Toxic metals and organometallic compounds such as aluminium, antimony, inorganic arsenic, beryllium, cadmium, chromium, cobalt, lead, alkyl lead, metallic mercury and its salts, organic mercury compounds, nickel, selenium and vanadium have all been recognized for some time as posing potential health risks to exposed persons. In some cases, epidemiological studies on relationships between internal dose and resulting effect/response in occupationally exposed workers have been studied, thus permitting the proposal of health-based biological limit values (see table 1).

Table 1. Metals: Reference values and biological limit values proposed by the American Conference of Governmental Industrial Hygienists (ACGIH), Deutsche Forschungsgemeinschaft (DFG), and Lauwerys and Hoet (L and H)

* Urine values are per gram of creatinine.
** EKA = Exposure equivalents for carcinogenic materials.
¹ Taken with some modifications from Lauwerys and Hoet 1993.
² From ACGIH 1996-97.
³ From DFG 1996.
⁴ Tentative maximum permissible concentrations (TMPCs) taken from Lauwerys and Hoet 1993.

One problem in seeking precise and accurate measurements of metals in biological materials is that the metallic substances of interest are often present in the media at very low levels. When biological monitoring consists of sampling and analyzing urine, as is often the case, it is usually performed on “spot” samples; correction of the results for the dilution of urine is thus usually advisable. Expression of the results per gram of creatinine is the method of standardization most frequently used. Analyses performed on too dilute or too concentrated urine samples are not reliable and should be repeated.

Aluminium

In industry, workers may be exposed to inorganic aluminium compounds by inhalation and possibly also by ingestion of dust containing aluminium. Aluminium is poorly absorbed by the oral route, but its absorption is increased by simultaneous intake of citrates. The rate of absorption of aluminium deposited in the lung is unknown; the bioavailability is probably dependent on the physicochemical characteristics of the particle. Urine is the main route of excretion of the absorbed aluminium. The concentration of aluminium in serum and in urine is determined by both the intensity of a recent exposure and the aluminium body burden. In persons non-occupationally exposed, aluminium concentration in serum is usually below 1 μg/100 ml and in urine rarely exceeds 30 μg/g creatinine. In subjects with normal renal function, urinary excretion of aluminium is a more sensitive indicator of aluminium exposure than its concentration in serum/plasma.

Data on welders suggest that the kinetics of aluminium excretion in urine involves a mechanism of two steps, the first one having a biological half-life of about eight hours. In workers who have been exposed for several years, some accumulation of the metal in the body effectively occurs and aluminium concentrations in serum and in urine are also influenced by the aluminium body burden. Aluminium is stored in several compartments of the body and excreted from these compartments at different rates over many years. High accumulation of aluminium in the body (bone, liver, brain) has also been found in patients suffering from renal insufficiency. Patients undergoing dialysis are at risk of bone toxicity and/or encephalopathy when their serum aluminium concentration chronically exceeds 20 μg/100 ml, but it is possible to detect signs of toxicity at even lower concentrations. The Commission of the European Communities has recommended that, in order to prevent aluminium toxicity, the concentration of aluminium in plasma should never exceed 20 μg/100 ml; a level above 10 μg/100 ml should lead to an increased monitoring frequency and health surveillance, and a concentration exceeding 6 μg/100 ml should be considered as evidence of an excessive build-up of the aluminium body burden.

Antimony

Inorganic antimony can enter the organism by ingestion or inhalation, but the rate of absorption is unknown. Absorbed pentavalent compounds are primarily excreted with urine and trivalent compounds via faeces. Retention of some antimony compounds is possible after long-term exposure. Normal concentrations of antimony in serum and urine are probably below 0.1 μg/100 ml and 1 μg/g creatinine, respectively.

A preliminary study on workers exposed to pentavalent antimony indicates that a time-weighted average exposure to 0.5 mg/m³ would lead to an increase in urinary antimony concentration of 35 μg/g creatinine during the shift.

Inorganic Arsenic

Inorganic arsenic can enter the organism via the gastrointestinal and respiratory tracts. The absorbed arsenic is mainly eliminated through the kidney either unchanged or after methylation. Inorganic arsenic is also excreted in the bile as a glutathione complex.

