Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations (1993) / Chapter Skim
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4 BIOLOGIC MARKERS OF LEAD TOXICITY
4 BIOLOGIC MARKERS OF LEAD TOXICITY
Pages 143-190
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From page 143... ...
This has also been the focus for biologic studies of the mechanisms of lead toxicity. Biologic markers are indicators of events in biologic systems or samples.
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From page 144... ...
For example, if clinical management or regulatory actions are to be effecfive, the timing of lead exposure that is reflected in a typical blood lead value should be known, as should dose-response relations Mat link He body lead concentration with adverse health effects. Leall Allserntion Humans absorb lead predominantly through the gastrointestinal and respiratory tracts.
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From page 145... ...
In nonoccupationally exposed populations, lead uptake from the gastrointestinal tract is its main route of absorption. For adults, the lead content of foods, tap water, and other beverages is of main concern for lead exposure.
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From page 146... ...
Particle size difference might account for the absorption difference between fasting and meals. Dietary lead absorption is considerably higher in children than in adults.
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From page 147... ...
, but rises at blood lead concentrations of about 50 lug/ or higher (DeSilva, 1981; Manton and Cook, 1984~. Lead is removed from whole blood, under steady-state conditions, with a half-life that depends on such factors as total body lead burden, age, magnitude of external exposure, and the method of measuring halflife (according to total circulating lead or absorbed exogenous fraction ~ ~ O ~ as measured by isotopic tracer)
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From page 148... ...
showed that tissue lead concentrations were lower in infants than in older children. Those in older children were not materially different from those in adult women.
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From page 149... ...
Lead content was symmetric in positional location, but not bone type. Lead concentrations rose with age in all sample types, and there was some longitudinal variation within a bone specimen, but not enough to preclude use of single measurements in bone analysis.
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From page 150... ...
About 8% of the total is eliminated through Hair and nails. · Whole-body lead elimination over the short term removes about 50~0% of the newly absorbed lead, with a half-life in adult volunteers of about 20 days (Rabinowi~ et al., 1976; Chamberlain et al., 1978~.
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From page 151... ...
Other nutrients that interact inversely with lead exposure are zinc (Chisolm, 1981; Markowitz and Rosen, 1981) and phosphorus (Heard and Chamberlain, 19821.
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From page 152... ...
Bone lead estimates show that lead concentration in 1-year-old infants is about 60% of that in 7year-olds not greatly at odds with He laboratory ratio of ~ :2 based on autopsy samples for about the same age interval. The models referred to are for essentially steady-state exposure with associated complete mixing of the linked lead pools, and they use f~rstorder kinetics.
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From page 153... ...
is an attempt to accommodate data that show that plasma lead manifests a concentrationdependent equilibrium with erythrocytes in humans and that blood lead concentration is nonlinear over a broad range of exposure. Workplace exposures represent the high end of the predictive range.
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From page 154... ...
Those simultaneous decreases have shifted attention to small lead exposures and their associated subtle adverse effects. Small exposures add considerably to the complexity of interpreting lead pharmacokinetics.
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From page 155... ...
A group of 136 poisoning patients whose blood lead concentrations were known at the outset were examined longitudinally. Of various exposure measures- erythrocyte protoporphyrin, coproporphyrin, urinary deltaaminolevulinic acid (ALA)
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From page 156... ...
With regard to fractional contributions of recent versus cumulative lead exposure to blood lead, various and numerous studies have shown that the major component of a given total blood lead concentration in a young child or adult is recent input, and
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From page 157... ...
, as shown in rank ordering; there might be at least two lead compartments that contribute to blood lead concentration, one of which is large enough to preserve statistical association (consisting of lead in bone) , although continuing exposure cannot be ruled out when blood lead concentrations are large.
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From page 158... ...
Rank order of serial blood lead measures generally preserved (David et al., 1982) · Generally, blood lead half-life is highly variable because of such factors as age, metabolic variability, total body burden, and concentration and duration of exposure.
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From page 159... ...
Plasma lead concentrations at steady state are extremely small, often less than I% of blood lead concentration, and rarely above ~ I/. Even at blood lead concentrations over 50-60 ,ug/~L, they go up to only a few micrograms per deciliter.
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From page 161... ...
·61 ~ ~ ~ 8~8 by_ =,~, ~= Al S ~ O ~ ~ In 00 ~ C ~ ~C ~ O ~ ~I ° ~ ~ 2 E 2 ~ ~ ~° ~ ~ Cal _ .
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From page 162... ...
As public-health concerns are increasingly shifted to smaller lead exposures, two aspects of bone lead rise in importance. The first is the increasing degree to which bone contributes lead to total blood lead concentration, especially during pregnancy and at later stages
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From page 163... ...
·63 5: at lo: I: · o o · m ._ ._ o U)
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From page 164... ...
Swedish retired lead workers; 3~5 years of lead exposure Swedish lead workers; work exposure variable; in viva analysis compared with chelatable lead Japanese lead workers at various ages Bone lead adds approximately 65 % to total blood lead in retirement; accounts for half-life of 5.6 years (Schulz et al., 1987a) Chelatable lead well correlated with trabecular, but not cortical bone (Schulz et al., 1987b)
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From page 165... ...
and walk. At these times of infant and child development, milk lead content accounts for less than 10% of blood lead concentrations (Rabinowitz et al., 1985b)
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From page 166... ...
It has also been reported that placental lead content increases with lead exposure (Roels et al., 1978; Khera et al., 1980; Mayer-Popken et al., 19861; and in a limited study of amniotic fluid lead concentrations, it was found that concentrations of lead at term (59.6 ~ 8.3 ng/mI) were significantly higher than maternal blood lead (40.4 + 18.2 ng/mI)
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From page 167... ...
