogenic effect of selenium. Our conclusion is that selenium might have a protective effect in occupational exposure against at least certain carcinogens causing lung cancer. Looking at the dominant worksites the workers have obviously been exposed to different concentrations of selenium over the years. As selenium has not been particularly under observation, few dust analyses are available, and so the dust load in exposed workers cannot be directly calculated. The excretion rates show individual differences. In three of the seven lung cancer cases we noted that, despite a considerable and continuous exposure to selenium in the course of their work, they had low selenium concentrations in their lung tissue at the time of death. Two other workers in the lung cancer group had also been working at worksites with considerable exposure to selenium. Raised cadmium levels were noted in the lung cancer group.(ABSTRACT TRUNCATED AT 250 WORDS)

Epithelial cells from the kidney were freshly isolated from rats pretreated by daily subcutaneous doses of CdCl2 in vivo (0.5-2 mg Cd/kg X 5). Such cells were incubated in vitro in media with different concentrations of cadmium chloride (0-200 micrograms Cd/ml). There was no inhibition of cell growth in such cells. However, in cells isolated from non-treated rats, in vitro exposure to the same concentrations of CdCl2 caused a dose dependent decrease in viability. When cells, isolated from non-treated rats were pretreated in vitro with CdCl2 (10 micrograms/ml) and subsequently exposed to cadmium chloride (0-200 micrograms/ml), a protective effect was observed, which was similar to the one observed in cells isolated from animals pretreated with CdCl2. The concentration of metallothionein in the cells treated with cadmium was increased. A lower uptake of cadmium chloride, in vitro has been observed in kidney cells pretreated in vivo or in vitro compared to nonpretreated cells. Subcellular distribution studies indicate that Cd-distribution was similar in pretreated and non-pretreated cells, but concentrations were generally lower in the pretreated cells. The decreased uptake of Cd by pretreated kidney cells is a sign of Cd-interference with cellular function. These changes are suggested as a contributing mechanism to the prevention of acute toxic effects of cadmium on the kidney.