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2 ADVERSE HEALTH EFFECTS OF EXPOSURE TO LEAD
Pages 31-98

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From page 31...
... And the effects are associated with magnitudes of lead exposure that are encountered by a sizable fraction of the population in developed countries and thus are potentially found in very large numbers of people. This chapter summarizes key points about the health effects of exposure of sensitive populations to lead.
From page 32...
... Central Nervous System Affects The nature of lead-associated overt central nervous system injury in children differs with the degree of lead exposure. Blood lead concentrations of about 100-150 ~g/~L are associated with a high probability of fulminant lead encephalopathy.
From page 33...
... In chronic high-dose lead exposure, aminoaciduria appears to be the most consistent nephropathic finding. In a group of children with blood lead concentrations of 40-120 ,ug/~L, Puesche!
From page 34...
... is much higher in adults than in children. Blood lead concentrations associated with adult encephalopathy are well above 120-150 ,ug/cIL.
From page 35...
... 121 PI20DUCnV~ MID Dl V[LOPM~TAL [PHI CTS ~eorotIuctive anti Early developmental Toxicity Reproductive toxicity resulting from the high-dose lead exposure is
From page 36...
... and preterm birth (OR = 2.3~. No systematic study has been conducted of the effects of increased lead stores on early fetal loss in women who may have incurred substantial lead exposures during their childhood or during a prior period of employment in a lead-related trade.
From page 37...
... The Boston study found an increased risk of intrauterine growth retardation, low birthweight, and small-for-gestational-age deliveries at cord blood lead concentrations of 15 ~g/~L or more. The Port Pirie study found that the relative risk of preterm delivery increased 2.~-fold for every 10,ug/~L increase in maternal blood lead.
From page 38...
... More specifically, they found that infants born to women with lead concentrations greater than ~ ~g/~L during pregnancy grew at a lower than expected rate if increased lead exposure continued during the first 15 months of life. Conversely, if postnatal lead exposure was small, the infants grew at a higher than expected rate; that suggests a catchup in growth after fetal growth suppression.
From page 39...
... (1975) noted lead-associated disturbances of reproductive competence in lead workers; blood lead concentrations of about 40 ~g/~L were associated with asthenospermia and hypospermia, and higher concentrations with teratospermia.
From page 40...
... Angle and Kuntzelman (1989) in a retrospective pilot study examined 30 children with increased blood lead concentrations (over 30 ,ug/~)
From page 41...
... In the Port Pirie study, developmental assessments were first administered at 2 years of age, at which time MDI scores from the Bayley Scales were not associated with average antenatal, maternal, or cord blood lead concentrations (Baghurst et al., 1987b; Wigg et al., 19g8~. In the Sydney cohort, neither maternal nor cord blood lead concentration was inversely related to any index of children's development at 6, 12, 24, 36, or 48 months (Cooney et al., 1989a,b)
From page 42...
... In the Port Pirie study, the absence of an association between antenatal or cord blood lead concentrations and 2-year Bayley scores could reflect the attenuation of an association that would have been detected if assessments had been carried out before age 2. Third, the impact of competing risks for poor development among disadvantaged infants might have overwhelmed} a persisting but small effect of prenatal lead exposure.
From page 43...
... In this cohort, the mean blood lead level at age 2 years was less than 7 ,ug/~L, with 90% of the values below 14 g/dI-. In the Port Pirie cohort, an increase from 10 to 31 ~g/dL in a cumulative index of postnatal blood lead concentrations (particularly concentrations up to age 4 years)
From page 44...
... Right ear auditory processing skills at age 5 years, assessed by the Filtered Word subtest of the Screening Test for Auditory Processing Disorders, were significantly associated with postnatal blood lead concentrations as well (Dietrich et al., 1992~. Scores on the Auditory Figure-Ground subtest were not associated with lead exposure.
From page 45...
... Each study is likely to contribute only part of the answer to the general question, "Under what exposure conditions do different populations of children manifest a lead-associated impact on growth and development? " It is clear that the complete answer to this question is unlikely to be simply "all" or "none." In summary, there is relatively little consistency across the set of prospective studies in terms of the association between indices of prenatal lead exposure and later cognitive function.
From page 46...
... Because each study has included a global assessment of children's intelligence, this outcome provides the strongest basis for interstudy comparison. To assess the degree to which the results of various studies support a common dose-response relationship between lead exposure and TQ, the mean I scores of children in different exposure groups from the various studies are plotted together in Figures 2-1 and 2-2.
From page 48...
... 48 C O as al C = ~ Al 0 ~5 0)
From page 49...
... 49 o l .= - ~ ct .
From page 50...
... to no ~4 A: · · s~ o ·~3 G D C C _ U)
From page 52...
... ~2 As cn o x CD o o U
From page 53...
... <~;~= en it .
From page 54...
