Effects Of Low-level Lead Exposure Research Articles

Lasting Adverse Effects of Low-Level Lead Exposure on Cognition and Heritable Susceptibilities

Lasting Adverse Effects of Low-Level Lead Exposure on Cognition and Heritable Susceptibilities

Stunting and lead: using causal mediation analysis to better understand how environmental lead exposure affects cognitive outcomes in children

BackgroundMany children in Bangladesh experience poor nutritional status and environmental lead exposure, both of which are associated with lower scores on neurodevelopmental assessments. Recent studies have suggested that part of lead’s adverse effects on neurodevelopment are caused in part by lead’s effect on growth. New statistical methods are now available to evaluate potential causal pathways in observational studies. This study used a novel statistical method to test the hypothesis that stunting, a measure of linear growth related to poor nutrition, is a mediator and/or an effect modifier of the lead exposure’s adverse effect on cognitive development.MethodsParticipants were 734 children from a longitudinal birth cohort established in rural Bangladesh to study the health effects of prenatal and early childhood environmental metal exposures. Lead exposure was estimated using umbilical cord blood samples obtained at birth and blood obtained via venipuncture at age 20–40 months. Stunting was determined using the World Health Organization’s standards. Neurodevelopment was assessed at age 20–40 months years using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). We evaluated the effect of lead on stunting and whether the effect of lead on cognitive scores is modified by stunting status in multivariable regression analyses. We then conducted a novel 4-way mediation analysis that allows for exposure-mediator interaction to assess how much of the effect of lead on cognitive scores is explained by the pathway through stunting (mediation) and how much is explained by the interaction between lead and stunt (effect modification).ResultsStunting was not a mediator of the effect of lead in our analyses. Results suggested effect modification by stunting. In an area of Bangladesh with lower lead exposures (median umbilical cord blood lead concentration, 1.7 μg/dL), stunting modified the relationship between prenatal blood lead concentrations and cognitive score at age 2–3 years. A 1-unit increase in natural log cord blood lead concentration in the presence of stunting was associated with a 2.1-unit decrease in cognitive scores (β = − 2.10, SE = 0.71, P = 0.003). This interaction was not found in a second study site where lead exposures were higher (median umbilical cord blood lead concentration, 6.1 μg/dL, β = − 0.45, SE = 0.49, P = 0.360).ConclusionsWe used a novel method of mediation analysis to test whether stunting mediated the adverse effect of prenatal lead exposure on cognitive outcomes in Bangladesh. While we did not find that stunting acted as mediator of lead’s effect on cognitive development, we found significant effect modification by stunting. Our results suggest that children with stunting are more vulnerable to the adverse effects of low-level lead exposure.

Cumulative Effects of Low-Level Lead Exposure and Chronic Physiological Stress on Hepatic Dysfunction-A Preliminary Study.

Chronic physiological stress and hepatic injury were explored in this cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2007–2010. Lead exposure was measured using Blood Lead Levels (BLL), which were divided into quartiles of exposure based on the distribution within the database. Allostatic load (AL), a variable representing chronic physiological stress, was operationalized using ten clinical markers. The geometric mean values for markers of liver injury of interest (a) Aspartate Aminotransferase (AST), (b) Alanine Aminotransferase (ALT), (c) Alkaline Phosphatase (ALP), and (d) Gamma glutamyl-transferase (GGT) were explored in quartiles of lead exposure. Associations between AL and AST, ALT, ALP, and GGT among those exposed to lead were analyzed using linear regression models. In examining lead exposure in increasing quartiles, the geometric mean of the liver injury markers showed significant elevations as lead exposure levels increased. Simple linear regression revealed AL was positively associated with several markers of hepatic injury in all degrees of lead exposure. This study demonstrates the potential dangers of social and environmental exposures to liver health.

Low-level lead exposure is associated with aberrant sperm quality and reproductive hormone levels in Chinese male individuals: Results from the MARHCS study low-level lead exposure is associated with aberrant sperm quality.

Studies in animals suggest an adverse effect of high-level lead exposure on male reproductive outcomes. However, evidence of the effects of low-level lead exposure is inconsistent. The purpose of our study was to explore the relationship between low-level lead exposure from daily environmental contaminants and semen quality in a community population without occupational exposure. We recruited 751 students in the Male Reproductive Health in Chongqing College Students (MARHCS) study and 190 community males from Bishan, Chongqing. Eight urinary metals (Pb, Cd, As, Cu, Zn, Ni, Mn, and Cr), semen quality, and serum sex hormones were detected. Even if the blood lead concentration was below the US lead poisoning standard for children (100μg/L), a significant dose-response relationship was found between lead exposure and a decrease in semen quality. Multilinear regression showed that urinary Pb was negatively associated with sperm concentration, total sperm count, progressive motility and total sperm motility (regression coefficient:-0.074,-0.103,-0.024, and-0.014, respectively; p: <0.001, <0.001, 0.007, and <0.001, respectively), accompanied by decreased serum follicle-stimulating hormone, serum testosterone and the testosterone/luteinizing hormone ratio (β coefficient:-0.090,-0.082, and-0.020, respectively; p: 0.002, <0.001, and 0.021, respectively). Logistic regression also indicated that the risk of having abnormal semen quality was higher in the high Pb group (OR: 2.501, 95% CI: 1.411, 4.435, p=0.002) than in the low Pb group after adjusting for confounders, with a dose-response relationship in the trend test (p=0.007). Our results revealed an inverse association between Pb exposure at low levels and semen quality.

