Potential Health Risks to DOD Firing-Range Personnel from Recurrent Lead Exposure (2013) / Chapter Skim
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4 Noncancer Health Effects
4 Noncancer Health Effects
Pages 62-146
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From page 62... ...
As noted in Chapters 1 and 2, the committee specifically sought healtheffects data on blood lead levels (BLLs) under 40 µg/dL because the current standard of the Occupational Safety and Health Administration (OSHA)
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From page 63... ...
Effects on the central nervous system of lead workers include dose-related changes in cognitive and psychomotor performance and mood, neurodegenerative diseases, and neurophysiologic changes in the auditory, visual, and balance systems. Effects of occupational lead exposure on the peripheral nervous system at BLLs of 60-70 μg/dL are manifested as motor weakness with abnormalities in motor and sensory nerve conduction.
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From page 64... ...
Bone lead measurements capture both long-term cumulative exposure and past high lead exposure, which may be more important than current BLL. In contrast, EPA noted that occupational lead exposure measured by BLL, CBLI, and bone lead was associated with decreased cognitive and psychomotor performance, diminished peripheral sensory nerve function, slowing in visual evoked potentials and brainstem auditory evoked potentials, and abnormalities in postural sway.
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. In adults who had past occupational lead exposure, BLL and bone lead were associated with decrements in cognitive performance years after the cessation of occupational exposure.
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Neurobehavioral and Mood Effects NTP noted that studies of BLL and cognitive performance in older adults who had environmental lead exposure had mixed results (Payton et al. 1998; Nordberg et al.
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The authors concluded that BLLs under 10 µg/dL might enhance noise-induced hearing loss. In people who had environmental lead exposure, hearing loss was associated with bone lead (Park et al.
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(2001) reported that bone lead concentration was not associated with neurobehavioral performance in 803 Korean lead-exposed workers.
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Peak bone lead predicted lower cognitive performance and cognitive decline over 22 years. A statistically significant association of peak bone lead with performance on spatial ability, learning and memory, and total cognitive score was found only in workers who were over 55 years old.
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Multiple linear regression for each MRS measure and lead after adjustment for sex, age, and smoking found significant associations of increasing BLL and bone lead levels with decreases in gray and white matter in the occipital lobe. The strongest of the associations was of neuronal loss in the frontal lobe with BLL and patella lead level.
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were more strongly predictive of peripheral nerve impairment than BLL. Other studies examined peripheral sensory nerve function in the extremities with a quantitative sensory test, vibration threshold, that measures the integrity of large myelinated nerve fibers.
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. Linear regression, adjusted for age, found that BLL was significantly associated with peripheral auditory nerve conduction speed and CBLI was significantly associated with lower brainstem conduction speed.
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In 121 lead-exposed workers who had a mean BLL of 40 µg/dL, almost all sway measures were significantly larger than those in controls. The mean benchmark dose level of the current BLL for postural sway was 14.3 µg/dL.
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Sympathetic nerve function as seen in variations in R-R interval on electrocardiography and changes in finger blood flow with postural changes according to Doppler flowmetry were measured in 128 workers in the ceramic painting industry (mean BLL 13 µg/dL)
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(2003) examined the relationship between BLL and essential tremor in 100 cases from a medical center in New York City (mean BLL 3.3 µg/dL)
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Neurobehavioral performance showed decrements in various domains in neurobehavioral testing, including verbal and visual memory, visuospatial ability, motor and psychomotor speed, manual dexterity, attention, and executive functioning associated with BLLs and measures of cumulative exposure (CBLI and bone lead levels)
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age = 43 (11.0) y; weighted average BLL = of employment added suppressor performance when MANCOVA mean (SD)
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tibia lead = 20 μg/g; (digit symbol, digit span) , visuomotor function.
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Controls: mean BLL = 5.3 µg/dL; mean tibia lead = 5.8 µg/g; mean chelateable lead = NA Neurobehavioral tests 576 of above lead workers Baseline mean (SD) Various models demonstrated Declines in Schwartz et al.