Biologic markers of lead's effects are often confined in usefulness to a range of body burden of lead. As acceptable magnitudes of lead exposure have been reciuced, it has been necessary to re-evaluate the
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From page 168... ...
Some of the relevant characteristics of biologic markers based on disturbance of heme synthesis are presented in Table 4-7. Inhibition of the activity of the enzyme delta-ALA-D occurs at a very low body lead burden, indexed as blood lead; He threshold of this effect is 5 ~g/~L or even lower (Chisolm et al., 1985; EPA, 1986a)
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From page 169... ...
exists only at high blood lead concentrations (e.g., Okayama et al., 1989~; that rules out its use in young children and pregnant women who receive low-dose lead exposures. Reports of screening of high-risk children with colorimetric measurement of urinary ALA indicate poor correlation with blood lead concentrations (Blanksma et al., 1970; Specter et al., 1971; Chisolm et al., 1976~.
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From page 170... ...
170 Cam at: Ct et UP Cal In .
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From page 172... ...
The utility of EP accumulation in a rapid and cost-effective screening procedure for high-risk children in the United States was recognized early; it was so attractive for screening at the high blood lead concentrations common in the early 1970s that it became part of the screening method advanced by the U.S. Public Health Service in 1975 (CDC, 1975~.
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From page 173... ...
Inhibition leads to accumulation of the nucleotides, and ribosomal catabolism is retarded (Paglia and Valentine, 1975; Angle and McIntire, 1978; Buc and Kaplan, 19781; at high lead exposures, inhibition is severe enough to produce basophilic stippling from undegraded fragments. The blood-lead threshold for this effect, based on lead-exposed children, appears to be around 10 ~g/~L (Angle et al., 1982; Cook et al., 1986, 1987~.
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From page 174... ...
174 o x Ct o _, LLl o CD Cat U
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From page 175... ...
This marker of membrane ATPase has been examined quantitatively only in lead workers (Secchi et al., 1968; Raghavan et al., 1981) in whom it appears that the inhibition correlates well with membrane lead concentrations, but poorly with total blood lead.
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From page 176... ...
1 L? etevance of Current Markers of Affect for Low-Dose exposures The utility of commonly used biologic markers of effect is related to the range of body lead burden of concern.
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From page 177... ...
One would expect the rate to be even higher at lower blood lead concentrations, as seen in analysis of the Chicago screening population cited. Such measures as urinary ALA and CP apply mainly to relatively high lead exposures, having thresholds of about 40 ,ug/~.
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From page 178... ...
178 o f:L x l c_ o _ o cn cn :^ ce ._ o lo ~=~ E c D ~ ~- C C ~ G. ~ ~ 2 i -E ~ G e =3 ~ 3 Y o .
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From page 179... ...
(1990) found that, in erythrocytes from lead-exposed subjects or treated with lead in vitro, NAD-S activity is obliterated at lead concentrations at which Py-5'-N activity, itself a sensitive measure of lead exposure, still retains 50-70% of activity.
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From page 180... ...
measured Me protein in lead workers with various degrees of lead exposure. The protein was quantitated as two peaks, which suggested a heterogeneous protein.
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From page 181... ...
2vitamin D Such reductions with blood lead concentrations of 33-55 fig/ dE, furthermore, rival those seen in several disease states (Rosen et al., 1980; Mahat~fey et al., 1982b; Rosen and Chesney, 19831.
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From page 182... ...
. Evidence of an effect of lead on heme formation would constitute a far-reaching mechanistic clue to lead toxicity.
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From page 183... ...
. ~ , Generally, calcium deficiency increases lead toxicity (Mahaffey et al., 1973)
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From page 184... ...
The iron requirement of a normal pregnancy is approximately 500 ma, which is distributed to the fetus, placenta, and expanded maternal erythrocyte mass. It is critical to recognize that the groups of people who have the highest environmental lead exposures are also at greatest risk of iron deficiency (Mahaffey ant!
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From page 185... ...
The relative distribution of genetically susceptible segments of the population is of main concern when these segments suffer substantial lead exposure. For example, lead exposure and the hepatoporphyric genetic disorder acute intermittent porphyria both produce accumulation of potentially neurotoxic ALA in plasma and urine (e.g., EPA, 1986a)
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From page 186... ...
Studies directed to the hypothesis have entailed large exposures to lead, and it is not clear that low-dose lead exposure would effectively synergize neurologic manifestations of the attack stage of acute intermittent porphyria. Increased lead exposure affects the liver in various ways (EPA, 1986a)
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From page 187... ...
SUMMARY The absorption, distribution, retention and excretion of lead in sensitive populations from various sources affect both the biologic monitoring of lead exposure and toxic outcomes. The literature dealing with the quantitative aspects of lead toxicokinetics is extensive and supports a number of conclusions.
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From page 188... ...
For example, one must take account of the extent of such contributions to blood lead concentrations in planning the extent of control actions and concomitant population responses to lead regulatory actions. At low-dose lead exposures, which induce ellects that are of increasing concern, blooc]
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From page 189... ...
Bone lead measurement is the best way to assess body lead accumulation in such populations as high-risk urbanized young children, and it signals to the analyst and the policy-maker how rapidly lead is accumulating in bone. The role of this measure is enhanced considerably when techniques for integrating lifetime exposure are used in tandem with serial measurement of blood lead concentration in variably exposed young children or pregnant women.
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From page 190... ...
190 ME4SU~G LEND EXPOSURE '~ SE~S'! 'VE POPULATIONS some children and other sensitive people could be predisposed to increased lead intoxication because of genetic disorders and nutritional factors.
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