Risk factors of renal dysfunction and their interaction in level-low lead exposure paint workers

BackgroundTo explore the effect of low-level lead exposure on renal dysfunction in paint works, and analyze the interaction between low-level lead exposure and other influence factors of renal dysfunction.MethodsSeven hundred forty seven workers from Sany Heavy Industry Company and Xiangjiang Kansai Paint Company who have been exposed to paint were chosen by random cluster sampling. Their blood lead level and Urine β2-micro globulin level (renal dysfunction) were tested,risk factors of renal dysfunction in paint workers and their interactions were analyzed.ResultsThe prevalence of renal dysfunction was 12.37%. Risk factors of renal dysfunction in paint workers mainly included longer working years (OR = 1.699, 95% CI: 1.226~ 2.355), blood lead positive (OR = 2.847, 95% CI: 1.577~ 5.139) and hypertension (OR = 2.192, 95% CI: 1.103~ 4.359). Positive interaction existed between hypertension and low-level blood lead on renal dysfunction in paint workers, the RERI (Relative excess risk of interaction), API (Attributable proportions of interaction) and S(the synergy index) were 4.758, 54.5% and 2.604 respectively.ConclusionsLow-level lead exposure and hypertension not only have independent effect on renal dysfunction in paint workers, but also had obvious positive interaction in paint workers. Interventions aimed at blood lead and blood pressure at the same time will better prenvent from renal dysfunction.

Genetic polymorphisms of GRIN2A and GRIN2B modify the neurobehavioral effects of low-level lead exposure in children

Lead (Pb) is neurotoxic and children are highly susceptible to this effect, particularly within the context of continuous low-level Pb exposure. A current major challenge is identification of children who may be uniquely susceptible to Pb toxicity because of genetic predisposition. Learning and memory are among the neurobehavioral processes that are most notably affected by Pb exposure, and modification of N-methyl-D-aspartate receptors (NMDAR) that regulate these processes during development are postulated to underlie these adverse effects of Pb. We examined the hypothesis that polymorphic variants of genes encoding glutamate receptor, ionotropic, NMDAR subunits 2A and 2B, GRIN2A and GRIN2B, exacerbate the adverse effects of Pb exposure on these processes in children. Participants were subjects who participated as children in the Casa Pia Dental Amalgam Clinical Trial and for whom baseline blood Pb concentrations and annual neurobehavioral test results over the 7 year course of the clinical trial were available. Genotyping assays were performed for variants of GRIN2A (rs727605 and rs1070503) and GRIN2B (rs7301328 and rs1806201) on biological samples acquired from 330 of the original 507 trial participants. Regression modeling strategies were employed to evaluate the association between genotype status, Pb exposure, and neurobehavioral test outcomes. Numerous significant adverse interaction effects between variants of both GRIN2A and GRIN2B, individually and in combination, and Pb exposure were observed particularly among boys, preferentially within the domains of Learning & Memory and Executive Function. In contrast, very few interaction effects were observed among similarly genotyped girls with comparable Pb exposure. These findings support observations of an essential role of GRIN2A and GRIN2B on developmental processes underlying learning and memory as well as other neurological functions in children and demonstrate, further, modification of Pb effects on these processes by specific variants of both GRIN2A and GRIN2B genes. These observations highlight the importance of genetic factors in defining susceptibility to Pb neurotoxicity and may have important public health implications for future strategies aimed at protecting children and adolescents from potential health risks associated with low-level Pb exposure.

