ENVIRONMENTAL
RESEARCH
17.303-321
Widening
(1978)
Perspectives
A Review of Health
of Lead Toxicity
Effects of Lead Exposure PHILIPPE
in Adults
GRANDJEAN
Institute of Hygiene. University of Copenhagen, Denmark, Laboratory, Mount Sinai School of Medicine of the City News York, NeM* York 10029
and Emironmental University of New
Sciences York.
Received July 14, 1978 Lead has a wide range of applications. and its production and use result in contamination of the environment, including food and drinking water. Geochemical studies indicate that the majority of lead in ecosystems originated from industrial operations, and that human lead intake has increased IOO-fold above the “natural” level. prehistoric human skeletons contain about two orders of magnitude less lead than present-day samples. Biochemical interference with heme biosynthesis can be detected as a result of current lead exposures, inhibition of aminolevulinate dehydratase and accumulation of zinc protoporphyrin in erythrocytes being the earliest effects. Anemia is uncommon except for cases of lead poisoning, but even slightly increased lead absorption results in a decrease in hemoglobin concentrations. Modern neurobehavioral test methods have disclosed increased prevalence of psychological dysfunction associated with augmented lead absorption. Biochemical and behavioral changes occur below the recommended limit for blood lead concentration of 60 /.&IO0 ml. Several diagnostic tests for lead toxicity are available. The protoporphyrin concentration in the blood seems to be the best risk indicator. The highest occupational lead exposures occur in lead smelters and storage battery plants, but several other industrial operations may result in high lead levels. As much as 1% of the working population may have a significantly increased lead absorption with possible adverse effects.
UBIQUITY
OF LEAD POLLUTION
Useful physical and chemical properties make a wide spectrum of applications possible for lead and its compounds and alloys. Thus, lead is the most widely used nonferrous metal (Hernberg, 1976). Two decades ago, 113 different occupations were thought to entail an exposure to lead (Gafafer, 1964), and this number did not include indirect exposure (“bystanders”). Lead has been mined and manufactured for more than 2000 years. The present environmental lead pollution is particularly the result of the use of alkyl lead as a gasoline additive (Murozumi et al., 1969). The annual production of lead has been estimated at about 500-fold the total amount of lead circulating in the entire earth’s biomass (Elias et al., 1977). Even remote areas in Greenland and Antarctica have been shown to be polluted with lead (Murozumi et al., 1969). As determined by stable isotope measurements and comparison with alkaline earth concentrations, 90 to 99% of the lead in sedge and voles in a pristine valley in the Rocky Mountains originated from smelter fumes and gasoline (Hirao and Patterson, 1974; Elias et al., 1977). Patterson (1965) estimated a “natural” lead concentration in the air at about 0.0005 pg/n?, but in cities lead concentrations in air are lOOO- to lO,OOO-fold greater. An urban dweller may inhale as much as 60 pg of lead daily of which 35 to 303 0013-9351/78/0172-0303$02.00/0 Copyright @ 1978 by Academic Press: Inc. All rights of reproduction in any form reserved.
