Mercury, Pesiticides, Solvents, Thimerosal & Autism
References compiled for Generation Rescue by Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
April 24, 2009
Various studies have documented associations between autism and environmental pollutants such as mercury, other metals, pesticides, and solvents (eg, 1-5). Reviews summarize these relationships (eg, 6-7). Biomarkers and therapies are being described (eg, 8-13, 17, 20). Thimerosal in vaccines remains implicated in causing adverse neurodevelopment (eg, 14,21,26). Oxidative stress may be a common pathway in autism and other autism-spectrum disorders (eg, 22-24). Two recently published studies describe associations between autism and toxic landfills (25, 27).
Importantly, when infants and toddlers are deliberately injected with neurotoxicants such as aluminum or thimerosal, which is 49.6% ethylmercury by weight, the injections occur (a) in infants whose detox enzymes may not be fully expressed (eg, 28-29); (b) in infants or toddlers with a weak allele in one or more genes related to detoxification (eg, 30-31); and (c) in infants and toddlers who already have a body burden of numerous pollutants (eg, 32-37).
Models & Methodology. Studies that look at effects of single pollutants are likely to generate only weak associations, because any single pollutant within a human body is accompanied by a large number of pollutants and their interacting effects.
For instance, "In a study spearheaded by the Environmental Working Group (EWG) in collaboration with Commonweal, researchers at two major laboratories found an average of 200 industrial chemicals and pollutants in umbilical cord blood from 10 babies born in August and September of 2004 in U.S. hospitals. Tests revealed a total of 287 chemicals in the group. The umbilical cord blood of these 10 children, collected by Red Cross after the cord was cut, harbored pesticides, consumer product ingredients, and wastes from burning coal, gasoline, and garbage." (38).
Increasingly, researchers who study pollutants in breast milk, cord blood, infants, and toddlers would be well served, in the very least, to consider ramifications of the many intra-body pollutants, to consider subgroups defined by detox-gene polymorphisms. An example is provided by nutrients such as glutathione, which participates in many processes of detoxification. In a given embryo, fetus, infant, or toddler, if glutathione-related genes have a weak allele or if glutathione has become depleted in at least some cell types, then adverse effects - whether from thimerosal, aluminum, PBDEs, methylmercury, and other pollutants - are likelier to ensue.
As a major study concluded, the epidemics of autism and other autism-spectrum disorders (ASDs) are not just a matter of better diagnosis (39). Indeed, pollutants in various intra-body combinations are blessing us with children having atypicalities of brain development.
References:
1: Proximity to point sources of environmental mercury release as a predictor of autism prevalence.
Palmer RF et al. Health Place. 2009 Mar;15(1):18-24.
University of Texas Health Science Center
The objective of this study was to determine if proximity to sources of mercury pollution in 1998 were related to autism prevalence in 2002. Autism count data from the Texas Educational Agency and environmental mercury release data from the Environmental Protection Agency were used. 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). Distances to these sources were independent predictors after adjustment for relevant covariates. 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). While design limitations preclude interpretation of individual risk, further investigations of environmental risks to child development issues are warranted.
2: 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.
Public Health Institute, Oakland, California 94804
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.
3: Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay area.
Windham GC et al. Environ Health Perspect. 2006 Sep;114(9):1438-44.
California Department of Health Services, Richmond, California
OBJECTIVE: To explore possible associations between autism spectrum disorders (ASD) and environmental exposures, we linked the California autism surveillance system to estimated hazardous air pollutant (HAP) concentrations compiled by the U.S. Environmental Protection Agency. METHODS: Subjects included 284 children with ASD and 657 controls, born in 1994 in the San Francisco Bay area. We assigned exposure level by census tract of birth residence for 19 chemicals we identified as potential neurotoxicants, developmental toxicants, and/or endocrine disruptors from the 1996 HAPs database. Because concentrations of many of these were highly correlated, we combined the chemicals into mechanistic and structural groups, calculating summary index scores. We calculated ASD risk in the upper quartiles of these group scores or individual chemical concentrations compared with below the median, adjusting for demographic factors. RESULTS: The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs) , 1.1-2.1], but not for aromatic solvents. Adjusting for these three groups simultaneously led to decreased risks for the solvents and increased risk for metals (AORs for metals: fourth quartile = 1.7 ; 95% CI, 1.0-3.0 ; third quartile = 1.95 ; 95% CI, 1.2-3.1) . The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride. CONCLUSIONS: Our results suggest a potential association between autism and estimated metal concentrations, and possibly solvents, in ambient air around the birth residence, requiring confirmation and more refined exposure assessment in future studies.
4: Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas.
Palmer RF, Blanchard S, Stein Z, Mandell D, Miller C.
Health Place. 2006 Jun;12(2):203-9.
University of Texas Health Science Center
The association between environmentally released mercury, special education and autism rates in Texas was investigated using data from the Texas Education Department and the United States Environmental Protection Agency. A Poisson regression analysis adjusted for school district population size, economic and demographic factors was used. There was a significant increase in the rates of special education students and autism rates associated with increases in environmentally released mercury. 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. This ecological study suggests the need for further research regarding the association between environmentally released mercury and developmental disorders such as autism. These results have implications for policy planning and cost analysis.
5: 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.