... ~4 ._ CC o U' I: no, o cd c`o of ~ :S U' c K ._ CQ .
From page 55...
... displays the ~Q scores of children classified by blood lead concentration, which serves as an index of earlier and current lead exposures. Within each cohort' children with lower mean blood lead concentrations scored higher than children with higher mean concentrations, and the decline with increasing exposure was roughly monotonic.
From page 56...
... Schroeder et al. (1985~: regression of Stanford-Binet IQ Scores on blood lead concentrations; data represent apparently unadjusted regression of IQ on contemporary blood lead concentration among 6- to 12-year~lds; data selected for inclusion because they are most similar to those from traditional cross-sectional study.
From page 58...
... + Fergusson et al. _~ ~ 5 \ 10 15 20 25 Tooth Lead Gig)
From page 59...
... . Tooth lead concentrations vs.
From page 60...
... Not all studies report socioeconomic differences in vulnerability, however. In one study, the association between increased tooth lead and lower A was more prominent among boys than girls (Pocock et al 1987)
From page 61...
... There is relatively little consistency across studies in terms of whether verbal TQ or performance A is more strongly associated with lead exposure. Some studies report stronger associations for verbal A or surrogate scores (Needleman et al., 1979; Ernhart et al., 1981; Yule et
From page 62...
... Some studies report significant associations between lead exposure and mathematical skills (Fulton et al., 1987; Fergusson et al., 19881; others do not (Yule et al., 1981; Smith et al., 1983; Lansdown et al., 19861. In several studies, children with larger lead exposure did poorly on assessments of visual-spatial or visual-motor skills, with deficits apparent on figure reproduction, visual retention, mazes, eye-hand coordination, and construction tasks (Winneke et al., 1988; McBride et al., 1982; Bellinger et al., 1991a; Hansen et al., l989a,b)
From page 63...
... for learning disability among children with circumpuIpal-dentin lead concentrations greater than 16 ppm was 4.3 (the reference was the rate among children with concentrations less than 5 ppm) (Lyngbye et al., 19901.
From page 64...
... and failure to graduate from high school; the adjusted odds ratios were 5.8 and 7.4, respectively, when the prevalence among children with dentin lead concentrations below 10 ppm was used as the reference. In children, early neurobehavioral and other developmental effects have been reported at blood lead concentrations of 10 ~g/~L or even lower (and equivalent concentrations in other tissues)
From page 65...
... 30 40 50 FIGIlRE 2-3 Nonparametac smoothed plot of fill-scale IQ vs. dentin lead from Needleman et al.
From page 66...
... Bellinger et al. had reported that 20-month blood lead concentrations were associated with 57-month McCarthy General Cognitive Index in their prospective study of lead exposure.
From page 67...
... Figure 2~ shows a covariate-adjusted nonparametric smoothing of the McCarthy Scores for those children versus blood lead concentrations from Schwartz's reanalysis. A continuous dose-dependent decline is seen to start at ~ ,ug/~.
From page 68...
... FIGURE 2-5 Mean Bayley Mental Development Index in children aged 24 months, by umbilical cord lead group, after adjustment for covariates, from study of Bellinger and co-workers (1987a,b)
From page 69...
... The longest followup study, published recently by NeedIeman and co-workers (1990) , showed that some deficits persisted and showed a dose-dependent relationship with lead exposure.
From page 70...
... In the paper of Schwartz and co-workers (1986) , children's stature was associated with blood lead concentrations.
From page 71...
... One complication with nerve conduction velocity as a toxicity measure is that a dose-dependent biphasic response can be identified, i.e., a Ushaped dose-effect curve across studies and across a broad range of blood lead concentration (e.g., Schwartz et al., 1988; Winneke et al., 1989)
From page 72...
... , any CNS perturbations that occur in developing children should be regarded with the utmost concern. C~DBOVASCULA12 I FFI CTS H'uc~ensicn anal ~rcenanc Ever since Schedoff and Porockjakoff drew attention to the association of high blood pressure and ecIampsia in 1884, there has been increasing interest in this relationship.
From page 73...
... They studied 3,200 live births in Boston by white, middIe-cIass women. They examined umbilical-cord blood lead and reported a significant association with blood pressure at delivery and the presence of hypertension during pregnancy.
From page 74...
... . , , 15 20 FIGURE 2-9 Response of blood pressure to blood lead concentrations in rats (Boscolo and Carmignani, 1988~.
From page 75...
... . Figure 2-10 shows the estimated changes in systolic blood pressure for a change in blood lead from 10 lug/ to 5 ~g/~L from 11 recent studies of the association between blood lead and blood pressure (Schwartz, 1988; Orssaud et al., 1985; Kroumhout, 1988; Pocock et al.
From page 77...
... Kirkby and Gyntelberg (198S) reported that lead exposure was associated with electrocardiogram changes associated with ischemic heart disease.