Following a single oral exposure to a low dose of arsenate, 25 and 45% of the administered dose is excreted in urine within one and four days, respectively.

Following exposure to inorganic trivalent or pentavalent arsenic, the urinary excretion consists of 10 to 20% inorganic arsenic, 10 to 20% monomethylarsonic acid, and 60 to 80% cacodylic acid. Following occupational exposure to inorganic arsenic, the proportion of the arsenical species in urine depends on the time of sampling.

The organoarsenicals present in marine organisms are also easily absorbed by the gastrointestinal tract but are excreted for the most part unchanged.

Long-term toxic effects of arsenic (including the toxic effects on genes) result mainly from exposure to inorganic arsenic. Therefore, biological monitoring aims at assessing exposure to inorganic arsenic compounds. For this purpose, the specific determination of inorganic arsenic (As_i), monomethylarsonic acid (MMA), and cacodylic acid (DMA) in urine is the method of choice. However, since seafood consumption might still influence the excretion rate of DMA, the workers being tested should refrain from eating seafood during the 48 hours prior to urine collection.

In persons non-occupationally exposed to inorganic arsenic and who have not recently consumed a marine organism, the sum of these three arsenical species does not usually exceed 10 μg/g urinary creatinine. Higher values can be found in geographical areas where the drinking water contains significant amounts of arsenic.

It has been estimated that in the absence of seafood consumption, a time-weighted average exposure to 50 and 200 μg/m³ inorganic arsenic leads to mean urinary concentrations of the sum of the metabolites (As_i, MMA, DMA) in post-shift urine samples of 54 and 88 μg/g creatinine, respectively.

In the case of exposure to less soluble inorganic arsenic compounds (e.g., gallium arsenide), the determination of arsenic in urine will reflect the amount absorbed but not the total dose delivered to the body (lung, gastrointestinal tract).

Arsenic in hair is a good indicator of the amount of inorganic arsenic absorbed during the growth period of the hair. Organic arsenic of marine origin does not appear to be taken up in hair to the same degree as inorganic arsenic. Determination of arsenic concentration along the length of the hair may provide valuable information concerning the time of exposure and the length of the exposure period. However, the determination of arsenic in hair is not recommended when the ambient air is contaminated by arsenic, as it will not be possible to distinguish between endogenous arsenic and arsenic externally deposited on the hair. Arsenic levels in hair are usually below 1 mg/kg. Arsenic in nails has the same significance as arsenic in hair.

As with urine levels, blood arsenic levels may reflect the amount of arsenic recently absorbed, but the relation between the intensity of arsenic exposure and its concentration in blood has not yet been assessed.

Beryllium

Inhalation is the primary route of beryllium uptake for occupationally exposed persons. Long-term exposure can result in the storage of appreciable amounts of beryllium in lung tissues and in the skeleton, the ultimate site of storage. Elimination of absorbed beryllium occurs mainly via urine and only to a minor degree in the faeces.

Beryllium levels can be determined in blood and urine, but at present these analyses can be used only as qualitative tests to confirm exposure to the metal, since it is not known to what extent the concentrations of beryllium in blood and urine may be influenced by recent exposure and by the amount already stored in the body. Furthermore, it is difficult to interpret the limited published data on the excretion of beryllium in exposed workers, because usually the external exposure has not been adequately characterized and the analytical methods have different sensitivities and precision. Normal urinary and serum levels of beryllium are probably below
2 μg/g creatinine and 0.03 μg/100 ml, respectively.

However, the finding of a normal concentration of beryllium in urine is not sufficient evidence to exclude the possibility of past exposure to beryllium. Indeed, an increased urinary excretion of beryllium has not always been found in workers even though they have been exposed to beryllium in the past and have consequently developed pulmonary granulomatosis, a disease characterized by multiple granulomas, that is, nodules of inflammatory tissue, found in the lungs.