Laboratory of Molecular Psychiatry and Neurogenetics,
University Campus Bio-Medico, Rome, Italy.
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.
6: Sulfhydryl-reactive metals in autism.
Kern JK et al. J Toxicol Environ Health A. 2007 Apr 15;70(8):715-21.
University of Texas Southwestern Medical Center at Dallas
This study examined the difference between sulfhydryl-reactive metals (mercury, lead, arsenic, and cadmium) in the hair of 45 children with autism (1-6 yr of age) as compared to 45 gender-, age-, and race-matched typical children. Hair samples were measured with inductively coupled mass spectrometry. Some studies, such as Holmes et al. (2003), suggested that children with autism may be poor detoxifiers relative to normally developing children. Metals that are not eliminated sequester in the brain. Our study found that arsenic, cadmium, and lead were significantly lower in the hair of children with autism than in matched controls. Mercury was in the same direction (lower in autism) following the same pattern, but did not achieve statistical significance. The evidence from our study supports the notion that children with autism may have trouble excreting these metals, resulting in a higher body burden that may contribute to symptoms of autism.
7: Developmental neurotoxicity of industrial chemicals.
Grandjean P, Landrigan PJ. Lancet. 2006 Dec 16;368(9553):2167-78.
Institute of Public Health, University of Southern Denmark
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.
8. The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders.
Faber S et al. Biomarkers. 2009 Mar 11:1-10.
The Children's Institute, Pittsburgh, PA, USA.
The frequency of zinc deficiency, copper toxicity and low zinc/copper in children with autism spectrum disorders (ASDs) may indicate decrement in metallothionein system functioning. A retrospective review of plasma zinc, serum copper and zinc/copper was performed on data from 230 children with autistic disorder, pervasive developmental disorder-NOS and Asperger's syndrome. The entire cohort's mean zinc level was 77.2 mug dl(-1), mean copper level was 131.5 mug dl(-1), and mean Zn/Cu was 0.608, which was below the 0.7 cut-off of the lowest 2.5% of healthy children. The plasma zinc/serum copper ratio may be a biomarker of heavy metal, particularly mercury, toxicity in children with ASDs.
9. Biomarkers of environmental toxicity and susceptibility in autism.
Geier DA et al. J Neurol Sci. 2009 May 15;280(1-2):101-8.
Institute of Chronic Illnesses, Inc., Silver Spring, Maryland, USA.
Autism spectrum disorders (ASDs) may result from a combination of genetic/biochemical susceptibilities in the form of a reduced ability to excrete mercury and/or increased environmental exposure at key developmental times. Urinary porphyrins and transsulfuration metabolites in participants diagnosed with an ASD were examined. A prospective, blinded study was undertaken to evaluate a cohort of 28 participants with an ASD diagnosis for Childhood Autism Rating Scale (CARS) scores, urinary porphyrins, and transsulfuration metabolites. Testing was conducted using Vitamin Diagnostics, Inc. (CLIA-approved) and Laboratoire Philippe Auguste (ISO-approved). Participants with severe ASDs had significantly increased mercury intoxication-associated urinary porphyrins (pentacarboxyporphyrin, precoproporphyrin, and coproporphyrin) in comparison to participants with mild ASDs, whereas other urinary porphyrins were similar in both groups. Significantly decreased plasma levels of reduced glutathione (GSH), cysteine, and sulfate were observed among study participants relative to controls. In contrast, study participants had significantly increased plasma oxidized glutathione (GSSG) relative to controls. Mercury intoxication-associated urinary porphyrins were significantly correlated with increasing CARS scores and GSSG levels, whereas other urinary porphyrins did not show these relationships. The urinary porphyrin and CARS score correlations observed among study participants suggest that mercury intoxication is significantly associated with autistic symptoms. The transsulfuration abnormalities observed among study participants indicate that mercury intoxication was associated with increased oxidative stress and decreased detoxification capacity.
10. Porphyrinuria in childhood autistic disorder: implications for environmental
toxicity.
Nataf R et al. Toxicol Appl Pharmacol. 2006 Jul 15;214(2):99-100.
Laboratoire Philippe Auguste, Paris, France.
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.
13. Increased excretion of a lipid peroxidation biomarker in autism.
Ming X et al. Prostaglandins Leukot Essent Fatty Acids. 2005 Nov;73(5):379-84.
UMDNJ-New Jersey Medical School, Newark, 07103, USA.
It is thought that autism could result from an interaction between genetic and environmental factors with oxidative stress as a potential mechanism linking the two. One genetic factor may be altered oxidative-reductive capacity. This study tested the hypothesis that children with autism have increased oxidative stress. We evaluated children with autism for the presence of two oxidative stress biomarkers. Urinary excretion of 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-isoprostane-F2alpha (8-iso-PGF2alpha) were determined in 33 children with autism and 29 healthy controls. 8-iso-PGF2alpha levels were significantly higher in children with autism. The isoprostane levels in autistic subjects were variable with a bimodal distribution. The majority of autistic subjects showed a moderate increase in isoprostane levels while a smaller group of autistic children showed dramatic increases in their isoprostane levels. There was a trend of an increase in 8-OHdG levels in children with autism but it did not reach statistical significance. There was no significant correlation between the levels of the biomarkers and vitamin intake, dietary supplements, medicine, medical disorders, or history of regression. These results suggest that the lipid peroxidation biomarker is increased in this cohort of autistic children, especially in the subgroup of autistic children.
