Gunnar F. Nordberg

Biological monitoring of toxic metals

The biological monitoring of metals, when used properly, allows total exposure to a particular metal to be measured from various media. It takes into consideration inter- and intraindividual variations in uptake due to differences in metabolism and physical work load and can be used to identify individuals, or groups of individuals, with high exposure or at high risk. As many metals are retained for long periods, biological monitoring may not only provide information on recent exposure, but also on exposure which occurred a long time ago. Under optimal conditions, the concentration of a metal in biological media can be used to assess exposure, the concentration of the metal in the target or critical organ (ie, the organ where the adverse effects are first observed) and the risks for adverse effects. This paper gives an overview of several important aspects of biological monitoring but does not provide detailed information on particular metals.

Historical perspectives on cadmium toxicology.

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 1940s. 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 1970s. 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 1990s 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.

A kinetic model of cadmium metabolism in the human being

Abstract An eight-compartment kinetic model for the metabolism of cadmium was formulated based on animal and human tissue distribution data. The flow of cadmium between the compartments was generally assumed to follow first-order exponential functions. The 21 distribution coefficients were estimated by fitting the calculated cadmium concentrations in kidney, liver, urine, blood, and other tissues to the observed concentrations for Swedes with different smoking habits and with and without occupational cadmium exposure. The calculated tissue concentrations for Japanese persons also agreed with observed concentrations. The model was used to calculate the daily cadmium intake necessary to reach critical concentration in kidney cortex. The average renal cortex concentration would reach 200 μg/g at an average daily cadmium intake via food of 440 μg for a European-American population and 325 μg for a Japanese population.

In vivo measurements of lead in bone in long-term exposed lead smelter workers.

In-vivo measurements of lead concentrations in calcaneus (mainly trabecular bone) and tibia (mainly cortical bone) were performed by x-ray fluorescence (XRF) in 70 active and 30 retired lead smelter workers who had long-term exposure to lead. Comparison was made with 31 active and 10 retired truck assembly workers who had no known occupational exposure to lead. After physical examination, all participants provided blood and urine samples and answered a computerized questionnaire. Since 1950, blood lead has been determined repeatedly in lead workers at the smelter, which made it possible to calculate a time-integrated blood lead index for each worker. Lead concentrations in blood, urine, calcaneus, and tibia in active and retired lead workers were significantly higher than in the corresponding control groups (p < .001). The highest bone lead concentrations were found among retired lead workers (p < .001), which was the result of considerably higher lead exposure during 1940 to 1960. Lead concentrations in calcaneus in active lead workers were significantly higher than in tibia when expressed in ug of lead per gram of bone mineral, which suggests a quicker absorption over time in this mainly trabecular bone. The estimated biological half-times were 16 y in calcaneus (95% confidence interval [95% CI] = 11-29 y) and 27 y in tibia (95% CI = 16-98 y). A strong positive correlation was found between lead concentrations in calcaneus and tibia for all lead workers (r = 0.54; p < .001). A strong positive correlation was also found between the bone lead concentrations and the cumulative blood lead index. Blood lead, at the time of study, correlated well with bone lead concentrations in retired--but not in active--workers, reflecting the importance of the endogenous (skeletal) lead exposure. The findings in this study indicate that bone lead measurements by XRF can give a good index of long-term lead exposure. Tibia measurements offer a higher precision than calcaneus measurements. The method is of particular interest in epidemiologic studies of adverse health effects caused by long-term lead exposure.

Influence of Environmental Cadmium Exposure on Forearm Bone Density

Cadmium may have both direct and indirect effects on bone turnover. It is nephrotoxic and can interfere with vitamin D metabolism. Such perturbation may result in osteoporosis and osteomalacia. In this study, a total of 790 persons (302 males and 488 females) participated; they were all over 35 years old and resided in an area near a cadmium smelter in southeast China. All participants completed a questionnaire, and bone mineral density was measured by SPA‐4 single‐photon absorptiometry at the radius and ulna. Cadmium content of urine was determined by graphite‐furnace atomic absorption spectrophotometry as a measure of dose. The decline in bone mineral density with age in a heavily polluted area was greater than that in a control area for subjects over 60 years of age of both sexes (p < 0.05). In single regression, forearm bone densities were negatively correlated with urinary cadmium excretion in both males and females (p < 0.001), whereas stepwise regression showed that forearm bone density decreased linearly with age (p < 0.001) and urinary cadmium (p < 0.01) in both sexes, suggesting a dose‐effect relationship between cadmium dose and bone mineral density. Based on the World Health Organization criteria, (bone mineral density < −2.5 SDs below the normal young adult), the prevalence of osteoporosis in women increased from 34.0% in the control area to 51.9% in the heavily polluted area (p < 0.01) among subjects over 50 years old, and the odds ratio value was 2.09 (95% CI: 1.08–4.03) for the highly polluted area compared with the control area. A striking observation in the study was the marked increase of the prevalence of fracture in the cadmium‐polluted area in both sexes. It was concluded that environmental exposure to cadmium is associated with an increased loss of bone mineral density in both males and females, leading to osteoporosis and increased risk of fractures, especially in the elderly and in females.

