Mercury (Hg) and Lead (Pb) etc
in AD and ADHD

4. Is neurotoxicity associated with environmental trichloroethylene (TCE)?

Kilburn KH.
Arch Environ Health. 2002 Mar-Apr;57(2):113-20.

Individuals who lived near 2 electronic manufacturing plants were exposed to odorous chlorinated solvents by inhalation (directly) and by out gassing from well water. An exposure zone was defined by concentrations of trichloroethylene, 1,1,1-trichloroethane, tetrachloroethylene, and vinyl chloride in groundwater. The author adopted trichloroethylene as a "shorthand" for the exposure designation. Residents complained of impaired recall and concentration, and of dizziness; therefore, the focus of this investigation was brain functions. Neurobehavioral functions, Profile of Mood States, frequencies of 35 symptoms, and questionnaire responses provided by 236 residents from exposure zones were compared with responses provided by 161 unexposed regional referents and by 67 Phoenix residents who lived outside the exposure zone areas. Pulmonary functions were measured with spirometry. Residents of the exposure zones were compared with regional referents, and the former had significantly (p < .05) delayed simple and choice reaction times, impaired balance, delayed blink reflex latency R-1, and abnormal color discrimination. In addition, these individuals had impaired (1) cognitive functions, (2) attention and perceptual motor speed, and (3) recall. Individuals who lived in exposure zones had airway obstructions. Adverse mood state scores and frequencies of 33 of 35 symptoms were elevated. In conclusion, individuals who lived in the exposure zones had neurobehavioral impairments, reduced pulmonary functions, elevated Profile of Mood State scores, and excessive symptom frequencies.
PMID: 12194155

5. Neuropsychological impairment among former microelectronics workers

Bowler RM, Mergler D, Huel G, Harrison R, Cone J.
Neurotoxicology. 1991 Spring;12(1):87-103.

Although chemicals posing potential neurotoxic hazards are commonly used in the microelectronics industry, there has been no systematic study of possible chronic nervous system effects in microelectronics workers. The objective of the present study was to assess neuropsychological functions of a group of former microelectronics plant assembly workers and a group of referents, using a matched pair design. During employment, the former microelectronics workers had been exposed to multiple organic solvents, including trichloroethylene, xylene, chlorofluorocarbons and trichloroethane. Referents were recruited from the same geographic region. From a pool of 180 former workers and 157 referents, 67 pairs were matched on the basis of age, sex, ethnicity, educational level, sex and number of children. Comparison of results on the subtests of the California Neuropsychological Screening Battery-Revised (CNS-R) revealed significantly lower performance by the former microelectronics workers on tests of attention/concentration, verbal ability, memory functions, visuospatial functions, visuomotor speed, cognitive flexibility, psychomotor speed, and reaction time (t-test for pairs or Wilcoxon Signed Rank p less than 0.05). No significant differences were observed for performance on tests assessing mental status, visual recall, tactile function and learning. This overall pattern of impairment is consistent with organic solvent-related chronic toxic encephalopathy, and possible early stages of dementia. These findings underline the need for more studies among workers currently or previously employed in microelectronics industries.
PMID: 2014071

6. Increased subjective symptom prevalence among workers exposed to trichloroethylene at sub-OEL levels

Liu YT et al.
Tohoku J Exp Med. 1988 Jun;155(2):183-95.
http://tinyurl.com/6p8u2l

Over 100 workers exposed to trichloroethylene (TRI) mostly at less than 50 ppm during the production or vapor degreasing operation and about an equal number of the non-exposed control workers were examined for subjective symptoms, hematology, serum biochemistry, and sugar, protein and occult blood in urine. Essentially all the clinico-laboratory tests stayed normal, and there was no significant differences in the findings between the exposed and the controls. Thus, no clinically significant effects of TRI exposure were found in the blood and liver functions among the exposed workers as compared with the controls. The prevalence of the subjective symptoms was, however, significantly higher in the exposed group than in the controls, and dose-response relationship could be established in some selected symptoms such as nausea, heavy feeling in the head, forgetfulness, tremor in extremities, cramp in extremities and dry mouth, although the exposure was low. The findings warrant further attention to the effects of TRI especially on the central nervous system at the concentration lower than e.g., 50 ppm.
PMID: 3212780

7. Attention-deficit hyperactivity disorder and blood mercury level: a case-control study in chinese children

Cheuk DK, Wong V.
Neuropediatrics. 2006 Aug;37(4):234-40.

OBJECTIVE: To investigate the association between blood mercury level and attention-deficit hyperactivity disorder (ADHD) in Chinese children in Hong Kong. METHODS: Fifty-two children with ADHD aged below 18 years diagnosed by DSM IV criteria without perinatal brain insults, mental retardation or neurological deficits were recruited from a developmental assessment center. Fifty-nine normal controls were recruited from a nearby hospital. Blood mercury levels were measured by cold vapor atomic absorption spectrophotometry. RESULTS: The mean ages of cases and controls were 7.06 and 7.81 years respectively. Boys predominated (case = 44 [84.6 %], control = 44 [74.6 %]). There was significant difference in blood mercury levels between cases and controls (geometric mean 18.2 nmol/L [95 % CI 15.4 - 21.5 nmol/L] vs. 11.6 nmol/L [95 % CI 9.9 - 13.7 nmol/L], p < 0.001), which persists after adjustment for age, gender and parental occupational status (p < 0.001). The geometric mean blood mercury level was also significantly higher in children with inattentive (19.4 nmol/L, 95 % CI 13.3 - 28.5 nmol/L) and combined (18.0 nmol/L, 95 % CI 14.9 - 21.8 nmol/L) subtypes of ADHD. Blood mercury levels were above 29 nmol/L in 17 (26.9 %) cases and 6 (10.2 %) controls. Children with blood mercury level above 29 nmol/L had 9.69 times (95 % CI 2.57 - 36.5) higher risk of having ADHD after adjustment for confounding variables. CONCLUSION: High blood mercury level was associated with ADHD. Whether the relationship is causal requires further studies.
PMID: 17177150

8. Exposures to Environmental Toxicants and Attention Deficit Hyperactivity Disorder in U.S. Children

Joe M. Braun et al.
Environ Health Perspect 114:1904–1909 (2006)
http://www.ehponline.org/members/2006/9478/9478.html

Objective: The purpose of this study was to examine the association of exposures to tobacco smoke and environmental lead with attention deficit hyperactivity disorder (ADHD) .
Methods: Data were obtained from the National Health and Nutrition Examination Survey 1999–2002. Prenatal and postnatal tobacco exposure was based on parent report ; lead exposure was measured using blood lead concentration. ADHD was defined as having current stimulant medication use and parent report of ADHD diagnosed by a doctor or health professional.
Results: Of 4,704 children 4–15 years of age, 4.2% were reported to have ADHD and stimulant medication use, equivalent to 1.8 million children in the United States. In multivariable analysis, prenatal tobacco exposure [odds ratio (OR) = 2.5 ; 95% confidence interval (CI) , 1.2–5.2] and higher blood lead concentration (first vs. fifth quintile, OR = 4.1 ; 95% CI, 1.2–14.0) were significantly associated with ADHD. Postnatal tobacco smoke exposure was not associated with ADHD (OR = 0.6 ; 95% CI, 0.3–1.3 ; p = 0.22) . If causally linked, these data suggest that prenatal tobacco exposure accounts for 270,000 excess cases of ADHD, and lead exposure accounts for 290,000 excess cases of ADHD in U.S. children.
Conclusions: We conclude that exposure to prenatal tobacco and environmental lead are risk factors for ADHD in U.S. children.

9. Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas
Palmer RF et al.
Health Place. 2006 Jun;12(2):203-9.

"On average, for each 1,000 lb of environmentally released mercury, there was a 43% increase in the rate of special education services and a 61% increase in the rate of autism. The association between environmentally released mercury and special education rates were fully mediated by increased autism rates."

10. Proximity to point sources of environmental mercury release as a predictor of autism prevalence

Palmer RF et al.
Health Place. 2008 Feb 12.

"We found that for every 1000 pounds of industrial release, there was a corresponding 2.6% increase in autism rates (p<.05) and a 3.7% increase associated with power plant emissions(P<.05)... For every 10 miles from industrial or power plant sources, there was an associated decreased autism Incident Risk of 2.0% and 1.4%, respectively (p<.05)."

