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Behavioral Measures of Neurotoxicity (1990)

Chapter: The Health Effects of Environmental Lead Exosure: Closing Pandora's Box

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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Page 245
Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Page 246
Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Page 247
Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Page 248
Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Page 249
Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Page 250
Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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Suggested Citation:"The Health Effects of Environmental Lead Exosure: Closing Pandora's Box." National Research Council. 1990. Behavioral Measures of Neurotoxicity. Washington, DC: The National Academies Press. doi: 10.17226/1352.
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The Health Effects of Environmental Lead Exposure: Closing Pandora's Box Deborah C. Rice Lead has been recognized as a poison from ancient times to the present (Cantarow and Trumper, 1944; Oliver, 1914~. Over the last decade or so, attention has focused on the subtle effects of environ- mental exposure at levels presently considered "normal" in our in- dustrialized age [Landsdown and Yule, 1986; Mahaffey, 1985; Na- tional Academy of Sciences (NAS), 1980; Needleman, 1980; Rutter and Russell Jones, 1983~. The resultant research has inspired lively and sometimes heated debate concerning the nature and possible threshold of these effects. The recognition that lead produces intellectual im- pairment in children, as well as other health effects, has resulted in the progressive tightening of regulation of lead in the United States and other countries, including the phaseout of lead from gasoline [Environmental Protection Agency (EPA), 1984; see Johnson and Mason, 1984, for review of U.S. lead regulations]. Exploration over the last decade of the effects of environmental exposure to lead, neuropsychological and otherwise, represents a case study in the scientific and political procedures, problems, and fail- ures inherent in such an endeavor. As such it can be used as a model for discussion in light of the theme of Part III of this volume chemi- cal time bombs. All individuals in industrialized societies carry a significant body burden of lead, a situation that will take at least a generation to change even if lead were removed from the environment instantaneously tomorrow. What have been, and what can we antici- pate will be, the consequences of this mass exposure? What are the 243

244 DEBORAH C. RICE issues critical to this evaluation, and what should be clone differently in the future? HISTORY OF THE PRESENT PERSPECTIVE ON THE ENVIRONMENTAL NEUROTOXICITY OF LEAD Although legal is a common element in the earth's crust, its ubiqui- tous presence in bioavailable forms in the environment is due largely to the activities of humans (see Lin-Fu, 1985; Smith, 1986 for reviews). Lead has been used in metalworking and in pottery glazes for mil- lennia. The Romans used lead for plumbing as well as a sweetening agent in wine and other foods. The industrial revolution and the addition of lead to gasoline in the 1920s have resulted in dramatic increases in environmental lead levels (Elias et al., 1975~. Present blood levels of industrial populations are highly correlated with the amount of leader} gasoline in use (Hunter, 1986~. Present environmental levels are several orders of magnitude above preindustrial levels (NAS, 1980; see Table 1~. The bodily burden of lead in human bones is pres- ently 500-foIct greater than in prehistoric times, and the present diet of Americans contains 100 times more lead than prehistoric diets (NAS, 1980~. The inclusion of tetraethyllead as a gasoline aclctitive in the 1920s was a lan~lmark event that resulted in a steep increase in lead emit- ted into the environment (Elias et al., 1975~. The overtly toxic effects of lead were already recognized at that time; the use of lead as a TABLE 1 Comparison of Estimated Natural Levels of Lead in the Environment with Typical Present-Day Levels Natural Present Approximate Ratio, Medium Concentration Concentration Present/Natural Air Rural/remote 0.01-0.1 ng/m3 0.1-100 ng/m3 10-1,000 Inhabited 0.1-1.0 ng/m3 0.1-10 g/m3 100-10,000 Soil Rural/remote 5-25 g/g 5-50 g/g 1-2 Inhabited 5-25 g/g 1~5,000 g/g 2-200 Water Fresh Ocean Food 0.005-10 g/L 0.001 g/L 0.0001-0.1 g/g 0.01-10 g/g 0.005-10 g/L 1 0.005~.015 g/L 10 100 SOURCE: NAS (1980).

HEALTH EFFECTS OF ENVIRONMENTAL LEAD EXPOSURE 245 gasoline additive engendered grave warnings by health professionals concerning the potential threat to the general health as a result of lead exposure (Rosner and Markowitz, 1985~. This concern was based on occurrences of mortality and severe neurologic and psychiatric signs in workers exposed during manufacture of this additive. A committee convened by the Surgeon General warned in 1926 (in Rosner and Markowitz, 1985~: "It remains possible that if the use of leaded gasoline becomes widespread, conditions may arise very different from those studied by us.... Longer experience may show that even such slight storage of lead as was observed in these studies may lead eventually in susceptible individuals to recognizable or to chronic degenerative diseases of a less obvious character." Despite the rec- ommendation by the committee that the matter be studied further, the interests of the automotive and oil industries won out, lead re- mained in gasoline, and no further data were collected. In the 1940s, it was recognized by astute physicians that children who had been treated for lead poisoning suffered permanent sequelae in the form of neurological damage (Byers and Lord, 1943~. High- level lead exposure in children at that time was via lead-based paint. Byers and Lord reported poor school performance, impulsive behav- ior, short attention span, restlessness, and occasional neurological signs in these children. These observations were later replicated by other investigators Jenkins and Mellins, 1957; Perlstein and Attala, 1966; Thurston et al., 1955~. In the 1970s, concern arose in the United States and elsewhere that the tons of lead being introduced into the environment every year by the use of leaded gasoline, as well as other industrial processes, were producing significant health effects, particularly in children. The new concern was that common environmental levels of lead were producing intellectual impairment in children that had no overt signs of lead poisoning. Early in the decade, attention focused on children who had ingested lead-based paint (de le Burde and Choate, 1972; Lin-Fu, 1972~. Deficits in IQ, fine motor performance, and behavioral disorders such as distractibility and constant need for attention were observed in children who had never exhibited overt signs of lead intoxication. A new understanding of the insidious effects of lead on the intel- lectual capacity of a large number of children arose with the landmark study of Needleman et al. in 1979. These investigators reported decreased IQ and increased incidence of distractibility and inattention in middle- class children with no exposure to lead from paint. The conclusion to be drawn from this research was that environmental sources were responsible for the increased lead burden in these children, and that

