During the past 50 years, serious outbreaks of severe poisoning have focused attention on the potential hazards associated with the dissemination of heavy metals into the environment. Minamata disease takes its name from an outbreak of chronic methyl-mercury poisoning among the fish, cats, and residents of Minamata Bay, Japan. Itai-itai disease refers to chronic cadmium poisoning in another area of Japan from the ingestion of cadmium-contaminated rice and water. An outbreak of severe lead poisoning in both children and adults due to the burning of discarded battery casings in home cook stoves during the depression in Baltimore, Md., in 1931 alerted physicians to the syndrome of acute lead encephalopathy and to the fact that the ingestion of lead-pigment paints and lead-containing putty by children presented the greater public-health hazard.
During the past decade, technologic advances, coupled with widespread interest in environmental matters, have led to the finding that the dispersal of mercury, lead, and cadmium in the environment is widespread in industrialized societies. Many products in which they are used are ultimately discarded without reclamation of the mercury, lead, or cadmium for reuse. They tend to build up in soils, household dust, suspended particulates; river-, lake-, and seabeds; and aquatic life.
Not only are these metals widespread, but they tend to persist in the environment - methyl mercury in water and aquatic life and lead and cadmium primarily in soils and dust. In soils, these metals tend to persist in the surface layers, from which they are only slowly washed away. In the United States, there is now widespread activity in the restoration and renovation of old homes. The walls and woodwork of these old structures may contain substantial amounts of lead paint (and, to a limited extent, cadmium-containing paints). The renovation of old buildings must be undertaken with great precaution, as the fine particulate created, particularly in sanding, can pose a very substantial risk to young children and the pregnant woman's fetus.
The recent re-entry of women into the work place in great numbers raises the question particularly of risks to the fetus. Recent studies have also revealed that transport of occupational dusts from the workplace into the home on the clothing of workers can contaminate the home and result in significandy increased absorption of lead by young children. This article will present a review óf current knowledge on the environmental sources of these metals and their metabolism and effects in man. The limitations of current therapeutic methods serve to emphasize the importance of preventive approaches to the control of these hazards.
A comprehensive discussion of the toxicology of mercury and its compounds is well beyond the scope of this brief review. (The interested reader is referred to monographs in the bibliography.) Suffice it to say that the absorption, distribution, and principal target organs for the toxic effects of mercury differ according to the varying chemical properties of different mercury compounds. Older physicans may recall the era of 30 years or more ago when bichloride of mercury, an inorganic mercuric compound, was taken with suicidal intent: onset of severe and excruciatingly painful gastrointestinal manifestations was prompt and was quickly followed by renal failure.
Likewise, older pediatricians may recall the disappearance of acrodynia when the use of calomel teething powders was stopped. Acrodynia is one of several syndromes associated with chronic inorganic-mercury poisoning and is characterized by dermatologie, cardiovascular, hormonal, and neurobehavioral abnormalities.
However, far more toxic and of far greater concern, insofar as environmental contamination is concerned, are the alkyl organic mercury compounds - the most toxic of which is dimethyl mercury, the enologie agent in Minamata disease. In man, symptoms due to toxic amounts of alkyl mercury compounds are dominated by neurologic disturbances. Furthermore, the onset of symptoms may not occur until weeks or months after acute exposure to toxic doses. Most commonly, longterm exposure is followed by numbness and tingling in the lips, mouth, hands, and feet; dysarthria; ataxia; concentric constriction of visual fields; blurred vision; blindness; deafness; and a reduced level of consciousness. Congenital Minamata disease is characterized by signs of cerebral palsy. In one heavily contaminated area of Minamata Bay, the mental-deficiency rate among children born in the late 1950s was 27 percent.
The epidemic that occurred in Minamata Bay is considered one of the major industrial environmental pollution disasters of this century. A sharp increase in Minamata disease began in about 1953 and continued largely unabated for the next 10 to 15 years. Earlier recordings of cases of "mysterious madness," together with the finding of high mercury levels in umbilical cords preserved from earlier times in the traditional Japanese manner, suggest that the epidemic may actually have begun one or two decades earlier. Extensive investigation revealed that the Chisso Company, a manufacturer of acetaldehyde and vinyl chloride, was discharging wastes contaminated apparently with both inorganic mercury and methyl mercury into Minamata Bay.
