Could Lifetime Lead Exposure Play a Role in Limbic-predominant Age-related TDP-43 Encephalopathy (LATE)?

Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) is a disease in which the clinical presentation mimics that of Alzheimer's disease. TDP-43 proteinopathy associated with LATE has been identified in more than 20% of autopsies of community-dwelling adults over the age of 80. It is believed to contribute significantly toward tau-negative dementia. Heavy metals such as lead has also been linked to TDP-43 proteinopathy. In particular, lead triggers TDP-43 accumulation and disrupts TDP-43 homeostasis. However, the specific relationship between LATE and lead remains unknown. Before leaded gasoline was phased out during the 1970s and 1980s, average blood lead levels were 15 times what they are today. Thus, each successive birth cohort entering old age has had less cumulative lifeime exposure to lead. Lifetime exposure can be tracked in the tibia bone, where the half-life of lead is many decades. We hypothesize that lead plays a role in the development of LATE. There are two ways to explore the validity of this hypothesis. Generational differences in lead exposure should result in a steady decline in the prevalence of LATE among older adults. We propose the use of tibia bone lead levels be examined in conjunction with brain autopsies from different birth cohorts to examine the link between lead exposure and LATE prevalence, holding age constant. Furthermore, individuals with genetic polymorphisms that confer a greater lead absorption phenotype should display a higher degree of TDP-43 accumulation in autopsies. The results of such studies could provide insight into gene by environment interactions relevant to the development of LATE.

Dynamic Geochemistry of Tetraethyl Lead Dust during the 20th Century: Getting the Lead In, Out, and Translational Beyond.

This commentary provides a brief overview of policy decisions that permitted getting tetraethyl lead (TEL) into petrol; global geochemical lead-dust deposition evidence; 1975 catalytic converter requirements; concern about habitability of cities; a personal perspective on legacy lead research that accelerated getting TEL out of petrol; and translational beyond, including New Orleans pre- vs. post-Hurricane Katrina observations about legacy lead interventions that effectively improve urban children’s health outcomes.

Effects of lead on the adult brain: a 15-year exploration.

BACKGROUND: Historically, there has been minimal concern about the effect of adult lead exposure on the brain. Evidence from recent longitudinal studies raise concerns about the long-term effects of past exposure. METHODS: We initiated three independent longitudinal studies to determine whether cumulative lead exposure was associated with persistent or progressive brain effects. The studies include 1,109 former U.S. organolead manufacturing workers, 803 current and former inorganic lead workers in Korea, and 1,140 50- to 70-year-old Baltimore residents with environmental lead exposure. The organolead workers had past exposure to inorganic and tetraethyl lead (TEL); in the other two studies, exposure was to inorganic lead. In each of these studies, we measured blood lead and tibia and patella lead by 109Cd K-shell-induced X-ray fluorescence. RESULTS: Higher tibia lead was consistently associated with poorer measures of cognitive function. Longitudinal analysis of the Korean and organolead cohort indicate that the effect of lead is persistent. Moreover, MRI data on organolead workers indicates a possible progressive effect from past exposure; higher tibia lead was associated with lower brain volume. The latter study indicates that a difference in tibia lead equivalent to about one-sixth of the overall range was associated with a mean difference in these cognitive tests that was equivalent, on average, to what was observed for a five-year age difference. CONCLUSIONS: Our data suggest that a significant proportion of what is considered to be "normal" age-related cognitive decline may, in fact, be due to past exposure to neurotoxicants such as lead.

Past adult lead exposure is linked to neurodegeneration measured by brain MRI.

OBJECTIVE: To determine whether cumulative lead dose in former organolead workers was associated with MRI measures of white matter lesions (WML) and global and structure-specific brain volumes. METHODS: MRIs, tibia lead, and other measures were obtained from 532 former organolead workers with a mean age of 56 years and a mean of 18 years since last occupational exposure to lead. Cumulative lead dose was measured by tibia lead, obtained by X-ray fluorescence, and expressed as microg lead per gram of bone mineral (microg Pb/g). WML were evaluated using the Cardiovascular Health Study grading scale. A total of 21 global and specific brain regions were evaluated. RESULTS: A total of 36% of individuals had WML grade of 1 to 7 (0 to 9 scale). Increasing peak tibia lead was associated with increasing WML grade (p = 0.004). The adjusted OR for a 1 microg Pb/g increase in tibia lead was 1.042 (95% CI = 1.021, 1.063) for a CHS grade of 5+ (> or = 5 vs < 5). In linear regression, the coefficient for tibia lead was negative for associations with all structures. Higher tibia lead was significantly related to smaller total brain volume, frontal and total gray matter volume, and parietal white matter volume. Of nine smaller specific regions of interest, higher tibia lead was associated with smaller volumes for the cingulate gyrus and insula. CONCLUSIONS: These data suggest that cumulative lead dose is associated with persistent brain lesions, and may explain previous findings of a progressive decline in cognitive function.

