The role of hypersensitivity and the immune response in influencing susceptibility to metal toxicity.

The immune status of the individual is an additional variable which has to be taken into account in any consideration of factors which influence the metabolism and toxicity of metals. The commonly occurring phenomena are described resulting from increased cellular reactivity to platinum, mercury, gold, nickel, chromium, and beryllium, and an attempt has attempt has been made to classify these into the four types of immune response. The clinical effects can be very varied, giving rise to conjunctivitis, rhinitis, asthma, urticaria, contact dermatitis, proteinuria, nephrotic syndrome or blood dyscrasia. Of these effects, cutaneous hypersensitivity is the most common, affecting both industrial and general population groups. Metal compounds used in therapeutics and metals used in prostheses have also been responsible for hypersensitive reactions.

Renal tubular dysfunction and abnormalities of calcium metabolism in cadmium workers.

Tubular proteinuria is generally accepted as the critical effect following long-term, low-level exposure to cadmium as seen in an industrial environment. This effect may not be of immediate importance to the health of the individual, but the significance, in terms of long-term morbidity and mortality, of the renal tubular defect of which it is an indicator is not fully understood, and certain sequelae may have remained unrecognized due to inadequate follow-up.Follow-up studies have been performed in nine of 12 workers who were initially investigated in 1962. In six of the men exposures ranged from 28 to 45 years to cadmium sulfide dust and for shorter periods in the earlier years to cadmium oxide fume and dust. These six men had tubular proteinuria when first seen, and this has persisted in the five survivors. All six men had hypercalciuria, and two of them became recurrent stone formers. One man whose urinary calcium excretion later fell to a low level more recently developed vitamin D resistant osteomalacia. In addition, each of the six men had exhibited some, but not all, of a variety of biochemical abnormalities related to other proximal renal tubular defects, and the worker who developed osteomalacia had additional evidence of a distal tubular defect. The five survivors also have evidence of slowly progressive deterioration in glomerular function.Follow-up of this small group has shown that renal tubular dysfunction in cadmium workers may continue symptom-free for long intervals, but in a proportion of cases serious clinical effects may develop after a number of years.

Role of cobalt, iron, lead, manganese, mercury, platinum, selenium, and titanium in carcinogenesis.

The possible carcinogenicity of cobalt, iron, lead, manganese, mercury, platinum, selenium, and titanium is reviewed, taking into account epidemiological data, the results of animal experimental studies, data on mutagenic effects and on other in vitro test systems. Of the great variety of occupations where exposure to one of these metals may occur, only haematite mining has been clearly shown to involve an increased human cancer risk. While the possibility that haematite might in some way act as a carcinogen has to be taken into consideration it is more likely that other carcinogens are responsible. Certain platinum coordination complexes are used in cancer chemotherapy, are mutagenic, and likely to be carcinogenic. Cobalt, its oxide and sulfide, certain lead salts, one organomanganese, and one organotitanium compound have been shown to have a limited carcinogenic effect in experimental animal studies, and except for titanium appear to be mutagenic. Certain mercury compounds are mutagenic but none have been shown to be carcinogenic. The presently available data are inadequate to assess the possible carcinogenicity of selenium compounds, but a few observations suggest that selenium may suppress the effect of other carcinogens administered to experimental animals and may even be associated with lower cancer mortality rates in man. Epidemiological observations are essential for the assessment of a human cancer risk, but the difficulty in collecting past exposure data in occupational groups and the complexity of multiple occupational exposures with changes over time, limits the usefulness of retrospective epidemiological studies.

Renal function in relation to low levels of cadmium exposure in a group of smelter workers.

Blood and urine samples were obtained from 274 smelter workers and urine samples from 48 controls. Cadmium, beta 2-microglobulin, and creatinine were estimated in blood and urine, and total protein in urine. Concentrations of cadmium in urine (mean 2.0 nmole/mmole creatinine) and blood (mean 21.8 nmole/L) observed in the smelter workers confirmed that this group had absorbed more cadmium than the general population, but less than most other occupationally exposed groups studied. Mean beta 2-microglobulin in urine was not significantly different in the smelter workers and the controls. The mean total protein in urine was 20% higher in the smelter workers, a difference which was significant (p congruent to 0.01). There was no consistent picture within the smelter workers of a relationship between history of cadmium exposure and the effect measures of beta 2-microglobulin in urine and blood, total protein in urine, creatinine clearance and relative beta 2-microglobulin clearance. Small but significant positive correlation coefficients were observed between cadmium in urine and beta 2-microglobulin in urine (r = 0.13), total protein in urine (r = 0.23) and beta 2-microglobulin clearance (r = 0.15), although these may be artifactual.