Subsequent studies have shown that certain aquatic organisms can indeed convert inorganic mercury into methyl mercury and that the latter is consumed by fish. Indeed, it was the heavy consumers of fish in Minamata Bay - namely, fish, cats, birds, and fishermen and their families - that were primarily affected. However, the fact that less toxic forms of mercury can be converted in aquatic systems to methyl mercury, the most toxic form, together with the long residence time of mercury in aquatic systems, has led to a worldwide effort to curtail drastically the discharge of mercurycontaining pesticides and wastes into waterways.
Methyl mercury has also been used as a fungicide for the treatment of seed grain. In New Mexico, for example, a poor family fed methyl-mercury-treated seed grain to a hog and butchered and ate the hog, with disastrous consequences. Perhaps the most serious outbreak of methyl-mercury poisoning occurred in Iraq in the winter of 1971-72. This outbreak struck at least 6,500 persons and caused several hundred fatal cases. Rural peasants, unable to read the instructions (which were given in a foreign language), used the seed to bake bread. Some apparendy washed the dye off the grain and fed test doses to chickens and other animals. Seeing no immediate effect in the animals and unaware of the long latency between the onset of symptoms of disease and the ingestion of toxic amounts of methyl mercury, they baked bread from this grain and ate it. As in the Minamata Bay incident, apparendy healthy or only mildly affected pregnant women produced stillbirths or live infants with cerebral palsy, providing evidence of the severe fetotoxicity of this form of mercury.
Earlier experience in Minamata Bay indicated that chronic methyl-mercury poisoning induced a progressive and often fatal disease. Two-year follow-up studies among the affected Iraqi peasants suggest that some degree of recovery may occur and that the degree of recovery is related to the severity of the initial disease - which, in turn, can be related to the concentration of methyl mercury in blood. The fact that some degree of recovery was observed in Iraq suggests that the prognosis of poisoning of short duration (approximately three months in Iraq) may be somewhat better than in cases of very chronic overexposure. Many authorities believe that the manufacture of alkyl organomercuric compounds, such as methyl and ethyl mercury, should be banned worldwide.
The sources of mercury that pose hazards to living organisms, including man, may be related to its uses. In 1970, approximately 2,000 tons of mercury were produced in the United States, with major uses distributed as follows: electrical apparatus (25.9 percent), chlorine production (24.4 percent), paints (16.8 percent), dental preparations and pharmaceuticals (4.8 percent), agricultural pesticides (2.9 percent), and paper and pulp production (0.4 percent). Only minor portions of the total production of mercury-containing compounds are recycled, and the rest is finally released in some way into the atmosphere, surface waters, and soil or ends up in landfills, dumps, and refuse.
It is estimated that during the 50 years before 1970, 16,000,000 pounds of mercury-containing compounds were disseminated into the United States environment. In view of the ability of aquatic organisms to convert other forms of mercury into methyl mercury and in view of its accumulation of this in fish, it is clear that drastic efforts must be taken to prevent further dissipation of mercurycontaining compounds into waterways. This requires stringent control, particularly in chlorine production, agricultural pesticide applications, and paper and pulp production.
Substantial progress has been made in these areas. Mercurials are incorporated into mold- and mildew-resistant paints, particularly in latex paints, because they are potent slimicides and fungicides. For this purpose, aryl mercurials, such as phenyl and tolyl organomercurials, are used. These rather rapidly break down in the environment and, on absorption, begin to release inorganic mercuric ions and so are not such potent neurotoxins. A certain proportion of such compounds may, on breakdown, release mercury vapor into the air. Spills of metallic mercury in dental offices and in hospitals and other laboratories must be carefully and quickly cleaned up by appropriate and established techniques to prevent their permeation of cracks and other crevices in floors and the release of mercury vapor. Most health departments have or have access to mercury-vapor-monitoring devices.
Studies in man indicate that the biologic half-life of inorganic mercury compounds may range from 29 to 60 days but that the half-life of methyl mercury is somewhat longer, being about 70 to 100 days. Apparendy the half-life of methyl mercury is somewhat longer because inorganic mercury is released within the cell and then more slowly excreted. On the other hand, the absorption of methyl mercury from the gastrointestinal tract is virtually 100 percent, and a high proportion of this is concentrated in the brain.