Effects of low-level lead exposure on blood pressure in a population-based study in Southern Brazil

Particle mixing and irrigation of the seabed by benthic fauna (bioturbation) have major impacts on ecosystem functions such as remineralization of organic matter and sediment-water exchange. As a tribute to Prof. Gaston Desrosiers by the Nereis Park association, eighteen laboratories carried out a collaborative experiment to acquire a global snapshot of particle reworking by the polychaete Hediste diversicolor at 16 sites surrounding the Northern Atlantic. Organisms and soft sediments were collected during May – July at different geographical locations and, using a common laboratory protocol, particulate fluorescent tracers (‘luminophores’) were used to quantify particle transport over a 10-day period. Particle mixing was quantified using the maximum penetration depth of tracers (MPD), particle diffusive coefficients (Db), and non-local transport coefficients (r). Non-local coefficients (reflecting centimeter scale transport steps) ranged from 0.4 to 15 yr−1, and were not correlated across sites with any measured biological (biomass, biovolume) or environmental parameters (temperature, grain size, organic matter). Maximum penetration depths (MPD) averaged ~10.7 cm (6.5–14.5 cm), and were similar to the global average bioturbation depth inferred from short-lived radiochemical tracers. MPD was also not correlated with measures of size (individual biomass), but increased with grain size and decreased with temperature. Biodiffusion (Db) correlated inversely with individual biomass (size) and directly with temperature over the environmental range (Q10 ~ 1.7; 5–21 °C). The transport data were comparable in magnitude to rates reported for localized H. diversicolor populations of similar size, and confirmed some but not all correlations between sediment reworking and biological and environmental variables found in previous studies. The results imply that measures of particle reworking activities of a species from a single location can be generally extrapolated to different populations at similar conditions.

Low-level prenatal lead exposure and infant sensory function.

BackgroundLead is a pervasive neurotoxicant that has been associated with poorer cognitive, behavioral, and motor outcomes in children. The effects of lead on sensory function have not been well characterized. The aim of this study was to assess the effects of prenatal lead exposure on infant sensory function, as measured by auditory brainstem response (ABR) and grating visual acuity (VA).MethodsLead was measured in maternal blood in mid- and late-pregnancy (mean gestational age = 15.5 and 39.0 weeks, respectively) and umbilical cord blood in a cohort of full-term infants in rural northeastern China. ABR latencies (peaks I, III, V) were measured in newborns during unsedated sleep (n = 315). The ABR central-to-peripheral (C-P) ratio was calculated as the ratio between the III-V and I-III interpeak intervals. VA was measured in 6-week-olds using Teller Acuity Cards (n = 1019) and assigned as the narrowest grid the infant fixated on. Multivariate linear regression was used to evaluate relationships between tertiles of mid-pregnancy, late-pregnancy, or cord lead and newborn ABR or 6-week VA.ResultsHigher late-pregnancy lead levels were associated with higher ABR C-P ratios and lower VA. In covariate-adjusted analyses, mean C-P ratios were 4.6 and 3.2 % higher in infants whose mothers had lead > 3.8 μg/dL and lead = 2–3.8 μg/dL, respectively, than for infants whose mothers had lead < 2 μg/dL (p-trend =0.002). In adjusted analyses for VA, mean scores were 8.5 and 7.2 % lower for maternal lead > 3.8 μg/dL and lead = 2–3.8 μg/dL, respectively, compared to lead < 2 μg/dL (p-trend =0.009).ConclusionAuditory and visual systems maturation appears delayed in infants with higher prenatal lead exposure during late-pregnancy, even at relatively low levels. Both systems start myelinating in late gestation and mature rapidly in infancy. Higher ABR C-P ratio and lower grating VA scores suggest effects of low-level lead exposure on sensory system myelination.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-016-0148-6) contains supplementary material, which is available to authorized users.

Statistics and Policy Decisions: Issues in Statistical Analyses

When national policy decisions are to be guided by the results of statistical analyses, it is important, to avoid being misled to look beyond the authors’ conclusions and first to assess the study design, measurement and analytic methods, in order to decide whether a study’s conclusions rest on a solid foundation. In particular, observational studies must be carefully and critically evaluated. Using a study widely cited concerning the effects of low-level lead exposure and IQ, we illustrate several methodological errors, long known but often ignored. The goal is not to settle the controversies about the effect of lead on IQ, nor to disparage observational studies, for they are the foundation of all studies done to guide policy, but to encourage additional care in the use of such studies to address policy questions.

Seeds of toxicity? Erythrocytes and lead-associated kidney damage.

