4

Noncancer Health Effects

The adverse effects of lead on human health are well documented. Effects seen after lead exposure depend on the exposure dose and the absorbed dose, the duration of exposure, the timing of exposure during critical life stages, and host factors. The committee used the recent compilations of the toxicologic and epidemiologic studies of lead performed by the National Toxicology Program (NTP) and the US Environmental Protection Agency (EPA). Those reviews were used as a basis for identifying the primary noncancer health end points that would be of concern for firing-range personnel, including adverse effects on the adult nervous, hematopoietic, renal, reproductive, immune, and cardiovascular systems. Adverse effects in the developing fetus were also of concern. This chapter is organized along those lines.

As noted in Chapters 1 and 2, the committee specifically sought health-effects data on blood lead levels (BLLs) under 40 μg/dL because the current standard of the Occupational Safety and Health Administration (OSHA) aims to maintain BLLs below that concentration. Evidence on health effects at a corresponding estimated cumulative blood lead index (CBLI) of 1,600 μg-years/dL (that is, 40 years at 40 μg/dL) and tibia lead levels of 40-80 μg/g were also specifically sought.

ENVIRONMENTAL PROTECTION AGENCY AND NATIONAL TOXICOLOGY PROGRAM ASSESSMENTS

Three previous assessments were used by the committee for identifying key literature: the 2012 NTP Monograph on Health Effects of Low-Level Lead, the 2006 EPA Air Quality Criteria Document [AQCD] for Lead, and the 2012 EPA Integrated Science Assessment for Lead (Second External Review Draft). Each of the assessments provides background on lead exposure and lead toxicokinetics and includes a review of the primary epidemiologic or experimental literature for evidence that lead exposure is associated with adverse health effects. NTP’s assessment focuses on epidemiologic evidence at BLLs of under 5 or under 10 μg/dL and presents specific conclusions regarding each category of



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 62
4 Noncancer Health Effects The adverse effects of lead on human health are well documented. Effects seen after lead exposure depend on the exposure dose and the absorbed dose, the duration of exposure, the timing of exposure during critical life stages, and host factors. The committee used the recent compilations of the toxicologic and epi- demiologic studies of lead performed by the National Toxicology Program (NTP) and the US Environmental Protection Agency (EPA). Those reviews were used as a basis for identifying the primary noncancer health end points that would be of concern for firing-range personnel, including adverse effects on the adult nervous, hematopoietic, renal, reproductive, immune, and cardiovascular systems. Adverse effects in the developing fetus were also of concern. This chapter is organized along those lines. As noted in Chapters 1 and 2, the committee specifically sought health- effects data on blood lead levels (BLLs) under 40 µg/dL because the current standard of the Occupational Safety and Health Administration (OSHA) aims to maintain BLLs below that concentration. Evidence on health effects at a corre- sponding estimated cumulative blood lead index (CBLI) of 1,600 µg-years/dL (that is, 40 years at 40 µg/dL) and tibia lead levels of 40-80 µg/g were also spe- cifically sought. ENVIRONMENTAL PROTECTION AGENCY AND NATIONAL TOXICOLOGY PROGRAM ASSESSMENTS Three previous assessments were used by the committee for identifying key literature: the 2012 NTP Monograph on Health Effects of Low-Level Lead, the 2006 EPA Air Quality Criteria Document [AQCD] for Lead, and the 2012 EPA Integrated Science Assessment for Lead (Second External Review Draft). Each of the assessments provides background on lead exposure and lead toxi- cokinetics and includes a review of the primary epidemiologic or experimental literature for evidence that lead exposure is associated with adverse health ef- fects. NTP’s assessment focuses on epidemiologic evidence at BLLs of under 5 or under 10 μg/dL and presents specific conclusions regarding each category of 62

OCR for page 62
Noncancer Health Effects 63 health effect. EPA’s AQCD (2006) also identified health effects associated with BLLs under 10 μg/dL. EPA’s Integrated Science Assessment for Lead (2012) affirmed many of the conclusions reached in the AQCD (2006). The reader is referred to specific conclusions reached by those organizations and the commit- tee’s conclusions with respect to their relevance to Department of Defense per- sonnel who work on firing ranges. The committee also performed its own search for recent relevant literature on the health effects of lead to supplement those evaluations. NEUROLOGIC EFFECTS The adult nervous system is a critical target for the toxic effects of lead. Effects on the central nervous system of lead workers include dose-related changes in cognitive and psychomotor performance and mood, neurodegenera- tive 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. No peripheral motor or sensory symptoms are known to occur at BLLs under 40 μg/dL, but sensory nerve function is asso- ciated with lead dose. Potential modes of action for lead neurotoxicity include oxidative stress, inhibition of enzymes needed for energy production, decreased levels of neuro- transmitters and altered neurotransmitter release, and increased permeability of the blood-brain barrier (EPA 2012). Ultimately, lead-induced neurotoxicity in adults consists of changes in brain structure and neurochemistry, including white-matter changes, reduction in gray matter, and alterations in brain metabo- lites. Conclusions from the Environmental Protection Agency 2006 and 2012 and National Toxicology Program 2012 Lead Documents Environmental Protection Agency 2006 Air Quality Criteria Document EPA’s 2012 Integrated Science Assessment for Lead (Second External Re- view Draft) focused on updating the 2006 Air Quality Criteria Document for Lead (EPA 2006), so a summary of the key neurotoxic effects of lead in adults from the earlier document will be presented first. Studies of the effects of aging and their relationship with environmental lead exposure included the Veterans’ Administration Normative Aging Study established in 1961 in Boston and consisting of 2,280 healthy men 21-80 years old who are examined every 3 years (Payton et al. 1998; Rhodes et al. 2003; Wright et al. 2003; Weisskopf et al. 2004), the Kungsholmen Project on aging and dementia in Sweden (Nordberg et al. 2000), and the third National Health and Nutrition Examination Survey (NHANES III) (Krieg et al. 2005). There was

OCR for page 62
64 Potential Health Risks to DOD Firing-Range Personnel mixed evidence of a relationship between environmental lead exposure, as judged by current BLL, and impaired cognitive performance in adults. However, when bone lead was used as the measure of lead dose, the Normative Aging Study found significant associations with impaired neurocognitive performance. 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. Evidence in support of EPA’s conclusion included onset of diminished cognitive function and diminished psychomotor speed at a BLL of 18 µg/dL (Schwarz et al. 2001). However, in some studies, it was not the current BLL (under 30 µg/dL) but the measures of CBLI or bone lead concentration that were associated with poorer neurobehavioral performance (Lindgren et al. 1996; Bleecker et al. 1997; Hänninen et al. 1998; Bleecker et al. 2005a). The same relationship was found for peripheral sensory nerve studies most commonly associated with CBLI (Chia et 1996a,b; Kovala et al. 1997; Yokoyama et al. 1998). Changes in sensory nerve function occurred at BLLs of 28-30 µg/dL (Chuang et al. 2000; Bleecker et al. 2005b). Visual evoked potentials, measuring speed of conduction in the optic nerves, were prolonged beginning at BLLs of 17-20 µg/dL (Abbate et al. 1995). Slowed brainstem auditory evoked potentials were found to be associated with CBLI or weighted average BLL (Discalzi et al. 1992, 1993, Bleecker et al. 2003). A calculated benchmark dose for postural sway (measure of balance) was a current BLL of 14 µg/dL (Iwata et al. 2005). EPA identified a few publications that reported an increased risk of amyo- trophic lateral sclerosis (ALS) and motor neuron disease associated with past occupational lead exposure (Roelofs-Iverson et al. 1984; Armon et al. 1991; Gunnarsson et al. 1992; Chancellor et al. 1993; Kamel et al. 2002). The presence of the delta-aminolevulinic acid dehydratase (ALAD) 2 allele (ALAD2) increased that risk (odds ratio [OR] = 1.9; 95% confidence interval [CI]: 0.60, 6.3) (Kamel et al. 2003). Essential tremor, another neurodegenerative disorder, was associ- ated with low concurrent BLL (3 µg/dL) caused by exposure to environmental lead (Louis et al. 2003), but there was no information about past exposures, which might have been higher. The presence of the ALAD2 allele increased the odds of essential tremor by a factor of 30 compared with subjects that had only the ALAD1 allele (Louis et al. 2005). Environmental Protection Agency 2012 Integrated Science Assessment for Lead (Second External Review Draft) Neurobehavioral and Mood Effects EPA (2012) reviewed epidemiologic evidence of associations between en- vironmental lead exposure and neurobehavioral outcomes primarily from two

