Amyotrophic lateral sclerosis and lead: A systematic update.

Heavy metals are considered to be among the leading environmental factors that trigger amyotrophic lateral sclerosis (ALS). However, no convincing biopathological mechanism and therapeutic clinical implication of such metals in ALS pathogenesis have been established. This is partly attributable to the technical and scientific difficulties in demonstrating a direct and causative role of heavy metals in the onset of ALS in patients. However, a body of epidemiological, clinical and experimental evidences suggest that lead (Pb), more than other metals, could actually play a major role in the onset and progression of ALS. Here, to clarify the nature of the association and the causative role of Pb in ALS, we comprehensively reviewed the scientific literature of the last decade with objective database searches and the methods typically adopted in systematic reviews, critically analysing and summarising the various scientifically sound evidence on the relationship between ALS and Pb. From these tasks, we noted a number of multidisciplinary associations between ALS and Pb, and specifically the importance of occupational exposure to Pb in ALS development and/or progression. We also report the possible involvement of TAR DNA binding protein (TDP-43)-based molecular mechanism in Pb-mediated ALS, although these data rely on a single study, which included both in vitro experiments and an animal model, and are therefore still preliminary. Finally, we briefly examined whether this knowledge could inspire new targeted therapies and policies in the fight against ALS.

Effects of Vitamin D Receptor, Metallothionein 1A, and 2A Gene Polymorphisms on Toxicity of the Peripheral Nervous System in Chronically Lead-Exposed Workers.

Chronic exposure to lead is neurotoxic to the human peripheral sensory system. Variant vitamin D receptor (VDR) genes and polymorphisms of metallothioneins (MTs) are associated with different outcomes following lead toxicity. However, no evidence of a relationship between lead neurotoxicity and polymorphisms has previously been presented. In this study, we investigated the relationship between the polymorphisms of VDR, MT1A, and MT2A genes and lead toxicity following chronic occupational lead exposure. We measured vibration perception thresholds (VPT) and current perception thresholds (CPT) in 181 workers annually for five years. The outcome variables were correlated to the subject's index of long-term lead exposure. Polymorphisms of VDR, MT1A, and MT2A were defined. The potential confounders, including age, sex, height, smoking, alcohol consumption, and working life span, were also collected and analyzed using linear regression. The regression coefficients of some gene polymorphisms were at least 20 times larger than regression coefficients of time-weighted index of cumulative blood lead (TWICL) measures. All regression coefficients of TWICL increased slightly. MT1A rs11640851 (AA/CC) was associated with a statistically significant difference in all neurological outcomes except hand and foot VPT. MT1A rs8052394 was associated with statistically significant differences in hand and foot CPT 2000 Hz. In MT2A rs10636, those with the C allele showed a greater effect on hand CPT than those with the G allele. Among the VDR gene polymorphisms, the Apa rs7975232 (CC/AA) single nucleotide polymorphism was associated with the greatest difference in hand CPT. MT2A rs28366003 appeared to have a neural protective effect, whereas Apa (rs7975232) of VDR and MT2A rs10636 increased the neurotoxicity as measured by CPT in the hands. MT1A rs8052394 had a protective effect on large myelinated nerves. MT1A rs11640851 was associated with susceptibility to neurotoxicity.

Paresia radial bilateral secundaria a exposición crónica a plomo: reporte de un caso / Bilateral radial paresis secondary to chronic lead exposure: a case report

La exposición ocupacional al plomo continúa siendo un problema de salud pública que afecta mayoritariamente a trabajadores de países en vías de desarrollo. La exposición crónica produce síntomas similares a otras patologías clínicas motivo por el cual es importante poseer alto grado de sospecha. De acuerdo con los síntomas, signos y valor de plumbemia inicial, será necesario el alejamiento de la fuente y posterior tratamiento quelante con edetato cálcico disódico y/o dimercaprol. Presentamos un caso clínico de paresia radial bilateral por exposición crónica a plomo

Occupational exposure to lead continues to be a public health problem, affecting mainly workers of developing countries. Chronic exposure produces symptoms that can be confused with other clinical pathologies, which is why it is important to have a high degree of suspicion. According to the symptoms, signs and value of initial blood lead concentration, it will be necessary to remove from the source and posterior chelation with edetate calcium disodium and/or dimercaprol. We present a clinical case of bilateral radial paresis due to chronic lead exposure

Surface dental enamel lead levels and antisocial behavior in Brazilian adolescents.