Environmental lead contamination lingers despite decades of sharply declining use and release of the metal. As a consequence, low-level lead exposure remains common, with an average adult blood lead level in the general U.S. population of 1–2 μg/dL.1,2 Lead affects numerous organ systems, but specific mechanisms of damage are not always known. The authors of a new study in EHP present a hypothesis to explain lead-related toxicity in the kidney and support it with detailed in vivo and in vitro data.1 Current evidence suggests that kidney damage can occur at blood lead levels as low as 5 μg/dL.2 Specific populations, including people with preexisting kidney disease, diabetes, or hypertension, may be at even greater risk of effects of low-level lead exposure.2,3 Both in vivo and in vitro data highlight oxidative stress as a factor in lead-associated kidney damage, but it has been unclear how the stress is generated.1,2 A new study explores the role that aging red blood cells may play in lead-related kidney toxicity. In the current study, the researchers wove observations from previous investigations into a testable hypothesis. They took into account deposition of iron—presumably from iron-rich red blood cells (erythrocytes)—in kidneys of individuals with renal disorders. They also considered the kidney’s role in clearing erythrocytes from circulation as the cells become old or damaged. During a process called erythrophagocytosis, aging erythrocytes are enveloped and broken down by other cells. Erythrophagocytosis occurs primarily in cells of the spleen and liver, but proximal tubular epithelial cells in the kidney also have this capability. The signal that an erythrocyte needs to be removed from circulation comes from a compound called phosphatidylserine (PS). In a normal, healthy erythrocyte, PS is an internal cellular component, with no direct contact with the cell’s outer environment. Aged and damaged red blood cells begin to shift PS to the outer surface. Members of this research team previously found that lead exposure was associated with a surge in PS externalization, followed by enhanced erythrophagocytosis in the spleen.4 In this study the researchers hypothesized that lead exposure increases the number of PS-tagged erythrocytes, which are then consumed by the proximal tubular epithelial cells in the kidney. They further hypothesized that iron from the erythrocytes accumulates in the kidney cells, where it triggers the formation of reactive oxygen species, the first step in oxidative damage. The ultimate biological outcome of toxic exposures is frequently a combination of two factors—individual responses of multiple tissues and, subsequently, complex interactions of altered tissues—says study coauthor Jin-Ho Chung, a professor in the College of Pharmacy at Seoul National University. “We considered that lead-associated nephrotoxicity must be interpreted in the context of systems biology, rather than as sole and isolated damage to the kidney,” Chung says. Chung and his colleagues conducted a series of in vitro experiments with HK-2 cells5 and erythrocytes derived from volunteers’ blood samples. They showed that, in the absence of erythrocytes, the viability of lead-exposed HK-2 cells was not significantly different from the viability of unexposed HK-2 cells. A separate experiment demonstrated increased PS externalization in lead-exposed erythrocytes. And when lead-exposed erythrocytes were co-cultured with unexposed HK-2 cells, the HK-2 cells not only phagocytized the erythrocytes, but also showed increased production of reactive oxygen species, diminished viability, and greater expression of genes associated with kidney damage.1 Next, the in vitro findings were tested in rats. Samples of blood, spleen, and kidney tissue were collected from rats exposed to 0 or 1,000 ppm lead in drinking water for 12 weeks, then used for biochemical and histological analyses. These analyses revealed statistically significant changes consistent with kidney damage. A second 12-week experiment included tissue samples from rats that received 0, 250, or 1,000 ppm of lead acetate in drinking water; these results also supported the in vitro findings. The in vivo results also reflected two types of nephrotoxicity seen in epidemiological studies: proximal tubular nephropathy and interstitial fibrosis.1 William McClellan, a professor of medicine at Emory University in Atlanta who was not involved in the study, cautions against immediately extrapolating the findings to human health. He also notes that the findings will need replication. McClellan says, “I have a feeling that if they come up with comparable findings [for confirmation], there will be some strong interest in doing some human studies.”

Associations between blood lead level and substance use and sexually transmitted infection risk among adults in the United States

The effects of low-level lead exposure on neuropsychological status in the United States (US) general adult population have been reported, and the relationship between neuropsychiatric dysfunction and health risk behaviors including substance use and sexual risk taking is well established. However, the potential influence of lead exposure on risk-taking behavior has received little attention. Using the National Health and Nutrition Examination Survey (NHANES) 2005–2010, we estimated multivariable logistic regression models to measure odds ratios (ORs) and 95% confidence intervals (CIs) for the cross-sectional associations between blood lead level and risk behaviors including binge drinking, drug use, and indicator of sexually transmitted infection (STI) risk. STI indicators included past 12 month sexual risk behaviors (age mixing with partners who were at least five years younger or older and multiple partnerships), self-reported STI, and biologically-confirmed herpes simplex virus type 2 (HSV-2) infection. Dose–response like relationships were observed between blood lead and substance use, age mixing with younger and older partners, self-reported STI, and HSV-2. In addition, participants with lead levels in highest quartile versus those with levels in the lowest quartile had over three times the odds of binge drinking and over twice the odds of injection drug or cocaine use in the past 12 months, while being in one of the top two quartiles was significantly associated with 30–70% increased odds of multiple partnerships, sex with older partners, and self-reported and biologically confirmed STI. Results from this study suggested that lead exposure may contribute to substance use, sexual risk-taking, and STI. However, given limitations inherent in the cross-sectional nature of the study, additional studies that use longitudinal data and measure detailed temporal information are warranted.

