Article

Mercury, Lead, and Zinc in Baby Teeth of Children with Autism Versus Controls

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Abstract

This study determined the level of mercury, lead, and zinc in baby teeth of children with autism spectrum disorder (n = 15, age 6.1 +/- 2.2 yr) and typically developing children (n = 11, age = 7 +/- 1.7 yr). Children with autism had significantly (2.1-fold) higher levels of mercury but similar levels of lead and similar levels of zinc. Children with autism also had significantly higher usage of oral antibiotics during their first 12 mo of life, and possibly higher usage of oral antibiotics during their first 36 mo of life. Baby teeth are a good measure of cumulative exposure to toxic metals during fetal development and early infancy, so this study suggests that children with autism had a higher body burden of mercury during fetal/infant development. Antibiotic use is known to almost completely inhibit excretion of mercury in rats due to alteration of gut flora. Thus, higher use of oral antibiotics in the children with autism may have reduced their ability to excrete mercury, and hence may partially explain the higher level in baby teeth. Higher usage of oral antibiotics in infancy may also partially explain the high incidence of chronic gastrointestinal problems in individuals with autism.

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... The detailed map of the spatial distribution of ions in human primary teeth highlighted distinct patterns with key differences in enamel and dentine: very high Mn levels at the pulp-dentine junction and demarcated high Mn zone in prenatally formed dentine. This method may provide a chronological record of variation in elemental intensities in different regions of dental tissues that calcify at different times in life [42]. ...
... In a case of natal tooth a mother diseases, dietary habits, environment and lifestyle habits (cigarettes, drugs) are the most important factors influencing the trace elements concentration in dental tissues. At the time of intensive growth and development children are vulnerable to the toxic effects of heavy metal exposure [42]. The most prominent period is the prenatal life. ...
... Prenatal and early environmental exposures have been implicated in developmental disturbances in children [41,42]. The current study provides an examination of natal tooth and showed deposition of potentially toxic trace elements in dental tissues. ...
Article
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Purpose Tooth enamel might provide past chronological metabolic, nutritional status and trace metal exposure during development. Thus, the trace elements distribution embedded in tooth tissues represents an archive of the environmental conditions. The choice of biomarker is estimated as critical to the measurement of metal exposure. Natal teeth are defined as teeth being present at birth. Methods LA-ICP-MS provides a quantitative assessment of spatial distribution of trace elements in a natal tooth. The objective of the current study was to compare concentrations of building and other elements in a rare but reliable and valid biomarker - natal tooth. Results It have been reported presence of potentially toxic elements: Pb, Cu, Mn, Cd, Ni distributed in prenatally and perinatally formed enamel and dentine. Conclusions Analyses of deciduous enamel can provide answers into individuals’ earliest development, including critical pre- and perinatal period.
... They found significantly increased levels of Pb in red blood cells compared to neurotypical children (+41%) as well as increased levels in urine (+ 74%) (Adams et al., 2013). However, Adams and Romdalvik (2007) did not report a significantly increased level of Pb in the ASD children's teeth samples at around six years of age. Yassa (2014) conducted a study on 2-10 years old ASD children in Upper Egypt and found a significantly higher level of Pb in the blood and hair samples of ASD children compared with neurotypical counterparts. ...
... However, the real scale of the impact on humans is still to be established (Ye et al., 2017). Adams and Romdalvik (2007) found a significantly higher level of Hg (2.1-fold) in the teeth samples of ASD children (n = 15) compared with typically developing children (n = 11). They also reported that higher usage of oral antibiotics might have a negative role in the excretion of Hg from the body (Adams and Romdalvik, 2007). ...
... Adams and Romdalvik (2007) found a significantly higher level of Hg (2.1-fold) in the teeth samples of ASD children (n = 15) compared with typically developing children (n = 11). They also reported that higher usage of oral antibiotics might have a negative role in the excretion of Hg from the body (Adams and Romdalvik, 2007). A study on 45 ASD children and the same number of neurotypical children from Upper Egypt reported that the Hg concentrations in hair and blood were significantly higher in the ASD children compared with neurotypical children (Yassa, 2014). ...
Article
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, verbal and non-verbal communication, and stereotypic behaviors. Many studies support a significant relationship between many different environmental factors in ASD etiology. These factors include increased daily exposure to various toxic metal-based environmental pollutants, which represent a cause for concern in public health. This article reviews the most relevant toxic metals, commonly found, environmental pollutants, i.e., lead (Pb), mercury (Hg), aluminum (Al), and the metalloid arsenic (As). Additionally, it discusses how pollutants can be a possible pathogenetic cause of ASD through various mechanisms including neuroinflammation in different regions of the brain, fundamentally occurring through elevation of the proinflammatory profile of cytokines and aberrant expression of nuclear factor kappa B (NF-κB). Due to the worldwide increase in toxic environmental pollution, studies on the role of pollutants in neurodevelopmental disorders, including direct effects on the developing brain and the subjects' genetic susceptibility and polymorphism, are of utmost importance to achieve the best therapeutic approach and preventive strategies.
... 17 Two small case-control studies, one with 24 controls and the other with 11 controls, found an association between postnatal antibiotics and ASD. 9,18 With respect to ear infection, three small case-control studies found an association with ASD, 9,10,19 but one large case-control study found the opposite. 20 With respect to acetaminophen, a case-control study using Danish medical records found that prenatal exposure is associated with ASD 21 and a small case-control survey study found that postnatal exposure is associated with ASD. ...
... Such an effect could bias results in favor of associations between ASD and early weaning, 8,13,14 incidence of ear infection, 9,10,19 use of acetaminophen, 11,22 and use of antibiotics. 9,18 Relatedly, some of the existing literature seems to suggest that prenatal folate and postnatal oral vitamin D could be protective. 12,23,24,[36][37][38] However, the results from this study show no association between prenatal folate and the risk of ASD, and the results suggest that postnatal oral vitamin D is weakly associated with increased risk of ASD. ...
... Two smaller studies have previously found such an association, one of which also found an association with ear infection. 9,18 Antibiotics and ear infection are correlated variables. The correlation coefficient in Table 3 is 0.64. ...
Article
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Background While many studies have examined environmental risk factors for autism spectrum disorder (ASD), much of the research focus has been on prenatal or perinatal factors. Yet, the postnatal environment may affect the risk of ASD as well. Objective To determine whether a set of five postnatal variables are associated with ASD. These variables are: acetaminophen exposure, antibiotic exposure, incidence of ear infection, decreased duration of breastfeeding, and decreased consumption of oral vitamin D drops. Materials and methods An Internet-based survey was conducted. Participants were parents living in the USA with at least one biological child between 3 and 12 years of age. Potential participants were informed about the survey via postings on social media, websites, and listservs and were offered an opportunity to participate in a raffle as well. Participants were also recruited through the Interactive Autism Network. Results There were 1,741 completed survey responses. After exclusions, there remained 1,001 responses associated with children with ASD (cases) and 514 responses associated with children who do not have ASD (controls). In this data set, doses of postnatal acetaminophen (adjusted odds ratio [aOR] 1.016, CI: 1.003–1.032, p=0.026), courses of postnatal antibiotics (aOR 1.103, CI: 1.046–1.168, p<0.001), incidence of postnatal ear infection (aOR 1.137, CI: 1.046–1.236, p=0.003), and decreased duration of breastfeeding (aOR 0.948, CI: 0.932–0.965, p<0.001) are all associated with ASD when adjusted for eight demographic variables. A weak association between oral vitamin D drop exposure and ASD was also found when adjusted for breastfeeding and demographics (aOR 1.025, CI: 0.995–1.056, p=0.102). Conclusion This study adds to evidence that postnatal acetaminophen use, postnatal antibiotic use, incidence of ear infection, and early weaning are associated with an increased risk of ASD. It also finds that postnatal oral vitamin D drops are weakly associated with ASD when adjusted for breastfeeding and demographics.
... The Autism Spectrum Disorder (ASD) is a complex developmental disorder that impairs human communication and social behavior (Currenti, 2010). Recently, numerous studies have reported the influence of environmental and genetic factors on the neurodevelopment, leading to the appearance of ASD in different populations (Adams et al., 2007;Fido and Al-Saad, 2005;Mohamed et al., 2015;Yassa, 2014;Yasuda et al., 2013). Although the exact causes of ASD are unknown, it is generally believed that multiple genetic and environmental factors may be involved (Tamás et al., 2014). ...
... A study involving South Indian autistic children revealed a strong correlation between autism severity and the extent of trace element exposures (Lakshmi Priya and Geetha, 2011). Similar results were reported in several other studies conducted in different worldwide populations (Adams et al., 2007;Yassa, 2014;Yasuda et al., 2013). ...
... By our review of the literature, several dozen studies have explored the properties of teeth as indicators of mental health risk, in a mixture of clinical, community-based, and populationbased samples of youth (see Table 1). The overwhelming majority of research on teeth and mental health has investigated the associations of early life toxicants measured in primary teeth and risk for autism (30)(31)(32)(33)(34)(35)(36)46) in particular, as well as internalizing and externalizing problems (40,41), ADHD (37), schizophrenia (42,43), and neurodegenerative disorders (38,39) [see reviews by (47,48)]. The most recent generation of these toxicant teeth studies, which date back to the early 2010s, use mass-spectrometry technology paired with laser ablation. ...
... Early-life toxicant exposure (laser ablation) Autism Studies typically report differences in prenatal and early postnatal levels of heavy metals, as well as in the cyclic variation of metal concentrations, between children diagnosed with autism and controls. (30)(31)(32)(33)(34)(35)(36) ADHD Regularity and complexity of elemental cycles (for cobalt, lead, and vanadium) was reduced in children diagnosed with ADHD compared to those diagnosed with autism, along with other element specific features. ...
Article
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Mental disorders are among the most disabling health conditions globally. However, there remains a lack of valid, reliable, noninvasive, and inexpensive biomarkers to identify (at an early age) people who are at the greatest risk of experiencing a future mental health condition. Exfoliated primary teeth, when used in combination with established and emerging tools (e.g., family history, imaging, genetics, epigenetics), may provide important additional insights about vulnerability to mental illness. Teeth are especially promising because they develop in parallel with the brain and maintain a permanent record of environmental insults occurring during prenatal and perinatal development. Despite their potential, few empirical studies have investigated features of exfoliated teeth in relation to mental health. Here, we used micro-CT imaging to test the hypothesis that measures derived from exfoliated primary incisors associated with psychopathology symptoms in a community-based sample of children ( n = 37). We found that enamel volume (β = −0.77, 95% CI, −1.35 to −0.18, P = 0.01) had large negative associations with internalizing symptoms, and enamel mineral density (β = 0.77, 95% CI, 0.18–1.35, P = 0.01) had large positive associations with internalizing behavioral symptoms, even after stringent control for multiple testing. Pulp volume (β = −0.50, 95% CI, −0.90 to −0.09, P = 0.02) had a moderately-large negative association with externalizing behavioral symptoms, though these associations did not survive multiple testing correction. These results support the ongoing investigation of teeth as potential novel biomarkers of mental health risk.
... What is certain is that both conditions, food selectivity and gastrointestinal disorders require attention from the clinician. Further studies characterized by a more accurate methodology, both in the selection of the samples and in the development and use of more accurate diagnostic tools, could allow a more precise estimation of the prevalence of GI disorders in the ASD [138][139][140]. ...
... GI disorders such as intestinal pain, constipation and diarrhea are often associated with an altered composition of the gut microbiota [28,132,[140][141][142]. ...