11. In-home toxic chemical exposures and children with intellectual and developmental disabilities

Graff JC, Murphy L, Ekvall S, Gagnon M.
Pediatr Nurs. 2006 Nov-Dec;32(6):596-603.

Despite the focus on preventing toxic chemical exposures during pregnancy, the perinatal period, and childhood, health professionals have given little attention to the risks and effects of toxic chemical exposures on children with intellectual and developmental disabilities (DD). Children with DD may be at higher risk due to behaviors that persist past a developmentally appropriate age, communication skills, motor skills, nutrition issues, and health problems related to DD. This article examines exposure of children to lead, mercury, and environmental tobacco smoke, three toxicants known to affect children's health and development. The authors identify sources of these toxicants, examine research documenting their effects on children, consider strategies to prevent and manage exposure, identify characteristics and behaviors placing children with DD at increased risk of exposure, and discuss implications for health providers.
PMID: 17256300

12. Exposure to hexachlorobenzene during pregnancy and children's social behavior at 4 years of age

Ribas-Fitó N et al.
Environ Health Perspect. 2007 Mar;115(3):447-50.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17431497

BACKGROUND: Hexachlorobenzene (HCB) is an organochlorine chemical that has been used in agriculture and industrial processes. Behavioral impairment after HCB exposure has been described in animal models, but little information is available in humans. OBJECTIVES: Our goal was to study the association of prenatal exposure to HCB with the social behavior of preschool children. METHODS: Two birth cohorts in Ribera d'Ebre and Menorca (Spain) were set up between 1997 and 1999 (n = 475). The California Preschool Social Competence Scale and the Attention-Deficit Hyperactivity Disorder (ADHD) were scored by each 4-year-old child's teacher. Organochlorine compounds were measured in cord serum. Children's diet and parental sociodemographic information were obtained through questionnaire. RESULTS: Children with concentrations of HCB > 1.5 ng/mL at birth had a statistically significant increased risk of having poor Social Competence [relative risk (RR) = 4.04; 95% confidence interval (CI), 1.76-9.58] and ADHD (RR = 2.71; 95% CI, 1.05-6.96) scores. No association was found between HCB and the cognitive and psychomotor performance of these children. CONCLUSIONS: Prenatal exposure to current concentrations of HCB in Spain is associated with a decrease in the behavioral competence at preschool ages. These results should be considered when evaluating the potential neurotoxicologic effects of HCB.
PMID: 17431497

13: Indoor organophosphate and polybrominated flame retardants in Tokyo

Saito I, Onuki A, Seto H.
Indoor Air. 2007 Feb;17(1):28-36.

In Japan, organophosphate and polybrominated flame retardants are used in building materials and electric appliances to protect them from fire hazards. In this study, to identify the emission sources of these flame retardants to indoor air, the migration rates (flux) of organophosphate and polybrominated flame retardants from building materials and electrical appliances to solid extraction disks that were placed in contact with the interior surfaces were measured. In addition to the migration test, indoor air and outdoor air concentrations of these flame retardants were investigated. With regard to building materials in a newly built house, triethylphosphate (TEP) and tributylphosphate (TBP) were detected in the wall and ceiling coverings, and tris(2-butoxyethyl)phosphate (TBEP) was detected in the wooden flooring cleaned with a floor polish agent. With regard to electrical appliances, triphenylphosphate (TPHP) was predominantly detected in computer monitors and tris(2-chloroethyl) phosphate (TCEP) in television (TV) sets, with the highest median levels. Among the polybrominated compounds, only 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) was detected from a few old TV sets manufactured before 1995. In an indoor and outdoor air survey, nine organophosphates and nine polybrominated flame retardants were detected from indoor air. In outdoor air, only four organophosphate flame retardants were detected. The maximum level of indoor organophosphate compounds was 1260 ng/m(3) with tris(2-chloro-1-methylethyl) phosphate (TCPP), and that of polybrominated compounds was 29.5 ng/m(3) with hexabromocyclododecane (HBCD). Tetrabromobisphenol A (TBBPA) was not detected in this study, although it has the largest demand among flame retardants in Japan. The results of the migration test and the indoor air survey revealed that in indoor air, organophosphate compounds were more predominant than polybrominated compounds in Tokyo. PRACTICAL IMPLICATIONS: Polybrominated biphenyls (PBB) and polybrominated diphenyl ethers (PBDE) are commonly used as flame retardants in plastics. The use of these two compounds in electric appliances will be banned in 2007 by the EU Directives on waste electrical and electronic equipment (WEEE) and on the restriction of the use of certain hazardous substances (RoHS) in electrical and electronic equipment. In Japan, the use of PBB was banned and that of PBDE diminished in the early 1990s by the self-imposed controls of the Japanese Flame Retardants Conference (Akutu and Hori, 2004). In Japan, the predominantly used organic flame retardants were tetrabromobisphenol A and organophosphate compounds. Tetrabromobisphenol A has been reported to disrupt endocrine systems (Kitamura et al., 2005), and some organophosphate flame retardants were recently reported to have neurochemical hazardous effects. Furthermore, organophosphate compounds were suspected to cause endocrine-disrupting effects (Fang et al., 2003; Ohyama et al., 2005) or attention deficit hyperactivity disorder (ADHD) (Winrow et al., 2003). In this study, organophosphate and polybrominated flame retardants were surveyed in indoor environments in Tokyo.
PMID: 17257150

14. Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children

Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB, Whitehead R, Tang D, Whyatt RW.
Pediatrics. 2006 Dec;118(6):e1845-59. Epub 2006 Nov 20.
http://pediatrics.aappublications.org/cgi/content/full/118/6/e1845

OBJECTIVE: The purpose of this study was to investigate the impact of prenatal exposure to chlorpyrifos on 3-year neurodevelopment and behavior in a sample of inner-city minority children. METHODS: As part of an ongoing prospective cohort study in an inner-city minority population, neurotoxicant effects of prenatal exposure to chlorpyrifos were evaluated in 254 children through the first 3 years of life. This report examined cognitive and motor development at 12, 24, and 36 months (measured with the Bayley Scales of Infant Development II) and child behavior at 36 months (measured with the Child Behavior Checklist) as a function of chlorpyrifos levels in umbilical cord plasma. RESULTS: Highly exposed children (chlorpyrifos levels of >6.17 pg/g plasma) scored, on average, 6.5 points lower on the Bayley Psychomotor Development Index and 3.3 points lower on the Bayley Mental Development Index at 3 years of age compared with those with lower levels of exposure. Children exposed to higher, compared with lower, chlorpyrifos levels were also significantly more likely to experience Psychomotor Development Index and Mental Development Index delays, attention problems, attention-deficit/hyperactivity disorder problems, and pervasive developmental disorder problems at 3 years of age. CONCLUSIONS: The adjusted mean 36-month Psychomotor Development Index and Mental Development Index scores of the highly and lower exposed groups differed by only 7.1 and 3.0 points, respectively, but the proportion of delayed children in the high-exposure group, compared with the low-exposure group, was 5 times greater for the Psychomotor Development Index and 2.4 times greater for the Mental Development Index, increasing the number of children possibly needing early intervention services.
PMID: 17116700

15. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions

D'Amelio M et al.
Mol Psychiatry. 2005 Nov;10(11):1006-16.