14. Hepatitis B triple series vaccine and developmental disability in US children aged 1-9 years
Gallagher C; Goodman M. Toxicol Environ Chem 2008 90(5):997-1008.
Stony Brook University Medical Center, New York, USA
This study investigated the association between vaccination with the Hepatitis B triple series vaccine prior to 2000 and developmental disability in children aged 1-9 years (n = 1824), proxied by parental report that their child receives early intervention or special education services (EIS). National Health and Nutrition Examination Survey 1999-2000 data were analyzed and adjusted for survey design by Taylor Linearization using SAS version 9.1 software, with SAS callable SUDAAN version 9.0.1. The odds of receiving EIS were approximately nine times as great for vaccinated boys (n = 46) as for unvaccinated boys (n = 7), after adjustment for confounders. This study found statistically significant evidence to suggest that boys in United States who were vaccinated with the triple series Hepatitis B vaccine, during the time period in which vaccines were manufactured with thimerosal, were more susceptible to developmental disability than were unvaccinated boys.
15. Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal.
Waly M et al. Mol Psychiatry. 2004 Apr;9(4):358-70.
Northeastern University, Boston, MA 02115, USA.
Methylation events play a critical role in the ability of growth factors to promote normal development. Neurodevelopmental toxins, such as ethanol and heavy metals, interrupt growth factor signaling, raising the possibility that they might exert adverse effects on methylation. We found that insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated methionine synthase (MS) activity and folate-dependent methylation of phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and MAP-kinase-dependent mechanism. The stimulation of this pathway increased DNA methylation, while its inhibition increased methylation-sensitive gene expression. Ethanol potently interfered with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS activity, as well as folate-dependent phospholipid methylation: Cu(2+) promoted enzyme activity and methylation, while Cu(+), Pb(2+), Hg(2+) and Al(3+) were inhibitory. The ethylmercury-containing preservative thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an IC(50) of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.
16. Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors.
James SJ et al. Neurotoxicology. 2005 Jan;26(1):1-8.
University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute
Thimerosol is an antiseptic containing 49.5% ethyl mercury that has been used for years as a preservative in many infant vaccines and in flu vaccines. Environmental methyl mercury has been shown to be highly neurotoxic, especially to the developing brain. Because mercury has a high affinity for thiol (sulfhydryl (-SH)) groups, the thiol-containing antioxidant, glutathione (GSH), provides the major intracellular defense against mercury-induced neurotoxicity. Cultured neuroblastoma cells were found to have lower levels of GSH and increased sensitivity to thimerosol toxicity compared to glioblastoma cells that have higher basal levels of intracellular GSH. Thimerosal-induced cytotoxicity was associated with depletion of intracellular GSH in both cell lines. Pretreatment with 100 microM glutathione ethyl ester or N-acetylcysteine (NAC), but not methionine, resulted in a significant increase in intracellular GSH in both cell types. Further, pretreatment of the cells with glutathione ethyl ester or NAC prevented cytotoxicity with exposure to 15 microM Thimerosal. Although Thimerosal has been recently removed from most children's vaccines, it is still present in flu vaccines given to pregnant women, the elderly, and to children in developing countries. The potential protective effect of GSH or NAC against mercury toxicity warrants further research as possible adjunct therapy to individuals still receiving Thimerosal-containing vaccinations.
17. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism.
James SJ et al. Am J Clin Nutr. 2004 Dec;80(6):1611-7. {free online}
http://www.ajcn.org/cgi/content/full/80/6/1611
BACKGROUND: 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. OBJECTIVE: The purpose of this study was to evaluate plasma concentrations of metabolites in the methionine transmethylation and transsulfuration pathways in children diagnosed with autism. DESIGN: 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. RESULTS: 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. CONCLUSIONS: An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.
18. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism.
James SJ et al. Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):947-56. {free online}
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2610366&blobtype=pdf
Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.
19. How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis.
Deth R et al. Neurotoxicology. 2008 Jan;29(1):190-201.
Recently higher rates of autism diagnosis suggest involvement of environmental factors in causing this developmental disorder, in concert with genetic risk factors. Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. We review the metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase. Methionine synthase activity is required for dopamine-stimulated phospholipid methylation, a unique membrane-delimited signaling process mediated by the D4 dopamine receptor that promotes neuronal synchronization and attention, and synchrony is impaired in autism. Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects. On the basis of these observations, a "redox/methylation hypothesis of autism" is described, in which oxidative stress, initiated by environment factors in genetically vulnerable individuals, leads to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks.
20. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism.