304
PHILIPPE
GRANDJEAN
40% is absorbed [National Academy of Sciences, (NAS), 19721. In certain industrial facilities, air levels have been reported to exceed a standard of 100 &m3 adopted by some countries (World Health Organization (WHO), 1977). Moreover, atmospheric lead pollution not only adds to the respiratory lead intake, but it may also cause contamination of food. From geochemical data, Elias et al. (1977) calculated “natural” lead absorption to be about 0.3 puglday. Most recent studies of dietary lead intake have demonstrated figures about 200 to 300 Fg/day which would lead to a daily absorption of 20 to 30 &day (WHO, 1977), i.e., about loo-fold the calculated “natural” value. Such an increase in the lead exposure of the general population may be due to several factors, including the environmental pollution. The vast number of applications of lead, e.g., in lead glaze, crystal glass, pigments, siccatives, solder, and other alloys, may give off traces of lead to foods, adding to the dietary lead intake. Chow et al. (1974) found that canned tuna muscle contained about lOOOfold more lead than fresh muscle. Other canned products have proved high in lead as well (WHO, 1977). Cow’s milk contains a few micrograms of lead per liter, but processed milk and, especially, evaporated milk and formulas are much higher in lead (WHO, 1977). Wine has been found to contain 50 to 4000 pg of lead/liter (Boudene et al., 1975), and consumption of illicitly distilled whiskey has caused many cases of lead poisoning (Whitfield et al., 1972). Lead concentrations in deep seawaters are less than 0.1 pgliter (Chow and Patterson, 1966), and Patterson (1965) estimated a “natural” lead content in drinking water of about 0.5 pg/liter. A limit of 50 @liter is recommended by the U. S. Public Health Service, and this limit is rarely exceeded (NAS, 1972). Nevertheless, in areas with soft water, the levels may be much higher, especially if lead pipes are used (Beattie et al., 1972). Thus, it is apparent from the literature that the multitude of lead applications results in widespread environmental pollution and contamination of food and beverages. Occupational lead exposure, when present, further increases lead intake considerably. It appears that the lead pollution is ubiquitous and that lead intake of the general population is about two orders of magnitudes greater than the “natural” lead intake. LEAD RETENTION IN THE HUMAN BODY The toxicokinetics of lead exposure have been fairly well elucidated and are described in detail elsewhere (NAS, 1972; WHO, 1977). A total of 30 to 40 Fg of lead is absorbed per day by the average human being, but most of it is excreted, and only a few micrograms are retained in the body. Most lead is excreted in urine, and lead excretion in hair is negligible though hair lead concentrations are relatively high (Grandjean, 1978a). Lead is transported in the blood, about 95% being bound to erythrocytes. In the blood, lead has a biological half-life of about 25 days (Rabinowitz et al., 1976). Lead retained in soft tissues has a half-life of a few months (Rabinowitz et al. 1976), but the half-life in the brain may be somewhat longer (Grandjean, 1978~). More than 90% of the body lead burden is accumulated in the calcified tissues, and the lead level increases in these tissues at least up to the age of 40 years (Barry and Mossman, 1970; Schroeder and Tipton, 1968). Differences in exposure levels are reflected in the tissue lead burdens. Accord-
PERSPECTIVES
OF
LEAD
305
TOXICITY
ingly, attempts have been made to assess present differences in community lead exposures by analyzing blood and other biological samples for lead (Kehoe et al., 1933; Goldwater and Hoover, 1967). It appears that only isolated, primitive tribes have significantly lower lead levels than industrialized populations (Shapiro et al., 1975). However, since global air pollution adds to the lead exposure, a “natural” lead intake may not exist anywhere today. Since lead is predominantly retained in the calcified tissues, analyses of archeological bone finds are well suited to assess lead exposures in the past. Prehistoric Danish bone samples exhibited seven times less lead than modern samples (Grandjean and Holma, 1973; Grandjean, 1975). The ancient bones were, however, exposed to possible contaminating or leaching effects of soil water for up to 6000 years, and the quality control of the analytical procedures should have been more extensive. In a recent study, well-preserved tissues from prehistoric and historic populations of the Nile Valley were examined for lead (Grandjean et al., 1978~). The bodies had been buried in the desert of Sudanese Nubia without prior embalming, and the dry, hot climate caused partial mummification of the tissues, including brain and skin (Grandjean et al., 1978b). The oldest samples originated from the period 3300 to 2800 BC when almost no manmade lead pollution is thought to have been present. Samples of bones and teeth contained about lo- to loo-fold less lead than do modern specimens, thus confirming a markedly increased lead exposure of modern man (Table 1). It is possible, however, that the analyses of Nubian samples suffered from slight background contamination, and the “natural” levels may therefore be even lower (Grandjean et al., 1978~). A number of Nubian skulls contained mummified brain material which has been analyzed for lead, copper, and potassium (Grandjean et al., 1978b). It appears that much organic material and potassium were lost from the brain during the mummification process. The ratio between lead and copper concentrations was not significantly different from the ratio in 22 fresh brains from Denmark, but a large range was apparent in the Nubian samples. Many of the Nubian brain fragments were small, and surface contamination may have been significant though rigorous preparation procedures were used. Topographical variations in the retention of lead in the brain (Grandjean, 197%~) may have contributed to the large range of the results. Very little is known about the kinetics of trace elements during a natural mummification process, but it is possible that relatively much lead is retained in the brain in low-level lead exposure. TABLE “NATURAL” AND
Natural Normal
LEAD
AND
“NORMAL”
CONCENTRATIONS
1 DAILY
INTAKE
IN BONE
AND
OF LEAD,
TOOTHY
Daily absorption ( &day)
Bone lead (/au
Tooth lead ( ELg/g)
0.30 S-50
0.6 6-30
0.6 20-200
’ Data from Grandjean et al. (1978~). * Calculated value (Elias et al.. 1977).