Cadmium

In the occupational setting, absorption of cadmium occurs chiefly through inhalation. However, gastrointestinal absorption may significantly contribute to the internal dose of cadmium. One important characteristic of cadmium is its long biological half-life in the body, exceeding
10 years. In tissues, cadmium is mainly bound to metallothionein. In blood, it is mainly bound to red blood cells. In view of the property of cadmium to accumulate, any biological monitoring programme of population groups chronically exposed to cadmium should attempt to evaluate both the current and the integrated exposure.

By means of neutron activation, it is currently possible to carry out in vivo measurements of the amounts of cadmium accumulated in the main sites of storage, the kidneys and the liver. However, these techniques are not used routinely. So far, in the health surveillance of workers in industry or in large-scale studies on the general population, exposure to cadmium has usually been evaluated indirectly by measuring the metal in urine and blood.

The detailed kinetics of the action of cadmium in humans is not yet fully elucidated, but for practical purposes the following conclusions can be formulated regarding the significance of cadmium in blood and urine. In newly exposed workers, the levels of cadmium in blood increase progressively and after four to six months reach a concentration corresponding to the intensity of exposure. In persons with ongoing exposure to cadmium over a long period, the concentration of cadmium in the blood reflects mainly the average intake during recent months. The relative influence of the cadmium body burden on the cadmium level in the blood may be more important in persons who have accumulated a large amount of cadmium and have been removed from exposure. After cessation of exposure, the cadmium level in blood decreases relatively fast, with an initial half-time of two to three months. Depending on the body burden, the level may, however, remain higher than in control subjects. Several studies in humans and animals have indicated that the level of cadmium in urine can be interpreted as follows: in the absence of acute overexposure to cadmium, and as long as the storage capability of the kidney cortex is not exceeded or cadmium-induced nephropathy has not yet occurred, the level of cadmium in urine increases progressively with the amount of cadmium stored in the kidneys. Under such conditions, which prevail mainly in the general population and in workers moderately exposed to cadmium, there is a significant correlation between urinary cadmium and cadmium in the kidneys. If exposure to cadmium has been excessive, the cadmium-binding sites in the organism become progressively saturated and, despite continuous exposure, the cadmium concentration in the renal cortex levels off.

From this stage on, the absorbed cadmium cannot be further retained in that organ and it is rapidly excreted in the urine. Then at this stage, the concentration of urinary cadmium is influenced by both the body burden and the recent intake. If exposure is continued, some subjects may develop renal damage, which gives rise to a further increase of urinary cadmium as a result of the release of cadmium stored in the kidney and depressed reabsorption of circulating cadmium. However, after an episode of acute exposure, cadmium levels in urine may rapidly and briefly increase without reflecting an increase in the body burden.

Recent studies indicate that metallothionein in urine has the same biological significance. Good correlations have been observed between the urinary concentration of metallothionein and that of cadmium, independently of the intensity of exposure and the status of renal function.

The normal levels of cadmium in blood and in urine are usually below 0.5 μg/100 ml and
2 μg/g creatinine, respectively. They are higher in smokers than in nonsmokers. In workers chronically exposed to cadmium, the risk of renal impairment is negligible when urinary cadmium levels never exceed 10 μg/g creatinine. An accumulation of cadmium in the body which would lead to a urinary excretion exceeding this level should be prevented. However, some data suggest that certain renal markers (whose health significance is still unknown) may become abnormal for urinary cadmium values between 3 and 5 μg/g creatinine, so it seems reasonable to propose a lower biological limit value of 5 μg/g creatinine. For blood, a biological limit of 0.5 μg/100 ml has been proposed for long-term exposure. It is possible, however, that in the case of the general population exposed to cadmium via food or tobacco or in the elderly, who normally suffer a decline of renal function, the critical level in the renal cortex may be lower.

Chromium

The toxicity of chromium is attributable chiefly to its hexavalent compounds. The absorption of hexavalent compounds is relatively higher than the absorption of trivalent compounds. Elimination occurs mainly via urine.