Article
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Autism spectrum disorder (ASD) is a complex behavioral syndrome that is characterized by speech and language disorders, intellectual impairment, learning and motor dysfunctions. Several genetic and environmental factors are suspected to affect the ASD phenotype including air pollution, exposure to pesticides, maternal infections, inflammatory conditions, dietary factors or consumption of antibiotics during pregnancy. Many children with ASD shows abnormalities in gastrointestinal (GI) physiology, including increased intestinal permeability, overall microbiota alterations, and gut infection. Moreover, they are “picky eaters” and the existence of specific sensory patterns in ASD patients could represent one of the main aspects in hampering feeding. GI disorders are associated with an altered composition of the gut microbiota. Gut microbiome is able to communicate with brain activities through microbiota-derived signaling molecules, immune mediators, gut hormones as well as vagal and spinal afferent neurons. Since the diet induces changes in the intestinal microbiota and in the production of molecules, such as the SCFA, we wanted to investigate the role that nutritional intervention can have on GI microbiota composition and thus on its influence on behavior, GI symptoms and microbiota composition and report which are the beneficial effect on ASD conditions.
... Interestingly, the levels of heavy metal in blood, urine, teeth, hair, and related body fluid or tissues in ASD children are inconsistent. Some studies demonstrated that the levels of Pb, Hg, As, Cu, and Cd were significantly higher in the autism children than healthy controls [3], while the significantly reduced levels of Mg and Se were well associated with the severity of ASD [4]. Some studies even used chelating agents to reduce the blood levels of Pb and Hg and found that the symptoms of autism alleviated with the reduced blood Pb and Hg levels [5,6]. ...
... ± 5.04, p < 0.001 in urine was significantly increased [13]. Also, the levels of Hg, Pb, and Zn were measured in the teeth of ASD and healthy children, which showed that the teeth Hg level was significantly higher in the ASD children (2.1-fold) than the controls, while the Pb and Zn levels were similar between the two groups [3]. Furthermore, the Pb (31.9 µg/L in ASD children, and were significantly lower in ASD children than the controls [14]. ...
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Background The etiologies of autism spectrum disorder (ASD) are yet unclear. Previous studies suggested that ASD is associated with environmental heavy metals. Thus, the present study analyzed the levels of 41 heavy metals and the associated environmental factors in children with ASD. Methods The 25 children diagnosed with ASD were included in the case group (ASD group), while the 18 age- and gender-matched healthy children who came for routine care were included in the typical development group (TD group). The levels of heavy metal in the blood were measured in both groups. The questionnaire survey collected the demographic information, socioeconomic information, and risk factors of potential heavy metal sources for the analysis of risk factors. Results A total of 25 children were included in the ASD group and 18 in the TD group. The blood manganese (Mn) level was significantly higher in the ASD group than the TD group . The father’s educational level was significantly higher in the ASD group than the TD group. The living status was mainly scattered for the ASD children and daycare for the TD group. The frequency of book-reading, washing hand with sanitizer/soap, and the folic acid intake by the mother before pregnancy was significantly lower in the ASD group than the TD group, while the percentage of birth disorder history was significantly higher in the ASD group than the TD group. Binary logistic regression analysis showed that the folic acid intake by the mother before pregnancy and father’s education level beyond junior college were protective factors for ASD. Also, the frequencies of washing hands with sanitizer every time, sometimes, and hardly acted as protective factors for ASD. Conclusion Blood Mn level was significantly higher in ASD than TD, suggesting that environmental Mn exposure could be a risk factor of ASD in children. Folic acid intake by the mother before pregnancy and father’s education levels are protective factors for ASD. Concentrated heavy metal in the blood in prenatal or early life exposures which suggested ASD is needed in the future study.
... Among several studies carried out between 1999 and 2016, 74% of them revealed an essential link between ASD progression and mercury levels (Kern et al. 2016). Some studies revealed reports of increased mercury levels in teeth of ASD patients and demonstrated that enhanced mercury levels in the body might be due to reduced rate mercury excretion by excessive administration of oral antibiotics (Adams and Romdalvik 2007). An Egyptian study revealed greater mercury levels in the hair and blood samples of ASD patients (Yassa 2014). ...
... Various studies revealed the presence of mercury in teeth of ASD patients (Adams and Romdalvik 2007) ...
Article
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Autism spectrum disorder (ASD) is a developmental disorder of the brain characterized by shortfall in the social portfolio of an individual and abbreviated interactive and communication aspects rendering stereotypical behavior and pitfalls in a child’s memory, thinking, and learning capabilities. The incidence of ASD has accelerated since the past decade, portraying environment as one of the primary assets, comprising of metallic components aiming to curb the neurodevelopmental pathways in an individual. Many regulations like Clean Air Act and critical steps taken by countries all over the globe, like Sweden and the USA, have rendered the necessity to study the effects of environmental metallic components on ASD progression. The review focuses on the primary metallic components present in the environment (aluminum, lead, mercury, and arsenic), responsible for accelerating ASD symptoms by a set of general mechanisms like oxidative stress reduction, glycolysis suppression, microglial activation, and metalloprotein disruption, resulting in apoptotic signaling, neurotoxic effects, and neuroinflammatory responses. The effect of these metals can be retarded by certain protective strategies like chelation, dietary correction, certain agents (curcumin, mangiferin, selenium), and detoxification enhancement, which can necessarily halt the neurodegenerative effects. Graphical abstract
... This finding supports that of an earlier analysis of children's medical records from three different sites in the United States, which found children with ASD to take twice as many antibiotics as typically developing children before 2 years of age (Niehus and Lord 2006). Similarly, a medical history questionnaire administered to families in Arizona revealed antibiotic usage before age three to be more than twice as high in the ASD group compared to controls (Adams et al. 2007). Increased incidence of infections in children with ASD (Adams et al. 2016;Niehus and Lord 2006) may offer one explanation for the elevated use of antibiotics that has been reported in this population. ...
... Although there is a difference in means, the large standard deviations associated with these estimates obscure any meaningful difference in antibiotic use. This is in stark contrast to the findings of several previous studies that reported antibiotic use before age two to be approximately twice as high in children with ASD (House et al. 2016;Niehus and Lord 2006;Adams et al. 2007), perhaps due to differences in reporting methods between the studies. We also found that children reporting a GI symptom during late enrollment were more likely to have taken greater numbers of oral antibiotics earlier on than those children not reporting a late GI symptom (regardless of ASD or POP status), both in terms of the total number of fills as well as the prevalence of antibiotic use over time. ...
Article
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A retrospective analysis of administrative claims data from a large U.S. health insurer was performed to study a potential association between oral antibiotic use during early childhood and occurrence of later gastrointestinal (GI) symptoms in children with autism spectrum disorder (ASD). Among 3253 children with ASD, 37.0% had a GI-related diagnosis during the last 2 years of their 5-year health coverage enrollment period, compared to 20.0% of 278,370 children from the general population without an ASD diagnosis. Greater numbers of oral antibiotic fills during the first 3 years of enrollment were found to significantly increase the hazard rate of having a later GI-related diagnosis (adjusted hazard ratio 1.48; 95% confidence interval 1.34, 1.63) in children both with and without ASD.
... Antibiotics were used in the first 3 years of life by 84% of participants, with an average of seven rounds (median of three) across all participants (one round = 10 days), which is somewhat higher than that reported in several other studies for individuals with ASD, and much higher than that reported for typically developing individuals in those studies (Konstantareas and Homatidis 1987;Adams et al. 2006Adams et al. , 2007Adams et al. , 2008Niehus and Lord 2006). Although the question specified that the answer should be in rounds with one round equaling 10 days, it is possible that a few people responded with the number of days, therefore skewing our numbers to be slightly higher than those of other studies. ...
Article
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Objective: The objective of this study was to provide an evaluation of the benefits and adverse effects (AEs) of psychiatric and seizure medications commonly used for individuals with autism spectrum disorder (ASD). Methods: As part of the National Survey on Treatment Effectiveness for Autism, we report ratings of 26 psychiatric and seizure medications by 505 participants. Each medication was rated with a standardized scale for overall benefits, overall AEs, and specific symptoms affected. The frequency of use and net perceived benefit (overall benefit minus overall AE) are reported. Results: Most medications were rated as having a slightly greater benefit than AE. Six medications (lamotrigine, oxcarbazepine, clonidine, guanfacine, buspirone, and sertraline) had benefit ratings that were more than twice their adverse rating. Conversely, some medications had slightly negative net benefit ratings (worse AEs than benefits on average), including Adderall, Paroxetine, Quetiapine, Olanzapine, and Topiramate. However, there were wide variations in individual ratings of benefit and AEs, suggesting that clinical response to medications was highly variable, so these scores simply represent averages. A ranking of the top medications (those with the highest net perceived benefit) for each of 18 different symptoms is provided, which may provide some clinical guidance as to which medications may be most worth considering for a given symptom. A comparison of the survey results with the results of clinical trials shows generally good agreement in terms of medication benefits with some differences; in some cases the differences are because the clinical trials did not assess all of the symptoms assessed by this survey. Conclusions: It is hoped that physicians and their patients will find the survey results useful in selecting the most promising medications for a given symptom, and also for monitoring for likely benefits and AEs, especially for medications for which few or no studies have been carried out in ASD populations.
... Therefore, infant mercury poisoning caused by seafood consumption by the mother, pediatric vaccination, and prenatal use of antibiotics has been suggested to cause ASD [9]. Moreover, studies have reported that pre- [10][11][12] and postnatal exposure to antibiotics and acetaminophen increases the ASD risk [13][14][15][16]. ...
Article
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Autism spectrum disorder (ASD) is a developmental disorder that begins in early childhood and has been associated with several environmental and genetic factors. We aimed to conduct two-side meta-analyses to determine the association between ASD and pre- and postnatal antibiotic exposure in childhood. We searched PubMed, Embase, Web of Science, and Cochrane Library for articles published up to February 2019. We evaluated observational studies that assessed the association between ASD and antibiotic exposure. Of 1459 articles, nine studies were used in the meta-analysis. We found that early antibiotic exposure, including pre- and postnatal, significantly increased the ASD risk in children. Furthermore, early antibiotic exposure, including pre- and postnatal, was significantly increased in children with ASD. Specifically, prenatal antibiotic exposure was significantly increased in children with ASD; however, postnatal antibiotic exposure was not. Our results indicate an association between ASD and early antibiotic exposure; specifically, that prenatal antibiotic exposure is an important risk factor of ASD in children.
... Thus, higher use of oral antibiotics in the children is proposed to result in their reduced ability to excrete mercury. 7 So, average antibiotic usage in infancy was calculated by multiplying average number of episodes of illness with the average number of days of antibiotic days for each child. ...
Article
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Background: The role of heavy metals in the etio-pathogenesis of attention deficit hyperactivity disorder (ADHD) is a burning enigma. The available studies with discordant results are from different geographical localities with different monitoring, regulations and sociocultural backgrounds. The differential association of heavy metals with ADHD severity and phenotypes has not been adequately examined. Also, there are concerns about laboratory quality control. Therefore, the present case control study was formulated.Methods: Thirty children with ADHD diagnosed by DSM IV criteria and thirty group age matched controls were enrolled. Detailed perinatal, past, developmental and possible exposure history to various heavy metals was taken. Severity of ADHD was assessed using ConnersTM Parent reporting questionnaire. Blood level of metals was estimated by inductively coupled plasma- atomic emission spectroscopy (ICP-AES).Results: The mean blood lead, mercury, cadmium, arsenic, zinc were comparable in children with ADHD and group age matched controls. The mean blood lead, mercury and cadmium levels in study population was higher than found in studies from developed countries. Elevated arsenic, mercury and cadmium were found in both cases and controls. Blood zinc correlated significantly with inattention T score and blood mercury with hyperactivity-impulsitivity T score of Conners parent rating scale. Blood cadmium was present in greater proportion of predominant hyperactive-impulsive type patients.Conclusions: Zinc deficiency correlates with inattention; cadmium and mercury toxicity correlate with hyperactivity. Mean blood levels of heavy metals is elevated in a substantial proportion of study population. So, there is an urgent need for sensitization and environmental control.