James SJ et al. Am J Clin Nutr. 2009 Jan;89(1):425-30.
http://www.ajcn.org/cgi/content/full/89/1/425
BACKGROUND: Metabolic abnormalities and targeted treatment trials have been reported for several neurobehavioral disorders but are relatively understudied in autism. OBJECTIVE: The objective of this study was to determine whether or not treatment with the metabolic precursors, methylcobalamin and folinic acid, would improve plasma concentrations of transmethylation/transsulfuration metabolites and glutathione redox status in autistic children. DESIGN: In an open-label trial, 40 autistic children were treated with 75 microg/kg methylcobalamin (2 times/wk) and 400 microg folinic acid (2 times/d) for 3 mo. Metabolites in the transmethylation/transsulfuration pathway were measured before and after treatment and compared with values measured in age-matched control children. RESULTS: The results indicated that pretreatment metabolite concentrations in autistic children were significantly different from values in the control children. The 3-mo intervention resulted in significant increases in cysteine, cysteinylglycine, and glutathione concentrations (P < 0.001). The oxidized disulfide form of glutathione was decreased and the glutathione redox ratio increased after treatment (P < 0.008). Although mean metabolite concentrations were improved significantly after intervention, they remained below those in unaffected control children. CONCLUSION: The significant improvements observed in transmethylation metabolites and glutathione redox status after treatment suggest that targeted nutritional intervention with methylcobalamin and folinic acid may be of clinical benefit in some children who have autism. This trial was registered at (clinicaltrials.gov) as NCT00692315.
21. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism.
James SJ et al. FASEB J. 2009 Mar 23. [Epub ahead of print]
Research into the metabolic phenotype of autism has been relatively unexplored despite the fact that metabolic abnormalities have been implicated in the pathophysiology of several other neurobehavioral disorders. Plasma biomarkers of oxidative stress have been reported in autistic children; however, intracellular redox status has not yet been evaluated. Lymphoblastoid cells (LCLs) derived from autistic children and unaffected controls were used to assess relative concentrations of reduced glutathione (GSH) and oxidized disulfide glutathione (GSSG) in cell extracts and isolated mitochondria as a measure of intracellular redox capacity. The results indicated that the GSH/GSSG redox ratio was decreased and percentage oxidized glutathione increased in both cytosol and mitochondria in the autism LCLs. Exposure to oxidative stress via the sulfhydryl reagent thimerosal resulted in a greater decrease in the GSH/GSSG ratio and increase in free radical generation in autism compared to control cells. Acute exposure to physiological levels of nitric oxide decreased mitochondrial membrane potential to a greater extent in the autism LCLs, although GSH/GSSG and ATP concentrations were similarly decreased in both cell lines. These results suggest that the autism LCLs exhibit a reduced glutathione reserve capacity in both cytosol and mitochondria that may compromise antioxidant defense and detoxification capacity under prooxidant conditions.
22. Altered vascular phenotype in autism: correlation with oxidative stress.
Yao Y et al. Arch Neurol. 2006 Aug;63(8):1161-4. {free online}
School of Medicine, University of Pennsylvania
http://archneur.ama-assn.org/cgi/content/full/63/8/1161
BACKGROUND: Autism is a neurologic disorder characterized by impaired communication and social interaction. Results of previous studies showed biochemical evidence for abnormal platelet reactivity and altered blood flow in children with autism. OBJECTIVE: To evaluate the vascular phenotype in children with autism. DESIGN AND MAIN OUTCOME MEASURES: Urinary levels of isoprostane F(2alpha)-VI, a marker of lipid peroxidation; 2,3-dinor-thromboxane B(2), which reflects platelet activation; and 6-keto-prostaglandin F(1alpha), a marker of endothelium activation, were measured by means of gas chromatography-mass spectrometry in subjects with autism and healthy control subjects. SETTING AND SUBJECTS: Children with a clinical diagnosis of autism attending the Pfeiffer Treatment Center. RESULTS: Compared with controls, children with autism had significantly higher urinary levels of isoprostane F(2alpha)-VI, 2,3-dinor-thromboxane B(2), and 6-keto-prostaglandin F(1alpha). Lipid peroxidation levels directly correlated with both vascular biomarker ratios. CONCLUSION: Besides enhanced oxidative stress, platelet and vascular endothelium activation also could contribute to the development and clinical manifestations of autism.
23. Oxidative stress in autism.
Chauhan A, Chauhan V. Pathophysiology. 2006 Aug;13(3):171-81.
NYS Institute for Basic Research in Developmental Disabilities
Autism is a severe developmental disorder with poorly understood etiology. Oxidative stress in autism has been studied at the membrane level and also by measuring products of lipid peroxidation, detoxifying agents (such as glutathione), and antioxidants involved in the defense system against reactive oxygen species (ROS). Lipid peroxidation markers are elevated in autism, indicating that oxidative stress is increased in this disease. Levels of major antioxidant serum proteins, namely transferrin (iron-binding protein) and ceruloplasmin (copper-binding protein), are decreased in children with autism. There is a positive correlation between reduced levels of these proteins and loss of previously acquired language skills in children with autism. The alterations in ceruloplasmin and transferrin levels may lead to abnormal iron and copper metabolism in autism. The membrane phospholipids, the prime target of ROS, are also altered in autism. The levels of phosphatidylethanolamine (PE) are decreased, and phosphatidylserine (PS) levels are increased in the erythrocyte membrane of children with autism as compared to their unaffected siblings. Several studies have suggested alterations in the activities of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase in autism. Additionally, altered glutathione levels and homocysteine/methionine metabolism, increased inflammation, excitotoxicity, as well as mitochondrial and immune dysfunction have been suggested in autism. Furthermore, environmental and genetic factors may increase vulnerability to oxidative stress in autism. Taken together, these studies suggest increased oxidative stress in autism that may contribute to the development of this disease. A mechanism linking oxidative stress with membrane lipid abnormalities, inflammation, aberrant immune response, impaired energy metabolism and excitotoxicity, leading to clinical symptoms and pathogenesis of autism is proposed.