Organophosphates (OPs) are routinely used as pesticides in agriculture and as insecticides within the household. Our prior work on Reelin and APOE delineated a gene-environment interactive model of autism pathogenesis, whereby genetically vulnerable individuals prenatally exposed to OPs during critical periods in neurodevelopment could undergo altered neuronal migration, resulting in an autistic syndrome. Since household use of OPs is far greater in the USA than in Italy, this model was predicted to hold validity in North America, but not in Europe. Here, we indirectly test this hypothesis by assessing linkage/association between autism and variants of the paraoxonase gene (PON1) encoding paraoxonase, the enzyme responsible for OP detoxification. Three functional single nucleotide polymorphisms, PON1 C-108T, L55M, and Q192R, were assessed in 177 Italian and 107 Caucasian-American complete trios with primary autistic probands. As predicted, Caucasian-American and not Italian families display a significant association between autism and PON1 variants less active in vitro on the OP diazinon (R192), according to case-control contrasts (Q192R: chi2=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT chi2=5.26, 1 df, P<0.025), family-based association tests (Q192R and L55M: FBAT Z=2.291 and 2.435 respectively, P<0.025), and haplotype-based association tests (L55/R192: HBAT Z=2.430, P<0.025). These results are consistent with our model and provide further support for the hypothesis that concurrent genetic vulnerability and environmental OP exposure may possibly contribute to autism pathogenesis in a sizable subgroup of North American individuals.
PMID: 16027737

16. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley

Roberts EM et al.
Environ Health Perspect. 2007 Oct;115(10):1482-9.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2022638&blobtype=pdf

BACKGROUND: Ambient levels of pesticides ("pesticide drift") are detectable at residences near agricultural field sites. OBJECTIVE: Our goal was to evaluate the hypothesis that maternal residence near agricultural pesticide applications during key periods of gestation could be associated with the development of autism spectrum disorders (ASD) in children. METHODS: We identified 465 children with ASD born during 1996-1998 using the California Department of Developmental Services electronic files, and matched them by maternal date of last menstrual period to 6,975 live-born, normal-birth-weight, term infants as controls. We determined proximity to pesticide applications using California Department of Pesticide Regulation records refined using Department of Water Resources land use polygons. A staged analytic design applying a priori criteria to the results of conditional logistic regressions was employed to exclude associations likely due to multiple testing error. RESULTS: Of 249 unique hypotheses, four that described organochlorine pesticide applications--specifically those of dicofol and endosulfan--occurring during the period immediately before and concurrent with central nervous system embryogenesis (clinical weeks 1 through 8) met a priori criteria and were unlikely to be a result of multiple testing. Multivariate a posteriori models comparing children of mothers living within 500 m of field sites with the highest nonzero quartile of organochlorine poundage to those with mothers not living near field sites suggested an odds ratio for ASD of 6.1 (95% confidence interval, 2.4-15.3). ASD risk increased with the poundage of organochlorine applied and decreased with distance from field sites. CONCLUSIONS: The association between residential proximity to organochlorine pesticide applications during gestation and ASD among children should be further studied.
PMID: 17938740

17. Guidelines for developmental neurotoxicity and their impact on organophosphate pesticides: a personal view from an academic perspective

Slotkin TA.
Neurotoxicology. 2004 Jun;25(4):631-40.

The appropriate regulation of drugs, chemicals and environmental contaminants requires the establishment of clear and accepted guidelines for developmental neurotoxicity. Ideally, these guidelines should encompass the ability to assess widely disparate classes of compounds through routine tests, with high throughput and low cost. Increasingly, however, the progress in primary research from academic laboratories deviates from this goal, focusing instead on categorizing novel effects of toxicants, development of new testing paradigms, and extension of techniques into molecular biology. The differing objectives of academic science as opposed to those of regulatory agencies or industry, are driven in part, by the priorities of the agencies that fund primary research. Recent work on organophosphate pesticides (OPs) such as chlorpyrifos (CPF) illustrate this dichotomy. Originally, OPs were thought to affect brain development through their ability to elicit cholinesterase inhibition and consequent cholinergic hyperstimulation. This common mechanism allowed for parallels to be drawn between standard measures of systemic toxicity, gross morphological examinations, and exposure testing utilizing an easily-assessed surrogate endpoint, plasma cholinesterase activity. In the past decade, however, it has become increasingly evident that CPF, and probably other OPs, have direct effects on cellular processes that are unique to brain development, and that these effects are mechanistically unrelated to inhibition of cholinesterase. The identification and pursuit of these mechanisms and their consequences for brain development represent new and exciting scientific findings, while at the same obscuring the ability to sustain a uniform approach to neurotoxicity guidelines or biomarkers of exposure. In the future, a new set of test paradigms, relying on primary work in cell culture, invertebrates, or non-mammalian models, followed by more targeted examinations of specific processes in mammalian models, may unite cutting-edge academic research with the need for establishing flexible guidelines for developmental neurotoxicity.
PMID: 15183016

18. Are we on the threshold of a new theory of disease? Toxicant-induced loss of tolerance and its relationship to addiction and abdiction

Miller CS.
Toxicol Ind Health. 1999 Apr-Jun;15(3-4):284-94.

'Toxicant-induced loss of tolerance' (or TILT) describes a two-step disease process in which (1) certain chemical exposures, e.g., indoor air contaminants, chemical spills, or pesticide applications, cause certain susceptible persons to lose their prior natural tolerance for common chemicals, foods, and drugs (initiation); (2) subsequently, previously tolerated exposures trigger symptoms. Responses may manifest as addictive or abdictive (avoidant) behaviors. In some affected individuals, overlapping responses to common chemical, food, and drug exposures, as well as habituation to recurrent exposures, may hide (mask) responses to particular triggers. Accumulating evidence suggests that this disease process might underlie a broad array of medical illnesses including chronic fatigue, fibromyalgia, migraine headaches, depression, asthma, the unexplained illnesses of Gulf War veterans, multiple chemical sensitivity, and attention deficit disorder.
PMID: 10416280

19. Profile of patients with chemical injury and sensitivity

Ziem G, McTamney J.
Environ Health Perspect. 1997 Mar;105 Suppl 2:417-36.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1469804&blobtype=pdf

Patients reporting sensitivity to multiple chemicals at levels usually tolerated by the healthy population were administered standardized questionnaires to evaluate their symptoms and the exposures that aggravated these symptoms. Many patients were referred for medical tests. It is thought that patients with chemical sensitivity have organ abnormalities involving the liver, nervous system (brain, including limbic, peripheral, autonomic), immune system, and porphyrin metabolism, probably reflecting chemical injury to these systems. Laboratory results are not consistent with a psychologic origin of chemical sensitivity. Substantial overlap between chemical sensitivity, fibromyalgia, and chronic fatigue syndrome exists: the latter two conditions often involve chemical sensitivity and may even be the same disorder. Other disorders commonly seen in chemical sensitivity patients include headache (often migraine), chronic fatigue, musculoskeletal aching, chronic respiratory inflammation (rhinitis, sinusitis, laryngitis, asthma), attention deficit, and hyperactivity (affected younger children). Less common disorders include tremor, seizures, and mitral valve prolapse. Patients with these overlapping disorders should be evaluated for chemical sensitivity and excluded from control groups in future research. Agents whose exposures are associated with symptoms and suspected of causing onset of chemical sensitivity with chronic illness include gasoline, kerosene, natural gas, pesticides (especially chlordane and chlorpyrifos), solvents, new carpet and other renovation materials, adhesives/glues, fiberglass, carbonless copy paper, fabric softener, formaldehyde and glutaraldehyde, carpet shampoos (lauryl sulfate) and other cleaning agents, isocyanates, combustion products (poorly vented gas heaters, overheated batteries), and medications (dinitrochlorobenzene for warts, intranasally packed neosynephrine, prolonged antibiotics, and general anesthesia with petrochemicals). Multiple mechanisms of chemical injury that magnify response to exposures in chemically sensitive patients can include neurogenic inflammation (respiratory, gastrointestinal, genitourinary), kindling and time-dependent sensitization (neurologic), impaired porphyrin metabolism (multiple organs), and immune activation.
PMID: 9167975

20. Environmental evaluation of a child with developmental disability

Hussain J, Woolf AD, Sandel M, Shannon MW.
Pediatr Clin North Am. 2007 Feb;54(1):47-62, viii.

Children's health can be affected adversely by the environment in which they live. It is well recognized that some environmental chemicals are harmful to the brain, but the role these chemicals play in the development of specific disabilities such as attention deficit hyperactivity disorder and autism is not certain. Parents of children who have developmental disabilities often ask the primary care physician whether certain environmental toxicants might be the cause of the illness. A detailed environmental history and physical examination may help clarify whether there is a plausible relationship between an environmental toxicant and a child's disability.
PMID: 17306683

21. Developmental neurotoxicity of industrial chemicals

Grandjean P, Landrigan PJ.
Lancet. 2006 Dec 16;368(9553):2167-78.

Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.
PMID: 17174709

22. The toxicology of mercury and its chemical compounds

Clarkson TW, Magos L.
Crit Rev Toxicol. 2006 Sep;36(8):609-62.