246 DEBORAH C. RICE this environmental contamination at levels that had come to be re- garded as "normal" could be insidiously robbing children in industrialized countries of their intellectual birthright. Largely as a result of that study, the last decade has witnessed intense research into the health effects of lead and the sources of exposure of the general population. The issue has generated a great deal of political as well as scientific controversy. Involved have been physicians, epidemiologists, chem- ists, geologists, animal researchers, representatives of the lead indus- try, and members of a host of government agencies in a number of countries. The result of this intense scrutiny is that probably more is known about the health effects of lead than any other noncarcinogenic environmental contaminant. OVERVIEW OF MODERN STUDIES There have been a number of cross-sectional (retrospective) stud- ies since 1979 concerning the effects of lead on intellectual and other behavioral functions in children. The general trend has been to study children with increasingly lower body burdens of lead and to focus on middle class rather than disadvantaged children. These studies have been extensively reviewed (cf. Mahaffey, 1985; Rutter and Russell Jones, 1983), although new important studies have been published very recently. There are also several prospective studies going on, in which the mothers are recruited before the birth of their infants, and the infants are followed in a longitudinal manner. This design is stronger than a cross-sectional design, and these studies will undoubtedly continue to provide important information over the next several years. This section reviews recently published data from the prospective studies, as well as the new cross-sectional studies. Alternate meth- ods of testing for nervous system effects, as well as other recently reported health effects of lead, are described briefly. Prospective Studies Reproductive Effects It has long been recognized that industrial exposure to high lead levels produced an increased incidence of miscarriages and stillbirths, and that infants that did survive failed to thrive and exhibited neuro- logical abnormalities. Although the situation is less clear for lower exposure to lead, recent studies provide evidence that low-level lead exposure causes reproductive problems. Increased maternal blood lead levels are associated with increased incidence of preterm delivery (McMichael et al., 1986) and decreased gestational age (Dietrich et

HEALTH EFFECTS OF ENVIRONMENTAL LEAD EXPOSURE 247 al., 1987; Moore et al., 1982). Blood lead has also been found to be associated with increased spontaneous abortion (McMichael et al., 1986~. Higher lead burden may also be associated with minor but not major physical abnormalities (Needleman et al., 1984), although this is not a universal finding (Ernhart et al., 1985, 1986; McMichael et al., 1986~. Increased maternal blood lead level is also associated with abnormal reflexes, poor muscle tone, and neurological soft signs such as jitteriness, hypersensitivity, and abnormal cry in the infant (Ernhart et al., 1985, 1986~. It must be stressed that the maternal and infant blood lead levels in these studies were in the range considered normal or average for people in industrialized societies (2-15,ug/dL in most cases). It is well established that premature or small-for-date infants are at greater risk for a variety of behavioral and other health problems. Such children have more trouble in school and require special help more often than other children (Schraeger et al., 1966; Weiner et al., 1968~. Thus, these individuals are likely to represent an ongoing cost to society over and above any special medical intervention that might be associated with the neonatal period. Early Behavioral Effects of Perinatal Lead Exposure Obviously the functional effects of perinatal lead exposure are not separate from the effects discussed in the preceding section, but will in part be related to them. (In fact, controlling for effects such as gestational age in evaluation of behavioral effects may underestimate the effects of lead.) There are at least three prospective studies at present in which women are recruited during pregnancy and the offspring are monitored at specified ages. In one study by Bellinger and colleagues (Bellinger et al., 1987a) performance on the Bayley Mental Development Index (MDI) at 6, 12, and 24 months of age was associated with cord but not postnatal blood lead levels (Figure 1~. The difference between the high (mean 14.6,ug/dL) and low (mean 1.8 ,ug/dL) blood lead groups was ~7 points. Assessment of these chil- dren at 57 months of age (Bellinger et al., 1987b) revealed that perfor- mance on the General Cognitive Index of the McCarthy Scales was associated with blood lead levels at 24 but not 57 months of age (after adjusting for possible confounders). Blood levels averaged 6.8 ,ug/dL at 24 months and 6.4 ,ug/dL at 57 months. In the study by Dietrich and colleagues (Dietrich et al., 1987), it was found that each log unit increment in blood lead was associated with a covariate-adjusted reduction of 5.7 points on the MDI; the reduction was 8.0 points if the effects on gestational age and birth weight were included. One year after birth, prenatal blood lead lev-