306
PHILIPPE
GRANDJEAN
With the introduction in Nubia of different applications of lead, lead levels in bone and tooth increased (Grandjean er al., 1978~). According to Gilfillan (1965), lead poisoning was prevalent in ancient Rome due to lead water pipes, extensive use of lead as a wine additive and in drugs, etc. These applications were prevalent up to the present century (Grandjean, 1975). Very high lead concentrations have been discovered in archeological bone samples from periods between the 12th and 19th centuries (Jaworowski, 1968; Grandjean and Holma, 1973; Grandjean, 1975). Samples of hair from about the turn of the century contain much more lead than contemporary samples (Weiss et al., 1972). It is likely that the lead exposure in historical periods was higher than that of today due to ignorance, adulterations, and lack of official control measures (Grandjean, 1975). The significance of this is difficult to assess since very little is known of the adverse effects during these periods of time. Blood samples are the most commonly used source for the determination of lead retention in the body, but urine and hair have been used as well. The “natural” lead concentration in such specimens is not known, but a large number of studies have provided data concerning “normal” levels, i.e., levels found in the general population with no known excess lead exposure (WHO, 1977). Permissible biological limits corresponding to the air lead standard have been proposed (Table 2). ACUTE AND INSIDIOUS LEAD POISONING Fortunately, acute episodes of lead poisoning have become rare in adults. Depending upon the severity and duration of exposure, effects may range from lead colic to encephalopathy and death. Long-term effects of undue exposure to lead in adults include lead palsy, which often involves the extensor muscles of the hand and forearm resulting in “wrist drop” and is caused by a peripheral motor neuropathy. Anemia may be present as a result of hemolysis and inhibition of heme synthesis. Chronic nephropathy may be associated with long-lasting lead exposure. The gross indications of lead toxicity are described in detail elsewhere (Aub ef al., 1926; Cantarow and Trumper, 1944; NAS, 1972; WHO, 1977). The response of the organism to increased lead absorption is a graded one, related to the magnitude of exposure. Thus, the toxic effects constitute a continuous spectrum from subtle changes when the limits for homeostasis are exceeded to the severe injuries mentioned. Toxicity first manifests itself in certain target organs of the body [the most sensitive one is referred to as the “critical organ” (Nordberg, 1976)]. Commonly, the bone marrow is believed to be the critical organ in lead poisoning (Nordberg, 1976), but newer insights in central nervous system TABLE “NORMAL”
2
LEAD CONCENTRATIONS IN BLOOD, URINE, BIOLOGICAL LIMITS FOR OCCUPATIONAL
Blood
( pgl100 ml) Normal Exposure limit
IO-25 60
AND HAIR, AND THE CORRESPONDING LEAD EXPOSURE”
Urine (&liter)
Hair ( b4m
RESEARCH
17.303-321
Widening
(1978)
Perspectives
A Review of Health
of Lead Toxicity
Effects of Lead Exposure PHILIPPE
in Adults
GRANDJEAN
Institute of Hygiene. University of Copenhagen, Denmark, Laboratory, Mount Sinai School of Medicine of the City News York, NeM* York 10029
and Emironmental University of New
Sciences York.