Lead poisoning has been reportedly linked to a high risk of learning disabilities, aggression and criminal offenses. To study the association between lead exposure and antisocial/delinquent behavior, a cross-sectional study was conducted with 173 Brazilian youths aged 14-18 and their parents (n=93), living in impoverished neighborhoods of Bauru-SP, with high criminality indices. Self-Reported Delinquency (SRD) and Child Behavior Checklist (CBCL) questionnaires were used to evaluate delinquent/antisocial behavior. Body lead burdens were evaluated in surface dental enamel acid microbiopsies. The dental enamel lead levels (DELL) were quantified by graphite furnace atomic absorption spectrometry (GFAAS) and phosphorus content was measured using inductively coupled plasma optical emission spectrometry (ICP-OES). Logistic regression was used to identify associations between DELL and each scale defined by CBCL and SRD scores. Odd ratios adjusted for familial and social covariates, considering a group of youths exposed to high lead levels (>or=75 percentile), indicated that high DELL is associated with increased risk of exceeding the clinical score for somatic complaints, social problems, rule-breaking behavior and externalizing problems (CI 95%). High DELL was not found to be associated with elevated SRD scores. In conclusion, our data support the hypothesis that high-level lead exposure can trigger antisocial behavior, which calls for public policies to prevent lead poisoning.

Neurocognitive screening of lead-exposed andean adolescents and young adults.

This study was designed to assess the utility of two psychometric tests with putative minimal cultural bias for use in field screening of lead (Pb)-exposed Ecuadorian Andean workers. Specifically, the study evaluated the effectiveness in Pb-exposed adolescents and young adults of a nonverbal reasoning test standardized for younger children, and compared the findings with performance on a test of auditory memory. The Raven Coloured Progressive Matrices (RCPM) was used as a test of nonverbal intelligence, and the Digit Span subtest of the Wechsler IV intelligence scale was used to assess auditory memory/attention. The participants were 35 chronically Pb-exposed Pb-glazing workers, aged 12-21 yr. Blood lead (PbB) levels for the study group ranged from 3 to 86 microg/dl, with 65.7% of the group at and above 10 microg/dl. Zinc protoporphyrin heme ratios (ZPP/heme) ranged from 38 to 380 micromol/mol, with 57.1% of the participants showing abnormal ZPP/heme (>69 micromol/mol). ZPP/heme was significantly correlated with PbB levels, suggesting chronic Pb exposure. Performance on the RCPM was less than average on the U.S., British, and Puerto Rican norms, but average on the Peruvian norms. Significant inverse associations between PbB/ZPP concentrations and RCPM standard scores using the U.S., Puerto Rican, and Peruvian norms were observed, indicating decreasing RCPM test performance with increasing PbB and ZPP levels. RCPM scores were significantly correlated with performance on the Digit Span test for auditory memory. Mean Digit Span scale score was less than average, suggesting auditory memory/attention deficits. In conclusion, both the RCPM and Digit Span tests were found to be effective instruments for field screening of visual-spatial reasoning and auditory memory abilities, respectively, in Pb-exposed Andean adolescents and young adults.

Determinación del daño genotóxico de niños en relación a las mujeres en edad reproductiva por exposición a plomo y arsénico en Alto Lima - La Paz / Determination of the genotoxic harm of children with regard to the women of childbearing age by exposure to lead and arsenic in High *Lima - La Paz

Estudios epidemiológicos demostraron que la exposición ocupacional o accidental al plomo está asociada con mayor incidencia a tumores renales y cancer de pulmon y estómago. estudios in vivo mostraron un aumento de aberraciones cromosómicas y frecuencia de intercambio entre cromatides hermanas (ICH) en linfocitos de trabajadores expuestos a plomo, disminución de la fidelidad de la síntesis o reparación del ADN.

Environmental lead exposure and cognitive function in community-dwelling older adults.