248 DEBORAH C. RICE 120 a oh x ~ ~6 - c 0, 1 Cal ID 108 104 Cord Blood Lead Group ~ Low ~ Medium Hiah . ~ 0 6 12 18 24 Age at Testing (months) FIGURE 1 Mean Mental Development Index scores at four ages In infants according to lead level In umbilical cord blood. SOURCE: Bellinger et al. (1987a). els were negatively correlated with MDI, Bayley Psychomotor Devel- opment Index (PDI), and Bayley Infant Behavioral Record (IBR). The IBR revealed higher activity levels and more negative social-emo- tional response. In the third prospective study, in Port Pirie, South Australia (McMichael et al., 1986), a decrease of 2 points in the MDI scale for every 10 ~g/dL increase in blood lead levels was observed at 24 months of age. Performance was found to be more related to postnatal than prenatal blood lead levels; however, no assessment was performed before 2 years of age. It is possible that early testing would have revealed significant prenatal exposure effects. In a retrospective study, Winneke et al. (1985a,b) found that per- formance on a variety of neurobehavioral and intellectual tasks at 6- 7 years of age was attributable approximately equally to maternal levels at birth (average 9 ~g/dL) and to current blood levels in the children. Retrospective Studies on Correlation of l.ead Body Burden and Behavior in Grade School Children Since the study by Needleman and colleagues (Needleman et al., 1979), a number of investigators have examined the effects of moderate-

HEALTH EFFECTS OF ENVIRONMENTAL LEAD EXPOSURE 20 10 BASC Score Difference from School O Mean (Adjusted) -1 0 —20 _ I I I, I 1.5 2.0 2.5 l l 3.0 Log Blood Lead ~ ~ 1 10 15 20 25 30 5 249 Blood Lead (pg/dL) FIGURE 2 British Ability Scales Combined (BASC) score (mean and 95 percent confi- dence intervals) for groups of children ordered by blood lead. SOURCE: Fulton et al. (1987). level exposure on intellectual functioning in children. Such studies have usually included some measure of intelligence (IQj, school functioning, teachers' rating of classroom behavior, or specific mea- sures of attentional mechanisms. Most recent studies have utilized populations with lower body burdens of lead than the children assessed by Needleman. For example, Fulton et al. (1987) reported a linear relationship between intellectual functioning and log blood lead con- centration for blood lead values between approximately 5 and 25 ,ug/ dL (mean about 10 ,ug/dL) in children living in Edinburgh, with no indication of a threshold for lead effect (Figure 2~. Results were significant after adjusting for potential confounders. Another study of middle-class children in New Zealand (Silva et al., 1988) reported high correlations between log blood lead (mean 11 ,ug/dL) and mea- sures of inattention and hyperactivity, after adjusting for confounding variables. A number of other studies published since 1980 have also reported a negative association between lead body burden and performance (Hansen et al. 1987; Hatzakis et al., 1987; Hawk et al., 1986; Schroeder et al., 1985; Winneke and Kraemer, 1984; Winneke et al., 1983; Yule et al., 1981), although this finding has not been universal. (This issue is discussed in a later section.) Treater Behavioral Concomitants of Increased Lead Burden The consequences of early poor performance as a result of lead exposure in terms of grade retention or need for special education have been little investigated. In a follow-up of children from the

250 DEBORAH C RICE T^BLE 2 Indices of Academic Failure Dentine Lead Level Academy Aide Grade Retentions Low 17~ (8/4~ 13~ (2/4~ Midrange 18.6~ (13/70) 11.6~ (8/69) Elevated 36.4~ (8/22) 22.7~ (5/22) Total 20.9~ (29/139) 10.9~ (15/138) (2) = 3.~, ~ < 0.20. ~ ~(2) = 5.61, p < 0.10. a: I Needleman et aL (1979) study, BeUinger et aL (1984) reported a Ove- fold Increase in grade retention and a twofold increase in the need for academic aid in teenagers' based on tooth lead levels as 5 and 6 year aids (Table 2). Barrett (1978) reported a dose-related increase in Satisfactory school performance as a function of increased free erythrocyte protoporphyrin (PEP) levels (a measure of lead expo- sure). These results are not surprising in view of the effects of lead on classroom performance in the early grades. Needleman et aL (1979) reported dose-dependent disordered classroom behavior as measured by a teacher's rating scale (Figure 3). These results were replicated by Yule et aL (1981) and Lansdo~n et aL (1983) in Bribsh children and HatzaHs et aL (1987) ~ Greek children. Yule also reported that children Fin high lead leveb excited more deviant performance on tests of conduct problems, inattentive-passive' and hyperactivity scales. Such early attentional deficits and their associate behaviors place children at Ask for academic failure and behavior problems (Uorn and Packard' 1985\ It is hoped that investigators ~1 continue to follow the children tested initially in the early grades, collecting data on school performance' special needs, and antisocial behavior. Effects of Lead on Other Neuropsychologlcal Endpoints Lead is associated with increased reaction time (Figure 4) and in- creased errors on various performance tasks (Uat~akis et aL, 1987; Needleman, 1983; Winneke and Kraemer, 1984; Winneke et aL, 1983, 1985~,b~ Using the Second National Health and Nutrition Examina- bon Survey (NH^NES D) data base' Schwartz and coUeagues found an association between lead and increased hearing threshold in chip dren with blood leveb between 5 and 45 ~g/dL' with no threshold for