Received July 14, 1978 Lead has a wide range of applications. and its production and use result in contamination of the environment, including food and drinking water. Geochemical studies indicate that the majority of lead in ecosystems originated from industrial operations, and that human lead intake has increased IOO-fold above the “natural” level. prehistoric human skeletons contain about two orders of magnitude less lead than present-day samples. Biochemical interference with heme biosynthesis can be detected as a result of current lead exposures, inhibition of aminolevulinate dehydratase and accumulation of zinc protoporphyrin in erythrocytes being the earliest effects. Anemia is uncommon except for cases of lead poisoning, but even slightly increased lead absorption results in a decrease in hemoglobin concentrations. Modern neurobehavioral test methods have disclosed increased prevalence of psychological dysfunction associated with augmented lead absorption. Biochemical and behavioral changes occur below the recommended limit for blood lead concentration of 60 /.&IO0 ml. Several diagnostic tests for lead toxicity are available. The protoporphyrin concentration in the blood seems to be the best risk indicator. The highest occupational lead exposures occur in lead smelters and storage battery plants, but several other industrial operations may result in high lead levels. As much as 1% of the working population may have a significantly increased lead absorption with possible adverse effects.
UBIQUITY
OF LEAD POLLUTION
Useful physical and chemical properties make a wide spectrum of applications possible for lead and its compounds and alloys. Thus, lead is the most widely used nonferrous metal (Hernberg, 1976). Two decades ago, 113 different occupations were thought to entail an exposure to lead (Gafafer, 1964), and this number did not include indirect exposure (“bystanders”). Lead has been mined and manufactured for more than 2000 years. The present environmental lead pollution is particularly the result of the use of alkyl lead as a gasoline additive (Murozumi et al., 1969). The annual production of lead has been estimated at about 500-fold the total amount of lead circulating in the entire earth’s biomass (Elias et al., 1977). Even remote areas in Greenland and Antarctica have been shown to be polluted with lead (Murozumi et al., 1969). As determined by stable isotope measurements and comparison with alkaline earth concentrations, 90 to 99% of the lead in sedge and voles in a pristine valley in the Rocky Mountains originated from smelter fumes and gasoline (Hirao and Patterson, 1974; Elias et al., 1977). Patterson (1965) estimated a “natural” lead concentration in the air at about 0.0005 pg/n?, but in cities lead concentrations in air are lOOO- to lO,OOO-fold greater. An urban dweller may inhale as much as 60 pg of lead daily of which 35 to 303 0013-9351/78/0172-0303$02.00/0 Copyright @ 1978 by Academic Press: Inc. All rights of reproduction in any form reserved.