The ingestion of metallic mercury is generally without risk, as toxic amounts are not absorbed and virtually all of the metallic mercury passes into the feces. However, metallic mercury evaporates even at ordinary ambient temperatures, so that mercury vapor contaminates the air wherever the metal is exposed. Inhalation of mercury vapor causes cough, dyspnea, cyanosis, exudative bronchitis, and lethargy in overexposed workers.
The chemical form of mercury and its compounds, as well as the route of entry into the body (respiratory or gastrointestinal) apparently affect primarily the distribution of the assimilated mercury in the body. Experimental data indicate that all mercury compounds probably release mercuric ions within the cell and that it is the mercuric ion that is direcdy responsible for its toxic effects through inhibition of sulfhydryl-dependent enzymes, binding to protein and perhaps other mechanisms.
The spectrum of toxic clinical manifestations of mercury poisoning is wide, including neurologic, pulmonary, gastrointestinal, renal, cardiovascular, hormonal, and derma tolgic abnormalities. Minamata disease is, of course, the characteristic picture of chronic poisoning due to alkyl organomercury poisoning. Manifestations are exclusively due to central-nervous injury. Pulmonary insufficiency is associated with acute inhalation of mercury vapors and mercury-containing dusts. Chronic inhalation of mercury-containing dust may also produce neurologic abnormalities, including dysarthria, ataxia, and fine tremors. Chronic exposure to aryl organomercuric compounds (i.e., phenyl mercuric acetate) may cause acrodynia. Compounds with a high content of inorganic mercuric ions cause acute gastrointestinal and renal injury primarily.
Although chelation therapy with dimercaprol may be lifesaving in severe, acute inorganic poisoning due to mercuric ion, no beneficial role has been demonstrated for the use of any chelating agent in chronic mercury poisoning. The importance of a preventive approach cannot be emphasized too strongly. Government regulatory agencies have a vital role to play in preventing the dissemination of mercury into aquatic systems. While the present mercury content of edible fish does not pose a risk to such populations as that in the United States, who are not heavy consumers of fish, it may for such populations as the Japanese, who are very heavy consumers of fish. There is need for further study in regard to the mercury content of dust and sewage sludge, in particular. Progress in this area has been slow, owing to the analytic difficulties in measuring very low concentrations of mercury in environmental and biologic samples.
In 1860, Constantin Paul reported that the rates of stillbirth and spontaneous abortion were higher among women occupationally exposed to lead and with clinical symptoms of lead poisoning than were the rates among nonexposed women. During the next 50 years, Paul's observation was confirmed in other groups of women workers, and a British committee recommended in 1910 that, henceforth, women not be employed in the lead trades owing to the hazard to the fetus. It can be estimated in retrospect with a large degree of certainty that these women had blood lead concentrations well above the range of 80-100 Mg. Pb/ 100 ml. whole blood, which in turn is well above the range (5-35 y%. Pb/ 100 ml. of whole blood) found in the general population in the United States today.
Today, the risks to the fetus of minor elevations in blood lead concentration in pregnant women remain unknown. The experience of the last century emphasizes the need for precaution whenever pregnant women and young children are exposed to fine-particulate lead. Indeed, symptomatic cases of lead poisoning have occurred in recent years among men and women removing old lead paint in the course of renovating their homes.
At the turn of the century, pediatricians in Brisbane, Queensland, Australia, recognized that ingestion of lead paints by young children could cause a chronic and often fatal poisoning. The use of lead pigment in paints was banned in Queensland in 1935 but not in the adjacent state of New South Wales, where cases of lead encephalopathy in children due to paint ingestion are still seen today.
It was about 1935 when lead-paint poisoning ingestion was first recognized as a serious publichealth problem in the United States. Intensive efforts during the past decade in the United States finally led to the banning of lead additives in residential paints by the U.S. Consumer Product Safety Commission in 1978. Although the use of lead pigments in residential paints probably peaked in the United States about 1940 and thereafter declined slowly, its use in residential paints has dropped off to negligible amounts only during the past 10 to 15 years. There is, therefore, a substantial amount of lead in paints on both the interior and the exterior of the U.S. housing stock.