OBJECTIVE: To determine if long-term exposure to high levels of lead in the environment is associated with decrements in cognitive ability in older Americans. METHODS: We completed a cross-sectional analysis using multiple linear regression to evaluate associations of recent (in blood) and cumulative (in tibia) lead dose with cognitive function in 991 sociodemographically diverse, community-dwelling adults, aged 50 to 70 years, randomly selected from 65 contiguous neighborhoods in Baltimore, MD. Tibia lead was measured with (109)Cd induced K-shell X-ray fluorescence. Seven summary measures of cognitive function were created based on standard tests in these domains: language, processing speed, eye-hand coordination, executive functioning, verbal memory and learning, visual memory, and visuoconstruction. RESULTS: The mean (SD) blood lead level was 3.5 (2.2) microg/dL and tibia lead level was 18.7 (11.2) microg/g. Higher tibia lead levels were consistently associated with worse cognitive function in all seven domains after adjusting for age, sex, APOE-epsilon4, and testing technician (six domains p

Plumbism or lead intoxication mimicking an abdominal tumor.

The clinical presentation of lead intoxication may vary widely and in the absence of a high clinical index of suspicion, the diagnosis may be missed. The effects of lead on mitochondrial oxidative phosphorylation and its interaction with calcium-mediated processes explain the heterogenous presentation. In this case report, the diagnosis was finally made when bilateral wrist drop developed on top of abdominal cramps and anemia. Before, ascites raised the suspicion of a tumor. Therefore, each element of the triad of unexplained anemia, abdominal cramps, and bilateral wrist (or foot) drop should lead any physician to consider the diagnosis of lead intoxication. This case also illustrates the importance of a careful and meticulous social history in patient management.

The relationship between lead exposure, motor function and behaviour in Inuit preschool children.

The main focus of this study was to determine the role of behaviour in the relationship between postnatal lead exposure and motor function. The sample consisted of 110 preschoolers, of age 5, from Nunavik. Lead concentration was measured at birth and at testing time. Average lead levels were of 4.9 microg/dL (0.24 micromol/L) and 5.3 microg/dL (0.26 micromol/L) for cord and child blood, respectively. Children's balance and fine motor capacities were tested. A modified version of the IBR was used to assess behaviour. Postnatal blood lead concentrations correlated positively with both impulsivity and activity. Neither pre- nor postnatal blood lead concentration correlated with attention level. The children's scores on impulsivity (I) and activity (A) were summed to create the independent variable IA, which was tested as a potential mediator between lead exposure and two dependent variables: the coefficient of covariation in alternating hand movements and transversal sway in tandem position. Mediation was significant only for the latter variable. IA and attention were then tested as potential moderators in the relation between postnatal lead exposure and motor function. No significant interaction between independent variables could be observed. These results do not support the hypothesis that, at low levels of postnatal exposure, lead acts indirectly on motor function via behaviour. However, IA does act as a mediator in the relationship between postnatal blood lead concentration and transversal sway in tandem position.

Neurotóxicos medioambientales (y II). Metales: efectos adversos en el sistema nervioso fetal y posnatal / Environmental toxins. Metals: adverse effects on the fetal and postnatal nervous systems

Objetivo. Divulgar entre los pediatras la neurotoxicidad del plomo (Pb), mercurio (Hg), manganeso (Mn) y cadmio (Cd) sobre el SNC y las medidas preventivas para minimizar y eliminar su uso en los hábitats fetal, infantil y juvenil. Material y métodos. Revisión bibliográfica sistemática de los efectos del Pb, Hg, Mn, y Cd en el SNC en desarrollo. Búsqueda en las bases de datos Medline, Science Citation Index y Embase de los últimos 20 años de los trabajos observacionales de exposición a bajas dosis en humanos y de experimentación en animales. Resultados. 1) Los principales efectos neurotóxicos de la exposición fetal e infantil a niveles incrementados de Pb son: déficit de atención, disminución del rendimiento y fracaso escolar, impulsividad, agresividad y conducta delictiva; 2) la exposición a Hg en dosis altas provoca retraso mental, alteraciones visuales y de la marcha, y en bajas dosis, del lenguaje, la atención y la memoria; 3) en diversas comunidades autónomas, la población pediátrica supera los límites de seguridad de ingestión de Hg recomendados por la U.S. Environmental Pro-tection Agency; 4) el Mn provoca trastornos de hiperactividad y aprendizaje; 5) la leche materna contiene 6 μg/L de Mn, las fórmulas artificiales unos 77 μg/L, si han sido suplementadas, alrededor de 100 μg/L, y las fórmulas de soja, hasta 300 μg/L; y 6) la exposición al Cd produce trastornos de hiperactividad, alteraciones de la capacidad verbal y disminución del coeficiente intelectual. Conclusiones. 1) Los efectos del Pb, Hg, Mn y Cd sobre el SNC fetal e infantil pueden aparecer con niveles inferiores a los considerados como «seguros»; 2) los pediatras debemos recomendar alternativas para minimizar y eliminar los metales neurotóxicos del entorno infantil; 3) es necesario cuantificar la ingestión diaria de Hg y reducir de forma cautelar el consumo de algunos peces (atún, caballa, emperador, perca, lucio...) en niños, madres lactantes y en mujeres embarazadas y en edades fértiles; 4) los lactantes con fórmulas artificiales ingieren más cantidad de Mn; y 5) las unidades de salud medioambiental pediátrica deben poner en marcha las historias ambientales en los niños con enfermedades neurológicas

