PREVENTIVE

MEDICINE

4, 135-153 t 1975)

Subclinical Lead Poisoning: A Preventable Disease H. A. WALDRON Department

of Social

Medicine,

The Medical

School,

Birmingham

B15 2TJ,

England

Subclinical lead poisoning has been demonstrated to take several forms both in experimental animals and in humans. The most serious effects appear to be the production of hyperactivity in children and possibly in some adult delinquents. These effects are produced when the blood lead concentration is considerably lower than those which have formerly been associated with clinical poisoning and have hitherto been regarded as safe. The best means of preventing subclinical lead poisoning is by minimizing the release of lead into the environment since this will result in a reduction in the degree of absorption. Lead is a ubiquitous component of the environment, so preventive measures would need to include the provision and enforcement of adequate lead-in-food regulations; replacing lead as a component of domestic water systems: removing lead in paint and, finally, removing lead from petrol.

SUBCLINICAL

LEAD POISONING

Lead is one of the most useful metals known to man, and one of the most toxic. Its harmful effects have been known since antiquity, but the consumption of lead by industry has continued to rise, especially since the time of the Lndustrial Revolution. During the present century, the advent of the motor car has greatly increased the rate of lead utilization and world consumption is now in excess of 4 million tons a year and is increasing by about 3.5%/yr. The hazard to workers engaged in lead industries still exists, but in the technologically advanced countries, deaths from occupational lead poisoning have decreased through the century due to improved standards of hygiene. On the other hand, the dissemination of lead into the general environment has become greater, due in large measure to the use of lead in petrol, and this has added what Hammond (57) has described as a new dimension to the old problem of lead poisoning. Since lead is a stable chemical it accumulates in the environment and the progressive increment in environmental lead levels has caused levels in man to approach closer to the threshold of clinical poisoning than have any other environmental chemical pollutants (12). What is of even greater concern is the evidence that levels of lead which are not sufficient to produce the signs and symptoms of clinical poisoning are, nevertheless, capable of inducing damaging effects on health and behavior. Some of the more important aspects of what has become known as subclinical lead poisoning (125) are discussed in this paper, together with means of preventing what appears to be a grave public health problem.

13s Copyright All rights

0 1975 by Academic of rcproduc~ in my

Press. Inc. form reserved.

136

H.

A.

GENERAL

I. Enhanced Susceptibility

WALDRON

EFFECTS

to Infection

In a number of animal species, lead has been found to increase susceptibility to infection. In rats (106) and chicks (1 17) lead has been found to diminish resistance to bacterial endotoxins and in rats and primates, sublethal doses of lead may cause a massive sensitization to these substances (47). Intraperitoneal injections of lead nitrate have been shown to increase the susceptibility of mice to a strain of Salmonella typhimurium of limited pathogenicity by a factor of ten (58), and the administration of tetra-ethyl lead also renders rats more susceptible to salmonella infection ( 104). A number of different factors seem to be involved in producing this diminished resistance to infection. Lead has been shown to bind to antibodies ( 130) and also to diminish the level of circulating antibodies (68), probably by decreasing the number of cells which form them (69). Lead also interferes with the phagocytic activity of polymorphonuclear leukocytes (93) and impairs hepatic phagocyte activity (116). Finally, the inhalation by rats of a lead aerosol diminishes the number of alveolar macrophages in pulmonary washings (IO). This effect is specific for lead and may result in a reduction in the rate of clearance of particulate material from the lungs. This would apply equally to inhaled bacteria as to any other particle. 2. Effects of Reproduction and Mortality Another subclinical effect noted in rats and mice is an impairment of reproductive ability (99). Breeding animals were given water containing lead to the extent of 25 ppm, and mice on this regime produced fewer litters than control animals. There was a considerable increase in runting and in the number of early deaths. The effects were so severe that by the second generation insufficient animals remained to allow the experiment to continue. In rats the effects were not as severe. Although litter size was reduced, and runting and early death were common, litters were produced to the F3 generation. The effects of low lead levels on mortality in animals is not clear at present. In some early experiments, Schroeder and his colleagues ( IO I- 103) reported that in concentrations approximating to those in normal human tissues, lead increased the mortality rate in male and female rats and in male, but not female, mice. Growth was not adversely affected, neither were any pathological lesions discovered which could account for the increased mortality. Subsequently, however, it was discovered that these animals had been on a diet which was deficient in trivalent chromium which is an essential trace element for these species. When the animals were fed a diet with adequate chromium, lead did not increase the mortality rate but data from the new experiments suggested that the harmful effects due to chromium deficiency were enhanced by lead (100). 3. Effects on the Fetus Lead is teratogenic to a number of animal species, including the chick (19,63,1 17) and the hamster (50,5 1); but, although lead can cross the human