This review covers the toxicology of mercury and its compounds. Special attention is paid to those forms of mercury of current public health concern. Human exposure to the vapor of metallic mercury dates back to antiquity but continues today in occupational settings and from dental amalgam. Health risks from methylmercury in edible tissues of fish have been the subject of several large epidemiological investigations and continue to be the subject of intense debate. Ethylmercury in the form of a preservative, thimerosal, added to certain vaccines, is the most recent form of mercury that has become a public health concern. The review leads to general discussion of evolutionary aspects of mercury, protective and toxic mechanisms, and ends on a note that mercury is still an "element of mystery."
PMID: 16973445

23. Impact of prenatal methylmercury exposure on neurobehavioral function at age 14 years

Debes F et al.
Neurotoxicol Teratol. 2006 Sep-Oct;28(5):536-47.

A cohort of 1022 consecutive singleton births was generated during 1987-1988 in the Faroe Islands, where increased methylmercury exposure occurs from traditional seafood diets that include pilot whale meat. The prenatal exposure level was determined from mercury analyses of cord blood, cord tissue, and maternal hair. At age 14 years, 878 of 1010 living cohort members underwent detailed neurobehavioral examination. Eighteen participants with neurological disorders were excluded. Blood and hair samples obtained from the participants were analyzed for mercury. The neuropsychological test battery was designed based on the same criteria as applied at the examination at age 7 years. Multiple regression analysis was carried out and included adjustment for confounders. Indicators of prenatal methylmercury exposure were significantly associated with deficits in finger tapping speed, reaction time on a continued performance task, and cued naming. Postnatal methylmercury exposure had no discernible effect. These findings are similar to those obtained at age 7 years, and the relative contribution of mercury exposure to the predictive power of the multiple regression models was also similar. An analysis of the test score difference between results at 7 and 14 years suggested that mercury-associated deficits had not changed between the two examinations. In structural equation model analyses, the neuropsychological tests were separated into five groups; methylmercury exposure was significantly associated with deficits in motor, attention, and verbal tests. These findings are supported by independent assessment of neurophysiological outcomes. The effects on brain function associated with prenatal methylmercury exposure therefore appear to be multi-focal and permanent.
PMID: 16647838

24. Metal concentrations in hair and cognitive assessment in an adolescent population

Torrente M, Colomina MT, Domingo JL.
Biol Trace Elem Res. 2005 Jun;104(3):215-21.

The objective of this study was to establish the potential relationship between the levels of various metals in hair and cognitive functions in children living in zones of Tarragona (Catalonia, Spain) with different metal pollution levels. Thirty-nine boys and 61 girls (12-14 yr old) from various schools were selected for the study. The concentrations of cadmium (Cd), chromium (Cr), mercury (Hg), lead (Pb), manganese (Mn), nickel (Ni), and tin (Sn) in scalp hair were determined by inductively coupled plasma- mass spectrometry (ICP-MS). Attention, visuospatial capabilities, and abstract reasoning were assessed as indicators of cognitive impairment. Three categories of attention were defined: low, medium, and high. A significant negative correlation (p=0.019) between Pb levels in hair and attention was observed. Significant differences between Pb levels in hair in low- and medium-performance groups and those in the high-performance group were also found. Moreover, a positive correlation (p=0.048) between Hg hair concentrations and visuospatial capabilities was also noted.
PMID: 15930591

25. Mercury exposure in children: a review

Counter SA, Buchanan LH.
Toxicol Appl Pharmacol. 2004 Jul 15;198(2):209-30.

Exposure to toxic mercury (Hg) is a growing health hazard throughout the world today. Recent studies show that mercury exposure may occur in the environment, and increasingly in occupational and domestic settings. Children are particularly vulnerable to Hg intoxication, which may lead to impairment of the developing central nervous system, as well as pulmonary and nephrotic damage. Several sources of toxic Hg exposure in children have been reported in biomedical literature: (1) methylmercury, the most widespread source of Hg exposure, is most commonly the result of consumption of contaminated foods, primarily fish; (2) ethylmercury, which has been the subject of recent scientific inquiry in relation to the controversial pediatric vaccine preservative thimerosal; (3) elemental Hg vapor exposure through accidents and occupational and ritualistic practices; (4) inorganic Hg through the use of topical Hg-based skin creams and in infant teething powders; (5) metallic Hg in dental amalgams, which release Hg vapors, and Hg2+ in tissues. This review examines recent epidemiological studies of methylmercury exposure in children. Reports of elemental Hg vapor exposure in children through accidents and occupational practices, and the more recent observations of the increasing use of elemental Hg for magico-religious purposes in urban communities are also discussed. Studies of inorganic Hg exposure from the widespread use of topical beauty creams and teething powders, and fetal/neonatal Hg exposure from maternal dental amalgam fillings are reviewed. Considerable attention was given in this review to pediatric methylmercury exposure and neurodevelopment because it is the most thoroughly investigated Hg species. Each source of Hg exposure is reviewed in relation to specific pediatric health effects, particularly subtle neurodevelopmental disorders.
PMID: 15236954

26. Low level methylmercury exposure affects neuropsychological function in adults

Yokoo EM, Valente JG, Grattan L, Schmidt SL, Platt I, Silbergeld EK.
Environ Health. 2003 Jun 4;2(1):8.

BACKGROUND: The neurotoxic effects of methylmercury (MeHg) have been demonstrated in both human and animal studies. Both adult and fetal brains are susceptible to the effects of MeHg toxicity. However, the specific effects of adult exposures have been less well-documented than those of children with prenatal exposures. This is largely because few studies of MeHg exposures in adults have used sensitive neurological endpoints. The present study reports on the results of neuropsychological testing and hair mercury concentrations in adults (>17 yrs) living in fishing communities of Baixada Cuiabana (Mato Grosso) in the Pantanal region of Brazil. METHODS: A cross-sectional study was conducted in six villages on the Cuiaba River. Participants included 129 men and women older than 17 years of age. They were randomly selected in proportion to the age range and number of inhabitants in each village. Questionnaire information was collected on demographic variables, including education, occupation, and residence history. Mercury exposure was determined by analysis of hair using flameless atomic absorption spectrophotometry. The neurocognitive screening battery included tests from the Wechsler Memory Scale and the Wechsler Adult Intelligence Scale, Concentrated Attention Test of the Toulouse-Pierron Factorial Battery, the Manual Ability Subtests of the Tests of Mechanical Ability, and the Profile of Mood States. RESULTS: Mercury exposures in this population were associated with fish consumption. The hair mercury concentration in the 129 subjects ranged from 0.56 to 13.6 microg/g; the mean concentration was 4.2 +/- 2.4 micrograms/g and the median was 3.7 microg/g. Hair mercury levels were associated with detectable alterations in performance on tests of fine motor speed and dexterity, and concentration. Some aspects of verbal learning and memory were also disrupted by mercury exposure. The magnitude of the effects increased with hair mercury concentration, consistent with a dose-dependent effect. CONCLUSIONS: This study suggests that adults exposed to MeHg may be at risk for deficits in neurocognitive function. The functions disrupted in adults, namely attention, fine-motor function and verbal memory, are similar to some of those previously reported in children with prenatal exposures.
PMID: 12844364

27. Brain sites of movement disorder: genetic and environmental agents in neurodevelopmental perturbations

Palomo T, Beninger RJ, Kostrzewa RM, Archer T.
Neurotox Res. 2003;5(1-2):1-26.