24. Increase in Cerebellar Neurotrophin-3 and Oxidative Stress Markers in Autism.
Sajdel-Sulkowska EM et al. Cerebellum. 2009 Apr 9. [Epub ahead of print]
Harvard Medical School, Boston, MA
Autism is a neurodevelopmental disorder characterized by social and language deficits, ritualistic-repetitive behaviors and disturbance in motor functions. Data of imaging, head circumference studies, and Purkinje cell analysis suggest impaired brain growth and development. Both genetic predisposition and environmental triggers have been implicated in the etiology of autism, but the underlying cause remains unknown. Recently, we have reported an increase in 3-nitrotyrosine (3-NT), a marker of oxidative stress damage to proteins in autistic cerebella. In the present study, we further explored oxidative damage in the autistic cerebellum by measuring 8-hydroxydeoxyguanosine (8-OH-dG), a marker of DNA modification, in a subset of cases analyzed for 3-NT. We also explored the hypothesis that oxidative damage in autism is associated with altered expression of brain neurotrophins critical for normal brain growth and differentiation. The content of 8-OH-dG in cerebellar DNA isolated by the proteinase K method was measured using an enzyme-linked immunosorbent assay (ELISA); neurotrophin-3 (NT-3) levels in cerebellar homogenates were measured using NT-3 ELISA. Cerebellar 8-OH-dG showed trend towards higher levels with the increase of 63.4% observed in autism. Analysis of cerebellar NT-3 showed a significant (p = 0.034) increase (40.3%) in autism. Furthermore, there was a significant positive correlation between cerebellar NT-3 and 3-NT (r = 0.83; p = 0.0408). These data provide the first quantitative measure of brain NT-3 and show its increase in the autistic brain. Altered levels of brain NT-3 are likely to contribute to autistic pathology not only by affecting brain axonal targeting and synapse formation but also by further exacerbating oxidative stress and possibly contributing to Purkinje cell abnormalities.
25. Autism Spectrum Disorders and Identified Toxic Land Fills: Co-Occurrence Across States
Xue Ming et al. Environmental Health Insights 2008:2 55–59. {free online}
http://tinyurl.com/6xgsbz
It is believed that gene by environmental interactions contribute to the pathogenesis of autism spectrum disorders (ASD). We hypothesize that ASD are associated with early and repeated exposures to any of a number of toxicants or mixtures of toxicants. It is the cumulative effects of these repeated exposures acting upon genetically susceptible individuals that lead to the phenotypes of ASD. We report our initial observations of a considerable overlap of identified toxic landfills in the State of New Jersey and the residence of an ASD cohort, and a correlation between the identified toxic Superfund sites on each U.S. state and the total number of diagnosed cases of ASD in those states. The residence of 495 ASD patients in New Jersey by zip code and the toxic landfill sites were plotted on a map of Northern New Jersey. The area of highest ASD cases coincides with the highest density of toxic landfill sites while the area with lowest ASD cases has the lowest density of toxic landfill sites. Furthermore, the number of toxic Superfund sites and autism rate across 49 of the 50 states shows a statistically significant correlation (i.e. the number of identified superfund sites correlates with the rate of autism per 1000 residents in 49 of the states (p = 0.015; excluding the state of Oregon). These significant observations call for further organized studies to elucidate possible role(s) of environmental toxicants contributing to the pathogenesis of ASD.
26. Blood levels of mercury are related to diagnosis of autism: a reanalysis of an important data set.
Desoto MC, Hitlan RT. J Child Neurol. 2007 Nov;22(11):1308-11.
University of Northern Iowa
The question of what is leading to the apparent increase in autism is of great importance. Like the link between aspirin and heart attack, even a small effect can have major health implications. If there is any link between autism and mercury, it is absolutely crucial that the first reports of the question are not falsely stating that no link occurs. We have reanalyzed the data set originally reported by Ip et al. in 2004 and have found that the original p value was in error and that a significant relation does exist between the blood levels of mercury and diagnosis of an autism spectrum disorder. Moreover, the hair sample analysis results offer some support for the idea that persons with autism may be less efficient and more variable at eliminating mercury from the blood.
27. Ockham’s Razor and autism: The case for developmental neurotoxins contributing to a disease of neurodevelopment
M. Catherine DeSoto. NeuroToxicology xxx (2009) xxx–xxx (in press)
Much professional awareness regarding environmental triggers for ASD has been narrowly focused on a single possible exposure pathway (vaccines). Meanwhile, empirical support for environmental toxins as a broad class has been quietly accumulating. Recent research has shown that persons with ASD have comparatively higher levels of various toxins and are more likely to have reduced detoxifying ability, and, that rates of ASD may be higher in areas with greater pollution. This report documents that within the state with the highest rate of ASD, the rate is higher for schools near EPA Superfund sites, t(332) = 3.84, p = .0001. The reasons for the rise in diagnoses likely involve genetically predisposed individuals being exposed to various environmental triggers at higher rates than in past generations.