304
PHILIPPE
GRANDJEAN
40% is absorbed [National Academy of Sciences, (NAS), 19721. In certain industrial facilities, air levels have been reported to exceed a standard of 100 &m3 adopted by some countries (World Health Organization (WHO), 1977). Moreover, atmospheric lead pollution not only adds to the respiratory lead intake, but it may also cause contamination of food. From geochemical data, Elias et al. (1977) calculated “natural” lead absorption to be about 0.3 puglday. Most recent studies of dietary lead intake have demonstrated figures about 200 to 300 Fg/day which would lead to a daily absorption of 20 to 30 &day (WHO, 1977), i.e., about loo-fold the calculated “natural” value. Such an increase in the lead exposure of the general population may be due to several factors, including the environmental pollution. The vast number of applications of lead, e.g., in lead glaze, crystal glass, pigments, siccatives, solder, and other alloys, may give off traces of lead to foods, adding to the dietary lead intake. Chow et al. (1974) found that canned tuna muscle contained about lOOOfold more lead than fresh muscle. Other canned products have proved high in lead as well (WHO, 1977). Cow’s milk contains a few micrograms of lead per liter, but processed milk and, especially, evaporated milk and formulas are much higher in lead (WHO, 1977). Wine has been found to contain 50 to 4000 pg of lead/liter (Boudene et al., 1975), and consumption of illicitly distilled whiskey has caused many cases of lead poisoning (Whitfield et al., 1972). Lead concentrations in deep seawaters are less than 0.1 pgliter (Chow and Patterson, 1966), and Patterson (1965) estimated a “natural” lead content in drinking water of about 0.5 pg/liter. A limit of 50 @liter is recommended by the U. S. Public Health Service, and this limit is rarely exceeded (NAS, 1972). Nevertheless, in areas with soft water, the levels may be much higher, especially if lead pipes are used (Beattie et al., 1972). Thus, it is apparent from the literature that the multitude of lead applications results in widespread environmental pollution and contamination of food and beverages. Occupational lead exposure, when present, further increases lead intake considerably. It appears that the lead pollution is ubiquitous and that lead intake of the general population is about two orders of magnitudes greater than the “natural” lead intake. LEAD RETENTION IN THE HUMAN BODY The toxicokinetics of lead exposure have been fairly well elucidated and are described in detail elsewhere (NAS, 1972; WHO, 1977). A total of 30 to 40 Fg of lead is absorbed per day by the average human being, but most of it is excreted, and only a few micrograms are retained in the body. Most lead is excreted in urine, and lead excretion in hair is negligible though hair lead concentrations are relatively high (Grandjean, 1978a). Lead is transported in the blood, about 95% being bound to erythrocytes. In the blood, lead has a biological half-life of about 25 days (Rabinowitz et al., 1976). Lead retained in soft tissues has a half-life of a few months (Rabinowitz et al. 1976), but the half-life in the brain may be somewhat longer (Grandjean, 1978~). More than 90% of the body lead burden is accumulated in the calcified tissues, and the lead level increases in these tissues at least up to the age of 40 years (Barry and Mossman, 1970; Schroeder and Tipton, 1968). Differences in exposure levels are reflected in the tissue lead burdens. Accord-
PERSPECTIVES
OF
LEAD
305
TOXICITY
ingly, attempts have been made to assess present differences in community lead exposures by analyzing blood and other biological samples for lead (Kehoe et al., 1933; Goldwater and Hoover, 1967). It appears that only isolated, primitive tribes have significantly lower lead levels than industrialized populations (Shapiro et al., 1975). However, since global air pollution adds to the lead exposure, a “natural” lead intake may not exist anywhere today. Since lead is predominantly retained in the calcified tissues, analyses of archeological bone finds are well suited to assess lead exposures in the past. Prehistoric Danish bone samples exhibited seven times less lead than modern samples (Grandjean and Holma, 1973; Grandjean, 1975). The ancient bones were, however, exposed to possible contaminating or leaching effects of soil water for up to 6000 years, and the quality control of the analytical procedures should have been more extensive. In a recent study, well-preserved tissues from prehistoric and historic populations of the Nile Valley were examined for lead (Grandjean et al., 1978~). The bodies had been buried in the desert of Sudanese Nubia without prior embalming, and the dry, hot climate caused partial mummification of the tissues, including brain and skin (Grandjean et al., 1978b). The oldest samples originated from the period 3300 to 2800 BC when almost no manmade lead pollution is thought to have been present. Samples of bones and teeth contained about lo- to loo-fold less lead than do modern specimens, thus confirming a markedly increased lead exposure of modern man (Table 1). It is possible, however, that the analyses of Nubian samples suffered from slight background contamination, and the “natural” levels may therefore be even lower (Grandjean et al., 1978~). A number of Nubian skulls contained mummified brain material which has been analyzed for lead, copper, and potassium (Grandjean et al., 1978b). It appears that much organic material and potassium were lost from the brain during the mummification process. The ratio between lead and copper concentrations was not significantly different from the ratio in 22 fresh brains from Denmark, but a large range was apparent in the Nubian samples. Many of the Nubian brain fragments were small, and surface contamination may have been significant though rigorous preparation procedures were used. Topographical variations in the retention of lead in the brain (Grandjean, 197%~) may have contributed to the large range of the results. Very little is known about the kinetics of trace elements during a natural mummification process, but it is possible that relatively much lead is retained in the brain in low-level lead exposure. TABLE “NATURAL” AND
Natural Normal
LEAD
AND
“NORMAL”
CONCENTRATIONS
1 DAILY
INTAKE
IN BONE
AND
OF LEAD,
TOOTHY
Daily absorption ( &day)
Bone lead (/au
Tooth lead ( ELg/g)
0.30 S-50
0.6 6-30
0.6 20-200
’ Data from Grandjean et al. (1978~). * Calculated value (Elias et al.. 1977).