In assessing and assimilating the neurodevelopmental basis of the so-called movement disorders it is probably useful to establish certain concepts that will modulate both the variation and selection of affliction, mechanisms-processes and diversity of disease states. Both genetic, developmental and degenerative aberrations are to be encompassed within such an approach, as well as all deviations from the necessary components of behaviour that are generally understood to incorporate "normal" functioning. In the present treatise, both conditions of hyperactivity/hypoactivity, akinesia and bradykinesia together with a constellation of other symptoms and syndromes are considered in conjunction with the neuropharmacological and brain morphological alterations that may or may not accompany them, e.g. following neonatal denervation. As a case in point, the neuroanatomical and neurochemical points of interaction in Attention Deficit and Hyperactivity disorder (ADHD) are examined with reference to both the perinatal metallic and organic environment and genetic backgrounds. The role of apoptosis, as opposed to necrosis, in cell death during brain development necessitates careful considerations of the current explosion of evidence for brain nerve growth factors, neurotrophins and cytokines, and the processes regulating their appearance, release and fate. Some of these processes may possess putative inherited characteristics, like alpha-synuclein, others may to greater or lesser extents be endogenous or semi-endogenous (in food), like the tetrahydroisoquinolines, others exogenous until inhaled or injested through environmental accident, like heavy metals, e.g. mercury. Another central concept of neurodevelopment is cellular plasticity, thereby underlining the essential involvement of glutamate systems and N-methyl-D-aspartate receptor configurations. Finally, an essential assimilation of brain development in disease must delineate the relative merits of inherited as opposed to environmental risks not only for the commonly-regarded movement disorders, like Parkinson's disease, Huntington's disease and epilepsy, but also for afflictions bearing strong elements of psychosocial tragedy, like ADHD, autism and Savantism.
PMID: 12832221

28. Environmental factors associated with a spectrum of neurodevelopmental deficits

Mendola P, Selevan SG, Gutter S, Rice D.
Ment Retard Dev Disabil Res Rev. 2002;8(3):188-97.

A number of environmental agents have been shown to demonstrate neurotoxic effects either in human or laboratory animal studies. Critical windows of vulnerability to the effects of these agents occur both pre- and postnatally. The nervous system is relatively unique in that different parts are responsible for different functional domains, and these develop at different times (e.g., motor control, sensory, intelligence and attention). In addition, the many cell types in the brain have different windows of vulnerability with varying sensitivities to environmental agents. This review focuses on two environmental agents, lead and methylmercury, to illustrate the neurobehavioral and cognitive effects that can result from early life exposures. Special attention is paid to distinguishing between the effects detected following episodes of poisoning and those detected following lower dose exposures. Perinatal and childhood exposure to high doses of lead results in encephalopathy and convulsions. Lower-dose lead exposures have been associated with impairment in intellectual function and attention. At high levels of prenatal exposure, methylmercury produces mental retardation, cerebral palsy and visual and auditory deficits in children of exposed mothers. At lower levels of methylmercury exposure, the effects in children have been more subtle. Other environmental neurotoxicants that have been shown to produce developmental neurotoxicity include polychlorinated biphenyls (PCBs), dioxins, pesticides, ionizing radiation, environmental tobacco smoke, and maternal use of alcohol, tobacco, marijuana and cocaine. Exposure to environmental agents with neurotoxic effects can result in a spectrum of adverse outcomes from severe mental retardation and disability to more subtle changes in function depending on the timing and dose of the chemical agent. Copyright 2002 Wiley-Liss, Inc.
PMID: 12216063

29. The role of mercury in the pathogenesis of autism

Bernard S, Enayati A, Roger H, Binstock T, Redwood L.
Mol Psychiatry. 2002;7 Suppl 2:S42-3.
http://www.nature.com/mp/journal/v7/n2s/pdf/4001177a.pdf
PMID: 12142947

30. A meta-analysis for neurobehavioural results due to occupational mercury exposure

Meyer-Baron M, Schaeper M, Seeber A.
Arch Toxicol. 2002 Apr;76(3):127-36.

A meta-analysis for neurobehavioural test results of subjects occupationally exposed to mercury was carried out in order to find general tendencies and express possible deficits numerically. Out of 44 studies investigating neurobehavioural functions of occupationally exposed individuals, 12 studies provided the data required and were included in the analysis. In all, 14 neuropsychological tests with 20 different tasks were analysed. The results related to 686 exposed and 579 control subjects. Nine significant performance effects were shown for mean urinary concentrations between 18 and 34 microg Hg/g creatinine. The effects sizes (D(W+)) referred to attention (D(W+)=-0.40 and -0.46), memory (D(W+)=-0.38 and -0.40), construction (D(W+)=-0.20) and motor performance (D(W+)=-0.24, -0.40, -0.44 and -0.47). Additionally there was evidence for a dose-response relationship of effect sizes, if all test results were taken into account. Whether the effect sizes could be subject to overestimation was discussed, but there were no reasons for such an assumption. The results can be used as suggestions for new discussions about threshold limit values.
PMID: 11967617

31. In harm's way: toxic threats to child development

Stein J et al.
J Dev Behav Pediatr. 2002 Feb;23(1 Suppl):S13-22.

Developmental disabilities result from complex interactions of genetic, toxicologic (chemical), and social factors. Among these various causes, toxicologic exposures deserve special scrutiny because they are readily preventable. This article provides an introduction to some of the literature addressing the effects of these toxicologic exposures on the developing brain. This body of research demonstrates cause for serious concern that commonly encountered household and environmental chemicals contribute to developmental disabilities. The developing brain is uniquely susceptible to permanent impairment by exposure to environmental substances during time windows of vulnerability. Lead, mercury, and polychlorinated biphenyls (PCBs) have been extensively studied and found to impair development at levels of exposure currently experienced by significant portions of the general population. High-dose exposures to each of these chemicals cause catastrophic developmental effects. More recent research has revealed toxicity at progressively lower exposures, illustrating a "declining threshold of harm" commonly observed with improved understanding of developmental toxicants. For lead, mercury, and PCBs, recent studies reveal that background-population exposures contribute to a wide variety of problems, including impairments in attention, memory, learning, social behavior, and IQ. Unfortunately, for most chemicals there is little data with which to evaluate potential risks to neurodevelopment. Among the 3000 chemicals produced in highest volume (over 1 million lbs/yr), only 12 have been adequately tested for their effects on the developing brain. This is a matter of concern because the fetus and child are exposed to untold numbers, quantities, and combinations of substances whose safety has not been established. Child development can be better protected by more precautionary regulation of household and environmental chemicals. Meanwhile, health care providers and parents can play an important role in reducing exposures to a wide variety of known and suspected neurodevelopmental toxicants that are widely present in consumer products, food, the home, and wider community.
PMID: 11875286

32. Toxic threats to neurologic development of children

Schettler T.
Environ Health Perspect. 2001 Dec;109 Suppl 6:813-6.
http://www.ehponline.org/members/2001/suppl-6/813-816schettler/schettler-full.html

Learning disabilities, attention deficit hyperactivity disorder, developmental delays, and emotional and behavioral problems are among childhood disabilities of increasing concern. Interacting genetic, environmental, and social factors are important determinants of childhood brain development and function. For many reasons, however, studying neurodevelopmental vulnerabilities in children is challenging. Moreover, inadequate incidence and trend data interfere with full understanding of the magnitude of the problem. Despite these difficulties, extensive laboratory and clinical studies of several neurodevelopmental toxicants, including lead, mercury, polychlorinated biphenyls, alcohol, and nicotine, demonstrate the unique vulnerability of the developing brain to environmental agents at exposure levels that have no lasting effect in adults. Historically, understanding the effects of these toxicants on the developing brain has emerged slowly while generations of children are exposed to unsafe levels. Unfortunately, with few exceptions, neurodevelopmental toxicity data are missing for most industrial chemicals in widespread use, even when populationwide exposures are documented. The personal, family, and communitywide costs of developmental disabilities are profound. In addition to the need for more research, a preventive public health response requires mitigation of exposures to potential neurodevelopmental toxicants when available evidence establishes the plausibility of harm, despite residual toxicologic uncertainties.
PMID: 11744499

33. Effects of metals on the nervous system of humans and animals

Carpenter DO.
Int J Occup Med Environ Health. 2001;14(3):209-18.

Several metals have toxic actions on nerve cells and neurobehavorial functioning. These toxic actions can be expressed either as developmental effects or as an increased risk of neurodegenerative diseases in old age. The major metals causing neurobehavioral effects after developmental exposure are lead and methylmercury. Lead exposure in young children results in a permanent loss of IQ of approximately 5 to 7 IQ points, and also results in a shortened attention span and expression of anti-social behaviors. There is a critical time period (<2 years of age) for development of these effects, after which the effects do not appear to be reversible even if blood lead levels are lowered with chelation. Methylmercury has also been found to have effects on cognition at low doses, and prenatal exposure at higher levels can disrupt brain development. Metals have also been implicated in neurodegenerative diseases, although it is unlikely that they are the sole cause for any of them. Elevated aluminum levels in blood, usually resulting from kidney dialysis at home with well water containing high aluminum, result in dementia that is similar to but probably different from that of Alzheimer's disease. However, there is some epidemiological evidence for elevated risk of Alzheimer's in areas where there is high concentration of aluminum in drinking water. Other metals, especially lead, mercury, manganese and copper, have been implicated in amvotrophic lateral sclerosis and Parkinson's disease.
PMID: 11764847

34. Vaccines without thiomersal: why so necessary, why so long coming?

van't Veen AJ.
Drugs. 2001;61(5):565-72.