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252 50(3 - 450 - - y 400 As 350 300- Block I Block 11 Delay: as 1 as DEBORAH C. RICE Needleman et al. Yule et al. High Pb x= 35 ~g/dL Low Pb x= 24 ~g/dL High Pb x= 17 ~g/dL Low Pb x= 7.4 ~g~dL Block 111 Block IV 1 as as FIGURE 4 Performance of children on a simple reaction time task as function of blood lead levels (K1 = time on task). SOURCE: Needleman (1987b). effect (Schwartz and Otto, 1987) (Figure 5), as well as slowed nerve conduction velocity at blood lead levels above 20-30 ~g/dL (Schwartz et al., 1988~. Blood lead levels of 15 ~g/dL and below are also asso- ciated with changes in EEG pattern and auditory evoked potentials (Otto, 1987; Otto et al., 1981). Other Health Effects of Environmental Lead Exposure In addition to effects on the nervous system, low-level exposure to lead affects a number of important metabolic processes. The most widely recognized of these are changes in the hematopoietic system. High intake of lead produces anemia, an effect influenced by iron status. Lead also inhibits a number of enzymes involved in heme biosynthesis (see Moore and Goldberg, 1985 for review). The result is a buildup of some of the precursors involved in heme synthesis. Inhibition occurs at somewhat different levels for different enzymes, but some are reliably affected at blood lead values of 10415 ~g/dL, which are observed routinely in the general population. The buildup of blood protoporphyrins is the basis of the screening program for un-

HEALTH EFFECTS OF ENVIRONMENTAL LEAD EXPOSURE 253 due lead exposure of children [Centers for Disease Control (CDC), 1985], because these precursors are easier to measure than blooc! leacl itself. Aside from frank anemia observed only at relatively high blood lead levels, the significance of these biochemical changes is in their potential contribution to lead r~europa~ology and as markers of exposure. Lead interferes with vitamin D synthesis at low (environmental) levels (Rosen, 1985~. Such an effect has important health implica- tions in terms of calcium homeostasis, cell differentiation, and immunoregulatory capacity. Results from the NHANES II survey indicate that increased lead burden is associated with decreased stat- 11 10 9 J I m - o 8 a, ~ 7 ID ID ° 6 Q I A Cal A: 4 3 . 2 l · . . . . 0 5 10 15 20 25 30 35 40 As Blood lead level (pg/dL) FIGURE 5 Relationship of 2-kHz pure tone hearing thresholds and blood lead levels in 4,519 NHANES II subjects aged 14-19 years. - SOURCE: Schwartz and Otto (1987).

254 DEBORAH C. RICE ure in children (Schwartz et al., 1986~. Increased lead burden~has also been linked to increased blood pressure in males, again by using the NHANES II data base (Schwartz, 1986~. Both' effects may be medi- ated by effects on calcium homeostasis. .. .. CRITICAL ISSUES Markers of Lead Exposure Blood is a poor marker of lead exposure, because it indicates only recent exposure. Bone represents a record of total past exposure, but not the pattern over time, which may be of critical importance to the tvue and decree of neuronsvcholozical damage. Bone obviously can- ~ 1 V ~ ~ ~ v ~ not be utilized In human studies as a measure ot lean exposure, at- though the recent ability to determine in viva bone lead by use of x- ray fluorescence represents an important contribution that it is hoped will be utilized in future research. Deciduous teeth are probably a reasonable substitute for certain ages and have been utilized in some retrospective studies. Prospective studies provide the opportunity to measure lead exposure, currently performed by means of blood lead, at regular intervals from before birth onward. Such a design ensures that the history of lead exposure is known at least approximately and provides the opportunity to correlate behavior against current and past blood levels. Retrospective studies, on the other hand, suffer from the inability to determine both the pattern and the degree of past exposure to lead. Retrospective studies sometimes use only one blood lead measure as a marker of lead exposure, an important limi- tation. It is extremely relevant, for example, that two of three pro- spective studies found that performance at 2 years of age was corre- lated with in utero, but not postnatal, blood level. In the study that has reported results past 2 years of age, performance at 57 months was correlated 'wish blood levels at 24 months, but not 57 months, of age. If these studies had been performed retrospectively, the results would have been negative. The positive results being obtained in prospective studies deserve attention in a different vein. The implication of these findings is that the blood lead body burden of women, reflected by maternal and cord blood lead levels, is important to at least the early well-being of children. The women described in these studies, and their offspring, had blood lead levels that are typical in our environment the result of simply living in a present-day industrialized society. One impor- tant unanswered (and unaddressed) question is'the contribution of total maternal body burden, rather than blood level, to the risk to the