In persons non-occupationally exposed to chromium, the concentration of chromium in serum and in urine usually does not exceed 0.05 μg/100 ml and 2 μg/g creatinine, respectively. Recent exposure to soluble hexavalent chromium salts (e.g., in electroplaters and stainless steel welders) can be assessed by monitoring chromium level in urine at the end of the workshift. Studies carried out by several authors suggest the following relation: a TWA exposure of 0.025 or 0.05 mg/m³ hexavalent chromium is associated with an average concentration at the end of the exposure period of 15 or 30 μg/g creatinine, respectively. This relation is valid only on a group basis. Following exposure to 0.025 mg/m³ hexavalent chromium, the lower 95% confidence limit value is approximately 5 μg/g creatinine. Another study among stainless steel welders has found that a urinary chromium concentration on the order of 40 μg/l corresponds to an average exposure to 0.1 mg/m³ chromium trioxide.

Hexavalent chromium readily crosses cell membranes, but once inside the cell, it is reduced to trivalent chromium. The concentration of chromium in erythrocytes might be an indicator of the exposure intensity to hexavalent chromium during the lifetime of the red blood cells, but this does not apply to trivalent chromium.

To what extent monitoring chromium in urine is useful for health risk estimation remains to be assessed.

Cobalt

Once absorbed, by inhalation and to some extent via the oral route, cobalt (with a biological half-life of a few days) is eliminated mainly with urine. Exposure to soluble cobalt compounds leads to an increase of cobalt concentration in blood and urine.

The concentrations of cobalt in blood and in urine are influenced chiefly by recent exposure. In non-occupationally exposed subjects, urinary cobalt is usually below 2 μg/g creatinine and serum/plasma cobalt below 0.05 μg/100 ml.

For TWA exposures of 0.1 mg/m³ and 0.05 mg/m³, mean urinary levels ranging from about 30 to 75 μg/l and 30 to 40 μg/l, respectively, have been reported (using end-of-shift samples). Sampling time is important as there is a progressive increase in the urinary levels of cobalt during the workweek.

In workers exposed to cobalt oxides, cobalt salts, or cobalt metal powder in a refinery, a TWA of 0.05 mg/m³ has been found to lead to an average cobalt concentration of 33 and 46 μg/g creatinine in the urine collected at the end of the shift on Monday and Friday, respectively.

Lead

Inorganic lead, a cumulative toxin absorbed by the lungs and the gastrointestinal tract, is clearly the metal that has been most extensively studied; thus, of all the metal contaminants, the reliability of methods for assessing recent exposure or body burden by biological methods is greatest for lead.

In a steady-state exposure situation, lead in whole blood is considered to be the best indicator of the concentration of lead in soft tissues and hence of recent exposure. However, the increase of blood lead levels (Pb-B) becomes progressively smaller with increasing levels of lead exposure. When occupational exposure has been prolonged, cessation of exposure is not necessarily associated with a return of Pb-B to a pre-exposure (background) value because of the continuous release of lead from tissue depots. The normal blood and urinary lead levels are generally below 20 μg/100 ml and 50 μg/g creatinine, respectively. These levels may be influenced by the dietary habits and the place of residence of the subjects. The WHO has proposed 40 μg/100 ml as the maximal tolerable individual blood lead concentration for adult male workers, and 30 μg/100 ml for women of child-bearing age. In children, lower blood lead concentrations have been associated with adverse effects on the central nervous system. Lead level in urine increases exponentially with increasing Pb-B and under a steady-state situation is mainly a reflection of recent exposure.

The amount of lead excreted in urine after administration of a chelating agent (e.g., CaEDTA) reflects the mobilizable pool of lead. In control subjects, the amount of lead excreted in urine within 24 hours after intravenous administration of one gram of EDTA usually does not exceed 600 μg. It seems that under constant exposure, chelatable lead values reflect mainly blood and soft tissues lead pool, with only a small fraction derived from bones.

An x-ray fluorescence technique has been developed for measuring lead concentration in bones (phalanges, tibia, calcaneus, vertebrae), but presently the limit of detection of the technique restricts its use to occupationally exposed persons.

Determination of lead in hair has been proposed as a method of evaluating the mobilizable pool of lead. However, in occupational settings, it is difficult to distinguish between lead incorporated endogenously into hair and that simply adsorbed on its surface.