Platinum metal concentrations in urban road dust and soil in the United Kingdom.

Concentrations of Pt, Pd, Rh and Au in soils and road dusts taken from areas of high and low traffic flows in the London Borough of Richmond and from a section of the Kingston bypass (A3) at New Malden, Surrey, have been measured. High concentrations of platinum are associated with high traffic densities. Samples taken from streets of lower traffic flows were found to contain the lower concentrations of the ranges. These values correlated well with the levels of lead which were also high at roundabouts. If the preliminary results obtained in this study apply more generally throughout the UK, then the potential for exposure to enhanced levels of Pt would appear to be higher for road users and for those living in urban environments or along major highways.

Evaluation of selected publications on reference values for lead in blood.

As a part of the global Tracy project, whose aim is to define metal concentrations in tissues and body fluids of reference populations, more than 1000 papers published from 1980 to 1994 were scrutinized that presented tentative reference values for lead in blood in occupationally unexposed adult populations. Ten studies exemplifying criteria for proper sampling, analysis and data treatment are presented and discussed. Levels of lead in blood are influenced by numerous factors. Accordingly, a wide variation in blood lead concentrations was observed. As an example, in a global study in 1983 of nonsmoking female schoolteachers, the geometric mean value for lead in blood varied from 52 micrograms. l-1 in Tokyo, Japan, up to 193 micrograms. l-1 in Mexico City. The Tracy survey demonstrates the importance of factors such as age, gender, ethnicity, food, drinking and smoking habits, hobbies, season and year of sampling, residential area, and geographic location. Lead in blood was shown to be both time and area specific. Thus it was not possible to establish a general reference value for lead in blood.

Mortality of cadmium-exposed workers. A five-year update.

A cohort mortality study of cadmium-exposed workers initially followed to the end of 1979 has been updated for a further five years. The update has confirmed the findings of the original study with a significant excess risk from bronchitis related to intensity of exposure, although over the five-year period the excess mortality was no longer significant, a finding suggesting that the risk from bronchitis may now be declining in this cohort. In contrast, there is now a stronger indication of a excess risk from lung cancer related to intensity of exposure, significant for both the total and the five-year periods. There was again no increased risk from prostatic cancer, and from this and other studies it appears unlikely that cadmium, in the concentrations encountered in this and other recent studies, acts as a prostatic carcinogen. As in the initial study, there was no significant excess risk from hypertensive disease, nor any suggestion of an increased risk from cerebrovascular or renal disease.

International project for producing reference values for concentrations of trace elements in human blood and urine--TRACY.

In assessing the concentrations of toxic metals, such as cadmium, chromium, and mercury, in human blood and urine samples to determine whether they are abnormal or not, reliable reference values are needed from populations of nonoccupationally exposed subjects. Numerous publications present concentrations claimed to be typical for the study populations, but they can differ by up to an order of magnitude for a particular element. This is the consequence of general problems that are related to the definition of the reference groups, and the sampling and analytical procedures used, and that make it difficult to define typical and unbiased values. An international group of experts now establishes criteria and procedures to evaluate publications containing information on the concentrations of metals in tissues and body fluids for reference populations. These evaluations have been compiled in a data base (TRACY).

Mercury exposure and early effects: an overview.

OBJECTIVES: This paper was given as a keynote address at the conference on The Assessment of the Effects Due to Low Doses of Inorganic Mercury following Environmental and Occupational Exposures: Human and in vitro Studies on the Specific Mechanisms of Toxicity in Gargnano, Italy, in September 2001. METHODS: The most relevant literature over the past 40 years has been reviewed, and in particular, the proceedings of the World Health Organisation conferences on the health effects of inorganic and organic mercury exposure have been considered. RESULTS: In an uncontaminated environment the general population is exposed to mercury vapour from the atmosphere and from dental amalgam, while the diet, mainly from fish, is the principal source for methyl mercury absorption. Mercury vapour release from amalgam fillings increases with chewing, with absorption and uptake by the brain and kidneys. Infants exposed to phenyl mercury from treated diapers and young children ingesting mercurous chloride in teething powders have developed acrodynia (pink disease), and Kawasaki disease and the use of mercurial skin lightening creams has been followed by the development of the nephrotic syndrome. Both mercury compounds and mercury vapour have given rise to contact dermatitis in the general population. Epidemics of mercury poisoning have followed release of mercury into the environment from industrial activity, with uptake of methyl mercury from fish eating in Minamata Bay and uptake of both inorganic and methyl mercury following release of mercury vapour and deposition into waterways from gold recovery procedures in the Amazon basin. The ingestion of wheat and barley seed treated with an alkyl mercury fungicide for sowing, by a largely illiterate population in Iraq, led to a major outbreak of poisoning with a high fatality rate. Following exposure to mercury vapour, the earliest clinically observed adverse effects at urine mercury levels of the order of 30-100 mg/g creatinine, are objectively detectable tremor, psychological disorder and impaired nerve conduction velocity in sensitive subjects, with subjective symptoms of irritability, fatigue and anorexia. At these and at lower levels, proteinuria has also been observed. Both glomerular and tubular damage may occur at exposure levels lower than those giving rise to central nervous system effects. An immunological effect has also been observed in studies on clinically asymptomatic workers with low level exposure. CONCLUSIONS: As mercury can give rise to allergic and immunotoxic reactions which may be genetically regulated, in the absence of adequate dose-response studies for immunologically sensitive individuals, it has not been possible to set a level for mercury in blood or urine below which mercury related symptoms will not occur.