Ethyl-leaded gasoline: how a classic occupational disease became an international public health disaster.

The author describes the controversy about the use of tetraethyl lead (TEL) as a gasoline additive. Early warnings were ignored by industry, and as leaded gasoline became more profitable, scientists willing to support industry were financed as guardians of the scientific criteria for lead's health impacts. Controversy erupted in 1924 after refinery accidents left workers dying from violent insanity. In efforts to protect their profits, industry executives falsely claimed there was no alternative to leaded gasoline. Fifty years passed before scientific, court, and regulatory challenges had any influence. When independent research finally emerged, the results were damning enough to support an international phase-out of leaded gasoline.

The removal of lead from gasoline: historical and personal reflections.

Tetraethyllead (TEL) was first fabricated for use in gasoline in 1923. Shortly after manufacture began, workers at all three plants began to become floridly psychotic and die. A moratorium on TEL production was put into place, but was lifted in 1926. Between 1926 and 1965, the prevailing consensus was that lead toxicity occurred only at high levels of exposure and that lead in the atmosphere was harmless. Most of the data on lead toxicity issued from a single source, the Kettering Laboratory in Cincinnati. In 1959, the first warnings of adverse health effects of lead at silent doses were raised by Clair Patterson, a geochemist. In hearings before the Senate Committee on Public Works, Senator Edward Muskie raised the question of adverse health effects from airborne lead. As new data accumulated on health effects of lead at lower doses, the movement to remove lead from gasoline gained momentum, and the Environmental Protection Agency examined the question. The removal of lead would take place over the next 25 years, and its accomplishment would require a severe change in the federal stance regarding its hazard. This article details the interaction of various forces, industrial, regulatory, judicial, public health, and public interest, that were engaged in this contest and estimates the value of this step.

Evidence for obstructive and restrictive lung pathology among tetra-ethyl lead handlers and petrol tanker fillers at a petrochemical industry in Nigeria.

Described here is a computer predicted and computer measured pulmonary function in a randomly selected population sample of 111 men. These consisted of 36 primary school teachers (control), 35 Tetra-ethyl Lead handlers (TEL) and 40 Tanker Loaders (TL) at a petrochemical industry in Warri, Delta State, Nigeria. Productive cough and headache were commoner among the TL (45%, 38%) and the TEL handlers (43%, 31%). TEL handlers were 5 times likely to develop insomnia and other sleep disturbances than the control group. TL were more than 3 1/2 times more likely to develop nervousness than the control group. Measured FEF25-75% was significantly lower than its predicted value among the TEL handlers (56%) and TL (55%) when compared with the control group (36%) (P < 0.05 respectively). Although there were distinct reductions in the measured values of FEF75-85% among the TEL handlers (41%) and the TL (40%) compared to the control group (28%), this difference did not reach a level of significance when the TEL or the TL were compared individually to the control group. Predicted and measured forced mid expiratory flow time (FMFT) was not significantly varied among the cases and the control. There was statistically significant disparities (P < 0.005) in the values of predicted and measured maximum voluntary ventilation (litres) of the TEL handlers (47%) and of the TL (46%) compared with that of the control group (29%). The data suggest obstruction of the big and small airways of those occupationally exposed at a petrochemical factory in Nigeria especially the tetra-ethyl lead handlers and the tanker loaders. This data also suggests that pulmonary impairment may lead to an increased respiratory absorption of lead in its organic form. Efforts should be made to ascertain the degree of impairment and to treat the affected workers.

Blood lead levels of traffic- and gasoline-exposed professionals in the city of Athens.

During the past 10 y, blood lead levels in the population of Athens, Greece, have decreased steadily. This decrease has paralleled the reduction of tetraethyl lead in gasoline and the introduction of unleaded fuel. Blood lead levels and other parameters were studied in 42 gas-station employees, 47 taxi drivers, 47 bus drivers, and 36 controls, all of whom worked in Athens. The blood lead levels did not differ significantly among the four groups (5.64+/-1.7 microg/dl, 5.96+/-1.7 microg/dl, 5.88+/-1.3 microg/dl, and 5.76+/-1.7 microg/dl, respectively). Glutamic-oxaloacetic transaminase (i.e., aspartate aminotransferase) and glutamic-pyruvic transaminase (i.e., alanine aminotransferase) were elevated in gas-station employees, and the former was elevated in taxi drivers. Gas-station employees who smoked had higher blood lead levels than their nonsmoking counterparts. The absence of any difference in the blood lead levels of individuals for whom physical examinations were either normal or abnormal suggests that either lead was not the cause of increased blood lead levels or that its contribution may have been important in the past.