The determination of lead concentration in the circumpulpal dentine of deciduous teeth (baby teeth) has been used to estimate exposure to lead during early childhood.

Parameters reflecting the interference of lead with biological processes can also be used for assessing the intensity of exposure to lead. The biological parameters which are currently used are coproporphyrin in urine (COPRO-U), delta-aminolaevulinic acid in urine (ALA-U), erythrocyte protoporphyrin (EP, or zinc protoporphyrin), delta-aminolaevulinic acid dehydratase (ALA-D), and pyrimidine-5’-nucleotidase (P5N) in red blood cells. In steady-state situations, the changes in these parameters are positively (COPRO-U, ALA-U, EP) or negatively (ALA-D, P5N) correlated with lead blood levels. The urinary excretion of COPRO (mostly the III isomer) and ALA starts to increase when the concentration of lead in blood reaches a value of about 40 μg/100 ml. Erythrocyte protoporphyrin starts to increase significantly at levels of lead in blood of about 35 μg/100 ml in males and 25 μg/100 ml in females. After the termination of occupational exposure to lead, the erythrocyte protoporphyrin remains elevated out of proportion to current levels of lead in blood. In this case, the EP level is better correlated with the amount of chelatable lead excreted in urine than with lead in blood.

Slight iron deficiency will also cause an elevated protoporphyrin concentration in red blood cells. The red blood cell enzymes, ALA-D and P5N, are very sensitive to the inhibitory action of lead. Within the range of blood lead levels of 10 to 40 μg/100 ml, there is a close negative correlation between the activity of both enzymes and blood lead.

Alkyl Lead

In some countries, tetraethyllead and tetramethyllead are used as antiknock agents in automobile fuels. Lead in blood is not a good indicator of exposure to tetraalkyllead, whereas lead in urine seems to be useful for evaluating the risk of overexposure.

Manganese

In the occupational setting, manganese enters the body mainly through the lungs; absorption via the gastrointestinal tract is low and probably depends on a homeostatic mechanism. Manganese elimination occurs through the bile, with only small amounts excreted with urine.

The normal concentrations of manganese in urine, blood, and serum or plasma are usually less than 3 μg/g creatinine, 1 μg/100 ml, and 0.1 μg/100 ml, respectively.

It seems that, on an individual basis, neither manganese in blood nor manganese in urine are correlated to external exposure parameters.

There is apparently no direct relation between manganese concentration in biological material and the severity of chronic manganese poisoning. It is possible that, following occupational exposure to manganese, early adverse central nervous system effects might already be detected at biological levels close to normal values.

Metallic Mercury and its Inorganic Salts

Inhalation represents the main route of uptake of metallic mercury. The gastrointestinal absorption of metallic mercury is negligible. Inorganic mercury salts can be absorbed through the lungs (inhalation of inorganic mercury aerosol) as well as the gastrointestinal tract. The cutaneous absorption of metallic mercury and its inorganic salts is possible.

The biological half-life of mercury is of the order of two months in the kidney but is much longer in the central nervous system.

Inorganic mercury is excreted mainly with the faeces and urine. Small quantities are excreted through salivary, lacrimal and sweat glands. Mercury can also be detected in expired air during the few hours following exposure to mercury vapour. Under chronic exposure conditions there is, at least on a group basis, a relationship between the intensity of recent exposure to mercury vapour and the concentration of mercury in blood or urine. The early investigations, during which static samples were used for monitoring general workroom air, showed that an average mercury-air, Hg–air, concentration of 100 μg/m³ corresponds to average mercury levels in blood (Hg–B) and in urine (Hg–U) of 6 μg Hg/100 ml and 200 to 260 μg/l, respectively. More recent observations, particularly those assessing the contribution of the external micro-environment close to the respiratory tract of the workers, indicate that the air (μg/m³)/urine (μg/g creatinine)/ blood (μg/100ml) mercury relationship is approximately 1/1.2/0.045. Several epidemiological studies on workers exposed to mercury vapour have demonstrated that for long-term exposure, the critical effect levels of Hg–U and Hg–B are approximately 50 μg/g creatinine and 2 μg/100 ml, respectively.