While intact painted surfaces in well-maintained homes do not appear to pose a hazard, experience indicates that poor maintenance and deterioration of painted surfaces make the paint flakes, fine debris, and dust (due to caulking of some paints) more readily available to young children. Recent studies point to soil and household dust as important sources of lead, which may account for much of the moderate degree of increased lead absorption now being found in screening programs throughout the United States. It is becoming clear that the usual hand-to-mouth activity of young children in conjunction with dust exposure can often account for the findings and that pica need not necessarily be present, although pica certainly is a very important factor in the degree of increase in lead absorption associated· with acute lead encephalopathy.
It is still not possible to identify with certainty the various sources of lead in household dust. Probably the major contributors to lead in soil and household dust are paint, putty, and the fallout from automotive exhausts. The lead emitted in automotive exhausts is rapidly transformed into inorganic forms - lead oxide and lead sulfate. Regardless of what the relative contributions of various sources may be, increased lead absorption in the United States in children has always been found in association with old housing.
Sharp increases in lead absorption may occur when young children are present in the home when old paint is being removed by sanding and burning. Screening programs have also identified outbreaks associated with the transport of lead-containing occupational dusts on the clothing of workmen into their homes. Good industrial practice requires that workmen's protective clothing be changed and laundered at the place of their employment. There has been much study of increased lead absorption among children living in close proximity to large lead smelters, and it is generally agreed that these instances constitute "unacceptable exposures.'' Follow-up studies at the El Paso smelter indicate that emissions can, in fact, be reduced with appropriate engineering and industrial-hygiene procedures.
Insofar as "normal" exposure to lead is concerned, it is generally agreed that food rather than air and water is the major source of lead for man and that the lead content of food may be increased during processing. The Food and Drug Administration has recently announced its intention to reduce the lead content of food through improvements primarily in canning procedures over the next few years. There has been considerable study of lead in drinking water where the water is unusually acidic and lead in plumbing rather extensive, as it is in Scotland. The lead content of some drinking-water samples in Scodand is about 10 to 50 times greater than the lead content of drinking water in the United States. The vast majority of drinking-water samples analyzed in the United States have contained substantially less lead than the USPHS drinking-water standard (less than 50 ug. Pb /L. water), which, in turn, is less than the WHO limit (less than 100 Mg. Pb/L. water).
Once absorbed into the body, lead is only slowly metabolized, stored, and excreted. Recent rather elegant metabolic studies in adult volunteers indicate that the residence time of lead in the soft tissues is about 35 to 40 days and that the residence time of lead incorporated into bone is 25 to 30 years. A very small fraction of lead absorbed in bone apparendy turns over at the same rate as softtissue lead. Studies in young children indicate that the infant and young child absorb approximately 50 percent of dietary lead and that they retain about 50 percent of what is absorbed. Experimental studies indicate that a number of factors may affect the absorption of lead. In the experimental animal, increased dietary fat increases lead absorption, while induced dietary deficiencies of calcium, iron, zinc, and copper enhance its absorption and retention. An empty stomach and small particle size enhance lead absorption. The relationship between particle size and absorption helps to explain why the level of lead absorption may increase so rapidly in young children who are in homes during the sanding and burning of old paint. Lead freely crosses the placenta. Indeed, paired maternal and cord blood samples show that blood lead concentrations are virtually identical in mother and infant at the time of birth.
Acute lead encephalopathy and the severe sequelae that may follow this, the most severe form of lead poisoning, have become uncommon in the United States during the past decade. However, evidence, both clinical and experimental, strongly implicates degrees of increase in lead absorption insufficient to cause obvious clinical symptoms as one of the causative factors that contribute to impairing the development of the nervous system.
Byers and Lord were the first to point out that children with a record of recurrent clinical lead poisoning failed to succeed in school largely because of short attention span, perseveration, and visual motor-perceptual deficits, even though they showed relatively normal results on standard LQ. tests. Subsequent studies in asymptomatic children with long-bone x-rays positive for "lead lines" and blood lead concentrations judged to be in excess of 50 Mg. Pb/ 100 ml. of whole blood and who were not treated have confirmed the observations of Byers and Lord.
There is a worldwide consensus that blood lead concentrations maintained during the preschool years in excess of 50 Mg- Pb/ 100 ml. whole blood carry an unacceptable risk for subtle but long-lasting impairment of the nervous system. To what extent early and effective intervention to shorten the period of increased lead absorption can reduce such effects is yet unknown. Whether maintenance of blood lead concentrations in the range of 30-50 Mg. Pb /100 ml. whole blood carries a similar risk remains controversial, as various studies have given conflicting results. Nevertheless, this question is extremely important, inasmuch as screening studies reveal that from 5 to 20 percent of children in old housing in the United States today show this level of increase in lead absorption.