306
PHILIPPE
GRANDJEAN
With the introduction in Nubia of different applications of lead, lead levels in bone and tooth increased (Grandjean er al., 1978~). According to Gilfillan (1965), lead poisoning was prevalent in ancient Rome due to lead water pipes, extensive use of lead as a wine additive and in drugs, etc. These applications were prevalent up to the present century (Grandjean, 1975). Very high lead concentrations have been discovered in archeological bone samples from periods between the 12th and 19th centuries (Jaworowski, 1968; Grandjean and Holma, 1973; Grandjean, 1975). Samples of hair from about the turn of the century contain much more lead than contemporary samples (Weiss et al., 1972). It is likely that the lead exposure in historical periods was higher than that of today due to ignorance, adulterations, and lack of official control measures (Grandjean, 1975). The significance of this is difficult to assess since very little is known of the adverse effects during these periods of time. Blood samples are the most commonly used source for the determination of lead retention in the body, but urine and hair have been used as well. The “natural” lead concentration in such specimens is not known, but a large number of studies have provided data concerning “normal” levels, i.e., levels found in the general population with no known excess lead exposure (WHO, 1977). Permissible biological limits corresponding to the air lead standard have been proposed (Table 2). ACUTE AND INSIDIOUS LEAD POISONING Fortunately, acute episodes of lead poisoning have become rare in adults. Depending upon the severity and duration of exposure, effects may range from lead colic to encephalopathy and death. Long-term effects of undue exposure to lead in adults include lead palsy, which often involves the extensor muscles of the hand and forearm resulting in “wrist drop” and is caused by a peripheral motor neuropathy. Anemia may be present as a result of hemolysis and inhibition of heme synthesis. Chronic nephropathy may be associated with long-lasting lead exposure. The gross indications of lead toxicity are described in detail elsewhere (Aub ef al., 1926; Cantarow and Trumper, 1944; NAS, 1972; WHO, 1977). The response of the organism to increased lead absorption is a graded one, related to the magnitude of exposure. Thus, the toxic effects constitute a continuous spectrum from subtle changes when the limits for homeostasis are exceeded to the severe injuries mentioned. Toxicity first manifests itself in certain target organs of the body [the most sensitive one is referred to as the “critical organ” (Nordberg, 1976)]. Commonly, the bone marrow is believed to be the critical organ in lead poisoning (Nordberg, 1976), but newer insights in central nervous system TABLE “NORMAL”
2
LEAD CONCENTRATIONS IN BLOOD, URINE, BIOLOGICAL LIMITS FOR OCCUPATIONAL
Blood
( pgl100 ml) Normal Exposure limit
IO-25 60
AND HAIR, AND THE CORRESPONDING LEAD EXPOSURE”
Urine (&liter)
Hair ( b4m
