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.

Alkyllead compounds and their environmental toxicology.

Alkyllead compounds are man-made compounds in which a carbon atom of one or more organic molecules is bound to a lead atom. Tetraethyllead and tetramethyllead are the most common alkyllead compounds that were used primarily as gasoline additives for many years. Consequently, auto emissions have accounted for a major part of lead environmental pollution. Alkyllead compounds can readily enter living organisms as they are well absorbed via all major routes of entry. Because of their lipid solubility, the alkylleads can also readily cross the blood-brain barrier. The toxicokinetic information on organic lead can be used as biomarkers of exposure for monitoring exposed individuals. The organic alkyllead compounds are more toxic than the inorganic forms of lead. Neurotoxicity is the predominant effect of lead (both for organic and inorganic forms), although lead affects almost every organ of the body. The use of alkyllead compounds has declined over the last 20 years, due to the worldwide effort to eliminate the use of leaded gasoline. This achievement can be viewed as a great accomplishment of public health preventive measures.

[Diagnostic problems in case of environmental exposure to tetraethyl lead]. / Problemy diagnostyczne w przypadku srodowiskowego narazenia na czteroetylek olowiu.

UNLABELLED: The aim of this study was the presentation of the chronic tetraethyl lead poisoning of the 4 person family in the place of settlement. CASE REPORT: 15.5-years-old man was admitted to the regional Pediatric Ward because of changes of behavior, hallucinations, agitation. Nausea, vomiting, metallic taste and diarrhea were observed prior to the admission. In the case history, there were no data suggested of the toxic origin of the disorder . The CSF examination and CT of the brain were normal. Increased activity of CPK, ALT, AST, GTP, LDH in the blood were found. Paranoid syndrome was diagnosed by psychiatric evaluation. The patients' mother presented similar signs in almost the same time. The laboratory tests of the blood taken from the patients' father and older brother revealed the increase activity of the same enzymes (CPK, ALT, AST, LDH). All family was admitted to the Department of Clinical Toxicology in Kraków because of suspicion of the heavy metal poisoning. The toxicological laboratory test showed in all described patients the toxic serum lead concentration accordingly: 440 microg/l--older brother, 490 microg/l--father, 508 microg/l--mother and 635 microg/l--primary described patient. Because of the fact, that were no characteristic for lead poisoning changes in blood picture, the toxicological investigations were continued. As a result of these examinations presence of a diethyl lead in urine was confirmed. In the evaluation of the multiorgan damages connected with tetraethyl lead poisoning, we paid special attention on CSN dysfunctions. The USG and scintigraphy examinations revealed the liver damage. The different kinds of arrhythmias indicated on cardiovascular system damage. Based on clinical presentation and laboratory investigations the chronic tetraethyl lead poisoning was diagnosed.

[Clinical and biochemical aspects of accidental poisoning with tetraethyl lead in a 2.5 year old patient--long term observation]. / Kliniczne i biochemiczne aspekty przypadkowego zatrucia tetraetylkiem olowiu u 2,5 letniego dziecka--dlugofalowa obserwacja przypadku.

The paper describes an accidental, acute toxic exposure of a 2.5-year-old girl to tetraethyl lead. The authors discuss the clinical picture and treatment within the acute phase of intoxication as well as during the ambulatory follow-up of chronic sequelae of the exposure. Systemic, periodic monitoring of lead (Pb) levels in the blood (B-Pb) and urine (U-Pb) over a 2-year period gave the authors a unique opportunity to observe the dynamics of urinary excretion of this element. In the acute phase of intoxication the Pb blood value reached the plateau at the 46 micrograms/dl after 3 days from the exposure. Mild encephalopathy and gastrointestinal tract irritation was observed at that time. After 3 weeks of hospitalisation Pb levels decreased to the values 32 micrograms/dl whereas urinary Pb diminished from the initial 600 micrograms/L to 56 micrograms/L. During the 2-years outpatient follow-up Pb in the blood decreased to 7 micrograms/dl. Urinary Pb is still maintained above the population value's range. No detectable, permanent detrimental health effects were observed in the child. The girl is followed-up in annual intervals. Several other tissues are and will be assessed by non-invasive methods (e.g. hair, primary teeth) and analysed for accumulated Pb. The collected data will allow the authors for describing Pb distribution in the body as well as long term excretion in the growing and developing organism of the child.

Triethyl and trimethyl lead: effects on behavior, CNS morphology and concentrations of lead in blood and brain of rat.