In its most recent guidelines, the Center for Disease Control divides degrees of lead absorption into four risk classes according to blood lead range. The normal range (Class I) is defined by a blood lead concentration of less than 30 Mg. Pb/ 100 ml. whole bood. Moderate risk (Class II) is defined by the blood lead concentration of 30-49 Mg. Pb/ 100 ml. whole blood. High risk (Class ??) is defined by a blood lead range of 50-69 Mg- Pb/ 100 ml. whole blood, and urgent risk (Class IV) is defined by a blood lead concentration of 70 ug. Pb/ 100 ml. whole blood or more.
The degree of risk in these classifications is further modulated by the degree of elevation in erythrocyte protoporphyrin. Lead interferes with heme synthesis. Among the evidence of this interference is an elevation in erythrocyte protoporphyrin. Erythrocyte protoporphyrin is also increased in iron deficiency, so both the child's iron status and his lead-absorption status should be known for proper interpretation of this simple screening test, which has come into wide use during the past five years.
While the use of chelation therapy can be lifesaving in severe acute clinical lead poisoning, introduction of chelation therapy after the onset of symptoms does not prevent severe permanent sequelae among survivors. Today the only acceptable approach to management is the preventive approach. This requires a thorough environmental history, including parental occupational exposure, to identify the important sources of lead in the child's environment so that the child may be separated from them.
Because of the slow rate of metabolism of lead and the pervasiveness of lead exposure in the urban environment, long-term follow-up throughout the preschool years is mandatory. What effect the recent reduction in the lead content of gasoline will have on increased lead absorption in children remains to be seen. However, it is virtually certain that asymptomatic increased lead absorption and toxicity will remain a public-health problem in the United States until the old housing stock now in use is completely renovated or renewed.
Cadmium is a natural constituent of zinc ores, some ores containing up to 3 percent of cadmium sulfide. Not surprisingly, cadmium is a byproduct of zinc refining, and so its level of production is dependent on the rate of operation of the world's zinc smelters. In 1946, Dr. Hagino, a general practitioner, returned from the war to reopen a private clinic in Fuchu town, Toyama prefecture, Japan, which lies in the Jintsu River basin, downstream from a zinc- and lead-mining and smelting area. A number of patients visited Dr. Hagino with a painful bone disease, which he called "itai-itai byo," meaning "ouch-ouch disease."
At first, it was thought that itai-itai disease was a vitamin-D-deficient osteomalacia. Rice is a principal constituent of the diet of the inhabitants of this area and is grown locally in the Jintsu River valley. Subsequently, it was found that the average cadmium concentration of rice grown in this valley was more than 10 times higher (0.68 ug/gm. wet weight) than rice grown in other areas of Japan (0.066 /45/gm. wet weight). It was not until 1955 that Hagino and Kono reported itai-itai disease before a national audience in Japan, bringing national recognition to this disorder.
During the 15 to 20 years following their report, cadmium became implicated in this disorder and similar examples of itai-itai disease were found in other cadmium-polluted areas in Japan - with rice, shellfish, and organ meats found to be the principal dietary sources of excess cadmium. Although examples of itai-itai disease were found in cadmiumpolluted areas at all ages beyond the first decade of life, it was generally found principally in postmenopausal, multiparous women. Clinically, it is characterized by low back pain, disturbance of gait (duck waddle), kyphosis, restricted spinal movement, Milkman's pseudofractures, osteomalacia, proteinuria, glycosuria, increased serum alkaline phosphatase, decreased serum inorganic phosphate, and the appearance of the most specific objective sign of chronic cadmium toxicity: increased B2-microglobuIin in plasma and urine. A similar syndrome is known to occur in workers exposed to cadmium-oxide fumes, who, in addition, may have emphysema and pulmonary insufficiency.
Although the nuances of diagnosis and etiology are still debated in Japan, it is now generally considered that chronic cadmium poisoning is the principal etiologic factor and that the more severe clinical forms of disease occur when this is associated with deficient dietary intakes of calcium, probably vitamin D, and possibly iron and protein. Experimental studies have shown that cadmium interferes in the second hydroxylation step, which occurs in the renal tubular cells in the conversion of vitamin D to its most active form: 1 ,25-dihydroxycholecalciferol. This provides an explanation for the disturbance in calcium and phosphorus metabolism and the occurrence of osteomalacia and Milkman's syndrome. Itai-itai disease in Japan has alerted the world to the fact that contamination of man's food must be carefully monitored to prevent increase in contamination by cadmium.