... To the best of our knowledge, in deciduous teeth of children with ASD or ADHD, there have been only a handful of studies exploring element levels. Previously, teeth of children with ASD revealed two times higher levels of Hg but similar levels of Pb and Zn [12]. Also, tooth element levels in twins discordant for ASD were investigated and showed lower perinatal Mn levels, a drop in Zn levels during the prenatal period, and a marked increase postnatal and overall levels of Pb in the affected twin [13]. ...
Article
Background Environmental factors, including elemental homeostasis, have not been studied sufficiently in Neurodevelopmental Disorders (NDD). This study aims to compare the status of 13 elements in blood and deciduous teeth dentine of children having an autism spectrum disorder or attention deficit hyperactivity disorder with typically developing controls. Methods Elements including calcium, phosphorous, magnesium, iron, zinc, copper, chromium, manganese, mercury, lead, cadmium, molybdenum, and strontium in both deciduous teeth and blood were analyzed by inductively coupled plasma mass spectrometry. Results Strontium levels in both blood and teeth samples were found to be significantly lower in the NDD group. Additionally, blood cadmium and mercury levels, and copper/zinc ratio were higher in the NDD group. Conclusions Our results warrant further investigation in a large series of NDD examining symptom levels and genetic variations associated with elemental homeostasis.
... Our model proposes that teeth may serve as an additional, albeit novel, biomarker linking early-life psychosocial stress exposure to mental health risk ( Figure 2). Although this proposition has not yet been widely tested, recent work from at least eight studies on tooth-based markers of environmental toxins (e.g., pollutants, heavy metals) has provided some evidence that these physical exposures can be captured in teeth and used to predict risk for mental disorders such as schizophrenia and psychotic disorders (114,115), autism spectrum disorder (60,(116)(117)(118), and both internalizing and externalizing symptoms (119,120) ( Table 1). Whether toothbased markers of psychosocial stress can function as indicators of psychiatric risk will be a rich area of future inquiry. ...
Article
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Early-life adversity affects nearly half of all youths in the United States and is a known risk factor for psychiatric disorders across the life course. One strategy to prevent mental illness may be to target interventions toward children who are exposed to adversity, particularly during sensitive periods when these adversities may have even more enduring effects. However, a major obstacle impeding progress in this area is the lack of tools to reliably and validly measure the existence and timing of early-life adversity. In this review, we summarize empirical work across dentistry, anthropology, and archaeology on human tooth development and discuss how teeth preserve a time-resolved record of our life experiences. Specifically, we articulate how teeth have been examined in these fields as biological fossils in which the history of an individual's early-life experiences is permanently imprinted; this area of research is related to, but distinct from, studies of oral health. We then integrate these insights with knowledge about the role of psychosocial adversity in shaping psychopathology risk to present a working conceptual model, which proposes that teeth may be an understudied yet suggestive new tool to identify individuals at risk for mental health problems following early-life psychosocial stress exposure. We end by presenting a research agenda and discussion of future directions for rigorously testing this possibility and with a call to action for interdisciplinary research to meet the urgent need for new biomarkers of adversity and psychiatric outcomes.
... Gut microbiota dysbiosis may occur as a consequence of e.g., intake of antibiotics, is generally associated with several GI issues (e.g., abnormal intestinal permeability, celiac disease, gluten sensitivity, increased cytokine, chemokines and other inflammatory factors, diarrhea, and constipation), and is characterized by an increase of clostridial species and other bacteria (e.g., non-spore-forming anaerobes and microaerophilic bacteria, such as Desulfovibrio, Lactobacillus, Caloramator, Alistipes, Sarcina, Akkermansia, Sutterellaceae, Enterobacteriaceae, etc.), and a decrease of other bacterial species (e.g., Bifidobacterium, Coprococcus, Prevotella, and Veillonellaceae). Gut dysbiosis has been frequently observed in ASD children, as reported by several observational studies [23,[61][62][63][64][65][66][67][68][69][70][71][72][73]. ...
Article
In the last decade, the prevalence of autism spectrum disorders (ASD) has dramatically escalated worldwide. Currently available drugs mainly target some co-occurring symptoms of ASD, but are not effective on the core symptoms, namely impairments in communication and social interaction, and the presence of restricted and repetitive behaviors. On the other hand, transplantation of hematopoietic and mesenchymal stem cells in ASD children has been shown promising to stimulate the recruitment, proliferation, and differentiation of tissue-residing native stem cells, reducing inflammation, and improving some ASD symptoms. Moreover, several comorbidities have also been associated with ASD, such as immune dysregulation, gastrointestinal issues and gut microbiota dysbiosis. Non-pharmacological approaches, such as dietary supplementations with certain vitamins, omega-3 polyunsaturated fatty acids, probiotics, some phytochemicals (e.g., luteolin and sulforaphane), or overall diet interventions (e.g., gluten free and casein free diets) have been considered for the reduction of such comorbidities and the management of ASD. Here, interventional studies describing pharmacological and non-pharmacological treatments in ASD children and adolescents, along with stem cell-based therapies, are reviewed.
... Three of the ten papers found significant correlations between increased mercury exposure and ASD diagnosis (Adams, Romdalvik, Rama nujam, & Legator, 2007;Adams, Romdalvik, Levine, & Hu, 2008;Holmes et al., 2003), one of which (Adams et al., 2007) also found a significant correlation between ASD and a lower exposure to mercury. However, methodological issues could explain the lack of both consistency and strength of the association. ...
Article
Purpose. Autism Spectrum Disorders (ASDs) are neuropsych­iatric disorders that include Autistic Disorder, Asperger syn­drome and Pervasive Developmental Disorders-not otherwise specified (PDD­NOS). Prevalence rates of ASDs are reported to have increased in the last decade, raising concern amongst researchers, service providers, policymakers, and families. While current aetiological research is exploring the interface between genetic and environmental factors, exposure to heavy metals, in particular mercury has retained public interest. Methods. A systematic review of publications from 1980 to 2010 inclusive was used to examine the hypothesized link between ASD and mercury exposure. Hill's criteria for causation were applied to critically appraise the reviewed studies. Results. Reviewed studies failed to demonstrate strength and consistency of association as well as establish a temporal link between the onset of ASD symptoms and mercury exposure. Conclusions. The risk of developing and being diagnosed with an ASD as a result of mercury exposure remains unclear because of methodological flaws in studies conducted to date. Rigorous research is needed to provide adequate information to families, clinicians and decision­makers. They must be pro­vided with up­to­date, critically appraised information to help them make informed decisions.
... In this study, serum zinc levels were within the normal range of 70-120 μg/dl in all groups [52], and they were slightly higher in the groups of ASD, ADHD, and ASD-C groups with no significant value. Our study coincided with several previous studies that found no difference in serum zinc levels between ASD patients and controls [14,53]. Our results did not correspond with studies that found low levels of zinc in the children with ASD and ADHD compared with controls [15,54]. ...
Article
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Autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) are two developmental disorders that affect children worldwide, and are linked to both genetic and environmental factors. This study aims to investigate the levels of lead, manganese, and zinc in each of ASD, ADHD, and ASD with comorbid ADHD in Syrian children born or grown during the Syrian crisis. Lead and manganese were measured in the whole blood, and zinc was measured in the serum in 31 children with ASD, 29 children with ADHD, and 11 children with ASD with comorbid ADHD (ASD-C) compared with 30 healthy children, their ages ranged between 3 and 12 years. Blood lead levels were higher in the groups of ASD-C (245.42%), ASD (47.57%), and ADHD (14.19%) compared with control. Lead levels were significantly higher in children with ASD in the age of 5 or less compared with control, and they were also higher in the male ASD compared with females (P = 0.001). Blood manganese levels were lower in the groups of ASD-C (10.35%), ADHD (9.95%, P = 0.026), and ASD (9.64%, P = 0.046). However, serum zinc levels were within the reference range in all groups of study. Lead and manganese were positively correlated with each other (P = 0.01). Lead increase and manganese decrease may associate with the incidence of ASD, ADHD, or the co-occurrence of both of them together. Further studies are needed to examine the relationship between metal levels and the co-occurrence of ASD and ADHD together.
... 10 Mercury is considered as a risk factor for autism 4 since, according to previous studies, it has been recognized as a neurotrophic toxin. 11 Reduction in mercury content in hair 12 and teeth 13 of the children with autism aroused the low disposal of mercury hypothesis. Blaurock-Bush et al found that heavy metals are effective in the development of autism disorder. ...
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Background and objectives: There is a likelihood of a possible relationship between the concentrations of copper, lead, and mercury and autism. The present review was carried out to determine the relationship between the concentrations of these elements and autism by meta-analysis. Methods: In this study, searching Scopus, PubMed, and Science Direct databases, 18 articles conducted in different countries from 1982 to 2019 were collected. Studies' heterogeneity was investigated using the I2 index. The data were analyzed using R and STATA software. Results: In these 18 studies, 1797 patients (981 cases and 816 controls) aged 2 to 16 years were examined. Concentration of the samples (blood, hair, and nails) for both case and control groups was evaluated. There was no significant relationship between copper concentration and autism (SMD (95% CI): 0.02 (-1.16,1.20); I2=97.7%; P=0.972); there was a significant relationship between mercury concentration and autism (SMD (95% CI): 1.96 (0.56,3.35); I2=98.6%; P=0.006); there was also a significant relationship between lead concentration and autism (SMD (95% CI): 2.81 (1.64,3.98); I2=97.8%; P=0.000). Conclusion: There is, nevertheless, a significant relationship between mercury concentration and autism. Thus, the concentration of mercury can be listed as a pathogenic cause (disease-causing) for autism.
... El metil-mercurio, como agente químico industrial, ha sido relacionado con la etiopatogenia de los trastornos del neurodesarrollo (Grandjean y Landrigan, 2006) y durante las tres últimas décadas se han publicado numerosos estudios que investigan la asociación entre mercurio y autismo. La muestra del estudio CHARGE fue utilizada para comparar las concentraciones en sangre de mercurio entre sujetos con TEA y controles (Hertz-Picciotto et al., 2010); otros investigadores han determinado los niveles de mercurio en diferentes fluidos y tejidos corporales como la orina (Wright et al., 2010), el tejido cerebral (Khan et al., 2014), el pelo (Holmes et al., 2003) o los dientes (Adams et al., 2007), entre otros. Los trabajos actuales de revisión y meta-análisis en torno a este tema (Jafari et al., 2017;Kern et al., 2016) consideran que el mercurio es un importante factor causal en el autismo y sugieren que los mecanismos de detoxificación y excreción podrían estar alterados en estos sujetos, lo que conllevaría a una acumulación de esta sustancia en el organismo. ...
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Introducción y objetivos. Dadas las limitaciones en el tratamiento de los Trastornos del Espectro Autista (TEA), muchas familias recurren al uso de intervenciones alternativas. La dieta libre de gluten y caseína (DLGC) como enfoque etiopatogénico y terapéutico de los TEA ha recibido abundante atención bibliográfica y sigue siendo actualmente objeto de interés y controversia. La beta-casomorfina es un péptido derivado de las proteínas de la leche de vaca, llamada así por su procedencia (caseína) y por su actividad opioide similar a la morfina. Se ha postulado que los sujetos con TEA podrían tener altas concentraciones de estos biopéptidos que influirían en el origen y en el curso de los síntomas nucleares y periféricos del autismo. Los objetivos de esta investigación son: 1) Determinar la influencia de una DLGC sobre las alteraciones del comportamiento de niños y adolescentes diagnosticados de TEA y 2) Estudiar la relación entre los posibles cambios conductuales y los niveles urinarios de beta-casomorfina. Material y método. Se realizaron dos estudios de similares características pero con periodos de seguimiento diferentes, en diferentes momentos de tiempo y utilizando muestras distintas. Primero se realizó un estudio a 3 + 3 meses de seguimiento y años más tarde se replicó la metodología para un segundo estudio en el que se amplió la intervención a 6 + 6 meses. El tipo de diseño escogido para ambos estudios fue un ensayo clínico aleatorizado cruzado a simple ciego. El periodo de seguimiento se dividió en dos fases de la misma duración cada una (tres meses para el primer estudio y seis meses para el segundo). Cada participante recibió durante una fase dieta normal (con gluten y caseína) y durante la otra fase DLGC. Se asignó aleatoriamente el orden de intervención (empezar con dieta normal o DLGC) y se realizaron tres evaluaciones a lo largo del seguimiento (al inicio de cada estudio, tras la dieta normal y tras la DLGC). En cada evaluación se cumplimentaron cuestionarios de conducta y autismo, de seguimiento de la dieta y se determinaron los niveles de beta-casomorfina en orina. Resultados. En ninguno de los dos estudios (3 + 3 meses y 6 + 6 meses) se encontraron cambios significativos en las escalas de conducta ni en los niveles urinarios de beta-casomorfina tras la DLGC. Conclusiones. Una DLGC no produce cambios significativos en los síntomas comportamentales del autismo ni en los niveles urinarios de beta-casomorfina. Son necesarios futuros estudios que, además de eliminar el gluten y la caseína durante un periodo de tiempo suficiente (al menos 6 meses), incluyan elementos de placebo y doble ciego, así como otros marcadores biológicos para definir mejor a los sujetos que puedan beneficiarse de estas dietas.
