Article in British Medical Bulletin 68:167-182 (2003) by Lars Järup, Department of Epidemiology and Public Health, Imperial College, London, UK.
Abstract
The main threats to human health from heavy metals are associated with exposure to lead, cadmium, mercury and arsenic. These metals have been extensively studied and their effects on human health regularly reviewed by international bodies such as the WHO. Heavy metals have been used by humans for thousands of years. Although several adverse health effects of heavy metals have been known for a long time, exposure to heavy metals continues, and is even increasing in some parts of the world, in particular in less developed countries, though emissions have declined in most developed countries over the last 100 years. Cadmium compounds are currently mainly used in re-chargeable nickel-cadmium batteries. Cadmium emissions have increased dramatically during the 20th century, one reason being that cadmium-containing products are rarely re-cycled, but often dumped together with household waste. Cigarette smoking is a major source of cadmium exposure. In non-smokers, food is the most important source of cadmium exposure. Recent data indicate that adverse health effects of cadmium exposure may occur at lower exposure levels than previously anticipated, primarily in the form of kidney damage but possibly also bone effects and fractures. Many individuals in Europe already exceed these exposure levels and the margin is very narrow for large groups. Therefore, measures should be taken to reduce cadmium exposure in the general population in order to minimize the risk of adverse health effects. … The general population is exposed to lead from air and food in roughly equal proportions. During the last century, lead emissions to ambient air have caused considerable pollution, mainly due to lead emissions from petrol. Children are particularly susceptible to lead exposure due to high gastrointestinal uptake and the permeable blood-brain barrier. Blood levels in children should be reduced below the levels so far considered acceptable, recent data indicating that there may be neurotoxic effects of lead at lower levels of exposure than previously anticipated. Although lead in petrol has dramatically decreased over the last decades, thereby reducing environmental exposure, phasing out any remaining uses of lead additives in motor fuels should be encouraged. The use of lead-based paints should be abandoned, and lead should not be used in food containers. In particular, the public should be aware of glazed food containers, which may leach lead into food. Exposure to arsenic is mainly via intake of food and drinking water, food being the most important source in most populations. Long-term exposure to arsenic in drinking-water is mainly related to increased risks of skin cancer, but also some other cancers, as well as other skin lesions such as hyperkeratosis and pigmentation changes. Occupational exposure to arsenic, primarily by inhalation, is causally associated with lung cancer. Clear exposure-response relationships and high risks have been observed.
Extracts
Although there is no clear definition of what a heavy metal is, density is in most cases taken to be the defining factor. Heavy metals are thus commonly defined as those having a specific density of more than 5 g/cm3. The main threats to human health from heavy metals are associated with exposure to lead, cadmium, mercury and arsenic (arsenic is a metalloid, but is usually classified as a heavy metal). ...
Emissions of heavy metals to the environment occur via a wide range of processes and pathways, including to the air (e.g. during combustion, extraction and processing), to surface waters (via runoff and releases from storage and transport) and to the soil (and hence into groundwaters and crops) (see Chapter 1). Atmospheric emissions tend to be of greatest concern in terms of human health, both because of the quantities involved and the widespread dispersion and potential for exposure that often ensues. The spatial distributions of cadmium, lead and mercury emissions to the atmosphere in Europe can be found in the Meteorological Synthesizing Centre-East (MSC-E) website (http://www.msceast.org/hms/emission.html#Spatial). Lead emissions are mainly related to road transport and thus most uniformly distributed over space. Cadmium emissions are primarily associated with non-ferrous metallurgy and fuel combustion, whereas the spatial distribution of anthropogenic mercury emissions reflects mainly the level of coal consumption in different regions.
People may be exposed to potentially harmful chemical, physical and biological agents in air, food, water or soil. However, exposure does not result only from the presence of a harmful agent in the environment. The key word in the definition of exposure is contact2. There must be contact between the agent and the outer boundary of the human body, such as the airways, the skin or the mouth. Exposure is often defined as a function of concentration and time: "an event that occurs when there is contact at a boundary between a human and the environment with a contaminant of a specific concentration for an interval of time"3. For exposure to happen, therefore, co-existence of heavy metals and people has to occur (see Chapter 1).
Cadmium
... Health effects
Inhalation of cadmium fumes or particles can be life threatening, and although acute pulmonary effects and deaths are uncommon, sporadic cases still occur9,10. Cadmium exposure may cause kidney damage. The first sign of the renal lesion is usually a tubular dysfunction, evidenced by an increased excretion of low molecular weight proteins [such as ß2-microglobulin and {alpha}1-microglobulin (protein HC)] or enzymes [such as N-Acetyl-ß-D-glucosaminidase (NAG)]4,6. It has been suggested that the tubular damage is reversible11, but there is overwhelming evidence that the cadmium induced tubular damage is indeed irreversible4.