SUBCLINICAL

LEAD

POISONING

137

placental barrier (5), fetal malformations have not yet been reported. Stillbirth, however, used to be common in female lead workers, so much so, that women are prohibited from working in some parts of the lead industry in the United Kingdom. The very high bone lead concentrations in stillborn fetuses from the Birmingham (U.K.) area suggests that environmental lead levels may be a contributory factor in producing abortion (I 6). 4. Enzymatic

Effects

In the general population, a significant negative correlation is found between the blood lead concentration and the activity of the enzymes &amino laevulinic acid dehydratase (ALA-d) and sodium-potassium activated adenosinetriphosphatase (Na’-K+-ATPase) in circulating red cells (59,105). Whether these findings are important to the public health is not yet clear. In the case of ALA-d, which has no physiological function in the red cell, the effect is unlikely to be harmful per se, although it may be indicative of a more widespread enzymatic inhibition. Na+-K+-ATPase can serve to maintain the integrity of the red cell membrane and the demonstration that current levels of lead in the environment inhibit its function should be viewed with more concern, especially since it may be that this enzyme is also inhibited at other membrane sites. ASSOCIATION

1. Neurological

WITH SPECIFIC

DISEASES

Diseases

Lead has been claimed to be of aetiological significance in two neurological diseases, motor neurone disease (MND) and multiple sclerosis (MS), although in the case of MND, the association has been found mostly in patients who have had a history of occupational exposure to lead. In Aran’s (3) original description of the disease, three of his 1 1 patients had had contact with lead but he did not consider this to be of significance. Since then a number of authors have noted the association of varying degrees of upper and lower motor neurone damage with a history of exposure to lead, although its role in producing the symptoms is not well understood (22-24,76,110). In a detailed investigation of lead metabolism in 3 I patients with the disease, nine of whom may have had undue exposure to lead, there was no increased urinary lead excretion (42) nor was there any increase in bone lead concentration in another series of 74 patients (24). These studies do not exclude the possibility, however, that an early contact with lead can initiate a process of degeneration in the lower motor neurone which does not manifest itself clinically until several years later when biochemical evidence of increased absorption is no longer to be found. Campbell and his colleagues (24) consider that the lead released from bone may be a factor in the production of the disease and the symptomatic improvement which has been noted in some patients treated with chelating agents (24,76) adds support to the thesis that lead is causally related to the disease in at least some patients. The suggestion that MS may be due to lead absorption was strongly advocated by Cone many years ago (35) following his discovery that the cerebrospinal fluid

138

H.

A.

WALDRON

(CSF) of patients with the disease contained lead. When more sensitive techniques for lead analysis became available, however, it was realised that most people have traces of lead in their CSF and Cone’s theory fell out of favor. A later study, however, (25) revived the theory by demonstrating that some patients with the disease lived in relatively lead-rich environments and had high tooth lead concentrations, indicating that they had absorbed higher than normal amounts of lead from their surroundings. By contrast, Butler (18) was unable to show that any of his patients showed abnormalities in their lead metabolism. More recently Warren (126-128) has revived the theory for a second time by demonstrating that areas with a high incidence of the disease have high environmental lead levels and, in particular, have high concentrations of lead (and some other metals) in the soil. Lead is known to produce segmental demyelination in peripheral nerves (52,72) and in the central nervous system (96) and it is also reported to interfere with normal myelin metabolism of cells in tissue culture (37). Subclinical peripheral nerve damage has been demonstrated both in men exposed to lead in their occupation (107) and in children exposed to environmental sources (49). This damage results in a slowing of the velocity of the nerve impulse in the slowest conducting fibers and is likely to reflect damage to the myelin sheath. There are, of course, other theories which seek to explain the aetiology of MS, the most fashionable being the concept of damage by a slow virus (90). This theory is consistent with the notion that lead is also of aetiological significance since, by altering the integrity of the myelin sheath, lead might facilitate the access of the virus particles to the myelin-forming cells and an interference with the immunological mechanism might allow them to prosper within the cells. 2. Cardio-Vascular