The inorganic mercurial thiomersal (merthiolate) has been used as an effective preservative in numerous medical and non-medical products since the early 1930s. Both the potential toxicity of thiomersal and sensitisation to thiomersal in relation to the application of thiomersal-containing vaccines and immunoglobulins, especially in children, have been debated in the literature. The very low thiomersal concentrations [sic] in pharmacological and biological products are relatively non-toxic, but probably not in utero and during the first 6 months of life. The developing brain of the fetus is most susceptible to thiomersal and, therefore, women of childbearing age, in particular, should not receive thiomersal-containing products. Definitive data of doses at which developmental effects occur are not available. Moreover, revelation of subtle effects of toxicity needs long term observation of children. The ethylmercury radical of the thiomersal molecule appears to be the prominent sensitiser. The prevalence of thiomersal hypersensitivity in mostly selected populations varies up to 18%, but higher figures have been reported. The overall exposure to thiomersal differs considerably between countries. In many cases a positive routine patch test to thiomersal should be considered an accidental finding without or, probably more accurately, with low clinical relevance. In practice, some preventive measures can be taken with respect to thiomersal hypersensitivity. However, with regard to the debate on primary sensitisation during childhood and renewed attention for a reduction of children's exposure to mercury from all sources, the use of thiomersal should preferably be eliminated or at least be reduced. In 1999 the manufacturers of vaccines and immunoglobulins in the US and Europe were approached with this in mind. The potential toxicity in children seems to be of much more concern to them than the hidden sensitising properties of thiomersal. In The Netherlands, unlike many other countries, the exposure to thiomersal from pharmaceutical sources has already been reduced. Replacement of thiomersal in all products should have a high priority in all countries.
PMID: 11368282

35. A two-phased population epidemiological study of the safety of thimerosal-containing vaccines: a follow-up analysis

Geier DA, Geier MR.
Med Sci Monit. 2005 Apr;11(4):CR160-70. Epub 2005 Mar 24.

BACKGROUND: 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. MATERIAL/METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PMID: 15795695

36. Thimerosal exposure in infants and neurodevelopmental disorders: An assessment of computerized medical records in the Vaccine Safety Datalink

Young HA et al.
J Neurol Sci. 2008 May 14. [Epub ahead of print]

The study evaluated possible associations between neurodevelopmental disorders (NDs) and exposure to mercury (Hg) from Thimerosal-containing vaccines (TCVs) by examining the automated Vaccine Safety Datalink (VSD). A total of 278,624 subjects were identified in birth cohorts from 1990-1996 that had received their first oral polio vaccination by 3 months of age in the VSD. The birth cohort prevalence rate of medically diagnosed International Classification of Disease, 9th revision (ICD-9) specific NDs and control outcomes were calculated. Exposures to Hg from TCVs were calculated by birth cohort for specific exposure windows from birth-7 months and birth-13 months of age. Poisson regression analysis was used to model the association between the prevalence of outcomes and Hg doses from TCVs. Consistent significantly increased rate ratios were observed for autism, autism spectrum disorders, tics, attention deficit disorder, and emotional disturbances with Hg exposure from TCVs. By contrast, none of the control outcomes had significantly increased rate ratios with Hg exposure from TCVs. Routine childhood vaccination should be continued to help reduce the morbidity and mortality associated with infectious diseases, but efforts should be undertaken to remove Hg from vaccines. Additional studies should be conducted to further evaluate the relationship between Hg exposure and NDs.
PMID: 18482737

37. Neuropsychological effects associated with exposure to mercury vapor among former chloralkali workers

Mathiesen T, Ellingsen DG, Kjuus H.
Scand J Work Environ Health. 1999 Aug;25(4):342-50.

OBJECTIVES: This investigation studied possible neuropsychological effects among former chloralkali workers with past exposure to mercury vapor. METHODS: Seventy-five formerly exposed workers who had been examined with an extensive neuropsychological test battery were compared with 52 referents frequency-matched for age. The tests measured general cognitive function, motor and psychomotor function, attention, memory, and learning. The groups were similar in educational level, age, and verbal comprehension. The mean exposure time to mercury vapor in the index group was 7.9 (range 1.1-36.2) years with an annual mean urinary mercury concentration of 539 (range 41-2921) nmol/(l x year). The mean time since the cessation of exposure was 12.7 (range 1.0-35.0) years. RESULTS: Performance on the grooved pegboard (dominant hand 75.8 versus 70.9 seconds, P<0.05; nondominant hand 82.2 versus 76.3 seconds, P=0.02) and the Benton visual retention test (mean number of correct reproductions 6.9 versus 7.5, P<0.05) was poorer among the formerly exposed workers when compared with the referents. In addition the subjects who had experienced the highest intensity of exposure [cumulative urinary mercury index > or =550 nmol/(l x year)] had a poorer performance on the trailmaking test, part A and B, on the digit symbol test, and on the word pairs test (retention errors). CONCLUSIONS: The presented results suggest a slight persistent effect of mercury vapor exposure on the central nervous system, mainly involving motor functions and attention, but also possibly related to the visual system. Previous exposure does not seem to have affected the workers' general intellectual level or their ability to reason logically.
PMID: 10505660

38. Methylmercury exposure biomarkers as indicators of neurotoxicity in children aged 7 years

Grandjean P, Budtz-Jørgensen E, White RF, Jørgensen PJ, Weihe P, Debes F, Keiding N.
Am J Epidemiol. 1999 Aug 1;150(3):301-5.

The mercury concentration in blood or scalp hair has been widely used as a biomarker for methylmercury exposure. Because of the increased risks associated with exposures during prenatal and early postnatal development, biomarker results must be interpreted with regard to the age-dependent susceptibility. The authors compared regression coefficients for five sets of exposure biomarkers in 917 children from the Faroe Islands examined at birth, 1 year, and 7 years. Outcome variables were the results of neuropsychologic examination carried out in 1993-1994 at age 7 years. After adjustment for covariates, the cord-blood concentration showed the clearest associations with deficits in language, attention, and memory. Fine-motor function deficits were particularly associated with the maternal hair mercury at parturition. Mercury concentrations in the child's blood and hair at age 7 years were significant predictors only of performance on memory for visuospatial information. These findings emphasize the usefulness of the cord-blood mercury concentration as a main risk indicator. They also support the notion that the greatest susceptibility to methylmercury neurotoxicity occurs during late gestation, while early postnatal vulnerability is less, and they suggest that the time-dependent susceptibility may vary for different brain functions.
PMID: 10430235

39. Chronic elemental mercury intoxication: neuropsychological follow-up case study

Hua MS, Huang CC, Yang YJ.
Brain Inj. 1996 May;10(5):377-84.

In initial and follow-up investigations of neuropsychological function in a patient with elemental mercury intoxication, his scores were compared with those of a group of normal control subjects matched for sex, age and education. Each subject received a comprehensive neuropsychological examination including a personality inventory. On the initial examination the results indicated that the patient had a significant depression of performance intellectual functioning, impairments of attention, non-verbal short-term memory and visual judgement of angles and directions, psychomotor retardation and personality changes including depression, anxiety, desire to be alone, lack of interest and sensitivity to physical problems. Such an impairment picture is compatible with the previous observations of individuals with chronic exposure to elemental, organic or inorganic mercury. The follow-up study was undertaken about 1.5 years later. The results show that the patient's cognitive and personality functions were fully recovered. Our findings thus suggest a reversibility of impaired neuropsychological function in persons with elemental mercury poisoning if a prompt removal from the toxic environment is accomplished, together with proper medical treatment.
PMID: 8735667

40. Psychological effects of low exposure to mercury vapor: application of a computer-administered neurobehavioral evaluation system

Liang YX, Sun RK, Sun Y, Chen ZQ, Li LH.
Environ Res. 1993 Feb;60(2):320-7.