... The authors found that ASD children had 2.1 times the level of mercury in their teeth compared to controls. Children with ASD also had used significantly more antibiotics in their first 12 months of life as compared to controls (Adams et al., 2007). In 1981, Seko et al. reported mechanisms by which antibiotics lead to significant reductions in excretion of mercury administered to mice. ...
Article
Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental condition of unknown etiology. Mercury is a common, highly neurotoxic heavy metal. The similarities of neurologic manifestations of mercury exposure and ASD raise an intriguing hypothetical question: Is ASD, at least partially, a manifestation of mercury toxicity? The fetus is particularly vulnerable to mercury exposure from the "double jeopardy" combination of the genetics of his mother and his own genetics, as relates to mercury toxicity. In this paper, I review the evidence suggesting relationships between ASD and mercury toxicity. I suggest ways to confirm these relationships with genetic and epigenetic research. I propose a hypothesis associating mercury toxicity with ASD. This may present opportunities for further research in prevention and treatment of ASD.
... Heavy metals, especially lead and mercury, are listed among high-priority hazardous substances by the US Department of Health and Human Services since even low levels are associated with neurological dysfunction, including attention-deficit hyperactivity disorder (ADHD) and lower IQ, and increasing evidence is showing they contribute to the development of neurobehavioural disorders, including ASD (Kleine 2003;Fido and Al-Saad 2005;Wright et al. 2006;Adams et al. 2007;Kern et al. 2012Kern et al. , 2016Gorini et al. 2014). Some possible sources of heavy metals include industrial paint, chemical products, fertilizers, fish that are high in mercury, building materials, and aluminiumcontaining preservatives (thiomersal) present in vaccines and lead may be present in dirt near roads and paints of older houses, and toxic levels may accumulate in children with pica or those that eat paint chips (Kleine 2003;Geier et al. 2009). ...
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The present cross-sectional, hospital-based study was carried out on 146 Egyptian male children, 73 males with autism who were comparable with another 73 healthy age-and sex-matched children, recruited from the outpatients' psychiatric clinics of the Neuropsychiatric and Pediatric Departments of South Valley and Assiut University Hospitals, Egypt. Neuropsychological assessments of autistic males were done using CARS, short sensory profile, and intelligent quotients. Serum markers of mitochondrial dysfunction (lactate, pyruvate, and lactate to pyruvate ratio, creatine kinase (CK), L-carnitine, ammonia, lactate dehydrogenase, pyruvate kinase, alanine transaminase, and aspartate transaminase), oxidative stress, and blood levels of heavy metals (mercury, lead and aluminium) were measured. Serum cholesterol, cortisol, free testosterone, estradiol, dehyroepiandrostenedione, adenosine deaminase, and H.prlori antigen in stool were also performed. There was evidence of mitochondrial dysfunction among autistic children. Additionally, there were significantly lower serum total cholesterol, cortisol and estradiol as well as significantly higher dehydroepiandrostenedione (DHEA) and free testosterone (p<0.05 for all markers). Twenty-eight (38%) cases were positive for H.pylori antigen in their stool with significant higher serum ammonia and lower adenosine deaminase than in H.pylori- negative autistic children. Mitochondrial dysfunction, H.pylori infection, and low cholesterol were prevalent among autistic male children, which should be targeted during autism management.
... The possible association between exposure to Hg and autism spectrum disorder (ASD) has been investigated in several studies and conflicting findings have been reported. For example, some studies have found that individuals with ASD had significantly higher Hg levels versus typically developing (TD) controls as measured by levels in hair [13][14][15][16], urine [17], red blood cells [18][19][20], whole blood [21][22][23][24], and baby teeth [25]. In contrast, other studies reported significantly lower Hg levels in ASD cases than TD controls as measured in hair [26][27][28][29], or no significant difference in the Hg level between ASD cases and TD controls as measured in whole blood [30][31][32][33][34][35][36][37], hair [31,34], and urine [33,34,[38][39][40]. ...
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We investigated interactive roles of three metabolic glutathione S-transferase (GST) genes (GSTP1, GSTT1, and GSTM1) and autism spectrum disorder (ASD) status in relation to blood Hg concentrations (BHC) of Jamaican children. We used data from 266 children (2-8 years) with ASD and their 1:1 age- and sex-matched typically developing (TD) controls. After adjusting General Linear Models for child’s age, socioeconomic status, consumption of leafy vegetables, fried plantain, canned fish, and the interaction between GSTP1 and GSTT1, we found significant interactions between GSTP1 and ASD status in relation to BHC either in a co-dominant or dominant genetic model for GSTP1(P < 0.001, P = 0.007, respectively). In the co-dominant model for the Ile105Val GSTP1 polymorphism, geometric mean (GM) BHC in ASD cases with genotype Ile/Ile were significantly higher than in cases with the Ile/Val genotype (0.73 vs. 0.48 µg/L, P = 0.01). In contrast, in TD controls with the Ile/Val genotype GM BHC were significantly higher than in those with the Ile/Ile genotype (0.72 vs. 0.49 µg/L, P = 0.03) or the Val/Val genotype (0.72 vs. 0.51 µg/L, P = 0.04). Although our findings are consistent with the role of GSTP1 in detoxification of Hg, replication in other populations is warranted.
... There is a growing consensus among scientists and clinicians that ASDs ensue from an interaction between biological vulnerability factors and environmental or iatrogenic insults (Aicardi et al, 2009). This points to the importance of environmental factors and raises the possibility of an etiological role for toxic exposures: either prenatal, postnatal, or in some cumulative pattern that combines the effect of maternal, gestational, and infant exposures (Adams et al., 2007). ...
... In addition, a large number of animal model studies have suggested that Zn deficiency may lead to the clinical features of ASD in rats or mice, including impairment in social behavior, impairment in learning and memory changes, and depression-like behavior, which enhanced the association between Zn deficiency and ASD [18]. However, some studies showed higher concentration of Zn in the ASD group or no significant difference between the two groups [3,4,28,40,44]. Besides the factors mentioned above which may lead to the inconsistent results, the age of the included subjects may also act as a confounding factor for Zn. ...
Article
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Essential metal elements (EMEs) have essential roles in neurological development and maintenance of human homeostasis. We performed a case-control study to explore association between the risk of autism spectrum disorder (ASD) and the 11 EMEs [Calcium (Ca), potassium (K), magnesium (Mg), sodium (Na), manganese (Mn), selenium (Se), cobalt (Co), Molybdenum (Mo), copper (Cu), zinc (Zn), and iron (Fe)] in serum. Ninety-two autistic subjects (cases) and age-sex-matched healthy subjects (controls = 91) from Beijing, China were recruited. In addition, totally 109 mothers of recruited children participated in this study. ICP-AES and ICP-MS were applied to determine the concentration of 11 EMEs in serum. The concentrations of Ca, K, and Mg were significantly higher in the cases than in the controls (OR [95% CI]: 1.031 [1.006–1.058] for Ca; 1.081 [1.046–1.118] for K; 1.161 [1.012–1.331] for Mg), while the concentrations of Zn and Cu were significantly lower (0.997 [0.995–0.999] for Cu; 0.996 [0.992–1.000] for Zn). Clear dose-response relationships between EMEs concentrations and the risk of ASD, as well as the correlation between EME concentrations and the severity of ASD were observed for most of the above EMEs. Six and seven specific correlated pairs between mothers and children were found in the cases and controls separately. The overall profiles of the EMEs were changed in the cases as compared to the controls. This study suggested that the higher levels of Ca, K, and Mg and lower levels of Zn and Cu may be associated with an elevated risk of ASD.
... Высокий уровень ртути (в 2,1 раза выше нормы) был обнаружен и в образцах зубов детей с РАС [25]. ...
Article
The authors present a review of literature on the involvement of perinatal and postnatal mercury exposure in the pathogenesis of autistic spectrum disorders (ASD). A number of studies have shown a reliable association between perinatal and postnatal exposure to mercury and ASD development aa well as clinical and laboratory markers of the severity of these disorders. However the association was not confirmed in other studies. Such contradictions may be explained by differences in the composition of study groups, including geographical characteristics, and the influence of the factors related to mercury neurotoxicity.
... Increased Pb levels in hair samples of autistic children have been found by other authors (Fido and Al-Saad, 2005), while, Kern et al. presented statistically its lower levels (Kern et al., 2007). On the other hand, another study did not reveal significant differences in Pb levels in teeth (Adams et al., 2007) in children with autism and controls. Inappropriate concentrations of toxic metals might significantly increase the risk of ASD, however, which primarily concerns specific developmental periods (either pre-or postnatal) when individuals are more susceptible to the Abbreviations: Childhood Autism Rating Scale (CARS), glutathione-s-transferase (GST), Red Blood Cells (RBC), glutathione status (GSH/GSSG), glutathione reductase (GR), glutathione-s-transferase (GST), thioredoxin (Trx), thioredoxin reductase (TrxR), peroxidoxins (Prxs I and III), glutamate dehydrogenase (GDH), developmental delay (DD), pervasive developmental disorder (PDD), Antibody anti-maltose-binding protein (Anti-MBP), 3-nitrotyrosine (3-NT), healthy controls (HC). ...
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The identification of biomarkers as diagnostic tools and predictors of response to treatment of neurological developmental disorders (NDD) such as schizophrenia (SZ), attention deficit hyperactivity disorder (ADHD), or autism spectrum disorder (ASD), still remains an important challenge for clinical medicine. Metallomic profiles of ASD patients cover, besides essential elements such as cobalt, chromium, copper, iron, manganese, molyb-denum, zinc, selenium, also toxic metals burden of: aluminum, arsenic, mercury, lead, beryllium, nickel, cad-mium. Performed studies indicate that children with ASD present a reduced ability of eliminating toxic metals, which leads to these metals' accumulation and aggravation of autistic symptoms. Extensive metallomic studies allow a better understanding of the importance of trace elements as environmental factors in the pathogenesis of ASD. Even though a mineral imbalance is a fact in ASD, we are still expecting relevant tests and the elaboration of reference levels of trace elements as potential biomarkers useful in diagnosis, prevention, and treatment of ASD.
... Environmental factors' significance implies that hazardous exposures may have an etiological role: either prenatally, postnatally, or in a cumulative pattern that incorporates the impacts of maternal, gestational, and newborn exposures [10]. ...