From page 78...
... The best example of this developmental mechanism is the neural cell adhesion molecule discussed below. Second, lead interferes with signal transduction processes, especially those associated with neurotransmitter function, which may be reversible.
From page 79...
... Chronic lead exposure decreases the rate of NCAM desialylation and the conversion from the embryonic to adult stage in the rat cerebellum (Cookman et al. 1987; Regan, 1989, in press)
From page 80...
... For example, lead concentrations of 40 ~g/~L increased the frequency of miniature end plate potentials, but did not affect the presynaptic nor the end plate potential after direct stimulation (Atchison and Narahashi, 1984; Cooper et al., 1984; Manalis and Cooper, 1973~. In contrast, lead at higher concentrations blocked the evoked release of neurotransmitters in both the peripheral and central nervous system preparations.
From page 81...
... Thus, the Pb2+-protein interactions with Ca2+ receptor proteins and other proteins, such as those of heme biosynthesis, are beginning to be understood (Goering 1993~. Lead has diverse and complex actions on the calcium messenger system, emphasizing the importance of this pathway as a key molecular and cellular target of lead toxicity.
From page 82...
... can occur at lower blood lead concentrations (Meredith et al., 1978~. Recent evidence (Okayama et al., 1989)
From page 84...
... lead concentrations at a threshold of approximately 50 ~g/~. In children, as noted earlier, lead exposure affects hematocrit at a blood-lead threshold of approximately 20-25 ~g/~L (Schwartz et al., 1990~.
From page 85...
... A second investigation in children also documented a strong negative correlation between blood lead concentrations and serum I,25-(OH) 2vitamin D concentrations (Mahaffey et al., 1982b)
From page 86...
... ~6 ME4SU~G LEND exist SENSITIVE POPUIATBO~S TABLE 2-3 Vanous Tissues, Cell Types, and Functions Modulated by Vitamin D Hormone Tissue Cell Type Function Bone Osteoblasts Modulates cytosolic Gastrointestinal tract Enterocyte Mammary gland Mammary explants Parathyroid gland Parathyroid ca2+ Bone remodeling Mineral absorption Calcium uptake Phospholipid metabolism Pituitary gland GH4C, pituitary cell Prolactin synthesis Modulates cytosolic ca2+ Heart Cardiac muscle Calcium uptake Skin Fibroblasts, epidermal CGMO production Kidney Tubular cells Phosphate reabsorption Skeletal muscle Myoblasts Calcium uptake Pancreas ~ cells Insulin secretion Macrophage Phagocytosis Modulation of proto oncogenes (continued, next page) plasma metabolite concentrations in rats given high doses of lead orally.
From page 87...
... A number of studies have attempted to measure the functions affected by lead, and these are considered in the section of this chapter dealing with molecular mechanisms of lead toxicity.
From page 88...
... About a dozen occupational studies have considered lead exposure versus various types of cancers in such work categories as battery recycling, lead smelting, alky! lead manufacturing, plumbing, and pipefitting.
From page 89...
... documented induction of renal tumors when animals were fed either lead acetate or subacetate (soluble forms of lead)
From page 90...
... One can look to several kinds of experimental studies to garner clues as to what is occurring in humans who have subclinical lead exposures. Of particular interest are data on leadbinding proteins in experimental systems.
From page 91...
... Knowledge of the intracellular handling of lead in target tissues, such as the kidney and brain, is essential to an unclerstanding of the mechanisms of lead toxicity in target cell populations in these tissues. Soluble, high-aff~nity lead-binding proteins in the kidney and brain of rats were first reported by Oskarsson et al.
From page 92...
... The data suggest that the protein can play an early role in the formation of the pathognomonic cytoplasmic and intranucIear lead inclusion bodies. The inclusion bodies are the main intracellular storage sites for lead in proximal tubule cells after increased or chronic lead exposure (Goyer and Rhyne, 1973; Moore et al., 1973; Fowler et al., 1980; Shelton and Egle 1982; Oskarsson and Fowler 198Sa,b; Klann and Shelton 1989~.
From page 93...
... In children, blood lead concentrations around 10 lug/ are associated with disturbances in early physical and mental growth and in later intellectual functioning and academic achievement. Studies of electrophysiologic end points have suggested some of the changes in brain function that might mediate the apparent effects.
From page 96...
... ~6 is o o a, .
From page 97...
... This chapter documents that lead induces measurable increases in diastolic and systolic blood pressure in human populations and in experimental-animal models of environmentally induced blood-pressure changes. Lead exposure is not the only risk factor for hypertension, but is more amenable to reduction or prevention than behavioral factors that are refractory to change.
From page 98...
... 2. There is frequently a long delay between the onset of lead exposure and the development of toxic manifestations, impairing identification of causal relationships between functional and cellular or biochemical events.


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