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MRS imaging data, Case-control study of Exposed workers: Blood and bone lead levels Current and past lead Hsieh et al. 2009 brain N-acetyl aspartate 22 workers in lead-paint mean (SD)
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ar relationship with time- blood lead exposure assessed large = 44 (8) y; CPT in hand bone lead = 40 (23.8)
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Overall, historical BLLs more closely associated with peripheral nerve function than bone lead concentrations. No comparison group; no consideration of effect of smoking, alcohol use in this population.
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adjusting for age found BLL, with brainstem auditory currently exposed male time-weighted average time-weighted average BLL evoked potentials in lead-smelter workers; BLL = 39 (11.9) µg/dL; significantly associated with dose-dependent manner.
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. Hearing loss; audiometric Cases: 121 male workers Concurrent BLL: cases, Multiple regression found Lead exposure associated Chuang et al.
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From page 85... ...
breathing indicated that effects on cardiac parasympathetic activity occurred at BLLs of ≥30 µg/dL; mild decrease possibly occurred at ≥20 µg/dL. Abbreviations: BAEP, brainstem auditory evoked potential; BLL, blood lead level; BMD, benchmark dose; BMDL, benchmark dose level; CBLI, cumulative blood lead index; CES-D, Center for Epidemiological Studies-Depression Scale; CPT, current perception threshold; CV, coefficient of variation; ECG, electrocardiogram; EEG, electroencephalogram; GP, grooved pegboard; MANCOVA, multivariate analysis of covariance; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; OR, odds ratio; SD, standard deviation; SE, standard error; SRT, simple reaction time; WMC, white matter change; WRAT-R, wide range achievement test-revised.
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From page 86... ...
Conclusions from the 2012 Environmental Protection Agency and 2012 National Toxicology Program Lead Documents Environmental Protection Agency 2012 Integrated Science Assessment for Lead (Second External Review Draft) EPA's review of recent epidemiologic studies concerning environmental lead exposure and hematologic function concludes that there is strong evidence that exposure is associated with a variety of deleterious effects on hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and erythrocyte count and adverse effects on heme synthesis through the inhibition of several enzymes of the heme pathway.
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. Those seemingly disparate findings suggest a subclinical effect of bone lead burden on erythro
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and 15 nonexposed workers (mean BLL 9.9 µg/dL) found that the exposed workers had more than twice the erythrocyte intracellular calcium levels of nonexposed workers and that high intracellular calcium concentration was associated with increased osmotic fragility.
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Glycine Porphobilinogen ALA-Synthase ALA-Dehydratase + B6 CoA CoASH CO2 H 2O δ-Aminolevulinic acid PBG Succinyl-CoA Deaminase 4 NH3 ria Ferrocheletase Heme ond Hydroxy ch methylbilane o 2 H+ Mit Fe++ asm topl Urogen III C y Synthase H2O Protoporphyrin IX Vi Coproporphyrinogen III Uroporphyrinogen III Protogen Vi III Coprogen III Oxidase Oxidase 4 CO2 6 H+ 2 (CO2 + H+) Urogen III Protoporphrinogen III Decarboxylase FIGURE 4-1 The biosynthetic pathway of heme.
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of blood, workers occupationally exposed to lead (mean BLL 44 µg/dL) took longer to restore their predonation hemoglobin
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. There is now a voluminous literature on the relationship between environmental and occupational lead exposure and renal function.
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1994 HCT with patella with mean BLL of 8.4 µg/dL quintile of bone lead, those in relatively low lead but not BLL highest had decrease in Hgb, exposures in range HCT of 11 g/L, 0.03, respectively. of interest.
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Abbreviations: ALAD, delta-aminolevulinic acid dehydratase; ANOVA, analysis of variance; BLL, blood lead level; Hgb, hemoglobin; HCT, hematocrit; ZPP, zinc protoporphyrin.