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Autism is a severe developmental disease characterized by social disengagement, communication impairments, and repetitive/stereotypic behaviour. Although the pathophysiological etiologies of autism remain obscure and contentious in many cases, genetic and environmental variables (and their interactions) have been identified. While autism is recognized to have multiple causative reasons, ecological variables have gained considerable attention. The Global debate has centred on neurotoxins such as Mercury, Cobalt, and Aluminium, with some claiming that these and other toxic metals contribute to the disorder's development. The study is performed in Al-Anbar province (Iraq) between march to December 2020. Seventy-five autistic patients suffered from ASD characterized by DSM-V compared with twenty-five control. Heavy metals and trace element Mercury, aluminum, and cobalt in hair specimens are measured by atomic absorption spectrophotometer are shown as higher in Aluminium concentration in patients versus healthy Control, and Global Value, more than Aluminium contributed as environmental risk-factor for ASD, While the level of Cobalt is described high in children with autistic and slightly in healthy Control compare with Global Value. These results come from environmental contaminated in Iraq's. Additively, Mercury concentration is significantly higher in autistic patients than in Control. Still, the concentration of both autism and Control typical compared with Global Value and Mercury consider no-environmental risk-factor for Iraqi community’s.
... Autism is a serious neurodevelopment al disorder characterized by impairments in social interaction, verbal and nonverbal communication, and other restricted behaviors. The number of children reported with autistic spectrum disorders (ASDs) has increased dramatically during the last 10 years 7 . Toxic heavy metals as mercury, aluminum, and lead represent potential environmental hazardous factors that might lead to the ASD development 8 . ...
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ABSTRACT Adequate knowledge is required to determine the toxicity degree of heavy metals such as cadmium, lead and mercury in the human body causing adverse effects and chronic diseases like autism for kids. Microwave-assisted digestion, hair sampling using HNO3 solution combined with H2O2 hydrogen peroxide and the measurement by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) were used for the element determination. A study conducted on hair samples of 40 individuals ranging from 5 years - to 17 years (school age) living in Malang in 2017 aimed to determine the level of heavy metals (Cd, Pb and Hg) across autism and normal children technique (ICP-MS). The results of replicate analysis shows the following mean concentrations (µg/g), Autsim cd 4.34 ± 0.06, Pb 44.75 ± 0.56 Hg 1.70 ± 0.078 and Normal Cd 2.63 ± 0.04, Pb 48.49 ± 0.80 Hg, 1.54 ± 0.13, indicating a higher concentration compared to the standard certified value GBW07601. The higher concentration of all the heavy metals (Cd, Pb, and Hg) occurred in both normal children and children with autism disease. The comparison noted that cadmium percentage was higher than elemental mercury in children with autism and vice versa in normal children. Yet, the concentration of both elements was higher in children with autism. Nonetheless, lead was found higher in normal children. It is also supported by several studies confirming the relationship between organic mercury and nervous system including autism disease. On the other hand, in this study, we found no statistically significant differences in the concentrations of heavy metals (Pb, Cd, and Hg,) between the normal
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Lake Changpo (LC) is an artificial freshwater lake surrounded by wetlands and farmlands, inundated with water during the wet season, on the southwest coast of Korea. To investigate the temporal and spatial distribution of total mercury (THg) and methylmercury (MeHg) in LC and adjacent Cheonggye Bay (CB), water and sediment samples were collected five times from August 2009 to August 2010. In addition, fish samples were collected to examine Hg levels. The THg concentration in the unfiltered water of LC ranged from 1.6 to 5.0 ng/L and had a positive relationship with total suspended solids (TSS). This positive relation indicates that TSS is an important source of THg in LC. The MeHg levels were highest during August and ranged from 0.03 to 0.19 ng/L in unfiltered water and from 0.01 to 0.10 ng/L in filtered water. Both the THg and MeHg levels in the sediments were significantly correlated with the organic matter content of the sediments. Overlapping of the spatial and temporal distribution patterns of MeHg and %MeHg between the water column and sediments suggests that production and diffusion of MeHg from the sediment, particularly during warm summer, was the primary source of MeHg in the water column. In addition, higher THg and MeHg concentrations were found in catfish, a bottom-dweller fish. Thus, the higher THg and MeHg concentrations in LC compared to CB demonstrate that artificial lakes could be a significant site for Hg methylation and an additional source of MeHg to coastal seas.
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Background: We previously reported a significant interactive association between polymorphisms of GSTP1 and blood manganese concentrations (BMC) with autism spectrum disorder (ASD) in Jamaican children. In this paper, we investigate the same interactive association with ASD while adjusting for the mixture of four metals (lead, mercury, cadmium, and arsenic). Method: We used data from 163 case-control pairs of children 2-8 years of age from our autism project in Jamaica, in which we collected blood for heavy metals analysis at enrollment. To minimize potential multicollinearity between concentrations of the four metals, we generated a mixture index using generalized weighted quantile sum regression, which was used in conditional logistic regression models to control for the four metals while assessing the interactive association between GSTP1 and BMC with ASD. Results: Similar to the findings we reported previously, we found that in co-dominant and dominant models for GSTP1, among children with the Ile/Ile genotype, those with BMC > 12μg/L had 4.6 and 4.27 times higher odds of ASD compared to those with BMC < 12μg/L (adjusted Matched Odds Ratio (MOR) = 4.6, 95% CI: 1.21 - 17.42 and adjusted MOR = 4.27, 95% CI: 1.15 - 15.85, respectively). In the co-dominant model, for children with the Ile/Val and Val/Val genotypes, the adjusted MORs were 1.26 (95% CI: 0.32, 5.01) and 0.26 (95% CI: 0.05, 1.42), respectively. Conclusions: After adjusting for the mixture of four metals, the interactive association of BMC and GSTP1 with ASD remained significant with similar magnitude of associations. Results should be interpreted cautiously.
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Metals have been known to influence the physiology of our body since hundreds of years. Therefore, they have not only been explored as a treatment for various diseases but also used as poisons to end lives. However, despite some apparent effects of acute deficiency or excess of some metals, the association of abnormal metal levels with neuropsychiatric disorders such as schizophrenia and neurodevelopmental disorders such as ASD is a quite recent discovery. Here, we will highlight the reasons for the short history of metal abnormalities as a risk factor for ASD and discuss the initial findings that lead to the most recent studies.
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Autism spectrum disorder (ASD) is a complex neurobehavioral disorder that is believed to be multifactorial in origin. As the incidence of ASD is rising along with industrialization, and because certain metals have been linked to neurological problems, it is important to consider whether such metals may play a role in the development of ASD. Previously, we performed a meta-analysis of existing literature to examine the potential link between inorganic arsenic and lead exposure and ASD. This is a continuation of that study investigating the association of the exposure to aluminum (Al), cadmium (Cd), and mercury (Hg) and ASD. These metals were chosen because they are abundant in our environment, are known to cause neurological problems in humans, and have multiple published studies examining their potential links with ASD. Following the same approach as our previous paper, we conducted a systematic review of the existing literature and performed a meta-analysis to evaluate the current evidence regarding these metals and their potential relationship with autism. We reviewed 18 studies on Al, 18 on Cd, and 23 on Hg, and the individual studies showed inconsistent results. When the measurements were integrated into the meta-analysis, we found significant associations between all the metals and ASD, but the associations were not always in the same direction. Levels of Hg in hair, urine, and blood were all positively associated with ASD. Levels of Al in hair and urine were positively associated with ASD while levels of Al in blood were negatively associated. In comparison, levels of Cd in hair and urine were negatively associated with ASD. These results imply that, while these metals are all neurotoxic, their impact on the development of ASD and their modes of action could be different. Further researches are warrant to examine the longitudinal effects of these toxic metals on the risk of ASD, to assess the critical period when exposure may affect development, and to investigate potential factors that may enhance or ameliorate the effect of metals. Overall, these findings support policies that advocate limiting exposure to neurotoxic metals, particularly for pregnant women and young children, in order to help reduce the rising incidence of ASD.
Article
Background Exposure to many environmental chemicals, including metals, often does not occur in isolation, hence requires assessment of the associations between exposure to mixtures of chemicals and human health. Objectives To investigate associations of a metal mixture of lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) in children with autism spectrum disorder (ASD), additively or interactively with each of three glutathione S-transferase (GST) genes (GSTP1, GSTT1, and GSTM1). Method Using data from 266 case-control pairs of Jamaican children (2–8 years old), we fitted negative and positive generalized weighted quantile sum (gWQS) regression models to assess the aforementioned associations. Results Based on additive and interactive negative gWQS models adjusted for maternal age, parental education, child’s parish, and seafood consumption, we found inverse associations of the overall mixture score with ASD [MOR (95 % CI) = 0.70 (0.49, 0.99); P < 0.05) and [MOR (95 % CI) = 0.46 (0.25, 0.84); P = 0.01], respectively. In an unadjusted negative gWQS model, we found a marginally significant interaction between GSTP1 and a mixture of three metals (Pb, Hg, and Mn) (P = 0.07) while the association was no longer significant after adjustment for the same covariates (P = 0.24). Conclusions Differences in diet between ASD and control groups may play a role in the inverse associations we found. The possible interactive association between Mn and GSTP1 in ASD based on gWQS is consistent with our previous reports. However, possible interaction of GSTP1 with Pb and Hg in ASD requires further investigation and replication.
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The consumption of food products containing the non-caloric sweetener aspartame has increased since the 80’s, when these products were introduced in the market. Since then, several pieces of evidence suggest that aspartame may be potentially harmful to the nervous system, although some controversy on this subject still persists. Some research suggests an association between aspartame intake and metabolic damage to the central nervous system (CNS), such as changes in enzyme and neurotransmitter activities. Considering the possible adverse neuronal actions of aspartame, we consider it important to study the biological effects of this sweetener on the functional aspects of the CNS. Objective: To analyze the pertinent literature on important aspects of the possible neurophysiological alterations associated with aspartame consumption. Methods: We conducted a search for studies, whose strategy was developed for Embase, Medline, Lilacs and Pubmed databases, according to the descriptors: Aspartame, brain function and nervous system. We present here a narrative review of the literature over the period from 1992 to 2012. Conclusion: experimental and clinical studies indicate the risk of neural adverse reactions, which are associated with the use of aspartame, even in relatively low doses. This risk might be higher in developing organisms. Because of such evidence we recommend that the sweetener consumption, if any, should be performed with moderation and caution, under the guidance of a nutritionist or a medical doctor, in order to avoid aspartame-associated deleterious effects on brain function, mainly in children.
Article
Autism spectrum disorder (ASD) is a common childhood neurodevelopmental disorder that may be related to trace elements. However, reports on the relationship between them are still inconsistent. In this article, we conducted a meta-analysis on this issue. We searched the PubMed, EMBASE, and Cochrane databases as of November 15, 2019. A random-effects model was used, and subgroups of studies were analyzed using samples of different measurements. Twenty-two original articles were identified (18 trace elements, including a total of 1014 children with ASD and 999 healthy controls). In autistic children, the overall levels of barium (Ba), mercury (Hg), lithium (Li), and lead (Pb) were higher. There were significant differences in the levels of copper (Cu) in the hair and serum between autistic children and the control group. The levels of Hg, Li, Pb and selenium (Se) in the hair of autistic children were higher than those of healthy children, while the levels of zinc (Zn) in the blood were lower. Excessive exposure to toxic heavy metals and inadequate intake of essential metal elements may be associated with ASD. Preventing excessive exposure to toxic metals and correcting poor dietary behaviors may be beneficial for the prevention and treatment of the disease.
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Metal dyshomeostasis plays a significant role in various neurological diseases such as Alzheimer’s disease, Parkinson’s disease, Autism Spectrum Disorders (ASD), and many more. Like studies investigating the proteome, transcriptome, epigenome, microbiome, etc., for years, metallomics studies have focused on data from their domain, i.e., trace metal composition, only. Still, few have considered the links between other “omes,” which may together result in an individual’s specific pathologies. In particular, ASD have been reported to have multitudes of possible causal effects. Metallomics data focusing on metal deficiencies and dyshomeostasis can be linked to functions of metalloenzymes, metal transporters, and transcription factors, thus affecting the proteome and transcriptome. Furthermore, recent studies in ASD have emphasized the gut-brain axis, with alterations in the microbiome being linked to changes in the metabolome and inflammatory processes. However, the microbiome and other “omes” are heavily influenced by the metallome. Thus, here, we will summarize the known implications of a changed metallome for other “omes” in the body in the context of “omics” studies in ASD. We will highlight possible connections and propose a model that may explain the so far independently reported pathologies in ASD.