Exposure of man to cadmium is related to its uses and its movement subsequent to use in the environment. In 1968, the U.S. demand for cadmium was approximately 13,000,000 pounds. Of this, less than 5 percent is recovered and recycled for new industrial use. It is estimated that 80 to 90 percent is not recovered and is ultimately dispersed into the general environment.
Nonrecycled uses include electroplating (45 to 49 percent), paints and pigments (18 to 21 percent), plastics (15 percent), and metallurgical uses and fungicides (approximately 2 percent). In addition, superphosphate fertilizers may contain 2-20 ppm of cadmium. Among its industrial uses are the rustproofing of iron and such steel articles as tools, fittings, bearings, and hardware by electroplating. Yellow and orange pigments derived from cadmium sulfide and red pigments from cadmium sulfoselenides are used in paints, artists' colors, rubber, plastics, printing inks, wallpaper, leather, glass, and vitreous enamels. Inexpensive rubber mattings used in homes may contain cadmium in the backing, which can, as the mats deteriorate, contribute to the cadmium content of household dust.
Cadmium is dispersed by air into dustfall and soil. Sewage sludge is particularly rich in cadmium and other trace metals. Sewage sludge is being used increasingly as fertilizer for agricultural crops. There is now intensive investigation on the uptake of cadmium into the edible portion of crops and factors that influence this.
The pH of the soil is particularly important. Increasing soil acidity increases the plant's uptake of cadmium. Of particular concern is the uptake of cadmium into cereal grains. It is hoped that the cadmium content of foodstuffs can be kept within tolerable limits through limitations in the amounts of sewage sludge used per acre and through the control of such factors as soil acidity that influence the uptake of cadmium by plants.
The analysis of cadmium in biologic materials presents extraordinary difficulties, so accurate data are likely to be obtained in very few laboratories. Most of the reliable data during the past decade have come from a few laboratories in Sweden, Japan, and the United States. Quality control, a necessity in this matter, is monitored through international, interlaboratory comparison tests. Our knowledge about cadmium metabolism has increased substantially during the past decade, with important data on human beings coming from the study of workers occupationally exposed to cadmium. In industry, stringent dust control and automation of many industrial procedures are necessary to prevent severe and sometimes fatal disease.
Cadmium apparendy does not cross the placenta. The total body burden at birth is estimated at more than 1 Mg. of cadmium. However, the body burden increases progressively throughout life. At 45 years of age, the average body burden is currently estimated as follows: Japan 21 mg., United States 9 mg., and Sweden 6 mg. Cigarette smoking contributes almost as much as food. For nonsmokers in the United States and Sweden, the body burden at age 45 is approximately 5 mg. One-third of the total body burden is concentrated in the renal cortex. Lesser concentrations are found in the liver, the pancreas, and muscle.
The fact that the body burden increases throughout life is attributable to the long biologic half-life in man, which is estimated to range from 13 to 40 years. There is still considerable controversy concerning the critical concentration of cadmium in the renal cortex (i.e., concentration above which irreversible renal injury occurs). On the basis of autopsy data from workers occupationally exposed to cadmium, it was originally estimated that the critical concentration might be 200 Mg- Cd/gm. (wet weight) of renal cortical tissue. Accumulating evidence suggests that this should be reduced to perhaps as low as 50 Mg- Cd/gm. (wet weight) of renal cortical tissue, a value that is still somewhat above those found in autopsy material in the general population. One of the problems in making such an estimate is the observation that once irreversible renal injury has occurred and loss of renal substance sets in, the urinary excretion of cadmium increases and renal cadmium content decreases. Newer approaches using neutron activation in living subjects may facilitate future work on this important issue.
Physicians not involved in industrial medicine are perhaps familiar with acute oral cadmium poisoning, which in the past was associated with the use of cadmium-plated ice trays in refrigerators and the filling of worn plated silver pitchers or cadmiumplated buckets not intended for use with food or citrus and other acidic juices for picnics. Clinically, acute oral cadmium poisoning is characterized by a syndrome often indistinguishable from acute bacterial food poisoning; rapid onset of vomiting, abdominal pain, and diarrhea. Such poisoning is selflimited and of no concern insofar as chronic exposures are concerned.
