CoChat
Sign Up
Cited by 458Autism Spectrum Disorder ResearchHeavy Metal Exposure and ToxicityEffects and risks of endocrine disrupting chemicals

Environmental toxicants and autism spectrum disorders: a systematic review

Open access
Rossignol, D A, Genuis, S J, Frye, R E·2014·Translational Psychiatry
DOI 10.1038/tp.2014.4PMC PMC3944636
Open this paper in CoChat — free accountOpen PDF

Abstract

Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case-control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case-control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that solvent, phthalate and pesticide levels were associated with ASD, whereas PCB studies were mixed. Seven studies reported a relationship between autism severity and heavy metal biomarkers, suggesting evidence of a dose-effect relationship. Overall, the evidence linking biomarkers of toxicants with ASD (the second category) was weaker compared with the evidence associating estimated exposures to toxicants in the environment and ASD risk (the first category) because many of the biomarker studies contained small sample sizes and the relationships between biomarkers and ASD were inconsistent across studies. Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), δ-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). Notably, many of the reviewed studies had significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Because of the limitations of many of the reviewed studies, additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/tp.2014.4

Cites

16 of 16 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Our systematic review results were generally in concert with previous expert-based narrative reviews that addressed the association of ASD and environmental chemical exposures more broadly.

    “Our systematic review results were generally in concert with previous expert-based narrative reviews that addressed the association of ASD and environmental chemical exposures more broadly [18, 65–67].”

    From A Systematic Review and Meta-Analysis of Multiple Airborne Pollutants and Autism Spectrum Disorder (2016) · cites this paper as [67]

  • Studies of toxic metals and nutritional elements in ASD have yielded mixed results, with some reporting higher concentrations of toxic metals including lead and others finding no association.

    “Studies of toxic metals and nutritional elements in ASD have yielded mixed results. Although several studies reported higher concentrations of toxic metals in ASD, including the neurotoxin lead, others found no association10.”

    From Fetal and postnatal metal dysregulation in autism (2017) · cites this paper as [10]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 192