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Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome–interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring’s prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring’s prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.
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Historically, entities with a vested interest in a product that critics have suggested is harmful have consistently used research to back their claims that the product is safe. Prominent examples are: tobacco, lead, bisphenol A, and atrazine. Research literature indicates that about 80–90% of studies with industry affiliation found no harm from the product, while only about 10–20% of studies without industry affiliation found no harm. In parallel to other historical debates, recent studies examining a possible relationship between mercury (Hg) exposure and autism spectrum disorder (ASD) show a similar dichotomy. Studies sponsored and supported by industry or entities with an apparent conflict of interest have most often shown no evidence of harm or no “consistent” evidence of harm, while studies without such affiliations report positive evidence of a Hg/autism association. The potentially causal relationship between Hg exposure and ASD differs from other toxic products since there is a broad coalition of entities for whom a conflict of interest arises. These include influential governmental public health entities, the pharmaceutical industry, and even the coal burning industry. This review includes a systematic literature search of original studies on the potential relationship between Hg and ASD from 1999 to August 2015, finding that of the studies with public health and/or industry affiliation, 86% reported no relationship between Hg and ASD. However, among studies without public health and/or industry affiliation, only 21% find no relationship between Hg and ASD. The discrepancy in these results suggests a bias indicative of a conflict of interest.
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Large autism epidemics have recently been reported in the United States and the United Kingdom. Emerging epidemiologic evidence and biologic plausibility suggest an association between autistic spectrum disorders and mercury exposure. This study compares mercury excretion after a three-day treatment w ith a n o ral c helating a gent, m eso-2,3- dimercaptosuccinic acid (DMSA), in children with autistic spectrum disorders and a matched control population. Overall, urinary mercury concentrations were significantly higher in 221 children with autistic spectrum disorders than in 18 normal controls (Relative Increase (RI)=3.15; P < 0.0002). Additionally, vaccinated cases showed a significantly higher urinary mercury concentration than did vaccinated controls (RI=5.94; P < 0.005). Similar urinary mercury concentrations were observed among matched vacci- nated and unvaccinated controls, and no association was found between urinary cadmium or lead concentrations and autistic spectrum disorders. The observed urinary concentrations of mercury could plausibly have resulted from thimerosal in childhood vaccines, although other environmental sources and thimerosal in Rh (D) immune globulin administered to mothers may be contributory. Regardless of the mechanism by which children with autistic spectrum disorders have high urinary mercury concentrations, the DMSA treatment described in this study might be useful to diag- nose their present burden of mercury.
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We were initially highly skeptical that differences in the concentrations of thimerosal in vaccines would have any effect on the incidence rate of neurodevelopmental disorders after childhood immunization. This study presents the first epidemiologic evidence, based upon tens of millions of doses of vaccine administered in the United States, that associates increasing thimerosal from vaccines with neurodevelopmental disorders. Specifically, an analysis of the Vaccine Adverse Events Reporting System (VAERS) database showed statistical increases in the incidence rate of autism (relative risk [RR] = 6.0), mental retardation (RR = 6.1), and speech disorders (RR = 2.2) after thimerosal-containing diphtheria, tetanus, and acellular pertussis (DTaP) vaccines in comparison with thimerosal-free DTaP vaccines. The male/female ratio indicated that autism (17) and speech disorders (2.3) were reported more in males than females after thimerosal-containing DTaP vaccines, whereas mental retardation (1.2) was more evenly reported among male and female vaccine recipients. Controls were employed to determine if biases were present in the data, but none were found. It was determined that overall adverse reactions were reported in similar-aged populations after thimerosal-containing DTaP (2.4 +/- 3.2 years old) and thimerosal-free DTaP (2.1 +/- 2.8 years old) vaccinations. Acute control adverse reactions such as deaths (RR = 1.0), vasculitis (RR = 1.2), seizures (RR = 1.6), ED visits (RR = 1.4), total adverse reactions (RR = 1.4), and gastroenteritis (RR = 1.1) were reported similarly after thimerosal-containing and thimerosal-free DTaP vaccines. An association between neurodevelopmental disorders and thimerosal-containing DTaP vaccines was found, but additional studies should be conducted to confirm and extend this study.
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Varicella breakthrough, the occurrence of varicella disease >42 days after vaccination, is indicative of vaccination failure. A sevenfold increased risk of breakthrough among vaccinated children with asthma was observed in a 1996 varicella outbreak in a child care center. More recent outbreak investigations have also identified age at vaccination as a potential risk factor for breakthrough. We assessed the association of varicella breakthrough with asthma, steroids, age at varicella vaccination, and timing of measles-mumps-rubella (MMR) vaccination. We performed a retrospective cohort study among children born after 1993 and followed up through 1999 at 2 health maintenance organizations ([HMOs] A and B) in the United States. Information was obtained from automated vaccination, clinic, hospital discharge, and pharmacy records. We identified 268 and 97 breakthrough cases among 80 584 and 8181 children vaccinated against varicella at HMOs A and B, respectively. Varicella breakthrough was not associated with asthma, inhaled steroids prescribed at any time, and oral steroids prescribed before vaccination. An increased risk of varicella breakthrough was found in the 3 months immediately after prescription for oral steroids at HMO A (adjusted relative risk [aRR]: 2.4; 95% confidence interval [CI]: 1.3-4.4) and HMO B (aRR: 2.8; 95% CI: 1.0-7.8), when varicella vaccine was given before 15 months of age at HMO A (aRR: 1.4; 95% CI: 1.1-1.9), and when varicella vaccination followed MMR vaccine within 28 days at HMO A (aRR: 3.1; 95% CI: 1.5-6.4). Varicella vaccine failure in children was not associated with asthma or the use of inhaled steroids, but with the use of oral steroids. Administration of varicella vaccine before the age of 15 months may be associated with a slightly increased risk of breakthrough disease. As currently recommended, varicella vaccination should not be administered for 28 days after MMR vaccination.
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Reported rates of autism have increased sharply in the United States and the United Kingdom. One possible factor underlying these increases is increased exposure to mercury through thimerosal-containing vaccines, but vaccine exposures need to be evaluated in the context of cumulative exposures during gestation and early infancy. Differential rates of postnatal mercury elimination may explain why similar gestational and infant exposures produce variable neurological effects. First baby haircut samples were obtained from 94 children diagnosed with autism using Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV) criteria and 45 age- and gender-matched controls. Information on diet, dental amalgam fillings, vaccine history, Rho D immunoglobulin administration, and autism symptom severity was collected through a maternal survey questionnaire and clinical observation. Hair mercury levels in the autistic group were 0.47 ppm versus 3.63 ppm in controls, a significant difference. The mothers in the autistic group had significantly higher levels of mercury exposure through Rho D immunoglobulin injections and amalgam fillings than control mothers. Within the autistic group, hair mercury levels varied significantly across mildly, moderately, and severely autistic children, with mean group levels of 0.79, 0.46, and 0.21 ppm, respectively. Hair mercury levels among controls were significantly correlated with the number of the mothers' amalgam fillings and their fish consumption as well as exposure to mercury through childhood vaccines, correlations that were absent in the autistic group. Hair excretion patterns among autistic infants were significantly reduced relative to control. These data cast doubt on the efficacy of traditional hair analysis as a measure of total mercury exposure in a subset of the population. In light of the biological plausibility of mercury's role in neurodevelopmental disorders, the present study provides further insight into one possible mechanism by which early mercury exposures could increase the risk of autism.
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It has been suggested that thimerosal, a mercury-containing preservative in vaccines, is a risk factor for the development of autism. We examined whether discontinuing the use of thimerosal-containing vaccines in Denmark led to a decrease in the incidence of autism. Analysis of data from the Danish Psychiatric Central Research Register recording all psychiatric admissions since 1971, and all outpatient contacts in psychiatric departments in Denmark since 1995. All children between 2 and 10 years old who were diagnosed with autism during the period from 1971-2000. Annual and age-specific incidence for first day of first recorded admission with a diagnosis of autism in children between 2 and 10 years old. A total of 956 children with a male-to-female ratio of 3.5:1 had been diagnosed with autism during the period from 1971-2000. There was no trend toward an increase in the incidence of autism during that period when thimerosal was used in Denmark, up through 1990. From 1991 until 2000 the incidence increased and continued to rise after the removal of thimerosal from vaccines, including increases among children born after the discontinuation of thimerosal. The discontinuation of thimerosal-containing vaccines in Denmark in 1992 was followed by an increase in the incidence of autism. Our ecological data do not support a correlation between thimerosal-containing vaccines and the incidence of autism.
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Mercuric compounds are nephrotoxic and neurotoxic at high doses. Thimerosal, a preservative used widely in vaccine formulations, contains ethylmercury. Thus it has been suggested that childhood vaccination with thimerosal-containing vaccine could be causally related to neurodevelopmental disorders such as autism. To determine whether vaccination with a thimerosal-containing vaccine is associated with development of autism. Population-based cohort study of all children born in Denmark from January 1, 1990, until December 31, 1996 (N = 467 450) comparing children vaccinated with a thimerosal-containing vaccine with children vaccinated with a thimerosal-free formulation of the same vaccine. Rate ratio (RR) for autism and other autistic-spectrum disorders, including trend with dose of ethylmercury. During 2 986 654 person-years, we identified 440 autism cases and 787 cases of other autistic-spectrum disorders. The risk of autism and other autistic-spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and children vaccinated with thimerosal-free vaccine (RR, 0.85 [95% confidence interval [CI], 0.60-1.20] for autism; RR, 1.12 [95% CI, 0.88-1.43] for other autistic-spectrum disorders). Furthermore, we found no evidence of a dose-response association (increase in RR per 25 microg of ethylmercury, 0.98 [95% CI, 0.90-1.06] for autism and 1.03 [95% CI, 0.98-1.09] for other autistic-spectrum disorders). The results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development of autistic-spectrum disorders.
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The prevalence of autism in the US has risen from 1 in approximately 2500 in the mid-1980s to 1 in approximately 300 children in the mid-1990s. The purpose of this study was to evaluate whether mercury from thimerosal in childhood vaccines contributed to neurodevelopmental disorders. Neurodevelopmental disorder dose-response curves for increasing mercury doses of thimerosal in childhood vaccines were determined based upon examination of the Vaccine Adverse Events Reporting System (VAERS) database and the 2001 US' Department of Education Report. The instantaneous dosage of mercury children received in comparison to the Food and Drug Administration (FDA)'s maximum permissible dose for the oral ingestion of methylmercury was also determined. The dose-response curves showed increases in odds ratios of neurodevelopmental disorders from both the VAERS and US Department of Education data closely linearly correlated with increasing doses of mercury from thimerosal-containing childhood vaccines and that for overall odds ratios statistical significance was achieved. Similar slopes and linear regression coefficients for autism odds ratios in VAERS and the US Department of Education data help to mutually validate each other. Controls employed in the VAERS and US Department of Education data showed minimal biases. The evidence presented here shows that the occurrence of neurodevelopmental disorders following thimerosal-containing childhood vaccines does not appear to be coincidental.