Disease

Deaths from cerebral haemorrhage were unusually common amongst lead workers in the early years of the present century (88), but improvements in industrial hygiene have apparently eliminated this as an occupational hazard (79). There is recent evidence, however, to suggest that in the general community, lead is a factor in promoting coronary artery disease. The correlation between deaths from cardio-vascular disease (CVD) and soft water is well known as is the fact that soft water is more plumbo-solvent than hard water and it is found that bone lead levels are higher in patients dying from coronary artery disease in soft water than in hard water areas (40). The pathological lesions in the patients from soft water areas are also less marked than in those from hard water districts, suggesting that some process is altering the course of the disease. These findings in themselves are not enough to incriminate lead as being necessarily one of the causative agents and Sterling (113) is right to warn against the assumption that correlation implies a direct cause and effect relationship. Many other trace elements have also been incriminated (80) and in this complex situation, it is difficult to be certain which are the most significant. However, Moore and his co-workers (85) have shown that rats given water containing lead in a concentration equal to that found in Glasgow tap water develop biochemical and morphological changes in cardiac muscle after about 25 weeks. The biochemical

SUBCLINICAL

LEAD

POISONING

139

changes affect ALA-d activity and also the activity of ferrochelatase, which is essential for myoglobin production. The morphological changes principally occur in the mitochondria and electron-micrographs show that the structure becomes poorly defined and the cristae clumped and uneven. On the basis of their findings, these authors conclude that lead may play some part in the increased mortality due to myocardial infarction in soft water areas. 3. Malignant Disease Renal tumors can be induced in experimental animals by the administration of lead salts, either orally or by subcutaneous injections (11,123,133,134), but there are no reports that lead has this effect in humans. In hamsters, lead oxide acts as a co-carcinogen with benzo(a)pyrene and it is interesting that plumbers in the United Kingdom have a high Standardized Mortality Ratio from bronchial cancer (95). High mortality from lung cancer is found in industrial areas where there is a high atmospheric content of benzo(a)pyrene and other polycyclic hydrocarbons (8 1) and it is possible that atmospheric lead may be acting as a cocarcinogen in these areas. 4. Behavioral

Effects

As long ago as 1900, Robert Jones (62) pointed out a connection between occupational exposure to lead and insanity. In those days it seems that behavioral effects were a well recognized concomitant of lead absorption since Jones pointed out the fact that “lead has a far-reaching and subtle deleterious influence upon the nervous system is undoubted.” In the intervening years, however, this relationship appears to have been lost sight of, although in 1943, Byers and Lord (21) showed that lead encephalopathy frequently produced permanent neurological and psychological sequelae in the children affected. This classic piece of work was neglected to a large extent and the current widespread concern that present environmental lead levels are of an order sufficient to bring about behavioral disorders is, in a sense, a rediscovery. Several authors have confirmed the serious sequelae of lead encephalopathy in children. The American Academy of Pediatrics (2) has reported that at least 25% of children so affected will be left with permanent damage to the central nervous system, but other authorities have found the figure to be as high as 82% (89). The children most often show both behavioral and educational abnormalities, with or without impairment of IQ. In many, IQ is not impaired but the children experience educational difficulties because they are hyperactive and have a short attention span. Some are prone to impulsive behavior and show a tendency towards violence. The abnormal behavior produced may be so disruptive that the child has to be withdrawn from school or institutionalized (121). Should a child who has had one attack of lead encephalopathy be re-exposed to lead and suffer a further episode, then permanent cerebral damage is virtually certain (20,28). Lead encephalopathy is not an easy disease to diagnose unless the attending physician has a high index of suspicion and more cases would be diagnosed if each child admitted to hospital with encephalopathy were to have a

140

H.