Clair Patterson and Robert Kehoe's paradigm of "show me the data" on environmental lead poisoning.

In 1925, Robert A. Kehoe enunciated a paradigm predicated upon categorical distinction between expectations and conjecture ("show me the data" mentality) from hard scientific facts on exposure outcomes. It led to a precedent-setting system of voluntary self-regulation by lead industry as a model for environmental control and implicitly signaled the level of industrial responsibility for lead pollution. It combined a cascading uncertainty rule (there is always uncertainty to be found in a world of imperfect information) with a highly skewed cost-benefit concept (immediate benefits of tetraethyl lead additives must be weighed against possible future health hazards). Many studies were funded by the lead industry to develop a theoretical framework for the paradigm which served as a strong defensive strategy against lead critics. It resulted in an unfettered growth in automotive lead pollution to over 270,000 tons per year in the United States and 350,000 tons per year worldwide during the early 1970s. Clair Patterson is credited with being the first person to mount an effective challenge against the Kehoe paradigm, and with his success came an upsurge of activity and attention to the risks of environmental lead pollution on public health.

Simple visual reaction time in organolead manufacturing workers: comparison of different methods of modeling lead exposure and reaction time.

In March 1990, 222 organolead manufacturing workers and 62 nonexposed referents were administered a neurobehavioral test battery that included simple visual reaction time (SVRT). SVRT was measured over 44 trials with interstimulus intervals ranging from 1 to 10 sec in a random but fixed order for all study subjects. Different measures of lead exposure and dose (e.g., recent and cumulative exposure based on personal sampling data, exposed/nonexposed status, recent blood lead and zinc protoporphyrin levels, and peak and cumulative urine lead levels) were examined as predictors of several different parameters of SVRT (e.g., mean, median, truncated mean, and standard deviation of SVRT over 44 trials). The association varied, depending on the measures used for SVRT and lead exposure and dose. In linear regression analyses, the strongest and most consistent associations of lead exposure and dose were observed with the standard deviation of SVRT. In assessing the different exposure measures, strong and consistent associations were observed with blood lead levels at the time of SVRT testing, but not with recent or cumulative exposure measures. That is, stronger associations were observed with measures of relatively recent internal dose (i.e., blood lead level) than with cumulative measures (i.e., cumulative exposure). Future studies using SVRT should consider parameters of SVRT that have not been commonly used to date, such as the standard deviation of the SVRT.

[Examination of visual evoked potentials in persons exposed to prolonged contact with ethyl benzene vapors]. / Badanie wzrokowych potencjalów wywolanych u osób przewlekle narazonych na pary benzyny etylizowanej.

PURPOSE: The aim of this study is an estimation of the visual evoked potentials (VEP) of persons exposed to prolonged contact with leaded petrol. MATERIALS AND METHODS: A group of 90 males aged between 22 and 53, exposed to prolonged contact with leaded petrol for the period of between a few months to 30 years, was examined. Those examined were divided into three groups depending on the length of exposure: group 1 up to 10 years, group II-11-20 years, group III-20 years and more. The results were compared with those obtained from a group of 40 healthy age-matched males, not exposed to leaded petrol. In neurological and ophthalmological examinations no pathological symptoms were detected in both groups. The VEP examination was executed using pattern reversal (pr) and pattern flash (pf) stimulation. RESULTS: The frequent pathological record of VEP was an elongation in the latency of P-100 and reduction of response amplitude. Using pr stimulation, the reduction of the mean value of the amplitude for group III was found statistically significant (p < 0.01). In pf examination in group III mean latency of the P-100 was significantly statistically (p < 0.01) longer than in the control group. Significant reduction of the response amplitude in groups II (p < 0.01) and III (p < 0.001) was found in this type of stimulation. CONCLUSIONS: The results of studies indicate subclinical damage of the visual pathway particularly of persons exposed to leaded petrol vapour during work for longer than 20 years.

Case-control study of cancer risk in tetraethyl lead manufacturing.