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To assess the possible toxicity of thimerosal-containing vaccines (TCVs) among infants. A 2-phased retrospective cohort study was conducted using computerized health maintenance organization (HMO) databases. Phase I screened for associations between neurodevelopmental disorders and thimerosal exposure among 124 170 infants who were born during 1992 to 1999 at 2 HMOs (A and B). In phase II, the most common disorders associated with exposure in phase I were reevaluated among 16 717 children who were born during 1991 to 1997 in another HMO (C). Relative risks for neurodevelopmental disorders were calculated per increase of 12.5 micro g of estimated cumulative mercury exposure from TCVs in the first, third, and seventh months of life. In phase I at HMO A, cumulative exposure at 3 months resulted in a significant positive association with tics (relative risk [RR]: 1.89; 95% confidence interval [CI]: 1.05-3.38). At HMO B, increased risks of language delay were found for cumulative exposure at 3 months (RR: 1.13; 95% CI: 1.01-1.27) and 7 months (RR: 1.07; 95% CI: 1.01-1.13). In phase II at HMO C, no significant associations were found. In no analyses were significant increased risks found for autism or attention-deficit disorder. No consistent significant associations were found between TCVs and neurodevelopmental outcomes. Conflicting results were found at different HMOs for certain outcomes. For resolving the conflicting findings, studies with uniform neurodevelopmental assessments of children with a range of cumulative thimerosal exposures are needed.
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The purpose of the study was to evaluate the effects of MMR immunization and mercury from thimerosal-containing childhood vaccines on the prevalence of autism. Evaluations of the Biological Surveillance Summaries of the Centers for Disease Control and Prevention (CDC), the U.S. Department of Education datasets, and the CDC's yearly live birth estimates were undertaken It was determined that there was a close correlation between mercury doses from thimerosal--containing childhood vaccines and the prevalence of autism from the late 1980s through the mid-1990s. In contrast, there was a potential correlation between the number of primary pediatric measles-containing vaccines administered and the prevalence of autism during the 1980s. In addition, it was found that there were statistically significant odds ratios for the development of autism following increasing doses of mercury from thimerosal-containing vaccines (birth cohorts: 1985 and 1990-1995) in comparison to a baseline measurement (birth cohort: 1984). The contribution of thimerosal from childhood vaccines (>50% effect) was greater than MMR vaccine on the prevalence of autism observed in this study. The results of this study agree with a number of previously published studies. These studies have shown that there is biological plausibility and epidemiological evidence showing a direct relationship between increasing doses of mercury from thimerosal-containing vaccines and neurodevelopmental disorders, and measles-containing vaccines and serious neurological disorders. It is recommended that thimerosal be removed from all vaccines, and additional research be undertaken to produce a MMR vaccine with an improved safety profile.
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After concerns about the possible toxicity of thimerosal-containing vaccines in the United States, this study was designed to investigate whether there is a relationship between the amount of thimerosal that an infant receives via diphtheria-tetanus-whole-cell pertussis (DTP) or diphtheria-tetanus (DT) vaccination at a young age and subsequent neurodevelopmental disorders. A retrospective cohort study was performed using 109 863 children who were born from 1988 to 1997 and were registered in general practices in the United Kingdom that contributed to a research database. The disorders investigated were general developmental disorders, language or speech delay, tics, attention-deficit disorder, autism, unspecified developmental delays, behavior problems, encopresis, and enuresis. Exposure was defined according to the number of DTP/DT doses received by 3 and 4 months of age and also the cumulative age-specific DTP/DT exposure by 6 months. Each DTP/DT dose of vaccine contains 50 microg of thimerosal (25 microg of ethyl mercury). Hazard ratios (HRs) for the disorders were calculated per dose of DTP/DT vaccine or per unit of cumulative DTP/DT exposure. Only in 1 analysis for tics was there some evidence of a higher risk with increasing doses (Cox's HR: 1.50 per dose at 4 months; 95% confidence interval [CI]: 1.02-2.20). Statistically significant negative associations with increasing doses at 4 months were found for general developmental disorders (HR: 0.87; 95% CI: 0.81-0.93), unspecified developmental delay (HR: 0.80; 95% CI: 0.69-0.92), and attention-deficit disorder (HR: 0.79; 95% CI: 0.64-0.98). For the other disorders, there was no evidence of an association with thimerosal exposure. With the possible exception of tics, there was no evidence that thimerosal exposure via DTP/DT vaccines causes neurodevelopmental disorders.
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Although mercury has been proven to be a neurotoxicant, there is a lack of data to evaluate the causal relationship between mercury and autism. We aim to see if there is increased mercury exposure in children with autistic spectrum disorder. We performed a cross-sectional cohort study over a 5-month period in 2000 to compare the hair and blood mercury levels of children with autistic spectrum disorder (n = 82; mean age 7.2 years) and a control group of normal children (n = 55; mean age 7.8 years). There was no difference in the mean mercury levels. The mean blood mercury levels of the autistic and control groups were 19.53 and 17.68 nmol/L, respectively (P = .15), and the mean hair mercury levels of the autistic and control groups were 2.26 and 2.07 ppm, respectively (P = .79). Thus, the results from our cohort study with similar environmental mercury exposure indicate that there is no causal relationship between mercury as an environmental neurotoxin and autism.
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Autism is a complex neurodevelopmental disorder that usually presents in early childhood and that is thought to be influenced by genetic and environmental factors. Although abnormal metabolism of methionine and homocysteine has been associated with other neurologic diseases, these pathways have not been evaluated in persons with autism. The purpose of this study was to evaluate plasma concentrations of metabolites in the methionine transmethylation and transsulfuration pathways in children diagnosed with autism. Plasma concentrations of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), adenosine, homocysteine, cystathionine, cysteine, and oxidized and reduced glutathione were measured in 20 children with autism and in 33 control children. On the basis of the abnormal metabolic profile, a targeted nutritional intervention trial with folinic acid, betaine, and methylcobalamin was initiated in a subset of the autistic children. Relative to the control children, the children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of SAH, adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. The intervention trial was effective in normalizing the metabolic imbalance in the autistic children. An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.
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Thimerosal is an ethylmercury-containing preservative in vaccines. Toxicokinetic studies have shown children received doses of mercury from thimerosal-containing vaccines (TCVs) that were in excess of safety guidelines. Previously, an ecological study showing a significant association between TCVs and neurodevelopmental disorders (NDs) in the US was published in this journal. A two phased population-based epidemiological study was undertaken. Phase one evaluated reported NDs to the Vaccine Adverse Event Reporting System (VAERS) following thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis (DTaP) vaccines in comparison to thimerosal-free DTaP vaccines administered from 1997 through 2001. Phase two evaluated the automated Vaccine Safety Datalink (VSD) for cumulative exposures to mercury from TCVs at 1-, 2-, 3-, and 6-months-of-age for infants born from 1992 through 1997 and the eventual risk of developing NDs. Phase one showed significantly increased risks for autism, speech disorders, mental retardation, personality disorders, and thinking abnormalities reported to VAERS following thimerosal-containing DTaP vaccines in comparison to thimerosal-free DTaP vaccines. Phase two showed significant associations between cumulative exposures to thimerosal and the following types of NDs: unspecified developmental delay, tics, attention deficit disorder (ADD), language delay, speech delay, and neurodevelopmental delays in general. This study showed that exposure to mercury from TCVs administered in the US was a consistent significant risk factor for the development of NDs. It is clear from these data and other recent publications linking TCVs with NDs that additional ND research should be undertaken in the context of evaluating mercury-associated exposures and thimerosal-free vaccines should be made available.
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Thimerosal is a preservative that has been used in manufacturing vaccines since the 1930s. Reports have indicated that infants can receive ethylmercury (in the form of thimerosal) at or above the U.S. Environmental Protection Agency guidelines for methylmercury exposure, depending on the exact vaccinations, schedule, and size of the infant. In this study we compared the systemic disposition and brain distribution of total and inorganic mercury in infant monkeys after thimerosal exposure with those exposed to MeHg. Monkeys were exposed to MeHg (via oral gavage) or vaccines containing thimerosal (via intramuscular injection) at birth and 1, 2, and 3 weeks of age. Total blood Hg levels were determined 2, 4, and 7 days after each exposure. Total and inorganic brain Hg levels were assessed 2, 4, 7, or 28 days after the last exposure. The initial and terminal half-life of Hg in blood after thimerosal exposure was 2.1 and 8.6 days, respectively, which are significantly shorter than the elimination half-life of Hg after MeHg exposure at 21.5 days. Brain concentrations of total Hg were significantly lower by approximately 3-fold for the thimerosal-exposed monkeys when compared with the MeHg infants, whereas the average brain-to-blood concentration ratio was slightly higher for the thimerosal-exposed monkeys (3.5 +/- 0.5 vs. 2.5 +/- 0.3). A higher percentage of the total Hg in the brain was in the form of inorganic Hg for the thimerosal-exposed monkeys (34% vs. 7%). The results indicate that MeHg is not a suitable reference for risk assessment from exposure to thimerosal-derived Hg. Knowledge of the toxicokinetics and developmental toxicity of thimerosal is needed to afford a meaningful assessment of the developmental effects of thimerosal-containing vaccines.
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To address a possible environmental contribution to autism, we carried out a retrospective study on urinary porphyrin levels, a biomarker of environmental toxicity, in 269 children with neurodevelopmental and related disorders referred to a Paris clinic (2002-2004), including 106 with autistic disorder. Urinary porphyrin levels determined by high-performance liquid chromatography were compared between diagnostic groups including internal and external control groups. Coproporphyrin levels were elevated in children with autistic disorder relative to control groups. Elevation was maintained on normalization for age or to a control heme pathway metabolite (uroporphyrin) in the same samples. The elevation was significant (P < 0.001). Porphyrin levels were unchanged in Asperger's disorder, distinguishing it from autistic disorder. The atypical molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was also elevated in autistic disorder (P < 0.001) but not significantly in Asperger's. A subgroup with autistic disorder was treated with oral dimercaptosuccinic acid (DMSA) with a view to heavy metal removal. Following DMSA there was a significant (P = 0.002) drop in urinary porphyrin excretion. These data implicate environmental toxicity in childhood autistic disorder.
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The objective of this study was to assess the levels of 39 toxic metals and essential minerals in hair samples of children with autism spectrum disorders and their mothers compared to controls. Inductively coupled plasma-mass spectrometry was used to analyze the elemental content of the hair of children with autism spectrum disorders (n=51), a subset of their mothers (n=29), neurotypical children (n=40), and a subset of their mothers (n=25). All participants were recruited from Arizona. Iodine levels were 45% lower in the children with autism (p=0.005). Autistic children with pica had a 38% lower level of chromium (p=0.002). Autistic children with low muscle tone had very low levels of potassium (-66%, p=0.01) and high zinc (31%, p=0.01). The mothers of young children with autism had especially low levels of lithium (56% lower, p=0.005), and the young children (ages 3-6 yr) with autism also had low lithium (-30%, p=0.04). Low iodine levels are consistent with previous reports of abnormal thyroid function, which likely affected development of speech and cognitive skills. Low lithium in the mothers likely caused low levels of lithium in the young children, which could have affected their neurological and immunological development. Further investigations of iodine, lithium, and other elements are warranted.
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This review addresses an important area of environmental and mammalian toxicology by evaluating and comparing mercury-induced effects upon the immune responses of two evolutionarily divergent yet immunologically-related species. The mechanisms of mercury toxicology and immunotoxicology are described herein, including supporting data from the following: sources of exposure; bioavailability and biodistribution; metabolism; and laboratory and field investigations. Based upon the studies presented, the relative sensitivities of fish and human immune cells to mercury exposure are compared and contrasted with regard to mercury's ability to stimulate and/or suppress host immunocompetence. In addition, results from immune assays are compared to mercury tissue burdens, as well as to toxicological threshold level estimates. Such comparisons may help to resolve gaps in our knowledge regarding sensitivity of immunological assays, standardization of immunotoxicological techniques between species, and the extent to which the vertebrate immune system possesses functional reserve and redundancy in response to xenobiotics. A review of this type begins to provide support for the potential usefulness of fish immune cells to serve as indicators for human immunotoxicology risk assessment. Analysis of the reviewed studies supports the following conclusions in both lower and higher vertebrates: a threshold for mercury-induced immunotoxicological effects is likely; multiple exposure scenarios involving high and/or chronic exposures leading to increased body burdens are linked to increased risk of immunomodulation; and highly exposed and/or susceptible subpopulations are at greater risk of toxicological impact.