28. The ontogeny of drug metabolism enzymes and implications for adverse drug events.
Hines RN. Pharmacol Ther. 2008 May;118(2):250-67.
Profound changes in drug metabolizing enzyme (DME) expression occurs during development that impacts the risk of adverse drug events in the fetus and child. A review of our current knowledge suggests individual hepatic DME ontogeny can be categorized into one of three groups. Some enzymes, e.g., CYP3A7, are expressed at their highest level during the first trimester and either remain at high concentrations or decrease during gestation, but are silenced or expressed at low levels within one to two years after birth. SULT1A1 is an example of the second group of DME. These enzymes are expressed at relatively constant levels throughout gestation and minimal changes are observed postnatally. ADH1C is typical of the third DME group that are not expressed or are expressed at low levels in the fetus, usually during the second or third trimester. Substantial increases in enzyme levels are observed within the first one to two years after birth. Combined with our knowledge of other physiological factors during early life stages, knowledge regarding DME ontogeny has permitted the development of robust physiological based pharmacokinetic models and an improved capability to predict drug disposition in pediatric patients. This review will provide an overview of DME developmental expression patterns and discuss some implications of the data with regards to drug therapy. Common themes emerging from our current knowledge also will be discussed. Finally, the review will highlight gaps in knowledge that will be important to advance this field.
29: Ontogeny of human hepatic cytochromes P450.
Hines RN. J Biochem Mol Toxicol. 2007;21(4):169-75.
Significant changes in drug-metabolizing enzyme (DME) expression occur during ontogeny. Such changes can have a profound effect on therapeutic efficacy in the fetus and child, as well as the risk for adverse drug reactions. To gain a better understanding of DME ontogeny, enzyme contents for six key cytochromes P450 were measured in 240 human liver samples representing ages from 8 weeks gestation to 18 years. Where possible, both quantitative western blotting and activity assays with probe substrates were performed. Although oversimplified, the DME can be grouped into one of three categories. As typified by CYP3A7, some enzymes are expressed at their highest level during the first trimester and either remain at high concentrations or decrease during gestation and are silenced or expressed at low levels within 1-2 years after birth. These data cause one to query whether these enzymes have an important endogenous function. Representatives of a second group, CYP3A5 and CYP2C19, are expressed at relatively constant levels throughout gestation. Postnatal increases in CYP2C19 are observed within the first year, but not for CYP3A5. CYP2C9, 2E1, and 3A4 are more typical of a third group of enzymes that are not expressed or are expressed at low levels in the fetus with the onset of expression generally in either the second or third trimester. Substantial increases in expression are observed within the first 1-2 years after birth; however, considerable interindividual variability is observed in the immediate postnatal (1-6 months) onset or increase in expression of these enzymes, often resulting in a window of hypervariability.
F30. Regulatory polymorphisms and their contribution to interindividual differences in the expression of enzymes influencing drug and toxicant disposition.
Hines RN et al. Drug Metab Rev. 2008;40(2):263-301.
The unexpected paucity of human protein encoding genes suggested that polymorphisms altering gene expression might be more important than initially thought. From an evolutionary perspective, traits such as xenobiotic metabolism and transport that require a dynamic response to environmental changes would evolve more efficiently through variation in regulatory sequences versus coding variants. Such variation would be manifest as co-dominant traits and selection pressures would operate more efficiently because of their ability to impact fitness in the heterozygous state. Our current understanding of regulatory polymorphisms impacting drug disposition is reviewed including specific discussion regarding knowledge gaps and future research opportunities.
31. Genetic variation in glutathione-related genes and body burden of methylmercury.
Schläwicke Engström K et al. Environ Health Perspect. 2008 Jun;116(6):734-9. {free online}
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2430228&blobtype=pdf
BACKGROUND: Exposure to toxic methylmercury (MeHg) through fish consumption is a large problem worldwide, and it has led to governmental recommendations of reduced fish consumption and blacklisting of mercury-contaminated fish. The elimination kinetics of MeHg varies greatly among individuals. Knowledge about the reasons for such variation is of importance for improving the risk assessment for MeHg. One possible explanation is hereditary differences in MeHg metabolism. MeHg is eliminated from the body as a glutathione (GSH) conjugate. OBJECTIVES: We conducted this study to assess the influence of polymorphisms in GSH-synthesizing [glutamyl-cysteine ligase modifier subunit (GCLM-588) and glutamyl-cysteine ligase catalytic subunit (GCLC-129)] or GSH-conjugating [glutathione S-transferase pi 1 (GSTP1-105 and GSTP1-114)] genes on MeHg retention. METHODS: Based on information obtained from questionnaires, 292 subjects from northern Sweden had a high consumption of fish (lean/fat fish two to three times per week or more). We measured total Hg in erythrocytes (Ery-Hg) and long-chain n-3 polyunsaturated fatty acids in plasma (P-PUFA; an exposure marker for fish intake). RESULTS: The GSTP1 genotype modified Ery-Hg; effects were seen for GSTP1-105 and -114 separately, and combining them resulted in stronger effects. We found evidence of effect modification: individuals with zero or one variant allele demonstrated a steeper regression slope for Ery-Hg (p=0.038) compared with individuals with two or more variant alleles. The GCLM-588 genotype also influenced Ery-Hg (p=0.035): Individuals with the GCLM-588 TT genotype demonstrated the highest Ery-Hg, but we saw no evidence of effect modification with increasing P-PUFA. CONCLUSIONS: These results suggest a role of GSH-related polymorphisms in MeHg metabolism.