A computer-administered neurobehavioral evaluation system in a Chinese language version (NES-C) and a mood inventory of the profile of mood states (POMS) were applied to assess the psychological effects of low-level exposure to mercury vapor in a group of 88 workers (19 males and 69 females, with mean age of 34.2 years) exposed to mercury vapor (average duration of exposure 10.4 years). The well-matched group of 97 nonexposed workers was treated as the control. The intensity of current mercury vapor was relatively mild as reflected by the average level of mercury in the air of the workplace (0.033 mg/m3) and in urine (0.025 mg/liter). The results indicated that the profile of mood states posed was moving to the negative side in Hg-exposed group and most of the NES-C performances, in particular, the mental arithmetic, two-digit search, switching attention, visual choice reaction time, and finger tapping, were also significantly affected compared with those obtained from controls (P < 0.05-0.01). The present study and the previous study on the validation of the system suggest that the NES-C we developed is valid for the neurotoxicity screening among the working population exposed to neurotoxic agents.
PMID: 8472661

41. Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration

Yokel RA.
J Alzheimers Dis. 2006 Nov;10(2-3):223-53.

The etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier (the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-brain barrier are listed to illustrate the extensive possibilities for moving substances into and out of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting brain aluminum uptake by transferrin-receptor mediated endocytosis and of aluminum citrate by system Xc;{-} and an organic anion transporter, and results suggesting transporter-mediated aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by transferrin- and non-transferrin-dependent mechanisms which may include store-operated calcium channels, and the lack of transporter-mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes and Wilson's diseases, are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain lead uptake may involve a non-energy-dependent process, store-operated calcium channels, and/or an ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine that mimics methionine, enabling its transport by the L system. The putative roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake mechanisms for some metals have been identified, metal efflux from the brain has received little attention, preventing integration of all processes that contribute to brain metal concentrations.
PMID: 17119290

42. Inorganics and hormesis

Calabrese EJ, Baldwin LA.
Crit Rev Toxicol. 2003;33(3-4):215-304.

The article is a comprehensive review of the occurrence of hormetic dose-response relationships induced by inorganic agents, including toxic agents, of significant environmental and public health interest (e.g., arsenic, cadmium, lead, mercury, selenium, and zinc). Hormetic responses occurred in a wide range of biological models (i.e., plants, invertebrate and vertebrate animals) for a large and diverse array of endpoints. Particular attention was given to providing an assessment of the quantitative features of the dose-response relationships and underlying mechanisms that could account for the biphasic nature of the hormetic response. These findings indicate that hormetic responses commonly occur in appropriately designed experiments and are highly generalizeable with respect to biological model responses. The hormetic dose response should be seen as a reliable feature of the dose response for inorganic agents and will have an important impact on the estimated effects of such agents on environmental and human receptors.
PMID: 12809427

43. Methods and rationale for derivation of a reference dose for methylmercury by the U.S. EPA

Rice DC, Schoeny R, Mahaffey K.
Risk Anal. 2003 Feb;23(1):107-15.

In 2001, the U.S. Environmental Protection Agency derived a reference dose (RfD) for methylmercury, which is a daily intake that is likely to be without appreciable risk of deleterious effects during a lifetime. This derivation used a series of benchmark dose (BMD) analyses provided by a National Research Council (NRC) panel convened to assess the health effects of methylmercury. Analyses were performed for a number of endpoints from three large longitudinal cohort studies of the neuropsychological consequences of in utero exposure to methylmercury: the Faroe Islands, Seychelles Islands, and New Zealand studies. Adverse effects were identified in the Faroe Islands and New Zealand studies, but not in the Seychelles Islands. The NRC also performed an integrative analysis of all three studies. The EPA applied a total uncertainty factor (UF) of 10 for intrahuman toxicokinetic and toxicodynamic variability and uncertainty. Dose conversion from cord blood mercury concentrations to maternal methylmercury intake was performed using a one-compartment model. Derivation of potential RfDs from a number of endpoints from the Faroe Islands study converged on 0.1 microg/kg/day, as did the integrative analysis of all three studies. EPA identified several areas for which further information or analyses is needed. Perhaps the most immediately relevant is the ratio of cord:maternal blood mercury concentration, as well as the variability around this ratio. EPA assumed in its dose conversion that the ratio was 1.0; however, available data suggest it is perhaps 1.5-2.0. Verification of a deviation from unity presumably would be translated directly into comparable reduction in the RfD. Other areas that EPA identified as significant areas requiring further attention are cardiovascular consequences of methylmercury exposure and delayed neurotoxicity during aging as a result of previous developmental or adult exposure.
PMID: 12635727

44. Methylmercury alters glutamate transport in astrocytes

Aschner M, Yao CP, Allen JW, Tan KH.
Neurochem Int. 2000 Aug-Sep;37(2-3):199-206.

Methylmercury (MeHg) is a significant environmental contaminant that will continue to pose great risk to human health. Considerable attention in the scientific and health policy fora is focused on the question of whether MeHg intake from a diet high in fish is associated with aberrant CNS function. A number of recent studies (Kjellstrom et al., 1986: Kjellstrom, T., Kennedy, P., Wallis, S., Mantell, C., 1986. Physical and mental development of children with prenatal exposure to mercury from fish. Stage I: preliminary tests at age 4. Solna, Sweden. National Swedish Environmental Protection Board Report 3080, 1989: Kjellstrom, T., Kennedy, P., Wallis, S., Stewart, A., Friberg, L. et al., 1989. Physical and mental development of children with prenatal exposure to mercury from fish. Stage II: interviews and psychological tests at age 6. Solna, Sweden. National Swedish Environmental Protection Board Report 3642; McKeown-Eyssen et al., 1983: McKeown-Eyssen, G., Ruedy, J., Neims, A. , 1983. Methylmercury exposure in Northern Quebec II: neurologic findings in children. American Journal of Epidemiology 118, 470-479; Grandjean et al., 1997: Grandjean, P., Weihe, P., White, R. F., Debes, F., Araki, S., Yokoyama, K., Murata, K., Sorensen, N., Dahl, R., Jorgensen, P. J., 1997. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicology and Teratology 19, 417-428) suggest that fetal exposure at levels attained by mothers eating fish regularly during pregnancy are associated with neurological deficits in their offspring. Astrocytes play a key role in MeHg-induced excitotoxicity. (1) MeHg preferentially accumulates in astrocytes. (2) MeHg potently and specifically inhibits glutamate uptake in astrocytes. (3) Neuronal dysfunction is secondary to disturbances in astrocytes. (4) Co-application of nontoxic concentrations of MeHg and glutamate leads to the typical appearance of neuronal lesions associated with excitotoxic stimulation. (5) MeHg induces swelling of astrocytes. These observations are fully consistent with MeHg-induced dysregulation of excitatory amino acid homeostasis, and indicate that a glutamate-mediated excitotoxic mechanism is involved. This manuscript details the role of astrocytes in mediating MeHg-induced excitotoxicity, and elaborates on the protective role afforded by metallothioneins (MTs) in attenuating MeHg cytotoxicity.
PMID: 10812205

45. Exposure, metabolism, and toxicity of rare earths and related compounds
 
Hirano S, Suzuki KT.
Environ Health Perspect. 1996 Mar;104 Suppl 1:85-95.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1469566&blobtype=pdf

For the past three decades, most attention in heavy metal toxicology has been paid to cadmium, mercury, lead, chromium, nickel, vanadium, and tin because these metals widely polluted the environment. However, with the development of new materials in the last decade, the need for toxicological studies on those new materials has been increasing. A group of rare earths (RE) is a good example. Although some RE have been used for superconductors, plastic magnets, and ceramics, few toxicological data are available compared to other heavy metals described above. Because chemical properties of RE are very similar, it is plausible that their binding affinities to biomolecules, metabolism, and toxicity in the living system are also very similar. In this report, we present an overview of the metabolism and health hazards of RE and related compounds, including our recent studies.
PMID: 8722113

46. Exposure to toxic elements via breast milk

Oskarsson A, Palminger Hallén I, Sundberg J.
Analyst. 1995 Mar;120(3):765-70.