OCR for page 62
Noncancer Health Effects 65 studies—the Baltimore Memory Study and the Normative Aging Study. Results of those studies strengthened the association between cognitive performance and bone lead and probably reflect the effect of cumulative lead exposure on the brain (Shih et al. 2006; Weuve et al. 2006; Wang et al. 2007; Weisskopf et al. 2007; Rajan et al. 2008; Bandeen-Roche et al. 2009; Glass et al. 2009). Analysis of data from NHANES III revealed an association between concurrent BLL and lower neurobehavioral performance in particular age and genetic-variant sub- groups (Krieg and Butler 2009; Krieg et al. 2009, 2010). Mood disorders in young adults in the survey increased with a BLL of 2.11 µg/dL or above (Bou- chard et al. 2009). However another publication that used data from NHANES III but was not included in the EPA 2012 document examined all adults (20 years old or older) and found no consistent relationship between environmental lead exposure and depression (Golub and Winters 2010). In adults who had past occupational lead exposure, BLL and bone lead were associated with decrements in cognitive performance years after the cessa- tion of occupational exposure. The relationship between bone lead and cognitive performance was significant in workers older than 55 years old (Khalil et al. 2009a). Neurodegenerative Disease Two case-control studies published after 2006 found that BLL was associ- ated with ALS, but EPA had concerns about the contribution of “reverse causal- ity”. ALS decreases the ability to move the limbs, and this leads to increased demineralization of bone and release of lead from bone, which in turn increase BLLs. Thus, the disease could cause the increased BLL. In addition, there was bias in the study in that survival time increased with higher BLLs (Kamel et al. 2008; Fang et al. 2010). Parkinson disease was also reported to be associated with bone lead and whole-body lifetime exposure (Coon et al. 2006; Weisskopf et al. 2010), but EPA commented on the need to establish temporality between exposure and the onset of the disease and on the potential contribution of past exposure to manganese, a metal known to be associated with parkinsonism. Two additional studies reported the association of BLL and essential tremor, but the temporality between exposure and development of tremor was not established (Dogu et al. 2007; Louis et al. 2011) Sensory Organ Function New analyses have found an increase in hearing thresholds associated with bone lead in subjects in the Normative Aging Study (Park et al. 2010). In the occupational setting, people who had higher BLLs had significantly greater hearing loss (Chuang et al. 2007; Hwang et al. 2009).

OCR for page 62
66 Potential Health Risks to DOD Firing-Range Personnel National Toxicology Program 2012 Monograph on Effects of Low-Level Lead A recent NTP report examined the literature of neurotoxic outcomes asso- ciated with a BLL under 10 µg/dL. NTP concluded that the evidence that BLLs under 10 µg/dL were associated with the diagnosis of essential tremor was suffi- cient but that the evidence that BLLs under 5 µg/dL were associated was lim- ited. NTP also found limited evidence of an association between BLLs under 10 µg/dL and impaired cognitive function in older adults, psychologic effects, ALS, and reduced sensory function and auditory function. There were no studies of an association between BLLs of 10 µg/dL or lower and Alzheimer disease, Parkin- son disease, or sensory function or visual function. 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. 2000; Wright et al. 2003; Gao et al. 2008). According to data from NHANES III, neurobehavioral test performance in younger adults had no significant relationship with BLL (Krieg et al. 2005, 2009). However, studies that reported no association between neurologic outcome and BLL often found decreased neurobehavioral performance significantly associated with BLL (Weisskopf et al. 2004; Shih et al. 2006; Weuve et al. 2009). BLLs were associ- ated with psychiatric symptoms and mood disorders in young and older adults (Rhodes et al. 2003; Rajan et al. 2007; Bouchard et al. 2009). NTP concluded that the evidence was limited because of the small number of studies and be- cause there were multiple studies of a given cohort. However, as with all out- comes in adults, NTP noted that there were no data on whether BLLs were al- ways under 10 µg/dL from birth until the time of study. Neurodegenerative Effects NTP had the same concern as EPA (2012) that the association of BLL with ALS was influenced by reverse causality and by bias due to the increase in survival time with higher BLL (Kamel et al. 2008; Fang et al. 2010). NTP’s conclusion that there was sufficient evidence of an association between essential tremor and BLLs under 10 µg/dL was based on case-control studies conducted in two countries (Louis et al. 2003, 2005, 2011; Dogu et al. 2007). The evidence that essential tremor is associated with a BLL of 3 µg/dL is based on a small sample (300 essential tremor patients) in the two studies. Thus, NTP concluded that evidence of an association with a concurrent BLL under 5 µg/dL was lim- ited.

OCR for page 62
Noncancer Health Effects 67 Sensory Organ (Auditory) Effects In occupational studies, diminished hearing occurred primarily at frequen- cies over 3,000 Hz and began at a BLL of 7 µg/dL (Chuang et al. 2007; Hwang et al. 2009). The pattern of hearing loss was not the typical pattern seen in noise- induced hearing loss. The authors concluded that BLLs under 10 µg/dL might enhance noise-induced hearing loss. In people who had environmental lead ex- posure, hearing loss was associated with bone lead (Park et al. 2010). Other Studies Considered Mood and Occupational Lead Exposure Mood is evaluated with a neurologic-symptom questionnaire and a mood checklist or mood scale, such as the Center for Epidemiological Studies Depres- sion Scale (CES-D) and the Profile of Mood States (POMS), which screen on moods such as anger, confusion, depression, fatigue, anxiety and tension, and vigor. Those mood-rating scales differ slightly in content depending on the country in which they were developed. Mood change might be a primary out- come associated with exposure, but its evaluation is also necessary in adminis- tering neuropsychologic testing, inasmuch as mood may influence performance. In some occupational studies, mean BLLs of 29-43 µg/dL were associated with POMS subscales or items on a mood checklist (Maizlish et al. 1995; Hänninen et al. 1998; Niu et al. 2000), whereas other studies found no relationship be- tween BLLs of 27-38 µg/dL and measures of mood (Stollery et al. 1989; Chia et al. 1997; Osterberg et al. 1997; Lucchini et al. 2000). Results of administration of the CES-D screen for depression to 803 lead-exposed Korean workers were significantly associated with tibia lead (mean 37 µg/g) but not with BLL (mean 32 µg/dL) after adjustment for covariates (Schwartz et al. 2001). In some studies, difficulty in concentrating, irritability, fatigue, and mus- cle and joint pain were reported in workers who had a mean BLL of 43 µg/dL (Maizlish et al. 1995) or 27 µg/dL (Lucchini et al. 2000), whereas other studies with mean BLLs in the high 30s found no association with symptoms (Chia et al. 1997; Osterberg et al. 1997). Lucchini et al. (2000) estimated a BLL thresh- old of 12 µg/dL for a statistically significant increase in neurologic symptoms. Neurobehavioral Effects Tests are often used in neurobehavioral batteries to measure effects of lead exposure in different domains, such as attention and concentration (Digit Span), conceptual and executive functioning (Stroop and Trails B), visuoperceptive and visuoconstructive (Block Design), visuomotor (Reaction Time, Pegboard Test, Digit Symbol Substitution, and Trails A), verbal memory (Rey Auditory Verbal

OCR for page 62
68 Potential Health Risks to DOD Firing-Range Personnel Learning Test, Logical Memory, and Paired Associated Learning), and nonver- bal memory (Rey-Osterreith Complex Figure and Benton Visual Retention). In analyzing the association between lead exposure and test performance, adjust- ment for confounders is critical. Confounders include age, education (preferably a measure of verbal intelligence), depressive symptoms, alcohol use, and smoking. A study by Lindgren et al. (1996) of 467 Canadian lead-smelter workers was one of the first to evaluate the effects of cumulative lead exposure on the nervous system. The mean number of years of employment was 18, the mean BLL was 28 µg/dL, the time-weighted average BLL over a working lifetime was 40 µg/dL, and the mean CBLI was 765 µg-years/dL. CBLI exposure groups differed significantly in digit symbol, logical memory, Purdue dominant hand, and Trails A and B. No dose-effect relationship between BLL and neuropsy- chologic performance was found. In the smelter population, 256 currently em- ployed workers had a median score of 29 (range 19-30) in the screening test called the Mini-mental State Examination (MMSE). A dose-effect relationship between CBLI and MMSE was found only in the 78 workers who had a reading grade level less than 6 in the Wide Range Achievement Test (Revised). The absence of a dose-effect relationship in workers who had higher reading grade levels and the same CBLI was attributed to increased cognitive reserve (Bleecker et al. 2002). An in-depth examination of verbal learning and memory in the same population found no association with BLL, but with increasing CBLI or time-weighted average BLL over a working lifetime there was poorer storage and retrieval of previously learned verbal material. Alterations in the ability to organize materials in long-term memory interfered with retrieval effi- ciency. Those changes occurred in the group that had a mean time-weighted- average BLL of 41.2 ± 11.09 µg/dL and a CBLI of 813.1 ± 409.68 µg/g (Bleecker et al. 2005a). The one test sensitive to BLL in the population was Simple Reaction Time (SRT), which had a curvilinear relationship with increas- ing reaction time beginning at a BLL of about 30 µg/dL (Bleecker et al. 1997). Hänninen et al. (1998) studied neuropsychologic effects in lead-battery workers who had current BLLs under 50 µg/dL compared with those who had BLLs over 50 µg/dL in the past. They found that overall high, past exposure had the greatest effect on tests that required the encoding of complex visually pre- sented stimuli. The authors concluded that the effect of lead on brain function is better reflected by the history of the BLL, such as the CBLI, than by bone lead content. Some studies, particularly cross-sectional ones, that included measures of cumulative lead and current lead exposures found the strongest association be- tween BLL and neurobehavioral performance when the concurrent BLLs were high. Schwartz et al. (2001) reported that bone lead concentration was not asso- ciated with neurobehavioral performance in 803 Korean lead-exposed workers. In contrast, lead-exposed workers performed significantly worse than controls on SRT, Digit Span, Benton Visual Retention, Colored Progressive Matrices,