A.

WALDRON

radiographic examination of the long bones to search for the presence of a lead line. What is of graver concern, however, is the growing awareness that lead can cause behavioral disturbances in asymptomatic children. Pueschel and his colleagues (91) followed up a series of children who were found to have increased body burdens of lead on routine screening and were able to detect neurological or motor impairment in over one-quarter of the 42 traced after an interval of 18 months. There was some improvement in IQ, however, and they generally performed better during psychological testing than during their first examination when they were still exposed to lead. De la BurdC and Choate (45) have also shown that children with increased lead exposure have behavioral abnormalities as compared with matched controls. In their study of seventy 4-year-olds, the behavioral difficulties affected 25.7% and consisted mainly of a triad comprising extreme negativism, distractibility and a constant need for attention. A recent study on children from the east end of London, on the other hand, was unable to correlate IQ and single blood lead concentrations (73) but a rather more intensive study on children living in El Paso (129) showed that those with a blood lead 1 40 pg/lOO ml had a significant impairment of performance IQ which persisted even when their blood lead fell below 40. In the light of this evidence, it is disturbing to find that a high proportion of children living in some of the great American cities have been found to have blood lead concentrations in excess of 40 pug (Table 1). No comparable studies have been undertaken in the United Kingdom, but means of 30.9 and 29.6 pg were reported for two small series from Manchester and Glasgow, respectively (53,55). In the El Paso study, the group of children with blood lead concentrations > 40 pg was found to be no more hyperactive than the group with lower blood leads but this may have been because 40 pg is too high a value to allow discrimination. David and his colleagues (44) in New York studied children who were hyperactive and divided them into two groups, one consisting of children for whom a clear predisposing cause could be found for their hyperactivity and the other comprising children for whom there was no known cause. This latter group had higher blood lead concentrations and higher body burdens of lead than both BLOOD

LEAD

TABLE CONCENTRATIONS

1 IN URBAN

CHILDREN~

Blood lead concentration City

II

>40

Baltimore Chicago Washington New Haven Newark New York Philadelphia

2350 120,000 1158 1897 594 84,493 34%

28.2 20 22 29.8 38.9 28.7 32.3

a Based on data in Ref. (75).

>50

(&lOOml) >60

% of children >70

4 12

>80

2.2 9.5 9.5 5.9 14.9

2.2

SUBCLINICAL

LEAD

POISONING

141

the other group of hyperactive children and a group of normal children. David has since shown in a double-blind trial (43) that all the children with ‘pure’ hyperactivity (i.e., hyperactivity for no known cause) respond to de-leading therapy with penicillamine (or calcium EDTA) and that the improvement is permanent over a one year follow-up period. The mean blood lead concentration in these children was of the order of 30 pg and is in keeping with the observations made in animals that hyperactivity is one of the earliest behavioral effects of lead (109). Other animal studies have amply confirmed the ability of lead to induce hyperactive behavior (82,97,108,109). In some instances this abnormal behavior can be correlated with alteration in neuro-transmitter metabolism in the brain (97) and it seems likely, by analogy, that similar derangements underlie this abnormality in children. The similarity between the hyperactivity induced by lead in animals and “pure” hyperactivity in children is such that both respond paradoxically to a number of drugs; that is to say, amphetamine and methylphenidate reduce hyperactivity whilst phenobarbital increases the level of motor activity (109). This suggests that the basic neuropharmacological lesion is the same in both. In addition to these data concerning the effects of lead in children, there is also some evidence from two studies that aberrant behavior in adults is aetiologically linked in some cases with abnormal lead metabolism. In each case, lead metabolism amongst prison populations was being studied with a view to establish normal parameters for blood and urine lead concentration and urinary ALA excretion. The first study (77) measured blood lead concentrations among the inmates of two Swiss prisons and found them to be considerably higher than for two control groups of normal Swiss males (122). For the prisoners the means were 43.5 and 40.5 pg % and for blood donors and policemen the means were 22.4 and 21.7 lug %, respectively. By contrast, the urine lead concentration in the prisoners was lower than in the controls. In the second study conducted on American prisoners (7) it was again found that urinary lead concentrations were lower than in nonprisoners although in this instance, urinary ALA excretion was greater in the prisoners than the controls, indicating an increased interference with heme synthesis. It has been suggested (15) that the prisoners with high blood lead concentrations and low urinary lead excretion have an impairment of renal function which is incompatible with normal elimination of lead. Thus, even though the rate of absorption of lead from the environment may be no greater than normal, blood lead levels (and hence soft-tissue levels) build up to greater than normal because of the decreased rate of excretion, An investigation to test this hypothesis is currently under consideration. THE PREVENTION OF SUB-CLINICAL