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National Toxicology Program 2012 Monograph on Effects of Low-Level Lead Largely on the basis of a review of 13 large epidemiologic studies of the general population that examined associations between renal function and BLLs under 10 µg/dL, the NTP concluded that there was sufficient evidence that BLLs under 5 µg/dL are associated with adverse effects on renal function in adults. The 13 studies support relationships between concurrent BLL and renal function.
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From page 95... ...
Those and other so-called early-effect markers have not yet been sufficiently validated as predictors of clinical renal disease in populations exposed to nephrotoxic chemicals, but they serve as early indicators of toxicity. Epidemiologic studies of the relationship between lead exposure and renal function can be divided into three categories: studies of the general population, which experiences environmental exposure; studies of the contribution of lead to disease progression in those who have chronic kidney disease (CKD)
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. And in the Normative Aging Study, BLL and serum creatinine were associated even when serum creatinine was in the normal range (Kim et al.
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That effort was complicated by the fact that mean BLL did not differ among evaluations 1-3 in either sex. Nevertheless, both current and cumulative lead dose were associated with changes in renal function.
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A study in Nigeria described impaired creatinine clearance in 190 lead workers (mean BLL 50 µg/dL) compared with 80 controls but did not adjust for any covariates (Alasia et al.
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For example, a study of 33 normotensive men, 25 of whom were occupationally exposed to lead for weeks to months (mean BLL 35.6 µg/dL) , found positive exponential relationships between BLL and plasma renin activity, angiotensin, angiotensin-converting enzyme, and aldosterone levels (Campbell et al.
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From page 100... ...
2009 quartile was <1.1 µg/dL of BLL. Creatinine clearance, 820 women in Lund, Mean BLL = 22 µg/dL For each 1 µg/dL in BLL, Well-done study that Åkesson et al.
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may contribute to angiotensin- hypertension in converting enzyme, personnel. aldosterone Abbreviations: BLL, blood lead level; CaNa2EDTA, calcium disodium ethylenediamine tetraacetic acid; CKD, chronic kidney disease; DMSA, 2,3-dimercaptosuccinic acid; GFR, glomerular filtration rate; NHANES, National Health and Nutrition Examination Survey.
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From page 102... ...
EPA's review of recent epidemiologic studies of environmental lead exposure and reproductive function concludes that there is strong evidence that increasing lead exposure is associated with reduced male fecundity or fertility, decreases in sperm count, and reduced sperm velocity and motility. EPA's draft report further concludes that deleterious associations with sperm count and quality are observed in occupationally exposed men who have mean BLLs as low as 20-45 µg/dL.
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Prospective studies reviewed by the NTP provided limited evidence that prenatal exposure to BLLs under 10 µg/dL is associated with reduced postnatal growth in children. The NTP recognized that its conclusions about prenatal lead exposure were confounded by possible continuing postnatal exposure to lead (associated with BLLs under 10 µg/dL)
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. Nonoccupationally exposed controls had mean BLLs of 10-15 µg/dL.
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, but no correlations with other sperm alterations were observed. There is additional evidence that increasing seminal plasma lead concentrations are associated with alterations in two sperm functions required for fertilization: decreased motility, which is the major determinant of pregnancy outcome (Shulman et al.
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Those studies are limited in that they each used women who were seeking fertility assistance in an in vitro fertilization clinic where only a woman's lead levels were considered and thus ignored the potential contribution of lead to sperm dysfunction. The study by Silberstein et al.
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(2007) found that women in the highest one-third for plasma:blood lead ratio had a greater risk of spontaneous abortion than women in the lowest one-third, but no associations were found if whole blood or plasma alone was used.
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. Deficits in visual function in children were also seen at umbilical blood lead levels as low as 10.5 μg/dL (Rothenberg et al.