OCR for page 62
Noncancer Health Effects 69 Digit Symbol, and Purdue Pegboard after controlling for age, sex, and educa- tion. BLL was the best predictor of significant decrements in neurobehavioral performance on Trails B, Purdue Pegboard (four measures), and Pursuit Aiming (two measures). For those effects, an increase in BLL of 5 µg/dL was equivalent in its effects to an increase of 1.05 years in age. Use of Lowess lines for Purdue Pegboard (assembly) and Trails B suggested a threshold BLL of 18 µg/dL. Hwang et al. (2002) evaluated 212 consecutively enrolled workers from the above cohort of 803 Korean workers for protein kinase C (PKC) activity and the relationship between BLL and neurobehavioral performance. BLLs of 5-69 µg/dL were significantly associated with decrements in Trails B, SRT, and Pur- due Pegboard (three measures). PKC activity was measured by back- phosphorylation of erythrocyte membrane proteins and found not to be associ- ated with neurobehavioral test scores. However, dichotomization at the median revealed significant effect modification; the association of higher BLLs with poorer neurobehavioral performance occurred only in workers who had lower back-phosphorylation levels (which correspond to higher in vivo PKC activity). The authors suggested that PKC activity may identify a subpopulation at in- creased risk for neurobehavioral effects of lead. The cohort of Korean lead workers was studied longitudinally. The rela- tionship between occupational lead exposure and longitudinal decline in neuro- behavioral performance was assessed in 576 current and former Korean lead workers who completed testing at three visits at about yearly intervals (Schwartz et al. 2005). Cross-sectional associations of BLL and short-term change oc- curred with Trails A and B, Digit Symbol, Purdue Pegboard (four measures), and Pursuit Aiming after adjustment for covariates. However, longitudinal BLL was associated only with poorer performance on Purdue Pegboard (four meas- ures). Tibial bone lead was associated with Digit Symbol and Purdue Pegboard (dominant hand). For those effects, the effect of an increase in lead concentra- tion from the 25th to the 75th percentile was equivalent to an increase of 3.8 years of age for cross-sectional BLL, 0.9 year of age for historical tibia lead, and 4.8 years for longitudinal BLL. Long-term effects of occupational lead exposure have been evaluated in other studies. Khalil et al. (2009a) evaluated 83 lead-exposed workers and 51 controls 22 years after their initial neuropsychologic evaluation when the mean BLL was 40 µg/dL in workers and 7.2 µg/dL in controls. Twenty-two years later, their mean BLLs were 12 and 3 µg/dL, respectively. Mean bone lead ob- tained only at followup was 57 µg/g in workers and 12 µg/g in controls. BLL was not associated with any of the scores in five cognitive domains. Peak tibia lead was calculated to reflect bone lead level at the time that lead exposure ended. 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. The results sup- port a decline in cognitive performance with aging in lead-exposed workers.

OCR for page 62
70 Potential Health Risks to DOD Firing-Range Personnel Brain Anatomic and Biochemical Effects Eighty workers at the primary lead smelter previously described by Lindgren et al. (1996) underwent magnetic resonance imaging (MRI) of the brain. MRIs were graded by a neuroradiologist for white matter change (WMC) on a scale of none to lesions larger than 10 mm. Only the 61 workers under 50 years old were used in the analysis because of the large effect of age on WMC. Mean BLL in the group was 29 µg/dL, CBLI was 826 µg-years/dL, and bone lead was 39 µg/g. Logistic regression of WMC on lead exposure after control- ling for age, hypertension, triglycerides, C-reactive protein, smoking, and drink- ing found CBLI and bone lead significantly associated with WMC. A measure of psychomotor speed and dexterity, grooved pegboard, was significantly related to WMC and measures of lead exposure. Path analysis supported that the effect of CBLI and bone lead on psychomotor speed and dexterity was mediated by WMC (Bleecker et. al. 2007). Magnetic resonance spectroscopy (MRS) of the brain was used to examine the biochemical changes caused by lead (Hsieh et. al. 2009). Twenty-two lead workers (mean BLL 16.99 µg/dL, tibia lead 61.55 µg/g, and patella lead 66.29 µg/g) in a paint factory were compared with 18 healthy volunteers (mean BLL 3.4 µg/dL, tibia lead 18.51 µg/g, and patella lead 7.14 µg/g). Measures that re- flected neuronal loss and myelin alterations were lower in the lead-exposed workers primarily in the frontal and occipital lobes. 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 de- creases in gray and white matter in the occipital lobe. The strongest of the asso- ciations was of neuronal loss in the frontal lobe with BLL and patella lead level. It was suggested that those changes may contribute to poorer outcome in tests of memory and visual performance. Peripheral Nerve Function A meta-analysis of 32 publications of nerve-conduction studies and occu- pational lead exposure found BLL to be a weak predictor of peripheral nerve impairment (Davis and Svendsgaard 1990). Nerve-conduction testing includes analysis of latent period (time it takes for stimulatory impulse to initiate an evoked potential), conduction velocity, and amplitude. Reduced nerve- conduction velocities in lead-exposed subjects revealed that the median motor nerve was most sensitive. Nerve-conduction studies of workers in a lead-battery factory (Kovala et al. 1997) found that sensory amplitudes of the median and sural nerves corre- lated negatively with long-term exposure (CBLI and duration of exposure). Chia et al. (1996b) also found the strongest dose-effect relationship between median sensory conduction velocity and CBLI, whereas He et al. (1988) found sensory-

OCR for page 62
Noncancer Health Effects 71 conduction abnormalities related to BLL. Yokoyama et al. (1998) measured the distribution of conduction velocities in large myelinated fibers of the sensory median nerve twice (at a 1-year interval) in 17 gun-metal workers. They re- ported that measurements of chelatable lead (readily mobilized lead from soft tissue) were more strongly predictive of peripheral nerve impairment than BLL. Other studies examined peripheral sensory nerve function in the extremi- ties with a quantitative sensory test, vibration threshold, that measures the integ- rity of large myelinated nerve fibers. Kovala et al. (1997) found vibration threshold at the ankle to be related to CBLI and duration of exposure, whereas finger vibration threshold was associated with BLL (mean BLL 26 µg/dL and average BLL over the preceding 3 years 29 µg/dL). Overall, historical BLLs were more closely associated with peripheral nerve function than was bone lead in this population. In contrast, Schwartz et al. (2001) examined vibration thresh- olds and bone lead in 803 Korean workers and 135 controls and found that after adjustment for covariates tibia lead concentration (mean 37 µg/g) but not BLL (mean 32 µg/dL) was significantly associated with poorer vibration threshold in the dominant great toe but not the finger. In a followup study of 576 lead work- ers who completed three visits at yearly intervals, vibration threshold in the toe was associated with current BLL (mean 31 µg/dL), longitudinal BLL, and tibia lead (38 µg/g) after adjustment for covariates (Schwartz et al. 2005). Chuang et al. (2000) reported on vibration perception in the foot in 206 lead-battery work- ers. There was a significant association of BLL in the past 5 years (mean 32 µg/dL) and time-weighted average BLL over a working lifetime (mean 32 µg/dL) with vibration perception in the foot after adjustment for covariates, in- cluding the use of vibrating hand tools. Data analyses used a hockey-stick re- gression that uses two different curves to fit two regions of a dataset (Hudson 1966). The curve of foot vibration threshold vs mean BLL for the preceding 5 years showed an inflection point around 30 µg/dL; a positive linear relation above this point suggested a potential threshold. Bleecker et al. (2005b) examined peripheral nerve function in 80 smelter workers with Current Perception Threshold (CPT), a neuroselective test that measures integrity of the large and small myelinated nerve fibers and unmyeli- nated nerve fibers. CPT was not associated with BLL (mean 26 µg/dL) or bone lead (mean 40 µg/g). CPT for large myelinated nerve fibers had a curvilinear relationship with time-weighted average BLL over a working lifetime (mean 42 µg/dL), with an apparent threshold at 28 µg/dL. In regression analyses, CBLI and its associated exposure variables explained the increasing variance in CPT of large myelinated fibers and suggested that cumulative lead exposure intensity is more important than duration of exposure with regard to the peripheral nerv- ous system. At the highest BLL criterion, both large and small myelinated nerve fibers were impaired. Ergonomic stressors (used as a surrogate for active motor units) enhanced the effect of lead on the peripheral nervous system.