HEALTH EFFECTS OF ENVIRONMENTAL LEAD EXPOSURE 255 infant. Bone is the most significant level compartment in the body, and it is established that lead increases in bone throughout the life span of humans (Barry, 1975~. Because a large number of women are at present delaying childbearing until relatively late, they may be exposing their fetuses to an increased burden of lead as a result of mobilization from bone. The calcium turnover from bone increases during pregnancy and lactation, and there is some evidence that bone lead may be mobilized as well during pregnancy and lactation, long after exposure has ceased (Thompson et al., 1985~. The amount of lead in milk in humans is correlated with having lived for at least five years in a high-traffic area, regardless of whether this occurred during childhood or adulthood (Debeka et al., 1986~. Because women who were born in the 1950s and 1960s have, in general, a signifi- cantly higher total body burden of lead than previous generations (due to exposure by leaded gasoline), this represents a potentially important problem for years to come, despite the fact that lead in the environment is presently decreasing. Statistical Interpretation The interpretation of these human studies, perhaps particularly the retrospective one, depends to a great degree on the statistical methods employed. Statisticians involved in these studies often dis- agree among themselves on the most appropriate way in which to analyze the data. Although the resolution of such controversies is best left to the statisticians, there are matters of scientific interpretation that may be addressed here. An issue of critical importance is the potential for overcontrolling potential confounding variables. An example of overcontrolling mentioned above is control for gestational age, which itself may be affected by lead burden. Another example is the factoring out of mother's IQ and measures of socioeconomic status and maternal care scores, which may be influenced by the mother's lead burden, and may in turn influence the child's lead burden at birth as well as during childhood. A potential partial solution may be the choice of highly homogeneous populations for study, or even populations in which lead and the typical confounders vary inversely. For example, in the Boston prospective study (Bellinger et al., 1987b), families with higher socioeconomic standing tended to live in a more urban area, with the result that lead body burdens tended to be higher in this group. Consequently, the association between lead and infant performance became stronger when potential confounders were in- cluded in the analysis. An issue of extreme importance is the power of any study to de-

256 100 r 90 o 5 m cr co in [LJ o LLl G - ~ 30 80 70 50 40 20 10 · High Lead Low Lead E; DEBORAH C. RICE , 1 , 1 , , , 50 60 70 80 90 100 1 10 120 130 140 VERBAL l.Q. FIGURE 6 Cumulative frequency distribution of verbal IQ scores In high- and low- level lead subjects: A shift In me median of 6 points is associated with a fourfold increase In the risk of IQ below 80. SOURCE: Needleman (1983). tect an effect (reject the null hypothesis) if an effect is present. For example, in an analysis by Needleman (1987a) performed on 14 recent studies, for which power to detect an effect could be ascertained, the power varied from 0 to 0.52. Nine studies reported a significant effect (p < 0.05), two were in the right direction (p = 0.12~.15), and two showed no effect (the study with power = 0 was not analyzed). As pointed out by Needleman, the results taken together are indicative of a consistent effect of lead on intellectual performance of children. One issue mentioned routinely by both primary investigators and reviewers in relation to causality is the possibility of a phantom that is covariant with lead and is the actual causative agent of the intellec- tual impairment, as discussed by Needleman and Bellinger (1986~. This covariate would have to be in effect for inner city children exposed to paint and for middle-class children exposed directly or indirectly via tap water (as in Edinburgh) or fallout from gasoline. In addition,

HEALTH EFFECTS OF ENVIRONMENTAL LEAD EXPOS ARE 257 the covariant hypothesis ignores the large body of data from animals, particularly monkeys, that report behavioral deficits analogous to those found in children (i.e., deficits in attention and information process- ing). Another statement often made by reviewers with respect to the effects of lead is that they are small, representing only a few percent of the total variance. However, in general a 10-,ug/dL increase in blood lead results in about a 4-6 point decrease in intelligence. That degree of deficit represents 0.30-0.45 standard deviation of the normal dis- tribution and results in a significant shift of the population. For example, Needleman (1983) reported cumulative IQs in children with high and low lead levels for which the mean differed by 6 points. The resulting distributions revealed that the number of children with IQs below 80 increased by a factor of four in the high-lead group, whereas the number of children with IQs over 120 decreased by an equal amount (Figure 6~. If it is in fact the case that increasing blood lead levels from 5 to 15 ~g/dL (or from 0 to 10 ,ug/dL) shifts the popu- lation IQ by approximately 0.4 standard deviation, this represents a profound and calamitous health effect for any society. Adequacy of Behavioral Methodology One problem with the use of intelligence scales is that results are very heavily environmentally determined. This has often resulted in the effect of lead apparently decreasing when environmental factors such as socioeconomic status and scores of home care were included in the analyses. It therefore would be highly desirable to develop tests that were less environmentally influenced. Tests such as vigi- lance tasks or reaction time may be less environmentally determined than tests of IQ and seem to be sensitive to impairment by lead, as mentioned previously. A fruitful approach may be to adapt procedures proven to be sensitive to the effects of lead in animals, particularly monkeys, for use with children. Research from the University of Wisconsin, as well as from our laboratory, has shown consistent ef- fects on tests of attention and distractibility that could easily be adapted for children. Assessment of sensory system function, particularly by psychophysical means, seems a promising avenue of research and should reflect the diffuse damage produced by toxicants such as lead. For example, the decrement in hearing threshold as a function of increased blood lead (Schwartz and Otto, 1987), although small (and therefore requiring a large study to detect), undoubtedly represents subtle neuronal dam- age. It would be extremely interesting to test frequency or amplitude