A case-control study was conducted to investigate the relative risk of cancer detection among Du Pont employees who worked in a tetraethyl lead (TEL) manufacturing area. The study's objective was to determine whether the employees' risk of developing or dying from cancer was associated with occupational exposure to TEL. All malignant neoplasms detected in the active and pensioned employee population during the period 1956-1987 were studied. TEL exposure was estimated by the following measures: ever employed in the TEL area, years of employment in TEL, TEL exposure rank, and the TEL cumulative exposure index. TEL manufacturing exposed employees to both organic and inorganic lead compounds. Because the underlying data did not permit the exposure assessment to distinguish between organic and inorganic lead, the TEL exposure measures reflect exposure to the TEL manufacturing process itself. The effects of latency, cigarette smoking habits, and exposures to other known or suspected carcinogens at the plant were also assessed. A strong association was observed between exposure to the TEL manufacturing process and rectal cancer (the odds ratio was 3.7 with 90% confidence limits of 1.3-10.2 for the analysis of ever/never exposed to TEL). An exposure-response relationship was noted with a fourfold elevation in the odds ratio at the high-very high cumulative exposure level. These patterns were even more pronounced after assuming a 10 year latency. Similar results were obtained for cancers of the sigmoid colon. These findings suggest that exposure to the TEL manufacturing process may have played a causal role in the colorectal cancer experience at the plant. This position is supported by the graded exposure-response relationships, the consistency of the results across exposure measures, the specificity of the health outcome (i.e., colorectal cancer), and the strength of the association. However, the evidence for causality is not compelling. This is the first report of an association between TEL manufacturing and colorectal cancer, and the evidence is compatible with a wide range of causal (i.e., indirect vs. direct acting; initiating vs. promoting) and noncausal (i.e., statistical and methodological bias; coincidence) interpretations.

Clinical evaluation of 58 organolead manufacturing workers.

Fifty-eight workers were evaluated at a university-based occupational health clinic for potential health effects related to organic and inorganic lead exposures. The clinical evaluation included a history, physical, and laboratory examination, and in a subset of workers, neurobehavioral tests and nerve conduction studies. Workers reported symptoms that predominantly involved the central and peripheral nervous systems. Findings for which no alternative medical explanations could be found included neurobehavioral abnormalities (18 of 39 workers) and sensorimotor polyneuropathies (11 of 31 workers). The clinical presentation and evaluation of workers exposed to organic lead are discussed.

Early health effects and biological monitoring in persons occupationally exposed to tetraethyl lead.

Dependent on the level of occupational exposure to tetraethyl lead, the occurrence of early signs of toxicity and the urinary excretion of triethyl lead, diethyl lead and total lead compounds were investigated. This was done in the following cohorts in the province of Hubei, China: 277 workers at gasoline depots exposed to gasoline, 36 traffic policemen exposed to automobile exhaust and 342 public office workers (virtually non-exposed controls). Mean external tetraethyl lead exposure concentrations were 84.8 micrograms/m3 (as Pb) for the gasoline depot workers, 5.2 micrograms/m3 for traffic police and 1.1 microgram/m3 for the controls. No significant subclinical indications of organic lead toxicity were found in the group of traffic policemen compared with the controls. In the cohort of gasoline workers, however, there was a statistical increase (vs controls) in the frequency of appearance of tremor and of sinus bradycardia. When the cohort of gasoline workers was divided into subgroups of different ranges of exposure, dose-dependence was noted. In general, the urinary excretion of triethyl lead was very low compared to that of diethyl lead, which appears to be a sensitive and specific indicator of exposure to tetraethyl lead; total lead excretion did not correlate well with actual external tetraethyl lead exposure. On the basis of these data it seems that current occupational exposure limits for tetraethyl lead are inadequate and need to be revised. In addition, a biological limit, based on urinary diethyl lead excretion, may be proposed.

Influence of chronic low-level exposure to lead on plasma immunoglobulin concentration and cellular immune function in man.

The immunological status of individuals occupationally exposed to low levels of inorganic lead has been examined and compared with that of non-exposed, age and sex-matched controls. At the time of testing the exposed population had a mean (+/- SD) blood lead concentration of 38.4 +/- 5.6 micrograms X 100 ml-1 (n = 39) compared with a mean value of 11.8 +/- 2.2 micrograms X 100 ml-1 (n = 21) for the control group. No differences in the serum concentrations of IgG, IgA and IgM between the populations were observed and there existed no correlation between blood lead concentration and serum immunoglobulin levels. In addition assessment was made of the capacity of peripheral blood mononuclear cells to respond to the mitogen phytohaemagglutinin (PHA), a correlate of T cell function, and to spontaneously lyse cells of the erythroleukaemic cell line K562, a measure of NK cell function. In neither case was there a difference between exposed and control populations and no correlation between reactivity and blood lead concentration. Although previous studies in rodents have indicated that exposure to inorganic lead resulting in similar blood lead concentrations may compromise immune competence our data suggest that no similar effect occurs in man.

Peripheral neuropathy due to gasoline sniffing - A case report.

A case of polyneuropathy in a 14-year-old boy, a chronic gasoline sniffer, is reported. Clinical and electromyographic examination showed a symmetrical motor involvement, mainly distally and in the lower limbs. A sural nerve biopsy showed only slight changes, both of axonal and demyelinating type. The role of gasoline toxic substances in the etiology of this rare polyneuropathy is discussed.