Low Lead Exposure During Foetal and Early Postnatal Life Impairs Passive Avoidance Learning in Adulthood in Rats

This follow-up study investigated the effects of low-level lead exposure during prenatal and early postnatal period on learning and memory in rats immediately after exposure has ceased at weaning and later in their adulthood. Male Wistar-derived rats were exposed to lead (as 0.2 % lead acetate solution) through their mothers during pregnancy and lactation until they were weaned. Mothers of control rats were given tap water during pregnancy and lactation. All pups were weaned on tap water at 21 days of age and were followed up until 120 days old. Low-level lead exposure did not affect their body weight at any time during the experiment. Blood lead in the exposed rats was significantly higher on postnatal day 22 and dropped to control values by day 120. Passive avoidance test showed impaired memory retention in the exposed rats on postnatal days 25 and 120. This suggests that exposure to low-lead levels during foetal and early postnatal development of brain tissue can cause memory impairment that lasts into adulthood.

The association between low levels of lead in blood and occupational noise-induced hearing loss in steel workers

As the use of leaded gasoline has ceased in the last decade, background lead exposure has generally been reduced. The aim of this study was to examine the effect of low-level lead exposure on human hearing loss. This study was conducted in a steel plant and 412 workers were recruited from all over the plant. Personal information such as demographics and work history was obtained through a questionnaire. All subjects took part in an audiometric examination of hearing thresholds, for both ears, with air-conducted pure tones at frequencies of 500, 1000, 2000, 3000, 4000, 6000 and 8000 Hz. Subjects' blood samples were collected and analyzed for levels of manganese, copper, zinc, arsenic, cadmium and lead with inductive couple plasma-mass spectrometry. Meanwhile, noise levels in different working zones were determined using a sound level meter with A-weighting network. Only subjects with hearing loss difference of no more than 15 dB between both ears and had no congenital abnormalities were included in further data analysis. Lead was the only metal in blood found significantly correlated with hearing loss for most tested sound frequencies ( p < 0.05 to p < 0.0001). After adjustment for age and noise level, the logistic regression model analysis indicated that elevated blood lead over 7 μg/dL was significantly associated with hearing loss at the sound frequencies of 3000 through 8000 Hz with odds ratios raging from 3.06 to 6.26 ( p < 0.05 ~ p < 0.005). We concluded that elevated blood lead at level below 10 μg/dL might enhance the noise-induced hearing loss. Future research needs to further explore the detailed mechanism.

Bending science

Bending science is a fascinating and troubling investigation of the ways science is manipulated in the process of regulatory policy- and legal decision making. Thomas McGarity and Wendy Wagner, both University of Texas law professors, present an encyclopedia of endeavors, undertaken largely by industry, to distort scientific enterprise in order to promote self-interests. Like a number of recent books on this subject (1–5), this one presents a serious look at the mechanics of scientific manipulation and should be read by scientists, social scientists, legal scholars, and policy makers. It begins with an overview of the enormous sums of money at play that make science a high-stakes enterprise and place the very institution of science under attack: the profits of drug companies and how they affect the marketing of new drugs; the cost to manufacturers of industrial pollutant cleanup; and damages sought following occupational or consumer exposure to hazardous agents. As science is wrenched from the academy and plunged into the contentious worlds of politics, legal wrangling, and industrial decision making, the result is what the authors term “bent science”: knowledge with skewed objectivity and dubious accuracy, shaped by special interests. They doubt whether it is possible to protect the integrity of medical, environmental, and bench science from political and economic interests and call for more “adversarial procedures”: greater government, consumer, and legal oversight to protect scientists and to watch for undue influence over sponsored science. The book details the systematic methodology that has emerged over the past few decades to undermine scientists and society’s faith in their work. Examples are given of scientists and physicians well paid to attach their names — and their impressive publication records and prestigious institutional affiliations — to industry-produced articles, editorials, and commentaries. The authors identify instances where companies and entire industries have set up sham “research institutes” and purportedly scientific organizations to promote favorable opinions of their products. They examine examples of “expert panels” of industry-hired scientists paid to issue reports critiquing individuals who found dangers in the use of beryllium, the promotion of the antiobesity medication Fen-phen, and the production and sale of plastics, drug-eluting stents, asbestos products, and other materials. Casting doubt on findings that a product is potentially dangerous facilitates manipulation of OSHA, the EPA, the FDA, and other regulatory agencies, thereby prolonging the product’s use and sale. Many practices are reportedly used to undermine unwanted scientific information: “hiding science,” the practice of keeping unwanted results from public or regulatory view; attacking reliable research and proclaiming it “junk”; harassing scientists whose results undermine claims of safety or efficacy; and “packaging” of science via experts paid to promote a product. McGarity and Wagner make a good case that the distortion of science is systemic and not limited to a few industries behaving badly. Not unexpectedly, they detail the egregious activities of Big Tobacco, an industry that has become a poster child for amoral corporate behavior, and argue that these transgressions are merely representative of a much broader assault on science that has taken place since the end of World War II and has accelerated since the 1970s. One particularly disturbing aspect of attempts to bend science is the growing use of intimidation in the event that scientific research collides with industry self-interest. The case of Herbert Needleman, a pioneer in the discovery of the harmful effects of low-level lead exposure on young children, is particularly poignant. During the 1980s and early ’90s, he was accused by researchers supported by the lead industry and forced to defend his research before governmental and university panels. The decade of intensive investigation, public humiliation, and legal wrangling ended with his vindication and establishment of environmental health protections, but not without detriment to his research career and likely those of others. In the interest of transparency, I must acknowledge that Bending science hit close to home. In 2006, after the publication of Deceit and denial: the deadly politics of industrial pollution (5), my coauthor Gerald Markowitz and I found ourselves in the midst of a legal attack by the chemical industry to undermine conclusions reached in our book. Although, as in Needleman’s case, the experience ultimately did nothing to our standing in the academic community, it was searing and disruptive for many months. My experience certainly affected my reading of the book and predisposed me to accept its general message: that there are enormously powerful interests dedicated to bending science and creating doubt about the integrity of challenging research.