258 DEBORAH C. RICE difference thresholds in addition to absolute frequency thresholds, for two reasons. First, there is evidence that difference thresholds may degrade before absolute frequency thresholds (Stebbins, 1982) and would, therefore, provide a more sensitive indicator of lead neu- rotoxicity. Second, the ability to detect changes in frequency and amplitude is extremely important to the understanding of speech. Such testing may be especially relevant in view of the reported defi- cits on auditory processing as a result of lead exposure, reported by some investigators. Testing of visual system function may also prove a fruitful avenue of research. A number of investigations in animals as well as in workers occupationally exposed to lead report visual deficits, par- ticularly at low luminance, as a result of lead exposure. Such deficits probably~could be detected only by psychophysical techniques, because electrophysiological techniques cannot be used for low-luminance as- sessment of functions other than purely retinal. Detection of subtle effects may require testing of a large number of subjects. Does Head Contribute to Aging? It is well established from research on animals that lead produces neuronal degeneration, resulting in decreased numbers of nerve cells in various brain areas. Developmental lead exposure also results in a decrease in the amount of dendritic branching from nerve cells, rep- resenting a decrease in the ability of the nerve to communicate with its neighbors. It is also established that aging can produce these same effects. In fact, the brain areas affected most by lead and those that degenerate most quickly as a result of aging overlap to a great extent, at least in rodents and monkeys. Although there is presently no evidence for or against the hypothesis, it is conceivable that the effect of a lifetime of exposure to low levels of lead results in an acceleration of the normal process of degeneration of neural struc- tures. Weiss (1980) discussed the consequences on functional mental age of a very slight acceleration in loss of functional capacity beginning at age 25. One-tenth of one percent acceleration would result in a "brain age" of 95 at 40 years of age (Figure 7~. The actual situation could in fact be worse for certain individuals, because the deleterious effect of lead does not begin at age 25 but before birth. Additionally, the effects of lead on the nervous system of the developing organism may be more severe and different in kind than accelerated attrition of neurons. The effects of lead on blood pressure may also contribute to mani-

HEALTH EFFECTS OF ENVIRONMENTAL LEAD EXPOSURE 95 85 75 ID `~ 65 c ._ Cal co ._ Cal UJ 55 45 35 25 Al 1 I , , 1 ~ ~ b77 it_ . , ., i,0.1% , ~ - Effect of n % per year excess cell loss, beginning at age 25 1 1 25 35 45 55 65 75 Chronological age (years) 259 FIGURE 7 The "brain age" associated with different degrees of acceleration in the decline of brain functional capacity, if that decline begins at age 25. SOURCE: Weiss (1980). festation of diseases of aging, including heart and kidney disease, and stroke. The effects of lead on vitamin D metabolism may also have important lifetime repercussions. As pointed out by Grant (1986), "this effect is significant on two counts: (i) altered levels of 1,25- (OH)~-vitamin D not only affects calcium homeostasis (affecting min- ~ . . ~ . O eral metabolism, calcium as a second messenger and calcium as a mediator of cyclic nucleotide metabolism), but also likely affects its role in immunoregulation and mediation of tumerogenesis, and (ii) the effect of lead on 1,25-(OH)2-vitamin D is a particularly robust one, with blood levels of 30-50 ,ug/dL resulting in decreases in the hormone that overlap comparable degrees of decrease seen in severe kidney injury or certain genetic diseases." Thus lead is implicated in the compromise of the body's ability to repair tissue, fight disease, regu- late growth of abnormal cells, and maintain bone, among other effects. Such functions are often compromised in old age; lead may be con- tributing to these effects, particularly as a result of 1i-fetime exposure.

260 DEBORAH C. RICE Overview of Cost to Society Much of the cost of lead exposure is invisible. The consequences to society of decreasing the IQ of thousands of individuals from 130 to 125 points, or of a few from 160 to 155, are of great significance but cannot be measured either in monetary terms or in terms of human suffering. What can be measured monetarily is the cost of inclividu- als who require special services as a result of undue lead exposure. Such services may inclucle institutional care, special education, lost wages, hospitalization, and various forms of treatment. Also included should be the cost of monitoring children for lead exposure as well as various abatement programs. An analysis performed a decade ago (Provenzano, 1980) for the United States estimated the cost at $0.4 to $1.0 billion (1978 clollars) annually. Since that estimate was made, the criteria for considering a child at potential risk for leacl exposure have been made more conservative (CDC, 1985~. It is gen- erally recognized that blood lead levels above 15 ,ug/dL are undesir- able for children (cf. EPA, 1984; Grant, 1986~. About 15 percent of U.S. children have blood lead values above 15 ,ug/dL; the proportion is higher for poor and black children. This figure translates to 3 to 4 million U.S. children (Mushak and Crocchetti, 1987~. The Committee on Environmental Hazards (1987) recommends that all children at risk be tested for undue exposure by erythrocyte protoporphyrin lev- els at 12 months of age, with later follow-ups for high-risk children. It also recommends vigorous lead abatement programs. In addition, the 1978 analysis was performed before the relationships of lead to blood pressure, vitamin D metabolism, and calcium homeostasis were known. Thus a modern estimate of the cost would undoubtedly be substantially higher. Have Regulatory Agencies Been Slow to Act? It has been clear for centuries that lead is toxic. It has been clear for 15 years that lead is irreversibly neurotoxic to children, and for several years at least that lead at levels observed routinely contrib- utes to suboptimal behavioral functioning. Various U.S. federal agencies have been criticized for failing to act to protect the health of the public (Schoenbrod, 1980; Stein, 1980~. Regulation of lead in the United States (and other countries) is controlled by a number of different agencies (Billick, 1981) (Figure 8~. As pointed out by Schoenbrod (1980), this has provided an avenue for avoidance of action by blam- ing lead exposure on sources under the control of another agency. Various agencies have also blamed natural sources, despite the fact