Cadmium nephropathy.

Cadmium is an inessential trace metal which accumulates in human tissues from contamination of food, water or air. The kidney is the critical organ following long-term, low-level absorption either by inhalation or ingestion; accumulation occurring in tubular epithelium in the form of a cadmium-metallothionein complex, giving rise to tubular dysfunction. In a group of 12 cadmium workers some of whom were followed for up to 16 years, tubular proteinuria, renal glycosuria, aminoaciduria, hypercalciuria and defects of concentration and acidification have been observed. Two men became recurrent renal stone formers and 1 man, who had nephrocalcinosis when first seen, later developed vitamin D-resistant osteomalacia. Renal tubular dysfunction following cadmium exposure may continue symptom-free for long intervals, but in a proportion of cases serious clinical effects may eventually develop.

Prostatic cancer and chronic respiratory and renal disease in British cadmium workers: a case control study.

Deaths due to prostatic cancer, renal cancer, bronchitis or emphysema, and nephritis or nephrosis in three cohorts of cadmium workers have been investigated in a case-control study. Evidence of an association of risk for these diseases with intensity and duration of exposure to cadmium was sought. The only clearly statistically significant finding was of an association of deaths coded as bronchitis or emphysema with "high" levels of exposure to cadmium fume, which was related also to duration of exposure. There was suggestive evidence also (p congruent to 0.10) of an increased risk for nephritis or nephrosis after high exposure. Marginally increased risks were observed for prostatic cancer after high or "medium" exposure, but these were not statistically significant.

The mortality of cadmium workers.

In a study of the mortality of workers exposed to cadmium, a cohort of 6995 men born before 1940 and exposed to cadmium for more than one year between 1942 and 1970 was followed up until the end of 1979. Expected numbers of deaths were calculated with the method of person-years at risk. In all, 1902 men aged under 85 had died, compared with 1968 expected. In contrast to the findings of some other studies, no excess of deaths due to prostatic cancer, cerebrovascular disease, or renal disease was observed. There were marginally more deaths from lung cancer than expected, but this excess was not related to exposure levels. A statistically significant excess of deaths due to bronchitis showed a strong relation to duration and intensity of exposure, being predominantly in the small group of men with heavy past exposure to cadmium.

Lung cancer in a non-ferrous smelter: the role of cadmium.

Lung cancer mortality was examined in a cohort of 4393 men employed at a zinc-lead-cadmium smelter. There was an excess of lung cancer (overall SMR = 124.5, 95% confidence interval 107-144) which was particularly evident for those employed for more than 20 years. A statistically significant trend in SMRs with increasing duration of employment was apparent. Quantitative estimates of exposure to cadmium and ordinal rankings for lead, arsenic, zinc, sulphur dioxide, and dust were used to calculate cumulative exposures from job histories. Matched logistic regression was used to compare the cumulative exposures of cases of lung cancer to those of controls matched for date of birth and date of starting work and surviving at the time of death of the matched cases. The increasing risk of lung cancer associated with increasing duration of employment could not be accounted for by cadmium and did not appear to be restricted to any particular process or department. Although lung cancer mortality was associated with estimates of cumulative exposure to arsenic and to lead, it was not possible to determine whether the increased risk might be due to arsenic, lead, or to other contaminants in the smelter. These results are compared with findings from other non-ferrous smelters.

Is cadmium a human carcinogen?