Excitatory effects of low‐level lead exposure on action potential firing of pyramidal neurons in CA1 region of rat hippocampal slices

Lead is putatively regarded as an environmental neurotoxicant. Long-term low-level lead exposure causes cognitive deficits, but the mechanism remains to be elucidated. In the present study, the excitatory effects of low-level lead exposure on action potential (AP) firing of pyramidal neurons in CA1 region of rat hippocampal slices and the pathway through which lead induced these effects were studied with conventional whole-cell recording. Low-level lead (0.5 and 5 microM) exposure did not significantly change either voltage threshold or amplitude, duration, rise time, or rising velocity of single AP; conversely, 5 microM lead exposure significantly increased AP firing rates and reduced spike frequency adaptation. These excitatory effects of 5 microM lead were blocked by mibefradil, a selective blocker of T-type voltage-dependent calcium channels (VDCC), but not by verapamil and omega-conotoxin, selective blockers of L-type and N-type VDCC, respectively. Five micromolar lead could not change the excitability of pyramidal neurons when slices were perfused with calcium-free ACSF. In addition, the effects were abolished by inhibitors of two intracellular calcium release channels: 2-APB, an inhibitor of inositol trisphosphate receptors, and dantrolene, an inhibitor of ryanodine receptors, but not by thapsigargin, an inhibitor of endoplasmic reticulum calcium uptake. These results provide evidence for excitatory neurotoxicity of low-level lead exposure, contribution of T-type VDCC in the entrance of lead into neurons, and a possible involvement of calcium flux alteration during APs in this excitatory neurotoxicity.

Lead and Retinal Function: Low Prenatal Exposure Suggests Future Abnormality

The harmful effects of low-level lead exposure on the development of cognitive, auditory, and visual-motor functions in children are well documented, but few studies have focused on the effects of low-level lead exposure specifically on retinal and visual functions. A rodent study reported this month provides new evidence that low levels of gestational lead exposure (GLE) can cause permanent retinal abnormalities in adult offspring and supports existing evidence that prenatal lead exposure can affect retinal development and function in humans even at blood lead levels below 10 μg/dL, the level of concern identified by the Centers for Disease Control and Prevention [EHP 116:618–625; Fox et al.]. Researchers exposed two groups of female rats to lead in drinking water. A GLE group was exposed from 2 weeks before breeding through post-natal day 10 and a postnatal lead exposure (PLE) group from delivery through pup weaning. Each group was divided into four subgroups that were exposed to varying doses of lead (0 ppm [control], 27 ppm, 55 ppm, or 109 ppm). Maternal blood lead levels in the GLE rats were similar to those observed in human mothers whose children had experienced prenatal lead exposure. The researchers included the PLE group for comparison because in previous studies PLE caused rod-selective cell death (apoptosis) and decreased retinal electrical activity as measured by an electroretinogram (ERG). Previous studies have demonstrated that postnatal blood lead levels greater than 20 μg/dL in lead-exposed humans and animals cause decreased ERG amplitudes (“subnormality”), whereas children exposed gestationally or postnatally who had blood lead levels of 6–16 μg/dL exhibited increased ERG amplitudes (“supernormality”). In the current study, when offspring in the GLE group reached adulthood, the researchers tested the animals’ rod retinal function using an ERG, then counted the number of rods and cones in the rats’ eyes. (Rods are photoreceptors active in low light; cones provide color vision.) Last, the researchers measured the synthesis of retinal dopamine, a neurotransmitter that regulates several retinal processes, including cell survival and eye growth. Results from the GLE group showed an inverted dose–response curve typical of lead neurotoxicity. In adult offspring, low and moderate levels of GLE produced supernormal scoptic ERGs, increased numbers of rod cells and rod bipolar cells, and decreased dopamine synthesis and release in the absence of retinal injury, potentially heightening the likelihood of late-onset retinal degeneration. High levels of GLE produced opposite results. The authors note that the scotopic supernormal ERG can be a noninvasive biomarker of GLE. They also interpret the inverted dose–response curve as a sign of the retina’s long-term vulnerability to low-level lead exposure during gestation. They acknowledge their data may raise complex issues for risk assessment and indicate that dose-and state-dependent effects are important in neurotoxicity risk assessment.

