Etiologically Significant Pollutants and Mixtures

Advances in Autism Research
April 2010

In recent years, various pollutants have been found associated with autism. One of first such studies described a gene allele which associated autism with organophosphate insecticides in North America but not in Italy, this finding apparently related to different policies regarding sale of a certain class of pesticides (1). Soon thereafter, researchers in Texas reported that rates of special education and of autism were elevated in accord with higher levels of environmental mercury (2), Furthermore, autism rates were lower in relation to distance from a source of airborne mercury (3).

Another important study - this by Windham et al in 2006 - described "Autism spectrum disorders in relation to distribution of hazardous air pollutants in the san francisco bay area" and found significant associations between ASDs and "mercury, cadmium, nickel, trichloroethylene, and vinyl chloride" (4). The same research group also has found that organochlorine pesticide exposures were associated with autism (5) and that parental exposures are important (6), as is parental age (eg, 7).

Proximity to Superfund sites and their pollutants and their relation to autism rates are the focus of two studies (8-9); and a research team has hypothesized that de novo mutations reported in autism are being induced by parental exposure to pollutants (10-11).

Associations between pollutants and autism affirm the significance of clinical findings related to various pollutants (eg, 12-28), and pollutants other than those mentioned in this introductory merit attention (eg, 29-41).

A newly announced European Union study by the EU's Directorate-General for the Environment is titled, "State of the Art Report on Mixture Toxicity". As a scientists' news announcement (here) summarized on March 29, 2010, "The study showed that all the relevant research is unambiguous: the combined "cocktail effect" of environmental chemicals is greater and more toxic than the effect of the chemicals individually." The study itself is available here.

Amid this complexity of exposures and large numbers of intra-body pollutants, the concept Does a given pollutant (eg, vinyl; 34) cause autism? needs be replaced by other concepts. For instance, in conjunction with other intra-body pollutants, Is a given pollutant (eg, trichloroethylene; 4) etiologically significant as a co-factor contributing to autism or other ASDs?

Acknowledging intra-body "pollutant mixtures" amid models of autism causation and among gene-association investigations will help clarify the roles of pollutants as causal co-factors in the etiology of child developmental disorders including but not limited to autism.

References:

1. 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.
http://www.ncbi.nlm.nih.gov/pubmed/16027737

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.

2. 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.
http://www.ncbi.nlm.nih.gov/pubmed/16338635

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.

3. Proximity to point sources of environmental mercury release as a predictor of autism prevalence
Palmer RF, Blanchard S, Wood R.
Health Place. 2009 Mar;15(1):18-24
http://www.ncbi.nlm.nih.gov/pubmed/18353703

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.

4. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the san francisco bay area
Windham GC, Zhang L, Gunier R, Croen LA, Grether JK.
Environ Health Perspect. 2006 Sep;114(9):1438-44.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1570060/pdf/ehp0114-001438.pdf

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.

5. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley
Roberts EM, English PB, Grether JK, Windham GC, Somberg L, Wolff C.
Environ Health Perspect. 2007 Oct;115(10):1482-9.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2022638/pdf/ehp0115-001482.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.

6. Autism spectrum disorders in relation to parental occupation in technical fields
Windham GC, Fessel K, Grether JK.
Autism Res. 2009 Aug;2(4):183-91.
http://www.ncbi.nlm.nih.gov/pubmed/19606466

A previous study reported that fathers of children with autism spectrum disorders (ASD) were more likely to work as engineers, requiring "systemizing skills," and suggesting a distinct phenotype, but alternatively this may have been related to selection biases. We conducted a population-based study to explore whether fathers, or mothers, of children with ASD are over-represented in fields requiring highly technical skills. Subjects included 284 children with ASD and 659 gender-matched controls, born in 1994 in the San Francisco Bay Area. Parental occupation and industry were abstracted verbatim from birth certificates. Engineering, computer programming, and science were examined as highly technical occupations. To limit bias by parental socio-economic status, we selected a referent group of occupations that seemed professionally similar but of a less technical nature. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated by logistic regression, adjusting for parental age, education, and child race. Mothers of cases were somewhat more likely to work in hi-tech occupations (6.7%) than mothers of controls (4.0%, P=0.07), but little difference was observed among fathers, nor for engineering separately. Compared to parents in other "white collar" occupations, the adjusted OR for highly technical occupations among mothers was 2.5 (95% CI: 1.2-5.3) and among fathers was 1.3 (95% CI: 0.79-2.1), with no evidence of a joint effect observed. Our results regarding maternal occupation in technical fields being associated with ASD in offspring suggest further study to distinguish parental occupation as a phenotypic marker of genetic loading vs. other social or exposure factors.