The dose-related behavioral effects produced by triethyl (TEL) (2.6 to 7.9 mg/kg) and trimethyl lead (TML) (8.8 to 26.2 mg/kg) were assessed 2, 7, 14, 21 and 28 days following injection. TEL, but not TML, produced dose- and time-related decreases in body weight. Both agents decreased vertical and horizontal components of motor activity 2 days postdosing; increased activity was seen consistently in TEL-exposed rats 7 to 21 days after dosing. TML increased fore- and hindlimb strength for up to 28 days postdosing. TEL had no consistent effect on this measure. Both TEL and TML decreased responsiveness to an acoustic stimulus during the first two weeks postdosing. Latency to respond to a thermal stimulus was increased 2 to 14 days after TEL with the peak change occurring from 2 to 7 days. The peak of effect following TML was two weeks postdosing. In general, there was a significant correlation between both TEL and TML-induced changes in blood and brain lead levels and decreased sensitivity to a thermal stimulus. The apparent delayed onset of TML-induced neurobehavioral effects may be related to a longer time to obtain peak blood or brain levels. Histopathological assessment of rats 7 or 28 days after TEL and TML indicated that TEL caused structural abnormalities in the hippocampus and dorsal root ganglion, while TML produced changes primarily in the spinal cord and brain stem.

Quantitative analysis of total and trimethyl lead in mammalian tissues using ion exchange HPLC and atomic absorption spectrometric detection.

Measurement of total and trimethyl lead in mammalian tissue is described, using ion exchange/high performance liquid chromatography in tandem with flameless atomic absorption spectrometry for lead-specific detection. All lead forms in whole blood and homogenates of soft tissue--brain, kidney, and liver--were liberated from tissue binding by treatment with dilute (3N) HCl for a period of 18 hr. Trimethyl lead was partitioned into chloroform/ethyl acetate after media neutralization to pH of approximately 4 and saturation with sodium chloride. The extract was chromatographically analyzed on a Partisil SCX-10 cation exchange column, using 0.167M ammonium citrate in methanol:water (70:30) as mobile phase. Fractions of eluate were collected using a programmable fraction collector, and the fractions collected from 3.5 to 5.0 min were analyzed by atomic absorption spectrometry. Total lead in tissue was measured by acid wet digestion and flameless atomic absorption spectrometry. The difference in the values from both analyses provided a measure of any trimethyl lead metabolites.

Recreational gasoline sniffing: acute gasoline intoxication and latent organolead poisoning. Case reports and literature review.

Gasoline is a readily obtainable intoxicant that unfortunately lends itself to habitual abuse by sniffing, a practice found particularly among children and adolescents. The concerted effects of the multiple hydrocarbon and other constituents of gasoline result in a predictable acute toxic syndrome. Organoleads, primarily tetraethyl lead (TEL), cause a separate toxicologic symptom-sign complex that overlaps with the initial acute toxic syndrome. The different clinical symptomatology, effects on hemoglobin synthesis, and response to chelation therapy are all in keeping with the view that organolead poisoning is a separate and distinct toxicologic entity from that of classical elemental lead poisoning or "plumbism".

A new method for the analysis of tetramethyllead in blood.

In this paper a method for the determination of alkyllead compounds in blood is described. The method is based on extraction of the aklyllead compounds into an organic solvent, followed by separation by high-resolution gas chromatography. A graphite-furnace atomic absorption spectrophotometer is used as the detector. A detection limit of 0.01 micrograms/ml for tetramethyllead was obtained in blood samples. The method was used for the investigation of occupational exposure to tetramethyllead in gasoline. Blood samples from tank cleaners and gasoline pump servicemen showed detectable amounts of tetramethyllead. The reference group did not show any detectable levels of tetramethyllead.

Personnel monitoring for tetraalkyl lead in the workplace.

Personnel monitoring for alkyl lead and inorganic lead in air was carried out for six weeks on five workers in an alkyl lead manufacturing plant. Lead in air values were compared to biological values for lead blood, lead in urine, and delta aminoleuvlinic acid in urine. While variations in each of these measurements occurred, there was no correlation between any of these three measurements and lead in air. Measurements of atmospheric exposure to alkyl lead by personnel monitoring does not provide an accurate assessment of the degree of hazard to workers. When such measurements are performed frequently, they can provide information useful in controlling respiratory exposure. Biological monitoring of lead in urine as practiced by the alkyl lead industry remains the best protection against overexposure to organic lead.