In industry, cadmium-oxide-fume poisoning is a serious but well-known entity. Workers so poisoned complain of irritation of the eyes, headache, vertigo, dryness of the throat, cough, constriction of the chest, and weakness of the legs. Delayed effects may follow, including shivering, sweating, nausea, epigastric pain, and dyspnea. Chronic cadmium poisoning may lead to emphysema and proteinuria, the liver being largely bypassed when the route of entry is the respiratory tract. Ultimately, the cadmium absorbed via the respiratory tract is translocated to the renal cortex. A cadmium metallothionen appears important in the transport of cadmium in the circulation and its sequestration, particularly in liver and kidney. Its pathophysiologic significance is still a subject of considerable research.
Insofar as children are concerned, it would appear advisable to keep cadmium intake at the lowest feasible level, since it is poorly excreted and the body burden of cadmium increases steadily throughout life. Cadmium is found particularly in urban soils and dusts. The transport of dusts into housing on the clothing of workers occupationally exposed to cadmium should, of course, be prohibited. In view of the limited availability of cadmium analyses, it is not surprising that there are almost no epidemiologic data on cadmium levels in children. Although hypertension has been experimentally induced in animals, there are no data implicating cadmium in this disease in man. Hypertension is not a feature of chronic cadmium poisoning in workers. Avoidance of cigarette smoking can significantly reduce the accumulation of cadmium.
It seems clear from the foregoing that control of environmental contamination by cadmium and its entry into the food chain lies almost entirely within the purview of public health agencies, such as the Food and Drug Administration, the Department of Agriculture, and the Environmental Protection Agency. There is no known effective treatment for chronic cadmium poisoning other than supportive measures, which may retard somewhat the progress of chronic renal and pulmonary insufficiency. Experiments about two decades ago indicated that the use of chelating agents, if anything, intensified the toxic renal effects of cadmium through acceleration of translocation of this metal from other tissues to the renal cortex.
FACTORS INFLUENCING METAL TOXICITY
During the past decade, much research effort has been aimed at the study of factors that influence the absorption, distribution, and toxicity of mercury, lead, and cadmium. The experimental studies reveal the complexity of interactions, particularly among essential and nonessential trace metals. Few clinical data have yet been reported on this fascinating topic. Quite early in the study of methyl-mercury toxicity, it was discovered that apparently healthy fish with a higher content of methyl mercury also had higher levels of selenium. Although the protective effect of selenium was reproduced experimentally in fish, the mechanism by which selenium may protect against the toxicity of methyl mercury remains a mystery.
The majority of experimental studies have been devoted to the factors influencing the absorption of cadmium, lead, and mercury from the gastrointestinal tract. Absorption of these metals by the rat is age-related, being highest at the youngest age. For example, while the rat may absorb 80 to 90 percent of dietary lead and cadmium during the first few days of life, by the end of the first month of life less than 1 percent of these metals is absorbed by the rat. This observation has been confirmed for lead in man: while infants up to two years of age may absorb up to 50 percent of dietary lead, the adult absorbs no more than 5 to 10 percent of dietary lead.
In the experimental animal, increased lipid content in the diet further enhances the absorption of lead, cadmium, and inorganic mercury in the neonatal animal. Adequate dietary intakes of calcium, iron, and zinc suppress absorption of lead. Recent observations suggest that animals deficient in calcium and iron elaborate binding proteins in the intestinal mucosa that have an affinity for lead as well as calcium and iron. Direct competition is suggested, as lead is readily displaced when adequate amounts of calcium and iron are present simultaneously. The absorption of dietary lead is also inversely proportional to dietary zinc content in the rat. When both cadmium and lead are present in excess in the diet of the rat, absorption of lead is suppressed.
Presence of excess arsenic in diet, however, does not suppress absorption of lead by the rat. Veterinarians have observed that young horses grazing on grasses contaminated with both zinc and lead do not develop the toxic manifestations of lead poisoning (pharyngeal and laryngeal paralysis), although they do develop clinical evidence of zinc toxicity (an artnritislike syndrome). Complex experiments in which zinc, iron, lead, and copper are administered in various combinations to the rat reveal variations in toxic manifestations. For example, correction of iron deficiency alone will prevent anemia when excess lead is not present; however, correction of both iron and copper deficiency must be made to prevent anemia when excess lead is present. In the same animals, correction of iron deficiency only is apparently adequate to prevent the accumulation of excess lead in the kidney.