Effects of low-level lead exposure on the neurobehavioral development of infants and early intervention

To explore the effects of low-level lead exposure on infant's neurobehavioral development and evaluate the effects of early intervention. The study population consisted of 276 infants whose blood lead, cadmium, iron, zinc, copper, magnesium and calcium concentrations were measured by atomic absorption spectroscopy and developmental status were assessed using the Gesell developmental Diagnosis scales (GDDS) at 6 months of age. All study subjects was divided into three groups: 58 infants in control group, 162 infants in low lead group and 56 infants in high lead group. On the basis infants of both the low and high lead groups were provided with interventional measures for 3 months, and tests for the blood lead, cadmium, iron, zinc, copper, magnesium, calcium and GDDS were repeated for all infants both 12 and 18 months of ages. Infant' s developmental outcome revealed the developmental quotient was the lowest in the high lead group (86.74 +/- 9. 35), the lesser low in the low lead group (91.52 +/- 10.12) and the highest in control group (100.71 +/- 6.92). Changes in developmental quotient were detected in both the low and high lead groups with statistical significance (P < 0.05) after intervention measures adopted. However, the changes of developmental quotient were more remarkable in the low lead group and after the 18th month there was no statistical significance than control group (t = 1.721, P > 0.05) while the significant difference was found in between the high lead group and the control group (t = 23.495, P < 0.05). Low-level lead exposure interfered infant's neurobehavioral development and early intervention might improve infant's developmental quotient.

Effects of low-level lead exposure on blood pressure and function of the rat isolated heart

Objective:Exposure to low levels of lead acetate can induce hypertension in both humans and experimental animals. The exact mechanisms of lead-induced hypertension are not well understood, but its pathogenesis could be explained by the changes in heart rate and contractility.Materials and Methods:In the present study, the effects of exposure to 100 ppm of lead in drinking water (for periods of 4, 8, and 12 weeks) on blood pressure and some physiologic parameters (eg, electrocardiography [ECG], heart rate [HR], cardiac contractility, and coronary flow) of isolated beating rat heart was investigated using the Langendorff isolated heart apparatus. The isolated hearts were perfused with Krebs-Henseleit solution (37°C; pH 7.4; gassed with 95% O2 + 5% CO2). All data were digitized by a software program for further analysis.Results:The blood pressure in the 8- and 12-week lead-exposed groups was significantly increased as compared to the control group. The ECG showed arrhythmias and conduction abnormalities only in the late phases of exposure (12 weeks). The HR and contractility were significantly higher in the 8- and 12-week lead-treated rats but not in the 4-week group. No significant changes were observed in coronary flow.Conclusion:These results indicate that: 1) low levels of lead exposure do not significantly affect the ECG in the early phase, 2) low levels of lead exposure causes ECG changes in the late phases of exposure, and 3) this level of lead exposure can increase HR and cardiac contractility but has no effect on coronary flow.

Young Brains on Lead: Adult Neurological Consequences?