Continuing observations on cadmium-exposed workers have failed to yield evidence of an increased mortality from prostatic cancer, as initially suspected. There is, however, evidence of an increased mortality from lung cancer and, in at least two of the studies, of a dose-response relationship, but interpretation of these studies with regard to the role of cadmium is complicated by concurrent exposure to other known or suspected carcinogens, including arsenic, nickel, beryllium, chromium and heated mineral oils. An update of a long-term cohort mortality study from 17 plants in England employing a wide range of cadmium processes, while confirming an increased lung cancer risk related to intensity of cadmium exposure, shows some evidence of this risk also being associated with exposure to arsenic. It is thus not possible at present to attribute the excess mortality from lung cancer to cadmium owing to the presence of multiple confounding factors in the populations studied. Their role in the 17-plant study is currently being further investigated.

Birth weight of children and cadmium accumulation in placentas of female nickel-cadmium (long-life) battery workers.

In a retrospective epidemiological study on the birth weight of 266 children of 137 female workers in a nickel-cadmium battery factory, 157 children of workers occupationally exposed to cadmium were compared with 109 born to non-occupationally exposed workers. No effect of cadmium exposure on birth weight was detected, but a statistically significant effect on birth weight of smoking during pregnancy was observed. In a prospective study on the same population of female battery workers, 27 placentas were collected and the cadmium distribution and concentration in tissue subsamples determined. Placental cadmium concentrations were positively correlated with maternal blood cadmium. The cadmium concentration in placentas ranged from < 0.002 to 0.095 microgram/g (wet weight), the mean concentration +/- SD was 0.021 +/- 0.022 microgram/g (wet weight). Morphological and ultrastructural studies of placental tissues did not reveal any effect of cadmium. This study did not provide any evidence in support of the hypothesis that the placenta may be the critical organ in exposure to cadmium.

Subclinical neuropathy in lead workers.

Evidence is presented for a minimal defect of peripheral nerve function in a group of lead accumulator workers without clinical evidence of a neurological lesion. Of the 19 men examined, 13 had blood levels above 80 mug./100 ml. and seven had haemoglobin levels below 12 g./100 ml., showing that considerable exposure to lead was occurring.

Attendance at a London casualty department.

Patients who attended the casualty department of the Middlesex Hospital during one week in 1973 were interviewed. A predominantly young and working population used the department. Relatively few patients lived close to the hospital but many worked nearby. One third of all attendances were by patients who had been asked to return by casualty doctors. About half the new patients came of their own accord; the next largest group had been sent directly from work by an employer or occupational health service. Half the patients came with injuries, many of them superficial, although there were also serious accident cases. One fifth of the patients had no general practitioner whom they could consult. Age and geographical mobility were related to whether or not patients were registered with a general practitioner. The main reasons for not consulting a general practitioner were that patients felt they needed hospital treatment or that it was more convenient to attend the casualty department. It is suggested that the view that casual attenders with relatively trivial complaints should be encouraged to go to a general practitioner is not always applicable since social as well as medical circumstances determine whether or not patients decide to visit casualty.

Epidemiology of organomercury poisoning in Iraq. I. Incidence in a defined area and relationship to the eating of contaminated bread.

A survey was carried out in a defined area in rural Iraq where there had been many cases of organomercury poisoning following the consumption of bread contaminated by mercury, in order to determine the true incidence of the disorder. The results were compared with those obtained from a similar rural area from which few cases had been reported. A questionnaire was used to determine the amount of contaminated bread eaten and the frequency of symptoms; a simple clinical examination was performed and blood and hair samples were collected for estimation of total mercury concentration. Of 700 people over the age of 5 years in the high-exposure area, 66% admitted to having eaten contaminated bread, while none of the 864 persons in the low exposure area had done so. The mean period during which contaminated bread was eaten was 32 days, but some people had eaten it for as long as 3 months. A mean of 121 loaves was eaten, the maximum being 480 loaves. For the mean number of loaves the intake of methylmercury was likely to have been between 80 mg and 250 mg, but the people who had consumed the largest amount of contaminated bread may have ingested up to 1 000 mg of methylmercury over a 3-month period. Of those with signs of alkylmercury poisoning at the time of the survey, 80% had eaten more than 100 loaves, and 53 (71%) out of 75 persons who had eaten more than 200 loaves showed some evidence of poisoning.The incidence rate for poisoning was estimated at 271 per 1 000; this figure includes a mortality rate of 59 per 1 000, 32 per 1 000 cases with severe disability, 41 per 1 000 cases with mild or moderate disability and 138 per 1 000 cases with only subjective evidence of poisoning at the time of the study.