OCR for page 62
72 Potential Health Risks to DOD Firing-Range Personnel Evoked Potentials Visual evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs) measure speed of conduction in the nerves that run from the eyes and ears, respectively, to the relevant locations in the brain. On stimulation, nerves send signals in the form of “waves” that can be detected, and the time it takes for an impulse to initiate an evoked potential is latency. The VEP is the first positive wave and usually occurs at 100 ms (P100 latency) after the visual stimulus. That measure is very sensitive to demyelination of the optic nerve. BAEPs also have discrete waveforms. Wave I arises from the auditory nerve, and its latency reflects peripheral transmission time; wave III is generated pre- dominantly from the auditory pathway in the lower brainstem; and wave V is generated from the upper brainstem. The use of interpeak latencies helps distin- guish changes in peripheral auditory nerve latency from changes in brainstem transmission in the auditory pathway. Abbate et al. (1995) studied VEPs in 300 lead-exposed men (30-40 years old) in good health who had no other neurotoxic exposure. Their BLLs ranged from 17 to 60 µg/dL and were stratified into four groups for data analyses. P100 latency of VEPs was significantly prolonged in all the BLL groups. Prolonged VEP began at BLLs of 17-20 µg/dL. The contribution of age was not a concern, and careful screening ruled out other medical and eye conditions and other po- tential exposures. BAEPs in 49 lead-exposed workers (mean BLL 55 µg/dL; time-weighted average BLL over a working lifetime 54 µg/dL) and in age- and sex-matched controls were recorded (Discalzi et al. 1992). In workers who had a time- weighted average BLL over 50 µg/dL, conduction in the entire brainstem was slower. In a later publication, Discalzi et al. (1993) reported identical results in 22 battery storage workers who had a mean BLL of 47 µg/dL and a time- weighted average BLL of 48 µg/dL. BAEPs were measured in 359 currently employed smelter workers who had mean indexes of exposure of 17 years, BLL of 28 µg/dL, and CBLI of 719 µg-years/dL (Bleecker et al. 2003). 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. Groups were created on the basis of BAEP scores greater than clinical cut-off scores for peripheral auditory nerve conduction speed and brainstem conduction speed. For groups that had abnormal clinical BAEP values, the mean range of BLLs was 28.3 (± 7.8) to 34.8 (± 6.44) µg/dL and of CBLI was 723.0 (± 438.47) to 934.0 (± 352.80) µg-years/dL. Those results were all significantly higher than the ones in the group that had normal BAEPs. A case-control study in Taiwan (Chuang et al. 2007) in which workers re- ceived periodic health examinations found 121 people who had hearing thresh- olds above 25 dB and 173 controls who had normal hearing. Geometric mean

OCR for page 62
136 Potential Health Risks to DOD Firing-Range Personnel Hernberg, S., M. Nurminen, and J. Hasan. 1967. Nonrandom shortening of red cell sur- vival times in men exposed to lead. Environ. Res. 1(3):247-261. Horiguchi, S., I. Kiyota, G. Endo, K. Teramoto, K. Shinagawa, F. Wakitani, Y. Konishi, A. Kiyota, A. Ota, and H. Tanaka. 1992. Serum immunoglobulin and complement C3 levels in workers exposed to lead. Osaka City Med. J. 38(2):149-153. Hsieh, T.J., Y.C. Chen, C.W. Li, G.C. Liu, Y.W. Chiu, and H.Y. Chuang. 2009. A proton magnetic resonance spectroscopy study of the chronic lead effect on the basal gan- glion and frontal and occipital lobes in middle-age adults. Environ. Health Per- spect. 117(6):941-945. Hsu, P.C., H.Y. Chang, Y.L. Guo, Y.C. Liu, and T.S. Shih. 2009. Effect of smoking on blood lead levels in workers and role of reactive oxygen species in lead-induced sperm chromatin DNA damage. Fertil. Steril. 91(4):1096-1103. Hu, H., H. Watanabe, M. Payton, S. Korrick, and A. Rotnitzky. 1994. The relationship between bone lead and hemoglobin. JAMA 272(19):1512-1517. Hu, H., A. Aro, M. Payton, S. Korrick, D. Sparrow, S.T. Weiss, and A. Rotnitzky. 1996. The relationship of bone and blood lead to hypertension. The Normative Aging Study. JAMA 275(15):1171-1176. Hudson, D.J. 1966. Fitting segmented curves whose joint points have to be estimated. J. Am. Stat. Assoc.. 61(316):1097-1129. Humphrey, L.L., R. Fu, K. Rogers, M. Freeman, and M. Helfand. 2008. Homocysteine level and coronary heart disease incidence: A systematic review and meta-analysis. Mayo Clin. Proc. 83(11):1203-1212. Hwang, K.Y., B.K. Lee, J.P. Bressler, K. Bolla, W.F. Stewart, and B.S. Schwartz. 2002. Protein kinase C activity and the relations between blood lead and neurobehavioral function in lead workers. Environ. Health Perspect. 110(2):133-138. Hwang, Y.H., H.Y. Chiang, M.C. Yen-Jean, and J.D. Wang. 2009. The association be- tween low levels of lead in blood and occupational noise-induced hearing loss in steel workers. Sci. Total Environ. 408(1):43-49. Ishida, M., M. Ishizaki, and Y. Yamada. 1996. Decreases in postural change in finger blood flow in ceramic painters chronically exposed to low level lead. Am. J. Ind. Med. 29(5):547-553. Iwata, T., E. Yano, K. Karita, M. Dakeishi, and K. Murata. 2005. Critical dose of lead affecting postural balance in workers. Am. J. Ind. Med. 48(5):319-325. Jacobsen, C., K. Hartvigsen, M.K. Thomsen, L.F. Hansen, P. Lund, L.H. Skibsted, G. Hølmer, J. Adler-Nissen, and A.S. Meyer. 2001. Lipid oxidation in fish oil en- riched mayonnaise: Calcium disodium ethylenediaminetetraacetate, but not gallic acid, strongly inhibited oxidative deterioration. J. Agric. Food Chem. 49(2):1009- 1019. Jain, N.B., V. Potula, J. Schwartz, P.S. Vokonas, D. Sparrow, R.O. Wright, H. Nie, and H. Hu. 2007. Lead levels and ischemic heart disease in a prospective study of middle-aged and elderly men: The VA Normative Aging Study. Environ. Health Perspect. 115(6): 871-875. Jedrychowski, W., F.P. Perera, J. Jankowski, D. Mrozek-Budzyn, E. Mroz, E. Flak, S. Edwards, A. Skarupa, and I. Lisowska-Miszczyk. 2009. Very low prenatal expo- sure to lead and mental development of children in infancy and early childhood: Krakow prospective cohort study. Neuroepidemiology 32(4):270-278. Johnson, L. 1995. Efficiency of spermatogenesis. Microsc. Res. Tech. 32(5):385-422. Johnson, L., D.D. Varner, M.E. Roberts, T.L. Smith, G.E. Keillor, and W.L. Scrutchfield. 2000. Efficiency of spermatogenesis: A comparative approach. Anim. Reprod. Sci. 60-61:471-480.

OCR for page 62
Noncancer Health Effects 137 Kamel, F., D.M. Umbach, T.L. Munsat, J.M. Shefner, H. Hu, and D.P. Sandler. 2002. Lead exposure and amyotrophic lateral sclerosis. Epidemiology 13(3):311-319. Kamel, F., D.M. Umbach, T.A. Lehman, L.P. Park, T.L. Munsat, J.M. Shefner, D.P. Sandler, H. Hu, and J.A. Taylor. 2003. Amyotrophic lateral sclerosis, lead and ge- netic susceptibility: Polymorphisms in the delta-aminolevulinic acid dehydratase and vitamin D receptor genes. Environ. Health Perspect. 111(10):1335-1339. Kamel, F., D.M. Umbach, L. Stallone, M. Richards, H. Hu, and D.P. Sandler. 2008. As- sociation of lead exposure with survival in amyotrophic lateral sclerosis. Environ. Health Perspect. 116(7):943-947. Karita, K., E. Yano, M. Dakeishi, T. Iwata, and K. Murata. 2005. Benchmark dose of lead inducing anemia at the workplace. Risk Anal. 25(4):957-962. Kasperczyk, A., S. Kasperczyk, S. Horak, A. Ostalowska, E. Grucka-Mamczar, E. Romuk, A. Olejek, and E. Birkner. 2008. Assessment of semen function and lipid peroxida- tion among lead exposed men. Toxicol. Appl. Pharmacol. 228(3):378-384. Khalil, N., L.A. Morrow, H. Needleman, E.O. Talbott, J.W.Wilson, and J.A. Cauley. 2009a. Association of cumulative lead and neurocognitive function in an occupa- tional cohort. Neuropsychology 23(1):10-19. Khalil, N., J.W. Wilson, E.O. Talbott, L.A. Morrow, M.C. Hochberg, T.A. Hillier, S.B. Muldoon, S.R. Cummings, and J.A. Cauley. 2009b. Association of blood lead concentrations with mortality in older women: A prospective cohort study. Environ. Health 8:15. Khan, D.A., S. Qayyum, S. Saleem, and F.A. Khan. 2008. Lead-induced oxidative stress adversely affects health of the occupational workers. Toxicol. Ind. Health 24(9): 611-618. Kim, R., A. Rotnitsky, D. Sparrow, S. Weiss, C. Wager, and H. Hu. 1996. A longitudinal study of low-level lead exposure and impairment of renal function. The Normative Aging Study. JAMA 275(15):1177-1181. Korrick, S.A., D.J. Hunter, A. Rotnitzky, H. Hu, and F.E. Speizer. 1999. Lead and hypertension in a sample of middle-aged women. Am. J. Public Health 89(3):330- 335. Kovala, T., E. Matikainen, T. Mannelin, J. Erkkilä, V. Riihimäki, H. Hänninen, and A. Aitio. 1997. Effects of low level exposure to lead on neurophysiological functions among lead battery workers. Occup. Environ. Med. 54(7):487-493. Krieg, E.F., Jr., and M.A. Butler. 2009. Blood lead, serum homocysteine, and neurobe- havioral test performance in the Third National Health and Nutrition Examination Survey. Neurotoxicology 30(2):281-289. Krieg, E.F., Jr., D.W. Chrislip, C.J. Crespo, W.S. Brightwell, R.L. Ehrenberg, and D.A. Otto. 2005. The relationship between blood lead levels and neurobehavioral test performance in NHANES III and related occupational studies. Public Health Rep. 120(3):240-251. Krieg, E.F., Jr., M.A. Butler, M.H. Chang, T. Liu, A. Yesupriya. M.L. Lindegren, and N. Dowling. 2009. Lead and cognitive function in ALAD genotypes in the Third Na- tional Health and Nutrition Examination Survey. Neurotoxicol. Teratol. 31(6):364- 371. Krieg, E.F., Jr., M.A. Butler, M.H. Chang., T. Liu, A. Yesupriya, N. Dowling, and M.L. Lindegren. 2010. Lead and cognitive function in VDR genotypes in the Third Na- tional Health and Nutrition Examination Survey. Neurotoxicol. Teratol. 32(2):262- 272. Kuo, H.W., T.Y. Hsiao, and J.S. Lai. 2001. Immunological effects of long-term lead ex- posure among Taiwanese workers. Arch. Toxicol. 75(10):569-573.