WHO6 estimated that a urinary excretion of 10 nmol/mmol creatinine (corresponding to circa 200 mg Cd/kg kidney cortex) would constitute a 'critical limit' below which kidney damage would not occur. However, WHO calculated that circa 10% of individuals with this kidney concentration would be affected by tubular damage. Several reports have since shown that kidney damage and/or bone effects are likely to occur at lower kidney cadmium levels. European studies have shown signs of cadmium induced kidney damage in the general population at urinary cadmium levels around 2-3 µg Cd/g creatinine12,13.
The initial tubular damage may progress to more severe kidney damage, and already in 1950 it was reported that some cadmium exposed workers had developed decreased glomerular filtration rate (GFR)14. This has been confirmed in later studies of occupationally exposed workers15,16. An excess risk of kidney stones, possibly related to an increased excretion of calcium in urine following the tubular damage, has been shown in several studies4.
Recently, an association between cadmium exposure and chronic renal failure [end stage renal disease (ESRD)] was shown17. Using a registry of patients, who had been treated for uraemia, the investigators found a double risk of ESRD in persons living close to (<2>Cancer
The IARC has classified cadmium as a human carcinogen (group I) on the basis of sufficient evidence in both humans and experimental animals22. IARC, however, noted that the assessment was based on few studies of lung cancer in occupationally exposed populations, often with imperfect exposure data, and without the capability to consider possible confounding by smoking and other associated exposures (such as nickel and arsenic). Cadmium has been associated with prostate cancer, but both positive and negative studies have been published. Early data indicated an association between cadmium exposure and kidney cancer23. Later studies have not been able clearly to confirm this, but a large multi-centre study showed a (borderline) significant over-all excess risk of renal-cell cancer, although a negative dose-response relationship did not support a causal relation24. Furthermore, a population-based multicentre-study of renal cell carcinoma found an excess risk in occupationally exposed persons25. In summary, the evidence for cadmium as a human carcinogen is rather weak, in particular after oral exposure. Therefore, a classification of cadmium as 'probably carcinogenic to humans' (IARC group 2A) would be more appropriate. This conclusion also complies with the EC classification of some cadmium compounds (Carcinogen Category 2; Annex 1 to the directive 67/548/EEC).
Lead
... Occupational exposure to inorganic lead occurs in mines and smelters as well as welding of lead painted metal, and in battery plants. Low or moderate exposure may take place in the glass industry. High levels of air emissions may pollute areas near lead mines and smelters. Airborne lead can be deposited on soil and water, thus reaching humans via the food chain.
Up to 50% of inhaled inorganic lead may be absorbed in the lungs. Adults take up 10-15% of lead in food, whereas children may absorb up to 50% via the gastrointestinal tract. Lead in blood is bound to erythrocytes, and elimination is slow and principally via urine. Lead is accumulated in the skeleton, and is only slowly released from this body compartment. Half-life of lead in blood is about 1 month and in the skeleton 20-30 years35.
In adults, inorganic lead does not penetrate the blood-brain barrier, whereas this barrier is less developed in children. The high gastrointestinal uptake and the permeable blood-brain barrier make children especially susceptible to lead exposure and subsequent brain damage. Organic lead compounds penetrate body and cell membranes. Tetramethyl lead and tetraethyl lead penetrate the skin easily. These compounds may also cross the blood-brain barrier in adults, and thus adults may suffer from lead encephalopathy related to acute poisoning by organic lead compounds.
... Health effects
The symptoms of acute lead poisoning are headache, irritability, abdominal pain and various symptoms related to the nervous system. Lead encephalopathy is characterized by sleeplessness and restlessness. Children may be affected by behavioural disturbances, learning and concentration difficulties. In severe cases of lead encephalopathy, the affected person may suffer from acute psychosis, confusion and reduced consciousness. People who have been exposed to lead for a long time may suffer from memory deterioration, prolonged reaction time and reduced ability to understand. Individuals with average blood lead levels under 3 µmol/l may show signs of peripheral nerve symptoms with reduced nerve conduction velocity and reduced dermal sensibility. If the neuropathy is severe the lesion may be permanent. The classical picture includes a dark blue lead sulphide line at the gingival margin. In less serious cases, the most obvious sign of lead poisoning is disturbance of haemoglobin synthesis, and long-term lead exposure may lead to anaemia.
Recent research has shown that long-term low-level lead exposure in children may also lead to diminished intellectual capacity. Figure 3 shows a meta-analysis of four prospective studies using mean blood lead level over a number of years. The combined evidence suggests a weighted mean decrease in IQ of 2 points for a 0.48 µmol/l (10 µg/dl) increase in blood lead level (95% confidence interval from -0.3 points to -3.6 points)35.
Acute exposure to lead is known to cause proximal renal tubular damage35. Long-term lead exposure may also give rise to kidney damage and, in a recent study of Egyptian policemen, urinary excretion of NAG was positively correlated with duration of exposure to lead from automobile exhaust, blood lead and nail lead36. Despite intensive efforts to define the relationship between body burden of lead and blood pressure or other effects on the cardiovascular system, no causal relationship has been demonstrated in humans35. …
Blood lead levels in children below 10 µmg/dl have so far been considered acceptable, but recent data indicate that there may be toxicological effects of lead at lower levels of exposure than previously anticipated. There is also evidence that certain genetic and environmental factors can increase the detrimental effects of lead on neural development, thereby rendering certain children more vulnerable to lead neurotoxicity38.