LEAD POISONING

Preventing the subclinical effects of lead requires that the total amount of lead released into the environment is reduced, thus lessening the amount available for absorption. Lead is a ubiquitous component of the environment and the importance of the different sources varies to some extent according to the place of residence and the age of the individual.

142

H.

A.

WALDRON

1. Lead in Food

Lead in food represents the major source of lead under normal circumstances and there are regulations governing the lead content of food (Table 2). The United Kingdom regulations stipulate a maximum of 2 ppm for most foods with the exception of some which are listed in the schedule to the regulations. The most important of the excepted foods are canned meat and fish and canned meat and fish pastes for which a higher maximum of 5 ppm is permitted. Fresh apples and pears are allowed to contain up to 3 ppm on the basis that lead-containing insecticides are still used in some areas from which the fruit is imported. Canned baby food may contain only 0.5 ppm of lead following the finding that some canned baby foods contained high levels of lead (83). One of the more curious features of the regulations is that fish (including shell-fish) is permitted to contain a higher concentration of lead if the lead is “naturally” present. The definition of ‘natural’ lead is not given in the text of the regulations, nor is any justification made for exempting fish from control. This is particularly unfortunate since of all food items, fish, and especially shell-fish, are the most liable to be heavily contaminated because of the discharge of industrial waste and sewage sludge into the waters around the coast (Table 3). The United Kingdom regulations have recently been subjected to a critical review (14) and the conclusion has been drawn that, as they stand, they are inadequate on toxicological grounds. For example, if all food actually contained the permitted 2 ppm, one kilogram would provide 2000 pg of lead, which is twice the daily intake from all sources which has been found capable of producing clinical poisoning in children within a few months (6) and is some seven times the maximum intake proposed for children by a committee of the United States Public Health Service (64). By this reckoning, even if all food contained the lower permitted limit of 0.5 ppm, it could not be regarded as safe. The emphasis placed on children when considering lead intake from food can be justified on the following grounds: (i) children are more susceptible to the toxic effects of lead and (ii) the rate of gastrointestinal absorption is greater in children than in adults by a factor of about 5 (1) and the younger the child, the greater the rate of absorption (70). Thus, regulations should be formed with a view to protecting the most vulnerable section of the community and the maximum limit should apply to all food which children are liable to eat.

LEAD

LEVELS

PERMITTED Item

All foods except where otherwise specified Canned foods Fresh fruit Canned baby food

TABLE 2 IN FOOD IN THE UNITED Maximum

level

2.0 5.0 3.0 0.5

KINGDOM @pm)

SUBCLINICAL

LEAD

CONCENTRATIONS

LEAD

143

POISONING

TABLE

3

IN

FISH

AND

SHELL-FISH”

Lead concentration Sample Fishb Flounder Plaice Pollack Pout Whiting Shell-fish’ Limpet Limpet Limpet Mussel Mussel Shrimp Shrimp Winkle Winkle

(ppm)

Mean

Range

Subclinical lead poisoning: a preventable disease.

PREVENTIVE MEDICINE 4, 135-153 t 1975) Subclinical Lead Poisoning: A Preventable Disease H. A. WALDRON Department of Social Medicine, The Medica...
1MB Sizes 0 Downloads 0 Views