OCR for page 62
138 Potential Health Risks to DOD Firing-Range Personnel Lal, B., G. Goldstein, and J.P. Bressler. 1996. Role of anion exchange and thiol groups in the regulation of potassium efflux by lead in human erythrocytes. J. Cell. Physiol. 167(2):222-228. Lamadrid-Figueroa, H., M.M. Téllez-Rojo, M. Hernández-Avila, B. Trejo-Valdivia, M. Solano-González, A. Mercado-Garcia, D. Smith, H. Hu, and R.O. Wright. 2007. Association between the plasma/whole blood lead ratio and history of spontaneous abortion: A nested cross-sectional study. BMC Pregnancy Childbirth 7:22. Lanceraux, E. 1881. Nephrite et arthrite saturnines: Coincidence de ces affections: Paral- lele avec la nephrite et l’arthrite gouteusses. Arch. Gen. Med. 6:641-647. Lasley, S.M., and M.E. Gilbert. 1996. Presynaptic glutamatergic function in dentate gyrus in vivo is diminished by chronic exposure to inorganic lead. Brain Res. 736(1-2):125-134. Li, P.J., Y.Z. Sheng, Q.Y. Wang, L.Y. Gu, and Y.L. Wang. 2000. Transfer of lead via placenta and breast milk in human. Biomed. Environ. Sci. 13(2):85-89. Lilis, R., J. Eisinger, W. Blumberg, A. Fischbein, and I.J. Selikoff. 1978. Hemoglobin, serum iron and zinc protoporphyrin in lead-exposed workers. Environ. Health Per- spect. 25:97-102. Lin, J.L., D.T. Lin-Tan, K.H. Hsu, and C.C. Yu. 2003. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N. Engl. J. Med. 348(4):277-286. Lin, J.L., D.T. Lin-Tan, C.C. Yu, Y.J. Li, Y.Y. Huang, and K.L. Li. 2006a. Environ- mental exposure to lead and progressive diabetic nephropathy in patients with type II diabetes. Kidney Int. 69(11):2049-2056. Lin, J.L., D.T. Lin-Tan, Y.J. Li, K.H. Chen, and Y.L. Huang. 2006b. Low-level environ- mental exposure to lead and progressive chronic kidney diseases. Am. J. Med. 119(8):707e1-707e9. Lin, J.L., D.T. Lin-Tan, C.W. Hsu, T.H. Yen, K.H. Chen, H.H. Hsu, T.C. Ho, and K.H. Hsu. 2011. Association of blood lead levels with mortality in patients on maintenance hemodialysis. Am. J. Med. 124(4):350-358. Lindgren, K.N., V.L. Masten, D.P. Ford, and M.L. Bleecker. 1996. Relation of cumula- tive exposure to inorganic lead and neuropsychological test performance. Occup. Environ. Med. 53(7):472-477. Louis, E.D., E.C. Jurewicz, L. Applegate, P. Factor-Litvak, M. Parides, I. Andrews, V. Slavkovich, J.H. Graziano, S. Carroll, and A. Todd. 2003. Association between es- sential tremor and blood lead concentration. Environ. Health Perspect. 111(14):1707-1711. Louis, E.D., L. Applegate, J.H. Graziano, M. Parides, V. Slavkovich, and H.K. Bhat. 2005. Interaction between blood lead concentration and delta-amino-levulinic acid dehydratase gene polymorphisms increases the odds of essential tremor. Mov. Disord. 20(9):1170-1177. Louis, E.D., P. Factor-Litvak, M. Gerbin, V. Slavkovich, J.H. Graziano, W. Jiang, and W. Zheng. 2011. Blood harmane, blood lead, and severity of hand tremor: Evi- dence of additive effects. Neurotoxicology 32(2):227-232. Lucchini, R., E. Albini, I. Cortesi, D. Placidi, E. Bergamaschi, F. Traversa, and L. Alessio. 2000. Assessment of neurobehavioral performance as a function of cur- rent and cumulative occupational lead exposure. Neurotoxicology 21(5):805-811. Lustberg, M., and E. Silbergeld. 2002. Blood lead levels and mortality. Arch. Intern. Med. 162(21):2443-2449.

OCR for page 62
Noncancer Health Effects 139 Luster, M.I., P.P. Simeonova, and D.R. Germolec. 2001. Immunotoxicology. Encyclope- dia of Life Sciences, Nature Publishing Group [online]. Available: http://immune web.xxmu.edu.cn/reading/innate/13.pdf [accessed Sept. 26, 2012]. Maizlish, N.A., G. Parra, and O. Feo. 1995. Neurobehavioral evaluation of Venezuelan workers exposed to inorganic lead. Occup. Environ. Med. 52(6):408-414. Martignoni, E., C. Tassorelli, G. Nappi, R. Zangaglia, C. Pacchetti, and F. Blandini. 2007. Homocysteine and Parkinson’s disease: A dangerous liaison? J. Neurol. Sci. 257(1-2):31-37. Martin, D., T.A. Glass, K. Bandeen-Roche, A.C. Todd, W. Shi, and B.S. Schwartz. 2006. Association of blood lead and tibia lead with blood pressure and hypertension in a community sample of older adults. Am. J. Epidemiol. 163(5):467-478. Meeker, J.D., M.G. Rossano, B. Protas, M.P. Diamond, E. Puscheck, D. Daly, N. Paneth, and J.J. Wirth. 2008. Cadmium, lead, and other metals in relation to semen quality: Human evidence for molybdenum as a male reproductive toxicant. Environ. Health Perspect. 116(11):1473-1479. Mendiola, J., J.M. Moreno, M. Roca, N. Vergara-Juarez, M.J. Martinez-Garcia, A. Gar- cia-Sanchez, B. Elvira-Rendueles, S. Moreno-Grau, J.J. Lopez-Espin, J. Ten, R. Bernabeu, and A.M. Torres-Cantero. 2011. Relationships between heavy metal concentrations in three different body fluids and male reproductive parameters: A pilot study. Environ. Health 10(1):6. Mishra, K.P. 2009. Lead exposure and its impact on immune system: A review. Toxicol. In Vitro 23(6):969-972. Mishra, K.P., V.K. Singh, R. Rani, V.S. Yadav, V. Chandran, S.P. Srivastava, and P.K. Seth. 2003. Effect of lead exposure on the immune response of some occupation- ally exposed individuals. Toxicology 188(2-3):251-259. Mishra, K.P., U.K. Chauhan, and S. Naik. 2006. Effect of lead exposure on serum immu- noglobulins and reactive nitrogen and oxygen intermediate. Hum. Exp. Toxicol. 25(11):661-665. Mishra, K.P., R. Rani, V.S. Yadav, and S. Naik, S. 2010. Effect of lead exposure on lym- phocyte subsets and activation markers. Immunopharmacol. Immunotoxicol. 32(3):446-449. Muntner, P., A. Menke, K.B. DeSalvo, F.A. Rabito, and V. Batuman. 2005. Continued decline in blood lead levels among adults in the United States: The National Health and Nutrition Examination Surveys. Arch. Intern. Med. 165(18):2155- 2161. Naha, N., and A.R. Chowdhury. 2006. Inorganic lead exposure in battery and paint fac- tory: Effect on human sperm structure and functional activity. J. UOEH 28(2):151- 171. Naha, N., and B. Manna. 2007. Mechanism of lead induced effects on human spermato- zoa after occupational exposure. Kathmandu University Medical Journal 5(17):85- 94 [online]. Available: http://www.kumj.com.np/issue/17/85-94.pdf Naicker, N., S.A. Norris, A. Mathee, P. Becker, and L. Richter. 2010. Lead exposure is associated with a delay in the onset of puberty in South African adolescent fe- males: Findings from the Birth to Twenty cohort. Sci. Total Environ. 408(2):4949- 4954. Navas-Acien, A., E. Guallar, E.K. Silbergeld, and S.J. Rothenberg. 2007. Lead exposure and cardiovascular disease–a systematic review. Environ. Health Perspect. 115(3): 472-482.