IARC classified lead as a 'possible human carcinogen' based on sufficient animal data and insufficient human data in 1987. Since then a few studies have been published, the overall evidence for lead as a carcinogen being only weak, the most likely candidates are lung cancer, stomach cancer and gliomas39.
Arsenic
... Smelting of non-ferrous metals and the production of energy from fossil fuel are the two major industrial processes that lead to arsenic contamination of air, water and soil, smelting activities being the largest single anthropogenic source of atmospheric pollution41.
... Contaminated soils such as mine-tailings are also a potential source of arsenic exposure40.
... Absorption of arsenic in inhaled airborne particles is highly dependent on the solubility and the size of particles. Soluble arsenic compounds are easily absorbed from the gastrointestinal tract. However, inorganic arsenic is extensively methylated in humans and the metabolites are excreted in the urine40.
Arsenic (or metabolites) concentrations in blood, hair, nails and urine have been used as biomarkers of exposure. Arsenic in hair and nails can be useful indicators of past arsenic exposure, if care is taken to avoid external arsenic contamination of the samples. Speciated metabolites in urine expressed as either inorganic arsenic or the sum of metabolites (inorganic arsenic + MMA + DMA) is generally the best estimate of recent arsenic dose. However, consumption of certain seafood may confound estimation of inorganic arsenic exposure, and should thus be avoided before urine sampling40.
Health effects
Inorganic arsenic is acutely toxic and intake of large quantities leads to gastrointestinal symptoms, severe disturbances of the cardiovascular and central nervous systems, and eventually death. In survivors, bone marrow depression, haemolysis, hepatomegaly, melanosis, polyneuropathy and encephalopathy may be observed. Ingestion of inorganic arsenic may induce peripheral vascular disease, which in its extreme form leads to gangrenous changes (black foot disease, only reported in Taiwan).
Populations exposed to arsenic via drinking water show excess risk of mortality from lung, bladder and kidney cancer, the risk increasing with increasing exposure. There is also an increased risk of skin cancer and other skin lesions, such as hyperkeratosis and pigmentation changes.
Studies on various populations exposed to arsenic by inhalation, such as smelter workers, pesticide manufacturers and miners in many different countries consistently demonstrate an excess lung cancer. Although all these groups are exposed to other chemicals in addition to arsenic, there is no other common factor that could explain the findings. The lung cancer risk increases with increasing arsenic exposure in all relevant studies, and confounding by smoking does not explain the findings.
The latest WHO evaluation40 concludes that arsenic exposure via drinking water is causally related to cancer in the lungs, kidney, bladder and skin, the last of which is preceded by directly observable precancerous lesions. Uncertainties in the estimation of past exposures are important when assessing the exposure-response relationships, but it would seem that drinking water arsenic concentrations of approximately 100 µg/l have led to cancer at these sites, and that precursors of skin cancer have been associated with levels of 50-100 µg/l.
The relationships between arsenic exposure and other health effects are less clear. There is relatively strong evidence for hypertension and cardiovascular disease, but the evidence is only suggestive for diabetes and reproductive effects and weak for cerebrovascular disease, long-term neurological effects, and cancer at sites other than lung, bladder, kidney and skin40.
Conclusions
Recent data indicate that adverse health effects of cadmium exposure, primarily in the form of renal tubular damage but possibly also effects on bone and fractures, may occur at lower exposure levels than previously anticipated. Many individuals in Europe already exceed these exposure levels and the margin is very narrow for large groups. Therefore, measures should be taken to reduce cadmium exposure in the general population in order to minimize the risk of adverse health effects.
The general population does not face a significant health risk from methylmercury, although certain groups with high fish consumption may attain blood levels associated with a low risk of neurological damage to adults. Since there is a risk to the fetus in particular, pregnant women should avoid a high intake of certain fish, such as shark, swordfish and tuna. Fish, such as pike, walleye and bass, taken from polluted fresh waters should especially be avoided.
There has been a debate on the safety of dental amalgams and claims have been made that mercury from amalgam may cause a variety of diseases, but to date no studies have been able to show any associations between amalgam fillings and ill health.
Children are particularly vulnerable to lead exposure. Blood levels in children should be reduced below the levels so far considered acceptable, recent data indicating that there may be neurotoxic effects of lead at lower levels of exposure than previously anticipated. Although lead in petrol has dramatically declined over the last decades, thereby reducing environmental exposure, there is a need to phase out any remaining uses of lead additives in motor fuels. The use of lead-based paints should also be abandoned, and lead should not be used in food containers. In particular, the public should be aware of glazed food containers, which may leach lead into food.
Long-term exposure to arsenic in drinking water is mainly related to increased risks of skin cancer, but also some other cancers, and other skin lesions such as hyperkeratosis and pigmentation changes. Occupational exposure to arsenic, primarily by inhalation, is causally associated with lung cancer. Clear exposure-response relationships and high risks have been observed.
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