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and brainstem auditory evoked responses in newborns, 3-month-old infants, and 67-month-old children (Rothenberg et al.
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Decrease in seminal plasma zinc, in serum prolactin. Abbreviations: αT,extent of DNA denaturation per cell; BLL, blood lead level; COMP αT, percentage of sperm with increased sensitivity to DNA denaturation; PbS, seminal plasma lead concentration.
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TABLE 4-5 Key Studies of the Female Reproductive Effects of Lead Why Study Is Health Effects Population Characteristics Measures Adjusted Effect Estimates Relevant to DOD Reference Infertility Women receiving care in BLL >2.5 µg/dL OR (95% CI) : ≤2.5 µg/dL, 1.00 Relevant BLL.
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normal pregnancies that resulted in live birth at 37-42 weeks Miscarriage Women who had previous Maternal BLL = 62.4 IRR for plasma fraction tertiles: 1st Relevant to pregnant Lamadrid-Figueroa pregnancy and were µg/dL; plasma lead level tertile, 1.00 (Ref) ; 2nd tertile, 1.16 instructors on firing et al.
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linear relationship between untransformed BLL and gestational age in days; data adjusted for timing of lead test, maternal age, race, smoking, alcohol consumption, economics, parity, infant sex. Abbreviations: BLL, blood lead level; CI, confidence interval; IRR, incidence rate ratio; IVF, in vitro fertilization; OR, odds ratio; RR, relative risk; SD, standard deviation; UCSF, University of California, San Francisco.
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114 Potential Health Risks to DOD Firing-Range Personnel The exact mechanisms whereby lead interacts with the immune system remains unclear. However, several effects of lead on the immune system can be explained in the context of activation of the nuclear factor-κB (NF-κB)
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Noncancer Health Effects 115 In contrast, cell-mediated immunity is associated with T lymphocytes (such as CD3+, CD4+, and CD8+) that develop from pluripotent stem cells in bone marrow and migrate to the thymus to mature and differentiate.
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Uncertainty exists regarding the contributions of current lead exposures and cumulative lead stores in bone, but recent evidence on adults who had no occupational exposure has demonstrated altered concentrations of allergic IgE and specific cytokines in populations of adults who had BLLs of 1.9-7.0 µg/dL. On the basis of the consistency and coherence of findings across the continuum of related immune measures that demonstrated a stimulation of TH2 responses, combined with the supporting epidemiologic evidence on children, EPA concluded that there is a causal relationship between lead exposure and immune system effects.
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From page 117... ...
Even in those cases, however, there was inadequate evidence of an association owing to a general lack of investigations at lower BLLs and inconsistency in available data. The metric of bone lead could have been relevant in terms of a cumulative dose, but very few studies that examined changes in immune end points used non-BLL metrics.
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The mean air lead concentration was about 25 (± 19) µg/m3, and average BLLs of the workers were about 29 (± 15)
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conduction abnormalities, peripheral arterial disease, coronary heart disease, myocardial infarction, stroke, and cardiovascular mortality. Conclusions from the 2012 Environmental Protection Agency and 2012 National Toxicology Program Lead Documents Environmental Protection Agency 2012 Integrated Science Assessment for Lead (Second External Review Draft)
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(CD45+RA+) Significantly reduced Male workers in battery Mean BLL = 51.4 µg/dL p = 0.008 for salivary IgA Relatively similar Ewers et al.
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hallmark of type I workers in Korea hyersensitivity, and increase is associated with allergies. Significantly increased Male lead workers Mean BLL = 19 µg/dL p < 0.05 for changes in Relevant to BLL Sata et al.
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granulocytes significantly decreased after adjustment for age, sex, disease Abbreviations: ALAD, delta-aminolevulinic acid dehydratase; BLL, blood lead level; CD3+, CD4+, CD8+, cluster of differentiation (markers 3, 4, 8) ; CD45+RA+, naive memory T cells; CTL, cytotoxic T lymphocytes; HLA, human leukocyte antigen; IgA, IgG, IgE, immunoglobulin A, G, E; IL, interleukin; NKC, natural killer cells; TNF, tumor-necrosis factor; ZPP, zinc protoporphyrin.