Objective. To make pediatricians aware of the effects of the neurotoxicity of lead (Pb), mercury (Hg), manganese (Mn) and cadmium (Cd) on the CNS and inform them of the preventive measures that can minimize or eliminate their use in fetal, childhood and adolescent environments. Material and methods. A systematic literature search was carried out to explore the effects of Pb, Hg, Mn and Cd on the developing CNS. The search was carried out in the Medline, Science Citation Index and Embase databases and involved observational studies on low-dose exposure in humans and in laboratory animals over the past 20 years. Results. 1) The major neurotoxic effects derived from fetal and postnatal exposure to elevated levels of Pb are attention deficits, below average school performance, increased impulsiveness, aggressiveness and delinquent behavior. 2) Fetal exposure to high-dose Hg causes mental retardation and gait and visual disturbances, and fetal exposure to lower doses may cause lasting impairments in language, attention and memory. 3) In certain autonomous communities, the pediatric population surpasses the safety limits of Hg recommended by the US Environmental Protection Agency. 4) Mn causes hyperactivity and learning disabilities. 5) Breast milk contains 6 μg of Mn per liter; infant formulas about 77 μg/L; the latter, when supplemented, around 100 μg/L; and soy-based formulas up to 300 μg/L. 6) Exposure to Cd in children has been shown to result in hyperactivity and lower verbal and performance intelligence quotients. Conclusions. 1) The effects of Pb, Hg, Mn and Cd on the fetal and postnatal CNS can occur at lower levels of exposure considered "safe". 2) Pediatricians have to recommend alternatives to minimize and eliminate the neurotoxic metals in the childhood environment. 3) As a preventive measure, it is necessary to quantify and decrease the daily Hg intake of children, nursing mothers, pregnant women and women of reproductive age, and reduce the consumption of certain fish (tuna, mackerel, sword fish, perch, pike, etc.). 4) Formula-fed infants ingest a much greater quantity of Mn. 5) Pediatric Environmental Health Units should implement environmental histories in children with neurological disorders

The influence of milk intake on the lead toxicity to the sensory nervous system in lead workers.

The dietary calcium supplement has been suggested to children and pregnant women for prevention of lead toxicity, because of lead-calcium interaction. Lead workers were supplied free milk in Taiwan; however, part of workers did not drink milk due to lactose intolerance. The goal of this study is to evaluate the effects of milk-intake on the peripheral nervous system in workers with long-term lead exposure. We measured 181 workers' current perception thresholds (CPT) as neurological outcomes. The outcome variables were then correlated to the subject's milk intake, blood lead levels, and index of long-term lead exposure that was calculated by the subject's serial blood lead data in a period of working duration. The potential confounders, including age, gender, body height, smoking and alcohol consumption, were also collected and analyzed in multiple regressions. 23 workers who reported never or rarely drinking milk, which meant that they have suffered from diarrhea or abdomen discomfort after drinking milk since childhood, had higher blood lead parameters but not statistically significant, and higher thresholds in sensory nerve tests, especially, statistically significance on 5 and 250 Hz of hand CPTs, which represent C fiber and A-delta fiber. In multiple regression models with control of potential confounders, significant protective effects of milk intake were found on reducing hand CPTs, but not on foot CPTs. Our study, using measurement of sensory nerve CPTs, revealed that drinking milk (two bottles a day, about 700 g per day) might have an effect to protect lead peripheral neurotoxicity. The detail biochemical mechanisms need further investigations. However, reduction of occupational lead exposure is the essential way to protect lead neuropathy. The authors did not emphasize that offers of milk to workers could be instead of occupational hygiene efforts. Furthermore, lead workers with lactose intolerance might be more susceptible, and need more industrial hygiene interventions.