However, some recent studies seem to indicate that signs of adverse effects on the central nervous system or the kidney can already be observed at a urinary mercury level below 50 μg/g creatinine.

Normal urinary and blood levels are generally below 5 μg/g creatinine and 1 μg/100 ml, respectively. These values can be influenced by fish consumption and the number of mercury amalgam fillings in the teeth.

Organic Mercury Compounds

The organic mercury compounds are easily absorbed by all the routes. In blood, they are to be found mainly in red blood cells (around 90%). A distinction must be made, however, between the short chain alkyl compounds (mainly methylmercury), which are very stable and are resistant to biotransformation, and the aryl or alkoxyalkyl derivatives, which liberate inorganic mercury in vivo. For the latter compounds, the concentration of mercury in blood, as well as in urine, is probably indicative of the exposure intensity.

Under steady-state conditions, mercury in whole blood and in hair correlates with methylmercury body burden and with the risk of signs of methylmercury poisoning. In persons chronically exposed to alkyl mercury, the earliest signs of intoxication (paresthesia, sensory disturbances) may occur when the level of mercury in blood and in hair exceeds 20 μg/100 ml and 50 μg/g, respectively.

Nickel

Nickel is not a cumulative toxin and almost all the amount absorbed is excreted mainly via the urine, with a biological half-life of 17 to 39 hours. In non-occupationally exposed subjects, the urine and plasma concentrations of nickel are usually below 2 μg/g creatinine and 0.05 μg/100 ml, respectively.

The concentrations of nickel in plasma and in urine are good indicators of recent exposure to metallic nickel and its soluble compounds (e.g., during nickel electroplating or nickel battery production). Values within normal ranges usually indicate nonsignificant exposure and increased values are indicative of overexposure.

For workers exposed to soluble nickel compounds, a biological limit value of 30 μg/g creatinine (end of shift) has been tentatively proposed for nickel in urine.

In workers exposed to slightly soluble or insoluble nickel compounds, increased levels in body fluids generally indicate significant absorption or progressive release from the amount stored in the lungs; however, significant amounts of nickel may be deposited in the respiratory tract (nasal cavities, lungs) without any significant elevation of its plasma or urine concentration. Therefore, “normal” values have to be interpreted cautiously and do not necessarily indicate absence of health risk.

Selenium

Selenium is an essential trace element. Soluble selenium compounds seem to be easily absorbed through the lungs and the gastrointestinal tract. Selenium is mainly excreted in urine, but when exposure is very high it can also be excreted in exhaled air as dimethylselenide vapour. Normal selenium concentrations in serum and urine are dependent on daily intake, which may vary considerably in different parts of the world but are usually below 15 μg/100 ml and 25 μg/g creatinine, respectively. The concentration of selenium in urine is mainly a reflection of recent exposure. The relationship between the intensity of exposure and selenium concentration in urine has not yet been established.

It seems that the concentration in plasma (or serum) and urine mainly reflects short-term exposure, whereas the selenium content of erythrocytes reflects more long-term exposure.

Measuring selenium in blood or urine gives some information on selenium status. Currently it is more often used to detect a deficiency rather than an overexposure. Since the available data concerning the health risk of long-term exposure to selenium and the relationship between potential health risk and levels in biological media are too limited, no biological threshold value can be proposed.

Vanadium

In industry, vanadium is absorbed mainly via the pulmonary route. Oral absorption seems low (less than 1%). Vanadium is excreted in urine with a biological half-life of about 20 to 40 hours, and to a minor degree in faeces. Urinary vanadium seems to be a good indicator of recent exposure, but the relationship between uptake and vanadium levels in urine has not yet been sufficiently established. It has been suggested that the difference between post-shift and pre-shift urinary concentrations of vanadium permits the assessment of exposure during the workday, whereas urinary vanadium two days after cessation of exposure (Monday morning) would reflect accumulation of the metal in the body. In non-occupationally exposed persons, vanadium concentration in urine is usually below 1 μg/g creatinine. A tentative biological limit value of 50 μg/g creatinine (end of shift) has been proposed for vanadium in urine.

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