32. Polybrominated diphenyl ether (PBDE) flame retardants: environmental contamination, human body burden and potential adverse health effects.
Costa LG et al. Acta Biomed. 2008 Dec;79(3):172-83. {free online}
http://www.actabiomedica.it/data/2008/3_2008/costa.pdf
Polybrominated diphenyl ethers (PBDEs) are an important class of flame retardants, widely used in a variety of consumer products. In the past several years, PBDEs have become widespread environmental pollutants, and have been detected in water, soil, air, animals and human tissues. Exposure occurs in particular through the diet and the indoor environment. Infants and toddlers have the highest body burden, due to exposure via maternal milk and through house dust. Tetra-, penta- and hexa-BDEs are the congeners most commonly found in humans. Recent concerns on possible adverse health effects of PBDEs are focusing on their potential endocrine disrupting effects and on developmental neurotoxicity.
33. Concentrations of polybrominated diphenyl ethers, organochlorine compounds and nitro musks in mother's milk from Germany (Bavaria).
Raab U et al. Chemosphere. 2008 May;72(1):87-94.
The aim of this study was to determine a new spectrum of substances that will be selected for future breast milk monitoring in Bavaria, Germany. Up to now, the analysis of breast milk in Bavaria was limited to selected organochlorine pesticides (OCP) and polychlorinated biphenyls (PCB). Information on background levels of toxicologically interesting substances, such as dioxins and dioxin-like polychlorinated biphenyls (dl-PCB) or on flame retardants, such as polybrominated diphenyl ethers (PBDE) are very limited or not available for Bavaria. We present here levels on OCP, some nitro musks, indicator PCB, polychlorinated dibenzo-p-dioxins (PCDD), polychlorinated dibenzofurans (PCDF) and dl-PCB concentrations in breast milk collected at 12 weeks post-partum of 43 primiparous mothers living in Bavaria. The average concentrations of PCDD, PCDF and dl-PCB were 4.98, 4.93 and 9.92 pg WHO-TEQ g(-1) lipid, respectively. The mean contribution of PCDD, PCDF, non-ortho and mono-ortho PCB to the total WHO-TEQ is consistently about 25% each. Furthermore the concentration on PBDE in breast milk at two sampling points, 12 weeks and 16 weeks after delivery, were determined. Overall, 19 PBDE congeners were analysed, however the level of 12 PBDE congeners were below the limit of detection. BDE-153 and BDE-47 were the predominant congeners accounting for about 66% of the total PBDE. The means of the total concentrations of PBDE (five congeners) at the first and second sampling point were 1.90 and 2.03 ng g(-1) lipid, respectively. Based on our results the overall concentrations of the analysed substances in milk samples from Bavaria are consistent with the levels of breast milk samples of other European countries reflecting the low background body burden of these compounds.
34. Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants.
Costa LG, Giordano G. Neurotoxicology. 2007 Nov;28(6):1047-67. {free online}
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2118052&blobtype=pdf
Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants used in a variety of consumer products. In the past 25 years, PBDEs have become ubiquitous environmental contaminants. They have been detected in soil, air, sediments, birds, marine species, fish, house dust, and human tissues, blood and breast milk. Diet and house dust appear to be the major sources of PBDE exposure in the general population, though occupational exposure can also occur. Levels of PBDEs in human tissues are particularly high in North America, compared to Asian and European countries, and have been increasing in the past 30 years. Concentrations of PBDEs are particularly high in breast milk, resulting in high exposure of infants. In addition, for toddlers, dust has been estimated to account for a large percentage of exposure. PBDEs can also cross the placenta, as they have been detected in fetal blood and liver. Tetra-, penta- and hexaBDEs are most commonly present in human tissues. The current greatest concern for potential adverse effects of PBDEs relates to their developmental neurotoxicity. Pre- or postnatal exposure of mice or rats to various PBDEs has been shown to cause long-lasting changes in spontaneous motor activity, mostly characterized as hyperactivity or decreased habituation, and to disrupt performance in learning and memory tests. While a reduction in circulating thyroid hormone (T(4)) may contribute to the developmental neurotoxicity of PBDEs, direct effects on the developing brain have also been reported. Among these, PBDEs have been shown to affect signal transduction pathways and to cause oxidative stress. Levels of PBDEs causing developmental neurotoxicity in animals are not much dissimilar from levels found in highly exposed infants and toddlers.
35. Influence of breastfeeding in the accumulation of polybromodiphenyl ethers during the first years of child growth.
Carrizo D et al. Environ Sci Technol. 2007 Jul 15;41(14):4907-12.