Gilbert and colleagues examine the effect of chronic lowlevel lead exposure, occurring during development, on hippocampal neurogenesis and spatial learning in adulthood. The effects of lead exposure on cognitive and behavioral deficits in children leading to learning and memory impairments is well established, whereas there is little information on the long-term (adult) consequences of gestationally initiated lead exposure. One important issue that Gilbert and colleagues assess is the long-term consequences of chronic developmental low-level lead exposure in adult offspring. Secondly, Gilbert and colleagues are the first to report the effect of lead exposure on hippocampal neurogenesis. The work by Gilbert and colleagues is intriguing, in view of the fact that this paper attempts to integrate the consequences of developmental exposure to lead, known for its ability to impair cognitive functions, such as learning and memory, with a dysfunction in adult hippocampal neurogenesis. Chronic lead exposure initiated during development and continuing through adulthood (E16–PND75) resulted in a reduced survival of newly generated neurons in the dentate gyrus, but no effects on spatial learning and memory as assessed by the Morris water maze (MWM). As in other studies, discontinuation of lead at weaning did not result in observable differences from control animals in the chosen endpoint. Generally, the effects of developmental lead exposure on neurobehavioral deficits may or may not persist, and may be subtly manifested, but this paper emphasizes that lead exposure does have neurological consequences in the long term. Up until the early 1900s, lead poisoning was viewed largely as a disease of adults due to occupational exposure. However, the particular sensitivity of children to lead exposure quickly became recognized. In combination with higher rates of gastrointestinal tract absorption, the nervous systems of children are more vulnerable to the toxic effects of lead, making childhood exposure a great concern. Thus, much effort has been put into public awareness campaigns and government interventions to reduce the level of this environmental toxicant. Although mean national blood lead levels have decreased dramatically over the past 30 years in the United States, elevated levels are still found in specific areas, affecting mainly low-income, urban children and those living in older housing (Meyer et al., 2005). The most significant sources of lead continue to be old paint in homes built before 1978, lead pipes placed before the 1930s, and soil along highways and heavily traveled roads. A bimodal distribution of elevated blood lead levels in humans shows a peak for children (1–5 years of age) and a second one for adults >50 years of age (Pirkle et al., 1998). Therefore, despite intensive efforts to reduce lead use, exposure continues to be a major public health problem. Due to lead’s effects on children, the major focus of the literature has been on the acute effects of lead exposure in developing animals. Although there is considerable consensus about the toxic effects of high levels of lead, the effects of lowlevel lead exposure are less clear. Human epidemiological studies have consistently found a strong association between lead and IQ. However, there is still considerable debate on these manifestations, due to highly confounding variables such as socioeconomic status and quality of parenting. Animal studies have confirmed a significant interaction between developmental lead exposure and the nature and persistence of neurotoxic effects manifested in cognitive defects such as learning and memory, although these effects are highly ageand dose-dependent (Finkelstein et al., 1998). Numerous investigations focusing on the mechanism of lead neurotoxicity have found a wide array of effects, including apoptosis, excitotoxicity, interference with neurotransmitter storage and release mechanisms, alterations in second messengers, and damage to mitochondria (Lidsky and Schneider, 2003). Although there is no unifying mechanism, lead’s ability to substitute for calcium, and possibly zinc, is a factor common to many of its toxic actions. The disruption of dopaminergic functioning, which is involved in motor control and attention, as well as memory and executive functioning, can produce a host of behavioral problems, including attention deficit hyperactivity disorder and alterations in cognition (Brown et al., 1997). Also, lead has effects on glutamatergic transmission, which is a major player in both development and 1 To whom correspondence should be addressed. E-mail: bolivar@ wadsworth.org.

Study on the neurotoxic effects of low-level lead exposure in rats

To investigate effects of developmental lead exposure on nitric oxide synthase (NOS) activity in different brain regions and on N-methyl-D-aspartate (NMDA) receptor mRNA expression in the hippocampus of rats. On the basis of these observations, we explored possible mechanisms by which lead exposure leads to impaired learning and memorizing abilities in children. A series of rat animal models exposed to low levels of lead during the developing period was established (drinking water containing 0.025%, 0.05% and 0.075% lead acetate). NOS activities in the hippocampus, the cerebral cortex, the cerebellum and the brain stem were determined with fluorescence measurement and levels of mRNA expression of the NMDA receptor 2A (NR2A) subunit and NMDA receptor 2B (NR2B) subunit in the rat hippocampus were measured with Retro-translation (RT-PCR). There were no differences in the body weight of rat pups between any of the groups at any given time (P>0.05). The blood lead level of Pb-exposed rat pups showed a systematic pattern of change: at 14 d of age, it was lower than that at 7 d of age, then rising to the peak level at 21 d and finally falling to lower levels at 28 d. The hippocampal NOS activities of lead-exposed groups were all lower than that of the control group on the 21st and 28th day (P<0.01). NOS activities in the cerebellum of lead-exposed groups were all lower than that of the control group on the 21st and 28th day (P<0.001) and the NOS activity of the 0.025% group was significantly lower than that of the 0.05% and 0.075% groups on the 28th day (P<0.05). NOS activity in the cerebral cortex of the 0.075% group was significantly lower than that of the control, 0.025% and 0.05% groups on the four day spans (P<0.001). There was no significant difference of NOS activity in the brain stem between any lead-exposed group and the control group on the four day spans. In the 0.05% and the 0.075% groups, the level of NR2A mRNA expression was higher than that in the control group at 7 d and 14 d of age (P<0.05). In the 0.025% group, the level of NR2A was found to be higher than that in the control group at 7 d of age only (P<0.05). No significant differences were found for the levels of NR2B mRNA expression between any of the groups at any given time. NOS activity in the hippocampus, the cerebral cortex and the cerebellum are inhibited by lead exposure. The degree of the inhibitory effect depends on the time span of exposure and the lead concentration. Developmental low-level lead exposure was found to raise the level of NR2A mRNA expression in the hippocampus of rats. Developmental low-level lead exposure does not affect the level of NR2B mRNA expression in the hippocampus.