OCR for page 62
140 Potential Health Risks to DOD Firing-Range Personnel Navas-Acien, A., B.S. Schwartz, S.J. Rothenberg, H. Hu, E.K. Silbergeld, and E. Guallar. 2008. Bone lead levels and blood pressure endpoints: A meta-analysis. Epidemiology 19(3):496-504. Navas-Acien, A., M. Tellez-Plaza, E. Guallar, P. Muntner, E. Silbergeld, B. Jaar, and V. Weaver. 2009. Blood cadmium and lead and chronic kidney disease in US adults: A joint analysis. Am. J. Epidemiol. 170(9):1156-1164. Nawrot, T.S., L. Thijs, E.M. Den Hond, H.A. Roels, and J.A. Staessen. 2002. An epidemiological re-appraisal of the association between blood pressure and blood lead: A meta-analysis. J. Hum. Hypertens. 16(2):123-131. Niu, Q., S.C. He, H.Y. Li, J.Y. Wang, F.Y. Dai, and Y.L. Chen. 2000. A comprehensive neurobehavioral and neurophysiological study for low level lead-exposed workers. G. Ital. Med. Lav. Ergon. 22(4):299-304. Nomiyama, K., H. Nomiyama, S.J. Liu, Y.X. Tao, T. Nomiyama, and K. Omae. 2002. Lead induced increase of blood pressure in female lead workers. Occup. Environ. Med. 59(11):734-738. Nordberg, M., B. Windblad, L. Fratiglioni, and H. Basun. 2000. Lead concentrations in elderly urban people related to blood pressure and mental performance: Results from a population-based study. Am. J. Ind. Med. 38(3):290-294. NRC (National Research Council). 1993. Biologic markers of lead toxicity. Pp. 143-190 in Measuring Lead Exposure in Infants, Children and Other Sensitive Populations. Washington, DC: National Academy Press. NTP (National Toxicology Program). 2012. NTP Monograph on Health Effects of Low- Level Lead. Prepublication Copy. U.S. Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health. June 13, 2012 [online]. Available: http://ntp.niehs.nih.gov/?objectid=4F04B8EA- B187-9EF2-9F9413C68E76458E [accessed June 14, 2012]. Oldereid, N.B., Y. Thomassen, A. Attramadal, B. Olaisen, and K. Purvis. 1993. Concen- trations of lead, cadmium and zinc in the tissues of reproductive organs of men. J. Reprod. Fertil. 99(2):421-425. Osterberg, K., J. Börjesson, L. Gerhardsson, A. Schütz, and S. Skerfving. 1997. A neuro- behavioral study of long-term occupational inorganic lead exposure. Sci. Total En- viron. 201(1):39-51. Osterode, W., U. Barnas, and K. Geissler. 1999. Dose dependent reduction of erythroid progenitor cells and inappropriate erythropoietin response in exposure to lead: New aspects of anaemia induced by lead. Occup. Environ. Med. 56(2):106-109. Park, S.K., J. Schwartz, M. Weisskopf, D. Sparrow, P.S. Vokonas, R.O. Wright, B. Coull, H. Nie, and H. Hu. 2006. Low-level lead exposure, metabolic syndrome, and heart rate variability: The VA Normative Aging Study. Environ. Health Perspect. 114(11):1718-1724. Park, S.K., S. Elmarsafawy, B. Mukherjee, A. Spiro, III, P.S. Vokonas, H. Nie, M.G. Weisskopf, J. Schwartz, and H. Hu. 2010. Cumulative lead exposure and age- related hearing loss: The VA Normative Aging Study. Hear Res. 269(1-2):48-55. Payton, M., K.M. Riggs, A. Spiro, III, S.T. Weiss, and H. Hu. 1998. Relations of bone and blood lead to cognitive function: The VA Normative Aging Study. Neurotoxi- col. Teratol. 20(1):19-27. Perry, H.M., Jr, J.P. Miller, J.R. Fornoff, J.D. Baty, M.P. Sambhi, G. Rutan, D.W. Moskowitz, and S.E. Carmody. 1995. Early predictors of 15-year end-stage renal disease in hypertensive patients. Hypertension 25(4 Pt. 1):587- 594.

OCR for page 62
Noncancer Health Effects 141 Pinkerton, L., R.E. Biagini, E.M. Ward, R.D. Hull, J.A. Deddens, M.F. Boeniger, T.M. Schnorr, B.A. MacKenzie, and M.I. Luster. 1998. Immunologic findings among lead exposed workers. Am. J. Ind. Med. 33(4):400-408. Piomelli, S., B. Davidow, V. Guinee, P. Young, and G. Gay. 1973. The FEP [free eryth- rocyte porphyrin] test: A screening micromethod for lead poisoning. Pediatrics 51(2):254-259. Piomelli, S., A.A. Lamola, M.B. Poh-Fitzpatrick, C. Seaman, and L.C. Harber. 1975. Erythropoietic protoporphyria and lead intoxication: The molecular basis for dif- ference in cutaneous photosensitivity. I. Different rates of disappearance of pro- toporphyrin from the erythrocytes, both in vivo and in vitro. J. Clin. Invest. 56(6): 1519-1527. Piomelli, S., C. Seaman, D. Zullow, A. Curran, and B. Davidow. 1982. Threshold for lead damage to heme synthesis in urban children. Proc. Natl. Acad. Sci. USA 79(10):3335-3339. Plusquellec, P., G. Muckle, E. Dewailly, P. Ayotte, S.W. Jacobson, and J.L. Jacobson. 2007. The relation of low-level prenatal lead exposure to behavioral indicators of attention in Inuit infants in Arctic Quebec. Neurotoxicol. Teratol. 29(5):527-537. Poreba, R., P. Gac, M. Poreba, and R. Andrzejak. 2010. The relationship between occupational exposure to lead and manifestation of cardiovascular complications in persons with arterial hypertension. Toxicol. Appl. Pharmacol. 249(1):41-46. Poreba, R., P. Gac, M. Poreba, J. Antonowicz-Juchniewicz, and R. Andrzejak. 2011a. Relationship between occupational exposure to lead and local arterial stiffness and left ventricular diastolic function in individuals with arterial hypertension. Toxicol. Appl. Pharmacol. 254(3):342-348. Poreba, R., M. Poreba, P. Gac, and R. Andrzejak. 2011b. Ambulatory blood pressure monitoring and structural changes in carotid arteries in normotensive workers occupationally exposed to lead. Hum. Exp. Toxicol. 30(9):1174-1180. Poreba, R., M. Poreba, P. Gac, A. Steinmetz-Beck, B. Beck, W. Pilecki, R. Andrzejak, and M. Sobieszczanska. 2011c. Electrocardiographic changes in workers occupationally exposed to lead. Ann. Noninvasive Electrocardiol. 16(1):33-40. Qiao, N., M. Di Gioacchino, H. Shuchang, L. Youxin, R. Paganelli, and P. Boscolo. 2001. Effects of lead exposure in printing houses on immune and neurobehavioral functions of women. J. Occup. Health 43(5):271-277. Queiroz, M.L., M. Almeida, M.I. Gallao, and N.F. Hoehr. 1993. Defective neutrophil function in workers occupationally exposed to lead. Pharmacol. Toxicol. 72(2):73- 77. Queiroz, M.L., R.C. Perlingeiro, C. Bincoletto, M. Almeida, M.P. Cardoso, and D.C. Dantas. 1994. Immunoglobulin levels and cellular immune function in lead- exposed workers. Immunopharmacol. Immunotoxicol. 16(1):115-128. Quitanar-Escorza, M.A., M.T. Gonzalez-Martinez, L. Navarro, M. Maldonado, B. Are- valo, and J.V. Calderon-Salinas. 2007. Intracellular free calcium concentration and calcium transport in human erythrocytes of lead-exposed workers. Toxicol. Appl. Pharmacol. 220(1):1-8. Rajan, P., K.T. Kelsey, J.C. Schwartz, D.C. Bellinger, J. Weuve, D. Sparrow, A. Spiro, III, T.J. Smith, H. Nie, H. Hu, and R.O. Wright. 2007. Lead burden and psychiatric symptoms and the modifying influence of the delta-aminolevulinic acid dehydra- tase (ALAD) polymorphism: The VA Normative Aging Study. Am. J. Epidemiol. 166(12):1400-1408. Rajan, P., K.T. Kelsey, J.D. Schwartz, D.C. Bellinger, J. Weuve, A. Spiro, III, D. Spar- row, T.J. Smith, H. Nie, M.G. Weisskopf, H. Hu, and R.O. Wright. 2008. Interac-