Breast milk is the ideal nutrient for the newborn, but unfortunately also a route of excretion for some toxic substances. Very little attention has been paid to breast milk as a source of exposure to toxic elements. The dose-dependent excretion is breast milk and the uptake in the neonate of inorganic mercury, methylmercury and lead were studied in an experimental model for rats and mice. The transfer of mercury from plasma to milk was found to be higher in dams exposed to inorganic mercury than to methylmercury. In contrast, the uptake of mercury from milk was higher in the sucklings of dams exposed to methylmercury than to inorganic mercury. Pre- and postnatal exposure to methylmercury resulted in increased numbers and altered proportions of the thymocyte subpopulation and increased lymphocyte activities in the offspring of mice and also effects on the levels of noradrenaline and nerve growth factor in the developing brain of rats. Mercury in blood and breast milk in lactating women in Sweden was studied in relation to the exposure to mercury from, fish and amalgam. Low levels were found; the mean levels were 0.6 ng g-1 in milk and 2.3 ng g-1 in blood. There was a statistically significant correlation between mercury levels in blood and milk, showing that milk levels were approximately 30% of the levels in blood. Inorganic mercury exposure from amalgam was reflected in blood and milk mercury levels. Recent exposure to methylmercury from consumption of fish was reflected in mercury levels in the blood but not in milk.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 7741226

47. An analysis of autopsy brain tissue from infants prenatally exposed to methymercury

Lapham LW et al.
Neurotoxicology. 1995 Winter;16(4):689-704.

Brains from 32 neonatal autopsies from the Seychelles were examined histologically and analyzed for mercury levels. Six brain regions were sampled: frontal and occipital cortex, temporal cortex with hippocampus, basal ganglia with thalamus, cerebellum, and pons with medulla. Tissue blocks for histology and mercury analysis were taken from opposing faces to provide for correlation of findings. Similar studies were performed on 12 reference neonatal brains from Rochester, New York. No clear-cut developmental abnormality was found, but some brains exhibited low-grade, non-specific destructive changes. Total mercury levels, most of it in the organic form, were elevated in many of the Seychelles specimens. No correlation was demonstrated between mercury levels and degree or type of histologic change. There was considerable variability in total mercury for each anatomic region among the 32 Seychelles cases, as well as from one region to another in individual brains. All values of total mercury were under 300 ppb. Statistical analysis of mean mercury levels for each region demonstrated higher values in deep subcortical nuclei, brain stem, and cerebellum, phylogenetically older parts of the brain. When total mercury concentration of each region was paired with all other areas in the same brain and the paired values plotted for the entire group of brains, high correlations were obtained for all brain pairs, suggesting a strong concentration-dependent relationship between mercury intake and brain content. Analysis of mercury levels in separately dissected blocks of grey and white matter from 12 specimens revealed no significant differences between grey and white. In comparison with other human developmental studies and with experimental developmental studies in animals, where toxicity has been demonstrated with total mercury brain levels above 1,000 ppb, this study found no evidence of toxicity within a range of mercury levels below 300 ppb. Submicroscopic changes, subcellular alterations, subtle disturbances in the unfolding of brain architectonics -- none of these are excluded with methods used in this report. Further studies of threshold effects of MeHg on fetal brain are essential. That approximately half of the mercury resides in glial elements in white matter reinforces the need to focus attention upon glia as well as neurons during development.
PMID: 8714873

48. Principles of developmental neurotoxicology

Slikker W Jr.
Neurotoxicology. 1994 Spring;15(1):11-6.

With 4-8 percent of U.S. children exhibiting anatomical and/or functional deficits, and the occurrence of several tragic clinical syndromes resulting from developmental exposure to such agents as ethanol, lead and methylmercury, there is good reason to focus attention on the principles of developmental neurotoxicology. Various animal models have been used to confirm the developmental neurotoxicity that results from exposure to these agents, and along with clinical evidence, have implicated several other chemical classes such as antimitotics, insecticides, polyhalogenated hydrocarbons, psychoactive drugs, solvents and vitamins as specific agents with developmental neurotoxic potential. As for developmental toxicity in general, the nature and extent of neurotoxic effects are often dependent on the timing of exposure, and because stages of nervous system development can vary significantly between species in relation to the time of birth, variations in neurotoxic outcome across species are expected. There are several instances in which functional alterations (e.g., neuromotor development, locomotor activity, reactivity and/or habituation, learning and memory and sensory system modulation) have been observed at doses below those needed to produce other indicators of developmental toxicity. Neuroanatomical/neurohistological, neurochemical and neurophysiological endpoints have been used to substantiate these functional deficits and/or to describe adverse nervous system effects in the absence of functional data. As knowledge about the toxicological mechanisms underlying the expression of developmental neurotoxicity is increased, the ability to conduct quantitative risk assessments and protect human health will be enhanced.
PMID: 8090351

49. Side-effects: mercury contribution to body burden from dental amalgam

Reinhardt JW.
Adv Dent Res. 1992 Sep;6:110-3.
http://adr.iadrjournals.org/cgi/reprint/6/1/110

The purpose of this paper is to examine and report on studies that relate mercury levels in human tissues to the presence of dental amalgams, giving special attention to autopsy studies. Until recently, there have been few published studies examining the relationship between dental amalgams and tissue mercury levels. Improved and highly sensitive tissue analysis techniques have made it possible to measure elements in the concentration range of parts per billion. The fact that mercury can be absorbed and reach toxic levels in human tissues makes any and all exposure to that element of scientific interest. Dental amalgams have long been believed to be of little significance as contributors to the overall body burden of mercury, because the elemental form of mercury is rapidly consumed in the setting reaction of the restoration. Studies showing measurable elemental mercury vapor release from dental amalgams have raised renewed concern about amalgam safety. Mercury vapor absorption occurs through the lungs, with about 80% of the inhaled vapor being absorbed by the lungs and rapidly entering the bloodstream. Following distribution by blood circulation, mercury can enter and remain in certain tissues for longer periods of time, since the half-life of excretion is prolonged. Two of the primary target organs of concern are the central nervous system and kidneys.
PMID: 1292449

50. Immunotoxic effects of mercuric compounds on human lymphocytes and monocytes. I. Suppression of T-cell activation

Shenker BJ, Rooney C, Vitale L, Shapiro IM.
Immunopharmacol Immunotoxicol. 1992;14(3):539-53.

Considerable attention has been directed at defining the health deficits associated with exposure to mercurial compounds. While numerous studies have been conducted, the findings have been somewhat contradictory and have led to a confused understanding of the immunotoxicology of mercury. It is becoming clear, however, that the immunotoxic effects of heavy metals in general, and mercury in particular, are dependent upon the assays and source of cells. The major goal of our study was to assess whether low level mercury exposure modulates human T-cell function. Following treatment of T-cells with HgCl2 (0-1000 ng) and MeHgCl (0-100 ng), their activation by mitogens was evaluated. Both forms of mercury caused a dose dependent reduction in T cell proliferation, however, the effect was dependent upon the presence of monocytes. Moreover, in the absence of monocytes, HgCl2 enhance PMA induced T-cell proliferation. MeHgCl was approximately 5-10 times more potent than HgCl2. Mercury also inhibited the ability of these cells to synthesize and secrete IL-1. Analysis of the expression of activation markers on the cell surface indicated that one of the earliest markers of lymphocyte activation, CD69, was not effected by mercury. In comparison, T-cell expression of IL-2R and the transferrin receptor was impaired. Of particular interest, cells activated by mitogen for 24 hr became refractory to the immunotoxic effects of mercury. The results of this investigation clearly show that mercury-containing compounds are immunomodulatory; moreover, the decrease in T-cell function following exposure to mercury indicates that this metal is immunotoxic at very low exposure levels.
PMID: 1517533

51. The health effects of aluminium--a review

Cooke K, Gould MH.
J R Soc Health. 1991 Oct;111(5):163-8.

This review covers the occurrence of aluminium in soil, air, water and food. In addition, aluminium levels in body tissues and its movement within the body have been considered. The adverse effects of aluminium that have been reported in recent years include Alzheimer's disease, dementia and hyperactivity and learning disorders in children.
PMID: 1795349

52. Vaccine ingredients & schedule
http://www.generationrescue.org/pdf/080212.pdf 

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