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In this study, we evaluated doses of mercury from thimerosal-containing childhood immunizations in compari- son to US Federal Safety Guidelines and the effects of increasing doses of mercury o n t he i ncidence o f neurodevelopment disorders and heart disease. This study showed that children received mercury from this source in excess of the Federal Safety Guidelines for the oral ingestion of methylmercury. Our analyses showed increasing r elative r isks f or neurodevelopment disorders and heart disease with increasing doses of mercury. This study provides strong epidemiological evidence for a link between mercury exposure from thimerosal-containing childhood vaccines and neurodevelopment disorders.
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Background In 1999, concerns were raised that vaccines containing the preservative Thimerosal™ might increase the risk of autism and/or other neurodevelopmental disorders.
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Mercury toxicity and intoxication (poisoning) are realities that every American needs to face. Both the Environmental Protection Agency and National Academy of Science state that between 8 to 10% of American women have mercury levels that would render any child they gave birth to neurological disorders. One of six children in the USA have a neurodevelopmental disorder according to the Centers for Disease Control and Preven- tion. Yet our dentistry and medicine continue to expose all patients to mercury. This article discusses the obvious sources of mercury exposures that can be easily prevented. It also points out that genetic susceptibility and exposures to other materials that synergistically enhance mercury and ethyl- mercury toxicity need to be evaluated, and that by their existence prevent the actual determination of a "safe level" of mercury exposure for all. The mercury sources we consider are from dentistry and from drugs, mainly vaccines, that, in today's world are not only unnecessary sources, but also sources that are being increasingly recognized as being significantly deleterious to the health of many. © Copyright 2005, Pearblossom Private School, Inc.-Publishing Division.
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Human primary teeth have been used as indicators of heavy metal exposure for several decades, but the knowledge about the influence of factors such as tooth type and the presence of caries and roots on metal concentrations is limited. Samples of tooth powder from more than 1200 Norwegian primary teeth without fillings have been analyzed for lead, zinc and cadmium content, and 554 of them for mercury. The material represents all groups of tooth types (incisors, canines and molars), carious and non-carious teeth, and teeth with and without roots. Here we investigate how tooth group and the presence of caries and roots are related to metal concentrations in the teeth. We find that carious teeth have higher metal concentrations than non-carious teeth; the difference was statistically significant for lead, mercury and zinc. Teeth with roots have higher lead and zinc concentrations than teeth without roots. We find differences in metal concentrations between the tooth groups for lead, mercury and zinc. Significant, positive correlations are found between lead and the three other metals and between mercury and zinc. We conclude that metal concentrations in primary teeth are affected by the presence of caries and roots and by tooth group.
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Most strains of staphylococci, streptococci, yeasts and E. coli isolated from human faeces, could synthesize methylmercury compounds. In contrast, few strains of obligate anaerobes could do so. Up to 6 ng methylmercury/ml were formed in 44 h from 2 mug mercuric chloride.
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The frequency of ear infections, ear tube drainage, and deafness was examined through parental reports in autistic and yoke-matched, normal children. For the autistic group these difficulties were additionally examined as a function of the children's cognitive and communication abilities, verbal versus nonverbal status, sex, and degree of autistic symptomatology. Autistic children had a greater incidence of ear infections than matched normal peers. Lower-functioning children had an earlier onset of ear infections than their higher-functioning autistic peers. Ear infections coexisted with low-set ears, and with a higher autistic symptomatology score. The findings are discussed in terms of greater CNS vulnerability in the autistic children, which is likely present since embryogenesis. The possible adverse consequences of intermittent hearing loss on language, cognitive, and socioaffective development are considered.
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As bile is the main route of elimination of many metals, a large number of studies have been directed toward the characterization of the hepatobiliary transport of both endogenous and exogenous metals. Although some progress has been made, we still know little of the basic mechanisms involved in the hepatocellular uptake of metals, in their intracellular translocation and metabolism, or in their transport into bile. Our recent studies have focused on the last step in the hepatobiliary transport of mercury, namely, the secretion of the metal from liver cells into bile. The rate of secretion of methyl and inorganic mercury into bile was low in suckling rats and rapidly increased to adult rates soon after weaning. These changes closely followed similar developmental changes in the biliary secretion of reduced glutathione (GSH). When GSH secretion into bile was completely inhibited, without changing hepatic levels of GSH or mercury, mercury secretion was also completely blocked. Mercury secretion paralleled individual and sex-related differences in GSH secretion. At the same time, the secretion of mercury was independent of bile flow, of the thiol and mercury concentration gradients between bile and liver cells, and of those between bile and plasma. Our results, therefore, indicate a close coupling between the secretion of mercury and that of GSH. These in vivo findings, along with in vitro studies by others in vesicles isolated from the canalicular membrane of the liver cell, indicate a carrier-mediated transport system for GSH, but the nature of the linkage of this transport system with mercury secretion is not yet fully established. Our data and those in the literature are consistent with the involvement of at least two steps in the movement of mercury from liver cells to bile--the formation of a mercury-glutathione complex in the liver cell, followed by the secretion of this complex through a process closely linked to GSH secretion. The identification of GSH as an endogenous complexing agent in the transport of metals between tissues and body fluids now permits the design of therapeutic strategies aimed at exploiting this transport vehicle to effect the removal of metals via physiological routes of excretion. The present discussion considers the role of GSH in the hepatobiliary transport of metals. In doing so, a brief review is given of current understanding of hepatic GSH metabolism and transport.
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Dentine lead levels were measured from shed deciduous teeth of 761 Philadelphia schoolchildren with no prior history of lead poisoning and residing in two school districts, one considered high risk for lead exposure, and one considered low risk. Black children in public schools from areas of deteriorated housing had marked elevations of dentine lead (mean of 198 μg per gram, in 174 children), with 20 per cent of the children having levels in the range associated with toxicity. White children from newer housing had the lowest levels (mean of 41.7μg per gram, 304 children), but a group of white children from intact housing living near and attending school adjacent to a major lead processor also had elevations of dentine lead (mean of 136 μg per gram, 71 determinations). Lead exposure as defined by dentine lead levels is more serious and widespread than previously acknowledged, and extends to groups other than those traditionally accepted as at risk. (N Engl J Med 290:245–248, 1974).
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Mice fed either (1) a pelleted rodent diet, (2) evaporated milk, or (3) a synthetic diet (high protein, low fat) exhibited different rates of whole body mercury elimination and fecal mercury excretion after exposure (per os) to methylmercuric chloride. The percentage of the total mercury body burden present as mercuric mercury was highest (35.3%) in mice fed the synthetic diet (which had the highest rate of mercury elimination) and lowest (6.6%) in the animals having the lowest mercury elimination rate (milk-fed mice). Mice fed the synthetic diet had lower mercury concentrations and had a higher proportion of mercuric mercury in their tissues than the mice from the other dietary groups. Treatment of the mice with antibiotics throughout the experimental period to suppress the gut flora reduced fecal mercury excretion and the dietary differences in whole body retention of mercury. Tissue mercury concentrations and proportion of organic mercury in feces, cecal contents, liver, and kidneys were increased by antibiotic treatment of mice fed the pelleted or synthetic diets. These results are consistent with the theory that demethylation of methylmercury by intestinal microflora is a major factor determining the excretion rate of mercury.
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The interrelation between the biliary transport of glutathione (GSH) and of inorganic mercury was investigated in suckling and adult male and female rats. The 14-day-old rat secreted inorganic mercury into bile at one-seventh the rate of the 28-day-old rat. Development of the ability to secrete mercury paralleled development of the ability to secrete GSH. The inability of the 14-day-old rat to secrete mercury and GSH occurred despite hepatic tissue concentrations of both of these compounds which were similar to those of adult rats. In adult rats, inhibition of GSH secretion by sulfobromophthalein (BSP) administration resulted in a parallel inhibition of mercury secretion. Conversely, the increase in the rate of GSH secretion into bile after cysteine or GSH administration was accompanied by an increase in the rate of mercury secretion into bile. The changes in the biliary secretion of mercury and of GSH after treatment with cysteine or GSH were not closely parallel, probably because of the tissue redistribution of mercury effected by these sulfhydryl-containing compounds. Mercury secretion into bile was independent of the changes in bile flow produced by dehydrocholate (DHC) or hypertonic sucrose, but it was closely related to the rate of GSH secretion. Further, sex differences and individual variability in the biliary secretion of inorganic mercury were correlated with differing abilities to secrete GSH into bile. These results suggest that the biliary secretion of inorganic mercury is in large part dependent on the biliary transport of GSH.
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The effect of intestinal flora on the absorption and dispositon of mercury in tissues was investigated using conventional rats, and rats treated with antibiotics to eliminate their gut flora. Antibiotic-treated rats given [203Hg]-labeled methylmercuric chloride orally had significantly more mercury in their tissues, especially in kidney, brain, lung, blood, and skeletal muscle, and also excreted less mercury in the feces than conventional rats. Furthermore, in the kidneys of the antibiotic-treated rats, the proportion of mercury present as organic mercury was greater than in the kidneys of the conventional rats. The results suppport the hypothesis that the metabolism of methylmercuric chloride by the gut flora reduces the tissue content of mercury. When rats were administered 10 mg methylmercuric chloride/kg . day for 6 days, four of five of those given antibiotics developed neurological symptoms of toxicity, whereas only one of five conventional rats given methylmercuric chloride was affected.
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Seventy-nine primary (deciduous) teeth were excavated in 1978 underneath the floor of the stave church in Uvdal, Buskerud County, Norway. The mercury content of 57 teeth was measured by means of cold vapor atomic absorption spectrophotometry. As a comparison, 124 primary teeth from modern Norway were analyzed. A significant statistical difference was found between the two sets of material. In the Uvdal material a correlation was found between the mercury and copper contents. For the modern material a correlation was found between mercury and lead, and between mercury and zinc. The authors maintain that the values found for the Uvdal material represent base-line values for mercury in primary teeth, and probably reflect uptake from natural environmental sources only. Furthermore, these values may be used for reference in studies of other preindustrial, as well as modern, primary teeth. Our findings also indicate a higher level of mercury in modern than in preindustrial primary teeth in Norway.
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The ubiquitous nature of mercury in the environment, its global atmospheric cycling, and its toxicity to humans at levels that are uncomfortably close to exposures experienced by a proportion of the population are some of the current concerns associated with this pollutant. The purpose of this review is to critically evaluate the scientific quality of published reports involving human exposures to mercury and associated health outcomes as an aid in the risk evaluation of this chemical. A comprehensive review of the scientific literature involving human exposures to mercury was performed and each publication evaluated using a defined set of criteria that are considered standards in epidemiologic and toxicologic research. Severe, sometimes fatal, effects of mercury exposure at high levels were primarily reported as case studies. The disasters in Minamata, Japan, in the 1950s and in Iraq in 1971-1972 clearly demonstrated neurologic effects associated with ingestion of methylmercury both in adults and in infants exposed in utero. The effects were convincingly associated with methylmercury ingestion, despite limitations of the study design. Several well-conducted studies have investigated the effects of methylmercury at levels below those in the Iraq incident but have not provided clear evidence of an effect. The lower end of the dose-response curve constructed from the Iraq data therefore still needs to be confirmed. The studies of mercury exposure in the workplace were mainly of elemental or inorganic mercury, and effects that were observed at relatively low exposure levels were primarily neurologic and renal. Several studies have investigated effects associated with dental amalgam but have been rated as inconclusive because of methodologic deficiencies. In our overall evaluation, 29 of 110 occupational studies and 20 of 54 studies where exposure occurred in the natural environment provided at least suggestive evidence of an exposure-related effect.
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Autism is a syndrome characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movements, and sensory dysfunction. Recent epidemiological studies suggest that autism may affect 1 in 150 US children. Exposure to mercury can cause immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with autism, and the similarities extend to neuroanatomy, neurotransmitters, and biochemistry. Thimerosal, a preservative added to many vaccines, has become a major source of mercury in children who, within their firs