OCR for page 62
142 Potential Health Risks to DOD Firing-Range Personnel tion of the delta-aminolevulinic acid dehydratase polymorphism and lead burden on cognitive function: The VA Normative Aging Study. J. Occup. Environ. Med. 50(9):1053-1061. Ratzon, N., P. Froom, E. Leikin, E. Kristal-Boneh, and J. Ribak. 2000. Effect of exposure to lead on postural control in workers. Occup. Environ. Med. 57(3):201-203. Rhodes, D., A. Spiro, III, A. Aro, and H. Hu. 2003. Relationship of bone and blood lead levels to psychiatric symptoms: The Normative Aging Study. J. Occup. Enivon. Med. 45(11):1144-1151. Roelofs-Iverson, R.A., D.W. Mulder, L.R. Elveback, L.T. Kurland, and C.A. Molgaard. 1984. ALS and heavy metals: A pilot case-control study. Neurology 34(3):393- 395. Ronis, M.J., J. Gandy, and T. Badger. 1998. Endocrine mechanisms underlying reproduc- tive toxicity in the developing rat chronically exposed to dietary lead. J. Toxicol. Environ. Health A. 54(2):77-99. Rothenberg, S.J., A. Poblano, and L. Schnaas. 2000. Brainstem auditory evoked response at five years and prenatal and postnatal blood lead. Neurotoxicol. Teratol. 22(4):503-510. Rothenberg, S.J., L. Schnaas, M. Salgado-Valladares, E. Casanueva, A.M. Geller, H.K. Hudnell, and D.A. Fox. 2002. Increased ERG a- and b-wave amplitudes in 7- to 10-year-old children resulting from prenatal lead exposure. Invest. Ophthalmol. Vis. Sci. 43(6):2036-2044. Sakata, S., S. Shimizu, K. Ogoshi, K. Hirai, Y. Ohno, T. Kishi, J.B. Sherchand, M. Utsumi, M. Shibata, M. Takaki, M. Ueda, and I. Mori. 2007. Inverse relationship between serum erythropoietin and blood lead concentrations in Kathmandu tricy- cle taxi drivers. Int. Arch. Occup. Environ. Health 80(4):342-345. Sanín, L.H., T. González-Cossío, I. Romieu, K.E. Peterson, S. Ruíz, E. Palazuelos, M. Hernández-Avila, and H. Hu. 2001. Effect of maternal lead burden on infant weight and weight gain at one month of age among breastfed infants. Pediatrics 107(5):1016-1023. Sata, F., S. Araki, T. Tanigava, Y. Morita, S. Sakurai, and N. Katsuno. 1997. Changes in natural killer cell subpopulations in lead workers. Int. Arch. Occup. Environ. Health 69(5):306-310. Sata, F., S. Araki, T. Tanigawa, Y. Morita, S. Sakurai, A. Nakata, and N. Katsuno. 1998. Changes in T cell subpopulations in lead workers. Environ. Res. 76(1):61-64. Saxena, G., and S.J. Flora. 2004. Lead-induced oxidative stress and hematological altera- tions and their response to combined administration of calcium disodium EDTA with a thiol chelator in rats. J. Biochem. Mol. Toxicol. 18(4):221-233. Schafer, J.H., T.A. Glass, J. Bressler, A.C. Todd, and B.S. Schwartz. 2005. Blood lead is a predictor of homocysteine levels in a population-based study of older adults. Environ. Health Perspect. 113(1):31-35. Schwartz, B.S., B.K. Lee, G.S. Lee, W.F. Stewart, S.S. Lee, K.Y. Hwang, K.D. Ahn, Y.B. Kim, K.I. Bolla, D. Simon, P.J. Parsons, and A.C. Todd. 2001. Associations of blood lead, dimercaptosuccinic acid-chelatable lead, and tibia lead with neuro- behavioral test scores in South Korean lead workers. Am. J. Epidemiol. 153(5): 453-464. Schwartz, B.S., B.K. Lee, K. Bandeen-Roche, W. Stewart, K.I. Bolla, J. Links, V. Weaver, and A. Todd. 2005. Occupational lead exposure and longitudinal decline in neurobehavioral test scores. Epidemiology 16(1):106-113. Schwartz, J. 1991. Lead, blood pressure, and cardiovascular disease in men and women. Environ. Health Perspect. 91:71-75.

OCR for page 62
Noncancer Health Effects 143 Shea, T.B., J. Lyons-Weiler, and E. Rogers. 2002. Homocysteine, folate deprivation and Alzheimer neuropathology. J. Alzheimers Dis. 4(4):261-267. Shih, R.A., T.A. Glass, K. Bandeen-Roche, M.C. Carlson, K.I. Bolla, A.C. Todd, and B.S. Schwartz. 2006. Environmental lead exposure and cognitive function in community-dwelling older adults. Neurology 67(9):1556-1562. Shouman, A.E., and I.A. El-Safty. 2000. Effect of occupational lead-exposure on blood pressure, serum aldosterone level and plasma renin activity. J. Egypt Public Health Assoc. 75(1-2):73-91. Shulman, A., R. Hauser, S. Lipitz, Y. Frenkel, J. Dor, D. Bider, S. Mashiach, L. Yogev, and H. Yavetz. 1998. Sperm motility is a major determinant of pregnancy outcome following intrauterine insemination. J. Assist. Reprod. Genet. 15(6):381-385. Silberstein, T., O. Saphier, O. Paz-Tal, J.R. Trimarchi, L. Gonzalez, and D.L. Keefe. 2006. Lead concentrates in ovarian follicle compromises pregnancy. J. Trace Elem. Med. Biol. 20(3):205-207. Singh, A., C. Cullen, A. Dykeman, D. Rice, and W. Foster. 1993. Chronic lead exposure induces ultrastructural alterations in the monkey testis. J. Submicrosc. Cytol. Pathol. 25(4):479-486. Slivkova, J., M. Popelkova, P. Massanyi, S. Toporcerova, R. Stawarz, G. Formicki, N. Lukac, A. Putała, and M. Guzik. 2009. Concentration of trace elements in human semen and relation to spermatozoa quality. J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. 44(4):370-375. Sokol, R.Z., C.E. Madding, and R.S. Swerdloff. 1985. Lead toxicity and the hypotha- lamic-pituitary-testicular axis. Biol. Reprod. 33(3):722-728. Sorel, J.E., G. Heiss, H.A. Tyroler, W.B. Davis, S.B. Wing, and D.R. Ragland. 1991. Black-white differences in blood pressure among participants in NHANES II: The contribution of blood lead. Epidemiology 2(5):348-352. Staessen, J.A., R.R. Lauwerys, J.P. Buchet, C.J. Bulpitt, D. Rondia, Y. Van Renterghem, and A. Amery. 1992. Impairment of renal function with increasing blood lead con- centrations in the general population. N. Engl. J. Med. 327(3):151-156. Stampfer, M.J., M.R. Malinow, W.C. Willett, L.M. Newcomer, B. Upson, D. Ullmann, P.V. Tishler, and C.H. Hennekens. 1992. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. J. Am. Med. Assoc. 268(7):877-881. Stollery, B.T., H.A. Banks, D.E. Broadbent, and W.R. Lee. 1989. Cognitive functioning in lead workers. Br. J. Ind. Med. 46(10):698-707. Stone, B.A., J.M. Vargyas, G.E. Ringler, A.L. Stein, and R.P. Marrs. 1999. Determinants of the outcome of intrauterine insemination: Analysis of outcomes of 9963 con- secutive cycles. Am. J. Obstet. Gynecol. 180(6 Pt 1):1522-1534. Sun, L.R., and J.B. Suszkiw. 1994. Pb2+ activates potassium currents in bovine adrenal chromaffin cells. Neurosci. Lett. 182(1):41-43. Sun, Y., D. Sun, Z. Zhou, G. Zhu, H. Zhang, X. Chang, and T. Jin. 2008. Estimation of benchmark dose for bone damage and renal function in a Chinese male population occupationally exposed to lead. Ann. Occup. Hyg. 52(6):527-533. Swan, S.H. 2006. Does our environment affect our fertility? Some examples to help re- frame the question. Semin. Reprod. Med. 24(3):142-146. Telisman, S., B. Colak, A. Pizent, J. Jurasović, and P. Cvitković. 2007. Reproductive toxicity of low-level lead exposure in man. Environ. Res. 105(2):256-266. Teruya, K., H. Sakurai, K. Omae, T. Higashi, T. Muto, and Y. Kaneko. 1991. Effect of lead on cardiac parasympathetic function. Int. Arch. Occup. Environ. Health 62(8):549-553.