HEALTH EFFECTS OF ENVIRONMENTAL LEAD EXPOSURE FEDERAL AGENCY AREAS OF RES~NSIBILIb Ecodiagrana Showing Movenent Of Lead From The Environment To Man - Lead Ores (Gabna) Manutac~ring and OSHA l,~ Prom sour Distribution 1 ~ . Phum~m~s Health Effects CPSC NUT NSF HEW EPA HEALTH EFFECTS RESEARCH 261 Oxop~a SSU duds EPA Airbome Emission From Autos and Industry Gem ssion Levels ~ ~ Washed by Rain Soil Edible Pant Lite FDA EPA Sate L. vels ~ EN Lead Objects ~— ~ ~ l L Paint ~ I Industrial Wastes > Rhymers, Lakes. Oceans Drinking Water Plaster (Pea) CPSC Putty . Toys Hazard Red FDA Liners / / / Regulation / of HUD _/ | Aquatic Life POun.v. ME— ~ / ~ Inhalation ~ ~ Oral Intake by Man 1 Sate Residue Levels - CDC Gl Absorption - > Feces Blood ~ Red Blood Cells (Nondmusible) \ - CNS - Plasma Ligand ~ Teeth Bound Diffusive Hair Bone (Nondiffusible) 1 Reds ~ ~ Enosphalopathy Peripheral Anemia Neutopathy Screening Body Burden Treatment Kidney Mb~ Etre Tubular Dysfunction Endocrine Urinary Excretion Reprodwbve Cytogenetic FIGURE 8 Ecodiagram showing movement of lead in the environment and areas of U.S. federal agency responsibility for control of exposure. SOURCE: Billick (1981).

262 DEBORAH C. RICE that they contribute considerably less than 1 percent of the human lead burden (Settle and Patterson, 1980~. The perceived slowness of regulatory agencies to act is probably the result of a number of factors. One is the disagreement among scientists and statisticians working in the field. As discussed above, the reasons for the controversy are due at least in part to the follow- ing factors: Methodological limitations including inadequate markers of lead exposure, environment-influenced instruments of neuropsychological function, and choice of populations in which these environmental factors and lead exposure are highly correlated · Evaluating the data by simply counting studies as positive or negative, without looking at direction of effect across studies or power of individual studies to find an effect, and failure to perform meta- analyses Failure to utilize the animal literature in interpreting data from human studies · Failure to recognize that a "small" effect (i.e., 2 to 3 percent of variance) does not translate to "insignificant" In addition, there may be a reluctance on the part of regulatory agencies to regulate on the basis of psychological test data. For ex- ample, the EPA has focused on the effects of lead on heme synthesis and the hematopoietic system (EPA, 1984) and, more recently, on vitamin D metabolism (Grant, 1986~. This may represent a real reluctance to regulate on the basis of behavioral data; conversely, regulators may be sensitive to the potential legal ramifications of the controversy over low-level effects on psychological functioning. It is hoped that recent studies demonstrating effects on behavior and intellectual functioning in middle-class children at blood lead levels typical in our society, as well as the analyses based on the NHANES data, will persuade regulatory agencies in their decision-making processes. CLOSING PANDORA'S BOX The level of lead in the environment in bioavailable form, distrib- uted over the entire earth, has been increasing for thousands of years as a result of human activity. The industrial revolution accelerated the release of lead into the environment. The use of lead in paint still produces undue lead exposure in children, as a result of old paint in old houses and the present use of lead in paint for application to

HEALTH EFFECTS OF ENVIRONMENTAL LEAD EXPOSURE 263 metals. The decision in the 1920s to add lead to gasoline has resulted in virtually universal exposure of the entire populations of industri- alized countries. Humans now carry a lead burden 500 times that before lead mining began, and present intake is 100 times greater. The United States has legislated the phaseout of lead from gaso- line, and other countries are doing the same or contemplating such a move. Lead abatement and monitoring programs are in place in the inner cities, and children are being "treated" (by chelation) if exposure to lead reaches a specified level. The average level of lead in the blood of children as a result of these actions has decreased since the mid-1970s and will undoubtedly decrease even further. Can we therefore congratulate ourselves on our success in alleviating the problems produced by lead exposure and feel confident that lead toxicity will soon no longer be an issue to contend with? The answer is, unfortunately, no. The adverse effects of in utero lead exposure are being character- ized. The women presently in their childbearing years, and those that will be for the next 20 years, have been exposed during childhood to the highest lead levels since certain ancient civilizations. These individuals presumably carry a high level of lead in bone, which is available for mobilization into the fetus. In addition, there are millions of individuals who have had undue lead exposure as young children. Even if their exposure to lead decreases substantially, permanent damage has already been done. These individuals will be part of our society for another 60 to 70 years. The effects of lead on various biochemical functions, particularly calcium homeostasis, may stress a wide variety of functions over the course of the life span, resulting in premature breakdown of these functions and accelerated aging. The ongoing insult of lead to the brain may also result in an accelerated decrease in mental function- ing. These deleterious effects would presumably manifest themselves for a considerable period of time in our populations even if lead exposure ceased tomorrow. It is clear, then, that environmental lead indeed represents a chemical time bomb in two senses: First, exposure to lead over years or a lifetime may result in health effects late in life, as well as very early in life. (We cannot know this yet, because individuals exposed in the 1940s and 1950s will not reach old age until after the turn of the century.) Second, decisions made by industrialists and governments in the 1920s and before will have unavoidable effects on individuals not yet born. It will be at least one more generation before this particular Pandora's box can be closed.