7. Risk of autism and increasing maternal and paternal age in a large north American population
Grether JK, Anderson MC, Croen LA, Smith D, Windham GC.
Am J Epidemiol. 2009 Nov 1;170(9):1118-26
http://www.ncbi.nlm.nih.gov/pubmed/19783586

Previous studies are inconsistent regarding whether there are independent effects of maternal and paternal age on the risk of autism. Different biologic mechanisms are suggested by maternal and paternal age effects. The study population included all California singletons born in 1989-2002 (n = 7,550,026). Children with autism (n = 23,311) were identified through the California Department of Developmental Services and compared with the remainder of the study population, with parental ages and covariates obtained from birth certificates. Adjusted odds ratios and 95% confidence intervals were used to evaluate the risk of autism associated with increasing maternal and paternal age. In adjusted models that included age of the other parent and demographic covariates, a 10-year increase in maternal age was associated with a 38% increase in the odds ratio for autism (odds ratio = 1.38, 95% confidence interval: 1.32, 1.44), and a 10-year increase in paternal age was associated with a 22% increase (odds ratio = 1.22, 95% confidence interval: 1.18, 1.26). Maternal and paternal age effects were seen in subgroups defined by race/ethnicity and other covariates and were of greater magnitude among first-born compared with later-born children. Further studies are needed to help clarify the biologic mechanisms involved in the independent association of autism risk with increasing maternal and paternal age.

8. 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://www.la-press.com/redirect_file.php?fileId=1420&filename=EHI-2-Ming-et-al&fileType=pdf

Abstract: 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 landfi lls 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 landfi ll sites. Furthermore, the number of toxic Superfund sites and autism rate across 49 of the 50 states shows a statistically signifi cant 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.

9. Ockham's Razor and autism: the case for developmental neurotoxins contributing to a disease of neurodevelopment
DeSoto MC.
Neurotoxicology. 2009 May;30(3):331-7.
http://www.ncbi.nlm.nih.gov/pubmed/19442816

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.

10. Environmental risk factors for autism: do they help cause de novo genetic mutations that contribute to the disorder?
Kinney DK, Barch DH, Chayka B, Napoleon S, Munir KM.
Med Hypotheses. 2010 Jan;74(1):102-6. Epub 2009 Aug 21.
http://www.ncbi.nlm.nih.gov/pubmed/19699591

Recent research has discovered that a number of genetic risk factors for autism are de novo mutations. Advanced parental age at the time of conception is associated with increased risk for both autism and de novo mutations. We investigated the hypothesis that other environmental factors associated with increased risk for autism might also be mutagenic and contribute to autism by causing de novo mutations. A survey of the research literature identified 9 environmental factors for which increased pre-conceptual exposure appears to be associated with increased risk for autism. Five of these factors--mercury, cadmium, nickel, trichloroethylene, and vinyl chloride--are established mutagens. Another four--including residence in regions that are urbanized, located at higher latitudes, or experience high levels of precipitation--are associated with decreased sun exposure and increased risk for vitamin D deficiency. Vitamin D plays important roles in repairing DNA damage and protecting against oxidative stress--a key cause of DNA damage. Factors associated with vitamin D deficiency will thus contribute to higher mutation rates and impaired repair of DNA. We note how de novo mutations may also help explain why the concordance rate for autism is so markedly higher in monozygotic than dizygotic twins. De novo mutations may also explain in part why the prevalence of autism is so remarkably high, given the evidence for a strong role of genetic factors and the low fertility of individuals with autism--and resultant selection pressure against autism susceptibility genes. These several lines of evidence provide support for the hypothesis, and warrant new research approaches--which we suggest--to address limitations in existing studies. The hypothesis has implications for understanding possible etiologic roles of de novo mutations in autism, and it suggests possible approaches to primary prevention of the disorder, such as addressing widespread vitamin D deficiency and exposure to known mutagens.