Low Bone Density and Renal Dysfunction Following Environmental Cadmium Exposure in China

Abstract This paper presents the main findings of a study on health effects of environmental cadmium pollution in China, performed in 1998, i.e. approximately 25 years after the first warnings of such effects were published in Ambio. Forearm bone mineral density (BMD) and renal dysfunction were assessed in population groups exposed to cadmium via rice. Decreased BMD was found in postmenopausal women with elevated urinary cadmium (CdU) or cadmium in blood (CdB) and among men with elevated CdB. Also, clear and statistically significant dose-effect and dose-response relationships were found between CdB or CdU and renal dysfunction (increased excretion of retinol-binding protein). This is the first report of bone effects among Cd-exposed population groups in Asia outside Japan. The report is also of interest since it demonstrates that bone effects, a comparatively severe adverse health effect of Cd, in combination with renal dysfunction, still occurs in environmentally exposed population groups in Asia. Recent reports on bone effects in Cd-exposed population groups in Europe are discussed.

Cadmium-induced apoptosis and changes in expression of p53, c-jun and MT-I genes in testes and ventral prostate of rats

Apoptosis and a change in the expression of p53, c-jun and MT-I genes occurred in rats exposed to cadmium in a way known to cause carcinogenesis in testes and ventral prostate. In situ end labelling (ISEL), DNA electrophoresis, and RT-PCR methods were used in present study. Adult male Wistar rats were given a single (s.c.) injection of 0, 5, 10, or 20 micromol/kg CdCl2. Then 12, 48 or 96 h after administration of cadmium, animals were sacrificed. It was observed that cadmium markedly induced apoptosis in the testes at the dose of 5 micromol/kg while 10 and 20 micromol/kg cadmium caused more necrosis than apoptosis. Apoptosis in the ventral prostate was markedly induced by all the doses of cadmium and there was an obvious time- and dose-dependent relationship between apoptotic index (AI) and cadmium treatment. Far fewer apoptotic cells appeared in liver, compared to the testes and ventral prostate. p53 mRNA expression was clearly enhanced in the ventral prostate but clearly suppressed in the testes by cadmium exposure, and the time- and dose-effect was very clear. The expression level of p53 in the liver was not affected by cadmium treatment. Cadmium-induced overexpression of c-jun gene appeared at 12 h in the liver, but not until 96 h in the testes and ventral prostate. Although the MT-I gene was found to be expressed in all tissues, marked induction by cadmium of the expression of MT-I gene was only observed in the liver. These results indicate: (1) that apoptosis is an early mechanism of acute tissue damage by cadmium in the testes and ventral prostate; (2) that p53 and c-jun genes may be involved in cadmium-induced cytotoxicity (apoptosis) and related carcinogenicity in male reproductive tissues; and (3) that the enhanced expression of MT-I in the liver could protect this organ from cadmium-induced cytotoxicity (apoptosis) and carcinogenicity.

Distribution of 23 elements in the kidney, liver and lungs of workers from a smeltery and refinery in north Sweden exposed to a number of elements and of a control group

The levels of antimony, arsenic, cadmium, caesium, chromium, cobalt, copper, gold, iron, lanthanum, lead, manganese, mercury, molybdenum, phosphorus, rubidium, scandium, selenium, silver, tellurium, tin, tungsten and zinc in the kidney, liver and lungs of autopsy specimens from exposed workers in North Sweden, as well as from a control group, have been assayed quantitatively. The workers had been exposed to several elements and their compounds, e.g. lead, mercury, arsenic and cadmium, for long periods in arsenic, lead or selenium plants and in a lead or copper smelter. The chemical analysis was by neutron activation analysis and atomic absorption spectrophotometry. Median levels of antimony, arsenic, cadmium, chromium cobalt, lanthanum, lead or selenium in kidney, liver or lungs in the exposed worker group were found to be about 2 to 16 times as great as the corresponding levels for the control group. Long biological half-life values were observed for these elements, especially in lung tissue.

The Uptake of Mercury in the Brains of Mammals Exposed to Mercury Vapor and to Mercuric Salts

Rats, rabbits, and monkeys were exposed to mercury vapor (1 mg/cu m) for four hours, and uptake and distribution of mercury in the brain was compared with that of animals injected intravenously with the same dose of mercury as mercuric salts. Vapor-exposed animals showed a brain content about ten times higher than the injected animals. The results indicate that the higher uptake in brain following vapor exposure is a general phenomenon in mammals.

Pulmonary Epithelial Integrity in Children: Relationship to Ambient Ozone Exposure and Swimming Pool Attendance

Airway irritants such as ozone are known to impair lung function and induce airway inflammation. Clara cell protein (CC16) is a small anti-inflammatory protein secreted by the nonciliated bronchiolar Clara cells. CC16 in serum has been proposed as a noninvasive and sensitive marker of lung epithelial injury. In this study, we used lung function and serum CC16 concentration to examine the pulmonary responses to ambient O3 exposure and swimming pool attendance. The measurements were made on 57 children 10–11 years of age before and after outdoor exercise for 2 hr. Individual O3 exposure was estimated as the total exposure dose between 0700 hr until the second blood sample was obtained (mean O3 concentration/m3 × hours). The maximal 1-hr value was 118 μg/m3 (59 ppb), and the individual exposure dose ranged between 352 and 914 μg/m3hr. These O3 levels did not cause any significant changes in mean serum CC16 concentrations before or after outdoor exercise, nor was any decrease in lung function detected. However, children who regularly visited chlorinated indoor swimming pools had significantly lower CC16 levels in serum than did nonswimming children both before and after exercise (respectively, 57 ± 2.4 and 53 ± 1.7 μg/L vs. 8.2 ± 2.8 and 8.0 ± 2.6 μg/L; p < 0.002). These results indicate that repeated exposure to chlorination by-products in the air of indoor swimming pools has adverse effects on the Clara cell function in children. A possible relation between such damage to Clara cells and pulmonary morbidity (e.g., asthma) should be further investigated.