Maternal bone lead as an independent risk factor for fetal neurotoxicity: a prospective study.

OBJECTIVE: A number of prospective studies have examined lead levels in umbilical cord blood at birth as predictors of infant mental development. Although several have found significant inverse associations, others have not. Measurement of lead levels in maternal bone, now recognized as the source of much fetal exposure, has the potential to serve as a better or complementary predictor of lead's effect on the fetus. Our objective was to compare lead levels in umbilical cord blood and maternal bone as independent predictors of infant mental development using a prospective design. METHODS: We recruited women who were giving birth at 3 maternity hospitals in Mexico City that serve a homogeneous middle-class community. Umbilical cord blood lead levels were measured by graphite furnace atomic absorption spectroscopy, and maternal lead levels in cortical (tibial) and trabecular (patellar) bone were measured within 4 weeks of giving birth using a 109-Cd K-x-ray fluorescence instrument. At 24 months of age, each infant was assessed using the Bayley Scales of Infant Development-II (Spanish Version). RESULTS: A total of 197 mother-infant pairs completed this portion of the study and had data on all variables of interest. After adjustment for other well-known determinants of infant neurodevelopment, including maternal age, IQ, and education; paternal education; marital status; breastfeeding duration; infant gender; and infant illness, lead levels in umbilical cord blood and trabecular bone were significantly, independently, and inversely associated with the Mental Development Index (MDI) scores of the Bayley Scale. In relation to the lowest quartile of trabecular bone lead, the second, third, and fourth quartiles were associated with 5.4-, 7.2-, and 6.5-point decrements in adjusted MDI scores. A 2-fold increase in cord blood lead level (eg, from 5 to 10 micro g/dL) was associated with a 3.1-point decrement in MDI score, which is comparable to the magnitude of effect seen in previous studies. CONCLUSION: Higher maternal trabecular bone lead levels constitute an independent risk factor for impaired mental development in infants at 24 months of age. This effect is probably attributable to mobilization of maternal bone lead stores, a phenomenon that may constitute a significant public health problem in view of the long residence time of lead in bone.

Exposure to lead appears to selectively alter metabolism of cortical gray matter.

OBJECTIVE: The effects of lead poisoning on the development of children have been examined primarily in the context of behavioral and neuropsychological studies. The purpose of this study was to examine the in vivo use of magnetic resonance spectroscopy (MRS) for the evaluation of the neurotoxic effects of lead on the nervous system. MRS has the ability to monitor brain metabolism by detecting a number of neurochemicals among which is N-acetylaspartate, a metabolite shown to decrease in processes that involve neuronal loss. METHODS: In the present study we evaluated the metabolism of gray and white matter of frontal cortex using MRS in individuals with elevated blood lead levels and compared the results with those obtained on nonlead-exposed controls. RESULTS: Although all of the participants had normal MRI examinations of the brain, the lead-exposed individuals exhibited a significant reduction in the N-acetylaspartate/creatine and phosphocreatine ratios in frontal gray matter compared with the nonlead-exposed controls. CONCLUSIONS: The findings of this study suggest that lead has an effect on brain metabolites as detected by MRS in vivo. More specifically, we have found statistically significant reduced levels of brain metabolites in gray but not white matter in lead-exposed individuals. These results imply that MRS is able to detect metabolic abnormalities in individuals with lead poisoning.

[Inclusion of psychopathologic methods for diagnosis of early neurotoxic effects from lead and organic solvent mixtures]. / Einbeziehung psychopathologischer Verfahren zur Objektivierung von neurotoxischen Früheffekten durch Blei und Lösemittelgemische.

To verify occupational neurotoxic effects it will be necessary to enlist the help of clinical psychologists and psychiatrists. However, no unified professional test battery exists to date. 119 healthy workers (26 lead-exposed, 45 exposed to mixed organic solvents, and 48 controls) were tested using uniformly standardised psychological and psychiatric methods. Long-term lead-exposed employees showed an increased number of psychoneurovegetative symptoms and deficits in attention performance according to the results of the Seeber-PNF and the Brickenkamp-d2-tests. There was no difference between the control group and persons exposed to the organic solvents test. Many parameters correlated to the dose of the toxic agent in the lead-exposed group. SCL-90-R, AMDP, and HAMD merely hinted at differences between the exposed subjects and the controls. Psychological and pathopsychological methods are necessary but will not suffice to detect early effects after long-term exposure to lead or organic solvents.