11. Strong association of de novo copy number mutations with autism
Sebat J et al.
Science. 2007 Apr 20;316(5823):445-9.
http://www.ncbi.nlm.nih.gov/pubmed/17363630

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.

12. Sulfhydryl-reactive metals in autism
Kern JK, Grannemann BD, Trivedi MH, Adams JB.
J Toxicol Environ Health A. 2007 Apr 15;70(8):715-21.
http://www.ncbi.nlm.nih.gov/pubmed/17365626

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.

13. Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study
Lonsdale D, Shamberger RJ, Audhya T.
Neuro Endocrinol Lett. 2002 Aug;23(4):303-8.
http://www.ncbi.nlm.nih.gov/pubmed/12195231
http://www.nel.edu/23_4/NEL230402A02_Lonsdale.htm

OBJECTIVES: In a Pilot Study, the clinical and biochemical effects of thiamine tetrahydrofurfuryl disulfide (TTFD) on autistic spectrum children were investigated. SUBJECTS AND METHODS: Ten children were studied. Diagnosis was confirmed through the use of form E2, a computer assessed symptom score. For practical reasons, TTFD was administered twice daily for two months in the form of rectal suppositories, each containing 50 mg of TTFD. Symptomatic responses were determined through the use of the computer assessed Autism Treatment Evaluation Checklist (ATEC) forms. The erythrocyte transketolase (TKA) and thiamine pyrophosphate effect (TPPE), were measured at outset and on completion of the study to document intracellular thiamine deficiency. Urines from patients were examined at outset, after 30 days and after 60 days of treatment and the concentrations of SH-reactive metals, total protein, sulfate, sulfite, thiosulfate and thiocyanate were determined. The concentrations of metals in hair were also determined. RESULTS: At the beginning of the study thiamine deficiency was observed in 3 out of the 10 patients. Out of 10 patients, 6 had initial urine samples containing arsenic in greater concentration than healthy controls. Traces of mercury were seen in urines from all of these autistic children. Following administration of TTFD an increase in cadmium was seen in 2 children and in lead in one child. Nickel was increased in the urine of one patient during treatment. Sulfur metabolites in urine did not differ from those measured in healthy children. CONCLUSIONS: Thiamine tetrahydrofurfuryl disulfide appears to have a beneficial clinical effect on some autistic children, since 8 of the 10 children improved clinically. We obtained evidence of an association of this increasingly occurring disease with presence of urinary SH-reactive metals, arsenic in particular.

14.Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers.
Adams JB, Holloway CE, George F, Quig D.
Biol Trace Elem Res. 2006 Jun;110(3):193-209.

15. Mercury, lead, and zinc in baby teeth of children with autism versus controls.
Adams JB, Romdalvik J, Ramanujam VM, Legator MS.
J Toxicol Environ Health A. 2007 Jun;70(12):1046-51.

16. Biomarkers of environmental toxicity and susceptibility in autism.
Geier DA, Kern JK, Garver CR, Adams JB, Audhya T, Nataf R, Geier MR.
J Neurol Sci. 2009 May 15;280(1-2):101-8. Epub 2008 Sep 25.

17. The severity of autism is associated with toxic metal body burden and red blood cell glutathione levels.
Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, Zappia I, Newmark S, Gehn E, Rubin RA, Mitchell K, Bradstreet J, El-Dahr JM.
J Toxicol. 2009;2009:532640. Epub 2009 Aug 26.

18. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: part A--medical results.
Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, Zappia I, Newmark S, Gehn E, Rubin RA, Mitchell K, Bradstreet J, El-Dahr J.
BMC Clin Pharmacol. 2009 Oct 23;9:16.

19. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: part B - behavioral results.
Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, Zappia I, Newmark S, Gehn E, Rubin RA, Mitchell K, Bradstreet J, El-Dahr J.
BMC Clin Pharmacol. 2009 Oct 23;9:17.

20. The history of vaccinations in the light of the autism epidemic
Cave SF.
Altern Ther Health Med. 2008 Nov-Dec;14(6):54-7.

Autism has been characterized as a behavioral disorder since it was first described by Leo Kanner in 1943. The number of autistic children has increased over the last decade. The incidence of autism was 1 in 10000 before the 1970s and has steadily increased to 1 in 150 in 2008 with a male:female predominance of 4:1. The cause of this epidemic has remained unknown, but several hypotheses have been studied. Many of these suggest an environmental trigger, such as the ethyl mercury contained in the preservative thimerosal, which has been used in vaccines since 1931. Other possible triggers associated with vaccinations are chemical toxins and live viruses. James has published studies suggesting a genetic predisposition in the families of autistic children, exposing them to a deficiency in glutathione and an inability to detoxify heavy metals. Vargas has shown autism to encompass ongoing inflammation in the brains of autistic children. The Hannah Poling vaccine decision was a landmark case. Poling's family was awarded funds for ongoing medical care of an autistic child who was found to have mitochondrial dysfunction exacerbated by vaccines that left her with autistic behavior and seizures. Several studies have emerged supporting the fact that a significant number of autistic children do have mitochondrial dysfunction. The impact that the Poling case will have on the ability of parents of autistic children to gain access to funds to enable them to properly care for their children remains to be seen.

21. Evidence of Mitochondrial Dysfunction in Autism and Implications for Treatment
Daniel A. Rossignol, J. Jeffrey Bradstreet
American Journal of Biochemistry and Biotechnology 4 (2): 208-217, 2008
{free online}
http://www.scipub.org/fulltext/ajbb/ajbb42208-217.pdf

Classical mitochondrial diseases occur in a subset of individuals with autism and are usually caused by genetic anomalies or mitochondrial respiratory pathway deficits. However, in many cases of autism, there is evidence of mitochondrial dysfunction (MtD) without the classic features associated with mitochondrial disease. MtD appears to be more common in autism and presents with less severe signs and symptoms. It is not associated with discernable mitochondrial pathology in muscle biopsy specimens despite objective evidence of lowered mitochondrial functioning. Exposure to environmental toxins is the likely etiology for MtD in autism. This dysfunction then contributes to a number of diagnostic symptoms and comorbidities observed in autism including: cognitive impairment, language deficits, abnormal energy metabolism, chronic gastrointestinal problems, abnormalities in fatty acid oxidation, and increased oxidative stress. MtD and oxidative stress may also explain the high male to female ratio found in autism due to increased male vulnerability to these dysfunctions. Biomarkers for mitochondrial dysfunction have been identified, but seem widely under-utilized despite available therapeutic interventions. Nutritional supplementation to decrease oxidative stress along with factors to improve reduced glutathione, as well as hyperbaric oxygen therapy (HBOT) represent supported and rationale approaches. The underlying pathophysiology and autistic symptoms of affected individuals would be expected to either improve or cease worsening once effective treatment for MtD is implemented.

22. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism.
James SJ, Rose S, Melnyk S, Jernigan S, Blossom S, Pavliv O, Gaylor DW.
FASEB J. 2009 Aug;23(8):2374-83.

23. Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors.
James SJ, Slikker W 3rd, Melnyk S, New E, Pogribna M, Jernigan S.
Neurotoxicology. 2005 Jan;26(1):1-8.