The concentrations of polybromodiphenyl ethers (PBDEs) in children at birth (cord blood sera, n = 92) and at the age of 4 years (sera, n = 244) from a cohort established in Menorca Island (Balearic Island, Spain) were studied. This cohort is representative of a general European population that is fed a typical Mediterranean diet. Among the 13 congeners analyzed, BDE #47 was the most abundant in both types of samples, with mean values of 2.8 ng/g of lipid weight in cord blood sera and 2.9 ng/g of lipid weight in sera. The observed distributions of PBDEs paralleled the composition of the commercially available mixtures of pentabromodiphenyl ethers. The concentrations of most congeners were higher in females than in males, but the differences were not significant. PBDE in the sera of 4 year old children was higher among those having been fed with maternal milk than formula. The differences were statistically significant for the congeners found in higher concentrations (e.g., BDE #47 and BDE #99). This difference was consistentwith previous reports on polychlorobiphenyls or 4,4'-DDE, indicating that despite the short lactation period (about 4.5 months as an average in this cohort), breastfeeding was the determining factor for the body burden of these compounds at 4 years of age. The observed increases of average body burden of total PBDEs between birth and the first 4 years of growth were 65 and 10 ng for breastfed and formula fed children, respectively.
36. Mercury, lead, and zinc in baby teeth of children with autism versus controls.
Adams JB et al. J Toxicol Environ Health A. 2007 Jun;70(12):1046-51.
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.
37. Immune cell counts and risks of respiratory infections among infants exposed pre- and postnatally to organochlorine compounds: a prospective study.
Glynn A et al. Environ Health. 2008 Dec 4;7:62. {free online}
http://www.ehjournal.net/content/7/1/62
BACKGROUND: Early-life chemical exposure may influence immune system development, subsequently affecting child health. We investigated immunomodulatory potentials of polychlorinated biphenyls (PCBs) and p,p'-DDE in infants. METHODS: Prenatal exposure to PCBs and p,p'-DDE was estimated from maternal serum concentrations during pregnancy. Postnatal exposure was calculated from concentrations of the compounds in mother's milk, total number of nursing days, and percentage of full nursing each week during the 3 month nursing period. Number and types of infections among infants were registered by the mothers (N = 190). White blood cell counts (N = 86) and lymphocyte subsets (N = 52) were analyzed in a subgroup of infants at 3 months of age. RESULTS: Infants with the highest prenatal exposure to PCB congeners CB-28, CB-52 and CB-101 had an increased risk of respiratory infection during the study period. In contrast, the infection odds ratios (ORs) were highest among infants with the lowest prenatal mono-ortho PCB (CB-105, CB-118, CB-156, CB-167) and di-ortho PCB (CB-138, CB-153, CB-180) exposure, and postnatal mono- and di-ortho PCB, and p,p'-DDE exposure. Similar results were found for pre- and postnatal CB-153 exposure, a good marker for total PCB exposure. Altogether, a negative relationship was indicated between infections and total organochlorine compound exposure during the whole pre- and postnatal period. Prenatal exposure to CB-28, CB-52 and CB-101 was positively associated with numbers of lymphocytes and monocytes in infants 3 months after delivery. Prenatal exposure to p,p'-DDE was negatively associated with the percentage of eosinophils. No significant associations were found between PCB and p,p'-DDE exposure and numbers/percentages of lymphocyte subsets, after adjustment for potential confounders. CONCLUSION: This hypothesis generating study suggests that background exposure to PCBs and p,p'-DDE early in life modulate immune system development. Strong correlations between mono- and di-ortho PCBs, and p,p'-DDE exposures make it difficult to identify the most important contributor to the suggested immunomodulation, and to separate effects due to pre- and postnatal exposure. The suggested PCB and p,p'-DDE modulation of infection risks may have consequences for the health development during childhood, since respiratory infections early in life may be risk factors for asthma and middle ear infections.
38. Body Burden — The Pollution in Newborns
http://www.ewg.org/reports/bodyburden2/execsumm.php
39. The rise in autism and the role of age at diagnosis.
Hertz-Picciotto I, Delwiche L. Epidemiology. 2009 Jan;20(1):84-90.
University of California, Davis, California 95616
BACKGROUND: Autism prevalence in California, based on individuals eligible for state-funded services, rose throughout the 1990s. The extent to which this trend is explained by changes in age at diagnosis or inclusion of milder cases has not been previously evaluated. METHODS: Autism cases were identified from 1990 through 2006 in databases of the California Department of Developmental Services, which coordinates services for individuals with specific developmental disorders. The main outcomes were population incident cases younger than age 10 years for each quarter, cumulative incidence by age and birth year, age-specific incidence rates stratified by birth year, and proportions of diagnoses by age across birth years. RESULTS: Autism incidence in children rose throughout the period. Cumulative incidence to 5 years of age per 10,000 births rose consistently from 6.2 for 1990 births to 42.5 for 2001 births. Age-specific incidence rates increased most steeply for 2- and 3-year olds. The proportion diagnosed by age 5 years increased only slightly, from 54% for 1990 births to 61% for 1996 births. Changing age at diagnosis can explain a 12% increase, and inclusion of milder cases, a 56% increase. CONCLUSIONS: Autism incidence in California shows no sign yet of plateauing. Younger ages at diagnosis, differential migration, changes in diagnostic criteria, and inclusion of milder cases do not fully explain the observed increases. Other artifacts have yet to be quantified, and as a result, the extent to which the continued rise represents a true increase in the occurrence of autism remains unclear.
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