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From page 123... ...
The report also pointed out that uncertainty exists as to the lead exposure level, timing, frequency, and duration that contribute to the observed associations because the adult populations examined in the epidemiologic research probably had high past lead exposures. National Toxicology Program 2012 Monograph on Health Effects of Low-Level Lead The NTP concluded that there is sufficient evidence that BLLs under 10 µg/dL are associated with increased blood pressure and hypertension in adults but that the evidence is limited with respect to associations with cardiovascularrelated mortality and other cardiovascular end points, such as ECG conduction abnormalities, heart-rate variability, and clinical cardiovascular diseases.
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) BLL and tibia bone lead concentration of 31.4 (14.2)
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in a prospective cohort of veterans in the Boston, Massachusetts, area (Normative Aging Study: 83 cases and 754 noncases) with 10 years of followup.
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The average BLLs were 24.0-26.7 µg/dL in lead-exposed workers and 5.4-8.3 µg/dL in the healthy controls. A unit increase in BLL was associated with an increase of 0.02 (standard error [SE]
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From page 127... ...
However, as might be expected given mechanistic considerations, tibia lead was not associated with homocysteine concentrations. The lead studies conducted as part of the Normative Aging Study consistently showed associations between bone lead and subclinical measures of cardiovascular disease.
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From page 128... ...
bone lead in For 10-µg/g increase in tibia, Reflecting cumulative Navas-Acien et al. (3 prospective studies, Normative Aging Study: cross-sectional increase: SBP, exposure; summary 2008 5 cross-sectional studies, tibia, 22 (13)
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From page 129... ...
Abbreviations: BLL, blood lead level; CI, confidence interval; CHD, coronary heart disease; CV, cardiovascular; CVD: cardiovascular disease; DBP, diastolic blood pressure; HR, hazard ratio; OR, odds ratio; SBP, systolic blood pressure; SD, standard deviation.
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From page 130... ...
1979. Occupational lead poisoning in the United States: Clinical and biochemical findings related to blood lead levels.
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1997. Curvilinear relation ship between blood lead level and reaction time: Differential association with blood lead fractions derived from exogenous and endogenous sources.
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1997. Cumulative blood lead levels and neurobehavioral test performance.
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2007. Elevated blood lead concentrations in essential tremor: A case-control study in Mersin, Tur key.
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2009. Determination of blood lead levels in adult Bahraini citizens prior to the introduction of unleaded gasoline and the possible effect of elevated blood lead levels on the serum immunoglobulin IgG.
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2004. Serum IgE elevation correlates with blood lead levels in battery manufacturing workers.
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2007. Lead levels and ischemic heart disease in a prospective study of middle-aged and elderly men: The VA Normative Aging Study.
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2005. The relationship between blood lead levels and neurobehavioral test performance in NHANES III and related occupational studies.
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2011. Association of blood lead levels with mortality in patients on maintenance hemodialysis.
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2005. Continued decline in blood lead levels among adults in the United States: The National Health and Nutrition Examination Surveys.
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1998. Relations of bone and blood lead to cognitive function: The VA Normative Aging Study.
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polymorphism: The VA Normative Aging Study.
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2003. Relationship of bone and blood lead levels to psychiatric symptoms: The Normative Aging Study.
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1992. Impairment of renal function with increasing blood lead con centrations in the general population.
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2004. Lead, diabetes, hypertension, and renal function: The normative aging study.
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2009. A prospective study of bone lead concentration and death from all causes, cardiovascular diseases, and cancer in the Department of Veterans Affairs Normative Aging Study.
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2004. Environmental exposure to lead and progres sion of chronic renal diseases: A four-year prospective longitudinal study.
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