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266 DEBORAH C. RICE live and critical review of modern studies. Pp. 1-8 in Proc. 6th Internal. Conf. Heavy Metals in the Environment, S. E. Lindberg and T. C. Hut~inson, eds. Edinburgh: CEP Consultants. Needleman, H. L. 1987b. Introduction: Biomarkers in neurodevelopmental toxicol- ogy. Environ. Health Perspect. 74:149-152. Needleman, H. L., and D. J. Bellinger. 1986. Type II fallacies in the study of childhood exposure to lead at low dose: A critical and quantitative review. Proc. Internatl. Workshop on the Effects of Lead Exposure on Neurobehavioral Development, Edinburgh. Needleman, H. L., C. Gunnoe, A. Leviton, R. Reed, H. Peresie, C. Maher, and P. Barrett. 1979. Deficit in psychologic and classroom performance of children with elevated dentine lead levels. New Engl. J. Med. 300:689-695. Needleman, H. L., M. Rabinowitz, A. Leviton, S. Linn, and S. Schoenbaum. 1984. The relation between prenatal exposure to lead and congenital anomalies. J. Amer. Med. Assoc. 251:2956-2959. Oliver, T. 1914. Lead Poisoning from the Industrial Medical and Social Points of View. New York: Paul B. Hoeber. Otto, D. 1987. The assessment of neurotoxicity in children: Electrophysiological meth- ods. Pp. 139-158 in Toxic Substances and Mental Retardation. S. R. Schroeder, ed. Washington, D.C.: Amer. Assoc. on Mental Defic. Otto, D., V. Benignus, K. Muller, and C. Barton. 1981. Effects of age and body lead burden in young children. I. Slow cortical potentials. Electroencephalogr. Clin. Neurophysiol. 52:229-239. Perlstein, M. A., and R. Attala. 1966. Neurological sequelae of plumbism in children. Clin. Pediat. 5:292-298. Provenzano, G. 1980. The social costs of excessive lead exposure during childhood. Pp. 299-315 in Low Level Lead Exposure: The Clinical Implications of Current Research, H. L. Needleman, ed. New York: Raven Press. Rosen, J. F. 1985. Metabolic and cellular effects of lead: A guide to low level toxicity in children. Pp. 157-186 in Dietary and Environmental Lead: Human Health Effects, K. R. Mahaffey, ed. New York: Elsevier. Rosner, D. and G. Markowitz. 1985. A "gift of God"? The public health controversy over leaded gasoline during the 1920s. Amer. J. Public Health 75:344-352. Rutter, M., and R. Russell Jones. 1983. Lead vs. Health: Sources and Effects of Low Level Exposure. Chichester: Wiley & Sons. Schoenbrod, D. 1980. Why regulation of lead has failed. Pp. 259-266 in Low Level Lead Exposure: The Clinical Implications of Current Research, H. L. Needleman, ed. New York: Raven Press. Schrager, J., J. Lindy, S. Harrison, J. McDermott, and E. Killins. 1966. The hyperkinetic child: Some consensually validated behavioral correlates. Exceptional Children 32:665-667. Schroeder, S. R., B. Hawk, D. Otto, P. Mushak, and R. E. Hicks. 1985. Separating the effects of lead and social factors on I.Q. Environ. Res. 38:144-154. Schwartz, J. 1986. The relationship between blood lead levels and blood pressure. Pp. 379~14 in Health Effects of Lead, M. C. B. Hotz, ed. Ottawa: The Royal Society of Canada, Commission on Lead in the Environment. Schwartz, J., and D. Otto. 1987. Blood lead, hearing thresholds, and neurobehavioral development in children and youth. Arch. Environ. Health 42:153-160. Schwartz, J., C. Angle, and H. Pitcher. 1986. The relationship between childhood blood lead levels and stature. Pediat. 77:281-288. Schwartz, J., P. J. Landrigan, R. G. Feldman, E. K. Silbergeld, and E. L. Baker. 1988. Threshold effect in lead-induced peripheral neuropathy. J. Pediat. 112:12-17.

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Exposure to toxic chemicals—in the workplace and at home—is increasing every day. Human behavior can be affected by such exposure and can give important clues that a person or population is in danger. If we can understand the mechanisms of these changes, we can develop better ways of testing for toxic chemical exposure and, most important, better prevention programs.

This volume explores the emerging field of neurobehavioral toxicology and the potential of behavior studies as a noninvasive and economical means for risk assessment and monitoring. Pioneers in this field explore its promise for detecting environmental toxins, protecting us from exposure, and treating those who are exposed.

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