While it is not possible to extrapolate these experimental data direcdy to man, the data suggest that diets adequate in minerals - including calcium, magnesium, iron, copper, zinc, and, possibly, selenium - and adequate in protein but not excessive in fat may play a role in health maintenance in that they may reduce the absorption of nonessential metals over the long term. However, it is unlikely that even adequate diet can compensate for moderate to gross overexposures to these toxic metals. In the immature rat, dietary deficiencies of iron and zinc and excesses of lead, when administered separately, have been associated with somewhat similar adverse effects on neurobehavioral development. However, the possible effects of interactions among these metals on neurodevelopment have not been studied. Such complex studies would be more meaningful insofar as actual human exposures are concerned, as marginal dietary deficiencies and excessive environmental exposures to lead and cadmium, for example, are likely to occur in the same population.
Exposure of the family to heavy metals is primarily through dust, food, and, in certain locations, water. About one-half of present lead production and use is devoted to the manufacture of lead-acid batteries. In this usage, about 98 percent of the lead is recovered and recycled, while many of the remaining uses ultimately result in the dispersion of lead into the environment. However, the uses of cadmium and mercury result ultimately in the dispersion of 80 to 90 percent into the environment. All of these heavy metals ultimately come to rest in surface soil, aquatic bottoms, and sewage sludge. Thus, heavy metals can enter the home and its inhabitants in many ways. The principal routes of concern are food (mercury in fish and cadmium in grain) or dust. The dust may be tracked in on feet or brought on clothing and hair. If paints containing any of these metals have been used on the interior, as they deteriorate, they will contribute to the heavy-metal content of household dust.
Maintenance of residential surfaces in good repair and cleanliness are clearly important in suppressing this type of contamination. Good industrial practice, which prohibits the transport of heavy-metal-containing dust on the clothing and person of workmen from the workplace to the home, would prevent this type of contamination. Examples of this type of home contamination are currently being recognized. In the long run, the citizenry will be dependent on such government agencies as the Environmental Protection Agency, Food and Drug Administration, and Department of Agriculture for limiting the heavy-metal content of food. This, in turn, will depend on limiting further buildup of these substances in the environment largely through improved waste-disposal procedures.
Mercury and lead readily cross the placenta. Outbreaks of severe poisoning have demonstrated their fetotoxicity. Cadmium apparently does not cross the placenta. Postnatally, once these metals are assimilated into the body, they are very slowly excreted. In industrialized societies, the body burdens of lead and cadmium increase with age. Fortunately, 90 percent or more of the total body lead burden is sequestered in bone. There is no evidence that it is released rapidly enough from bone to cause toxicity in the soft tissues late in life. On the other hand, the half-life of cadmium is measured in decades, and one-third of the total body cadmium burden is concentrated in the renal cortex. The various toxic manifestations produced by excess of these metals in the tissues is dependent on both their chemical form and their route of entry into the body. Experimental studies, which have been confirmed to a limited extent in human beings, show that the immature rapidly growing mammal absorbs and retains these metals at a much higher rate than does the mature mammalian organism.
Particle size plays a role not only in respiratory rétention but also in absorption from the alimentary tract. Smaller particulates are much more readily absorbed than are large, visible particles. These factors, in conjunction with the hand-tomouth activity normally seen in many infants and young children, make dust a particularly important environmental source, emphasizing the need for a clean, well-maintained house. Young couples and pregnant women in particular must be cautious when renovating old homes, especially when sanding old painted surfaces. Prudence demands that respirators be used, particularly if ventilation is poor, and that the dust created be thoroughly cleaned up by wet cleaning methods.
When chelation therapy may be lifesaving in acute inorganic mercury and lead poisoning, it does not necessarily prevent serious sequelae. There are no safe and efficacious chelating agents for the treatment of chronic mercury and cadmium toxicity. The suspected benefits of chelation therapy in chronically increased lead absorption remain to be documented. In any case, therapeutic maneuvers cannot substitute for adequate preventive measures. Clearly, the only valid public-health approach in the long run is the preventive approach .
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