OCR for page 62
144 Potential Health Risks to DOD Firing-Range Personnel Travison, T.G., A.B. Araujo, A.B. O’Donnell, V. Kupelian, and J.B. McKinlay. 2007. A population-level decline in serum testosterone levels in American men. J. Clin. Endocrinol. Metab. 92(1):196-202. Tsaih, S.W., S. Korrick, J. Schwartz, C. Amarasiriwardena, A. Aro, D. Sparrow, and H. Hu. 2004. Lead, diabetes, hypertension, and renal function: The normative aging study. Environ. Health Perspect. 112(11):1178-1182. Tyl, R.W. 2005. Toxicity Testing, Developmental. Encyclopedia of Toxicology. W. Philip. New York, Elsevier: 262-276. Ukaejiofo, E.O., N. Thomas, and S.O. Ike. 2009. Haematological assessment of occupa- tional exposure to lead handlers in Enugu urban, Enugu State, Nigeria. Niger. J. Clin. Pract. 12(1):58-64. Undeger, U., N. Basaran, H. Canpinar, and E. Kansu. 1996. Immune alterations in lead- exposed workers. Toxicology 109(2-3):167-172. Valentino, M., M. Governa, I. Marchiseppe, and I. Visonă. 1991. Effects of lead on po- lymorphonuclear leukocyte (PMN) functions in occupationally exposed workers. Arch. Toxicol. 65(8):685-688. Valentino, M., V. Rapisarda, L. Santarelli, M. Bracci, M. Scorcelletti, L. Di Lorenzo, F. Cassano, and L. Soleo. 2007. Effect of lead on the levels of some immunoregula- tory cytokines in occupationally exposed workers. Hum. Exp. Toxicol. 26(7):551- 556. Vander, A.J. 1988. Chronic effects of lead on the renin-angiotensin system. Environ. Health Perspect. 78: 77-83. Vaziri, N.D. 2008. Mechanisms of lead-induced hypertension and cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 295(2):H454-H465. Verhoef, P., F.J. Kok, D.A. Kruyssen, E.G. Schouten, J.C. Witteman, D.E. Grobbee, P.M. Ueland, and H. Refsum. 1997. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 17(5):989-995. Wang, F.T., H. Hu, J. Schwartz, J. Weuve, A.S. Spiro, III, D. Sparrow, H.L. Nie, E.K. Silverman, S.T. Weiss, and R.O. Wright. 2007. Modifying effects of the HFE polymorphisms on the association between lead burden and cognitive decline. En- viron. Health Perspect. 115(8):1210-1215. Wang, L., P. Xun, Y. Zhao, X. Wang, L. Qian, and F. Chen. 2008. Effects of lead expo- sure on sperm concentrations and testes weight in male rats: A meta-regression analysis. J. Toxicol. Environ. Health A 71(7):454-463. Wasserman, G.A., X. Liu, D. Popovac, P. Factor-Litvak, J. Kline, C. Waternaux, N. LoI- acono, and J.H. Graziano. 2000. The Yugoslavia Prospective Lead Study: Contri- butions of prenatal and postnatal lead exposure to early intelligence. Neurotoxicol. Teratol. 22(6):811-818. Weaver, V.M., B.K. Lee, K.D. Ahn, A.C. Todd, W.F. Stewart, J. Wen, D.J. Simon, P.J. Parsons, and B.S. Schwartz. 2003. Associations of lead biomarkers with renal function in Korean lead workers. Occup. Environ. Med. 60(8):551-562. Weaver, V.M., B.K. Lee, A.C. Todd, K.D. Ahn, W. Shi, B.G. Jaar, K.T. Kelsey, M.E. Lustberg, E.K. Silbergeld, P.J. Parsons, J. Wen, and B.S. Schwartz. 2006. Effect modification by delta-aminolevulinic acid dehydratase, vitamin D receptor, and ni- tric oxide synthase gene polymorphisms on associations between patella lead and renal function in lead workers. Environ. Res. 102(1):61-69. Weaver, V.M., L.R. Ellis, B.K. Lee, A.C. Todd, W. Shi, K.D. Ahn, and B.S. Schwartz. 2008. Associations between patella lead and blood pressure in lead workers. Am. J. Ind. Med. 51(5):336-343.

OCR for page 62
Noncancer Health Effects 145 Weaver, V.M., M. Griswold, A.C.Todd, B.G.Jaar, K.D. Ahn, C.B. Thompson, and B.K. Lee. 2009. Longitudinal associations between lead dose and renal function in lead workers. Environ. Res. 109(1):101-107. Wedeen, R.P., J.K. Maesaka, B. Weiner, and G. A. Lipat. Occupational lead nephropa- thy. Am. J. Med. 59(5):630-641. Weisskopf, M.G., R.O. Wright, J. Schwartz, A. Spiro, III, D. Sparrow, A. Aro, and H. Hu. 2004. Cumulative lead exposure and prospective change in cognition among elderly men: The VA Normative Aging Study. Am. J. Epidemiol. 160(12):1184- 1193. Weisskopf, M.G., S.P. Proctor, R.O. Wright, J. Schwartz, A. Spiro, III, D. Sparrow, H. Nie, and H. Hu. 2007. Cumulative lead exposure and cognitive performance among elderly men. Epidemiology 18(1):59-66. Weisskopf, M.G., N. Jain, H. Nie, D. Sparrow, P. Vokonas, J. Schwartz, and H. Hu. 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. Circulation 120(12):1056-1064. Weisskopf, M.G., J. Weuve, H. Nie, M.H. Saint-Hilaire, L. Sudarsky, D.K. Simon, B. Hersh, J. Schwartz, R.O. Wright, and H. Hu. 2010. Association of cumulative lead exposure with Parkinson’s Disease. Environ. Health Perspect. 118(11):1609-1613. Weuve, J., K.T. Kelsey, J. Schwartz, D. Bellinger, R.O. Wright, P. Rajan, A. Spiro, III, D. Sparrow, A. Aro, and H. Hu. 2006. Delta-aminolevulinic acid dehydratase polymorphism and the relation between low level lead exposure and the Mini- Mental Status Examination in older men: The Normative Aging Study. Occup. Environ. Med. 63(11):746-753. Weuve, J., S.A. Korrick, M.A. Weisskopf, L.M. Ryan, J. Schwartz, H.L. Nie, F. Grod- stein, and H. Hu. 2009. Cumulative exposure to lead in relation to cognitive func- tion in older women. Eniviron. Health Perspect. 117(4):574-580. WHO (Word Health Organization). 2010. WHO Laboratory Manual for the Examination and Processing of Human Semen, 5th Ed. World Health Organization, Geneva [online]. Available: http://whqlibdoc.who.int/publications/2010/9789241547789_ eng.pdf [accessed Sept. 27, 2012]. Wiebe, J.P., and K.J. Barr. 1988. Effect of prenatal and neonatal exposure to lead on the affinity and number of estradiol receptors in the uterus. J. Toxicol. Environ. Health 24(4):451-460. Wiebe, J.P., K.J. Barr, and K.D. Buckingham. 1988. Effect of prenatal and neonatal ex- posure to lead on gonadotropin receptors and steroidogenesis in rat ovaries. J. Toxicol. Environ. Health 24(4):461-476. Wright, R.O., S.W. Tsaih, J. Schwartz, A. Spiro, III, K. McDonald, S.T. Weiss, and H. Hu. 2003. Lead exposure biomarkers and mini-mental status exam scores in older men. Epidemiology 14(6):713-718. Xu, B., S.E. Chia, M. Tsakok, and C.N. Ong. 1993. Trace elements in blood and seminal plasma and their relationship to sperm quality. Reprod. Toxicol. 7(6):613-618. Yakub, M., and M.P. Iqbal. 2010. Association of blood lead (Pb) and plasma homocysteine: A cross sectional survey in Karachi, Pakistan. PLoS One 5(7):e11706. Yin, Y., T. Zhang, Y. Dai, Y. Bao, X.Chen, and X. Lu. 2008. The effect of plasma lead on anembryonic pregnancy. Ann. N.Y. Acad. Sci. 1140:184-189. Yokoyama, K., S. Araki, K. Murata, Y. Morita, N. Katsuno, T. Tanigawa, N. Mori, J. Yokota, A. Ito, and E. Sakata. 1997. Subclinical vestibulo-cerebellar, anterior cerebellar lobe and spinocerebellar effects in lead workers in relation to concurrent and past exposure. Neurotoxicology 18(2):371-380.

OCR for page 62
146 Potential Health Risks to DOD Firing-Range Personnel Yokoyama, K., S. Araki, H. Aono, and K. Murata. 1998. Calcium disodium ethylenedia- minetetraacetate-chelated lead as a predictor for subclinical lead neurotoxicity: Follow-up study on gun-metal foundry workers. Int. Arch. Occup. Environ. Health 71(7):459-464. Yu, C.C., J.L. Lin, and D.T. Lin-Tan. 2004. Environmental exposure to lead and progres- sion of chronic renal diseases: A four-year prospective longitudinal study. J. Am. Soc. Nephrol. 15(4):1016-1022. Zhu, M., E.F. Fitzgerald, K.H. Gelberg, S. Lin, and C. Druschel. 2010. Maternal low- level lead exposure and fetal growth. Environ. Health Perspect. 118(10):1471- 1475.