24. The Frequency of Polymorphisms affecting Lead and Mercury Toxicity among Children with Autism
Shannon Rose et al.
American Journal of Biochemistry and Biotechnology 4(2): 85-94, 2008
{free online}
http://www.scipub.org/fulltext/ajbb/ajbb4285-94.pdf

25. Red-Cell Trace Minerals in Children with Autism
Joan Jory and Woody R. McGinnis
American Journal of Biochemistry and Biotechnology 4(2): 101-104, 2008
{free online}
http://www.scipub.org/fulltext/ajbb/ajbb42101-104.pdf

26. Altered Sulfur Amino Acid Metabolism In Immune Cells of Children Diagnosed With Autism
Jung H. Suh et al.
American Journal of Biochemistry and Biotechnology 4(2): 105-113, 2008
{free online}
http://www.scipub.org/fulltext/ajbb/ajbb42105-113.pdf

27. The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders.
Faber S, Zinn GM, Kern JC 2nd, Kingston HM.
Biomarkers. 2009 May;14(3):171-80.
http://www.ncbi.nlm.nih.gov/pubmed/19280374

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 microg dl(-1), mean copper level was 131.5 microg 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.

28. Nutritional and environmental approaches to preventing and treating autism and attention deficit hyperactivity disorder (ADHD): a review.

Curtis LT, Patel K.
J Altern Complement Med. 2008 Jan-Feb;14(1):79-85.

29. 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.

30. Environmental Factors and Limbic Vulnerability in Childhood Autism
Richard Lathe
American Journal of Biochemistry and Biotechnology 4(2): 183-197, 2008
{free online}
http://www.scipub.org/fulltext/ajbb/ajbb42183-197.pdf

31. Mini-review: Polybrominated diphenyl ether (PBDE) flame retardants as potential autism risk factors.

Messer A.
Physiol Behav. 2010 Jan 25. [Epub ahead of print]

32. Blood mercury concentrations in CHARGE Study children with and without autism.
Hertz-Picciotto I, Green PG, Delwiche L, Hansen R, Walker C, Pessah IN.
Environ Health Perspect. 2010 Jan;118(1):161-6.

33. Correlations Between Gene Expression and Mercury Levels in Blood of Boys With and Without Autism.
Stamova B et al.
Neurotox Res. 2009 Nov 24. [Epub ahead of print]

34. Associations between indoor environmental factors and parental-reported autistic spectrum disorders in children 6-8 years of age.
Larsson M, Weiss B, Janson S, Sundell J, Bornehag CG.
Neurotoxicology. 2009 Sep;30(5):822-31.

35. Autism spectrum disorders, attention deficit/hyperactivity disorder, and sleep disorders.
Ming X, Walters AS.
Curr Opin Pulm Med. 2009 Aug 26. [Epub ahead of print]

36. A comprehensive review of mercury provoked autism.
Geier DA, King PG, Sykes LK, Geier MR.
Indian J Med Res. 2008 Oct;128(4):383-411.

37. Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents.
Román GC.
J Neurol Sci. 2007 Nov 15;262(1-2):15-26.

38. Cultured lymphocytes from autistic children and non-autistic siblings up-regulate heat shock protein RNA in response to thimerosal challenge.

Walker SJ, Segal J, Aschner M.
Neurotoxicology. 2006 Sep;27(5):685-92.

39. {excellent review, free online}
A review of Thimerosal (Merthiolate) and its ethylmercury breakdown product: specific historical considerations regarding safety and effectiveness.
Geier DA, Sykes LK, Geier MR.
J Toxicol Environ Health B Crit Rev. 2007 Dec;10(8):575-96.
http://www.informaworld.com/smpp/content~db=all?content=10.1080/10937400701389875

40. Toxic effects of low doses of Bisphenol-A on human placental cells.
Benachour N, Aris A.
Toxicol Appl Pharmacol. 2009 Dec 15;241(3):322-8
synopsis at:
http://www.environmentalhealthnews.org/ehs/newscience/human-placental-cells-die-after-bpa-exposure/

41. Inhibition of human placental aromatase activity by hydroxylated polybrominated diphenyl ethers (OH-PBDEs).
Cantón RF, Scholten DE, Marsh G, de Jong PC, van den Berg M.
Toxicol Appl Pharmacol. 2008 Feb 15;227(1):68-75

This document prepared by
Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
April 2010