  1. Baio J. Prevalence of autism spectrum disorders--Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ 2012; 61: 1-19.
  2. Rice C. Prevalence of autism spectrum disorders--autism and developmental disabilities monitoring network, 14 sites, United States, 2002. MMWR 2007; 56: 12-28.
  3. Schaefer GB, Mendelsohn NJ. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med 2013; 15: 399-407.
  4. Rossignol DA, Frye RE. A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Psychiatry 2012; 17: 389-401.
  5. Ming X, Brimacombe M, Chaaban J, Zimmerman-Bier B, Wagner GC. Autism spectrum disorders: concurrent clinical disorders. J Child Neurol 2008; 23: 6-13.
  6. Herbert MR. Autism: a brain disorder or a disorder that affects the brain. Clin Neuropsychiatry 2005; 2: 354-379.
  7. Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet 2006; 368: 2167-2178.
  8. Goldman LR, Koduru S. Chemicals in the environment and developmental toxicity to children: a public health and policy perspective. Environ Health Per- spect 2000; 108: 443-448.
  9. Grandjean P, Perez M. Development neurotoxicity: implications of methylmer- cury research. Int J Environ Health 2008; 2: 417-428.
  10. Faustman EM, Silbernagel SM, Fenske RA, Burbacher TM, Ponce RA. Mechanisms underlying Children's susceptibility to environmental toxicants. Environ Health Perspect 2000; 108: 13-21.
  11. Lawler CP, Croen LA, Grether JK. Van de Water J. Identifying environmental contributions to autism: provocative clues and false leads. Ment Retard Dev Disabil Res Rev 2004; 10: 292-302.
  12. Herbert MR, Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG et al. Autism and environmental genomics. Neurotoxicology 2006; 27: 671-684.
  13. Livingston RJ, von Niederhausern A, Jegga AG, Crawford DC, Carlson CS, Rieder MJ et al. Pattern of sequence variation across 213 environmental response genes. Genome Res 2004; 14: 1821-1831.
  14. Lawler CP. The 'environment' for autism research: signs of improvement? Environ Health Perspect 2008; 116: A416-A417.
  15. Cheslack-Postava K, Rantakokko PV, Hinkka-Yli-Salomaki S, Surcel HM, McKeague IW, Kiviranta HA et al. Maternal serum persistent organic pollutants in the Finnish Prenatal Study of Autism: a pilot study. Neurotoxicol Teratol 2013; 38: 1-5.
  16. Eskenazi B, Marks AR, Bradman A, Harley K, Barr DB, Johnson C et al. Organo- phosphate pesticide exposure and neurodevelopment in young Mexican- American children. Environ Health Perspect 2007; 115: 792-798.
  17. Miodovnik A, Engel SM, Zhu C, Ye X, Soorya LV, Silva MJ et al. Endocrine dis- ruptors and childhood social impairment. Neurotoxicology 2011; 32: 261-267.
  18. Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB et al. Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children. Pediatrics 2006; 118: e1845-e1859.
  19. Felicetti T. Parents of autistic children: some notes on a chemical connection. Milieu Ther 1981; 1: 13-16.
  20. McCanlies EC, Fekedulegn D, Mnatsakanova A, Burchfiel CM, Sanderson WT, Charles LE et al. Parental occupational exposures and autism spectrum disorder. J Autism Dev Disord 2012; 42: 2323-2334.
  21. Roberts EM, English PB, Grether JK, Windham GC, Somberg L, Wolff C. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environ Health Perspect 2007; 115: 1482-1489.
  22. Roberts EM, English PB. Bayesian modeling of time-dependent vulnerability to environmental hazards: an example using autism and pesticide data. Stat Med 2013; 32: 2308-2319.
  23. Kalkbrenner AE, Daniels JL, Chen JC, Poole C, Emch M, Morrissey J. Perinatal exposure to hazardous air pollutants and autism spectrum disorders at age 8. Epidemiology 2010; 21: 631-641.
  24. Volk HE, Kerin T, Lurmann F, Hertz-Picciotto I, McConnell R, Campbell DB. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology 2013; 25: 44-47.
  25. Kim SM, Han DH, Lyoo HS, Min KJ, Kim KH, Renshaw P. Exposure to environ- mental toxins in mothers of children with autism spectrum disorder. Psychiatry Investig 2010; 7: 122-127.
  26. Windham GC, Sumner A, Li SX, Anderson M, Katz E, Croen LA et al. Use of birth certificates to examine maternal occupational exposures and autism spectrum disorders in offspring. Autism Res 2013; 6: 57-63.
  27. Pino-Lopez M, Romero-Ayuso DM. Parental occupational exposures and autism spectrum disorder in children. Rev Esp Salud Publica 2013; 87: 73-85.
  28. Garry VF, Harkins ME, Erickson LL, Long-Simpson LK, Holland SE, Burroughs BL. Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA. Environ Health Perspect 2002; 110: 441-449.
  29. Audouze K, Grandjean P. Application of computational systems biology to explore environmental toxicity hazards. Environ Health Perspect 2011; 119: 1754-1759.
  30. Ming X, Brimacombe M, Malek JH, Jani N, Wagner GC. Autism spectrum dis- orders and identified toxic land fills: co-occurrence across States. Environ Health Insights 2008; 2: 55-59.
  31. Desoto MC. Ockman's razor and autism: the case for developmental neurotoxins contributing to a disease of neurodevelopment. Neurotoxicology 2009; 30: 331-337.
  32. Jung CR, Lin YT, Hwang BF. Air pollution and newly diagnostic autism spectrum disorders: a population-based cohort study in Taiwan. PLoS One 2013; 8: e75510.
  33. Chang S, Crothers C, Lai S, Lamm S. Pediatric neurobehavioral diseases in Nevada counties with respect to perchlorate in drinking water: an ecological inquiry. Birth Defects Res A Clin Mol Teratol 2003; 67: 886-892.
  34. Palmer RF, Blanchard S, Stein Z, Mandell D, Miller C. Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas. Health Place 2006; 12: 203-209.
  35. Bartell SM, Lewandowski TA. Administrative censoring in ecological analyses of autism and a Bayesian solution. J Environ Public Health 2011; 2011: 202783.
  36. Lewandowski TA, Bartell SM, Yager JW, Levin L. An evaluation of surrogate chemical exposure measures and autism prevalence in Texas. J Toxicol Environ Health A 2009; 72: 1592-1603.
  37. Palmer RF, Blanchard S, Wood R. Proximity to point sources of environmental mercury release as a predictor of autism prevalence. Health Place 2009; 15: 18-24.
  38. Blanchard KS, Palmer RF, Stein Z. The value of ecologic studies: mercury con- centration in ambient air and the risk of autism. Rev Environ Health 2011; 26: 111-118.
  39. Schweikert C, Li Y, Dayya D, Yens D, Torrents M, Hsu DF. Analysis of autism prevalence and neurotoxins using combinatorial fusion and association rule mining. Ninth IEEE International Conference on Bioinformatics and Bioengi- neering 2009, 400-404.
  40. Rury J. Links between environmental mercury, special education, and autism in Louisiana. 2008 thesis, Louisiana State University: Baton Rouge, LA, USA, 2006.
  41. DeSoto MC, Hitlan RT. Fish consumption advisories and the surprising relation- ship to prevalence rate of developmental disability as reported by public schools. J Environ Prot 2012; 3: 1579-1589.
  42. Chrysochoou C, Rutishauser C, Rauber-Luthy C, Neuhaus T, Boltshauser E, Superti-Furga A. An 11-month-old boy with psychomotor regression and auto- aggressive behaviour. Eur J Pediatr 2003; 162: 559-561.
  43. Price CS, Thompson WW, Goodson B, Weintraub ES, Croen LA, Hinrichsen VL et al. Prenatal and infant exposure to thimerosal from vaccines and immu- noglobulins and risk of autism. Pediatrics 2010; 126: 656-664.
  44. Ip P, Wong V, Ho M, Lee J, Wong W. Mercury exposure in children with autistic spectrum disorder: case-control study. J Child Neurol 2004; 19: 431-434.
  45. Desoto MC, Hitlan RT. Blood levels of mercury are related to diagnosis of autism: a reanalysis of an important data set. J Child Neurol 2007; 22: 1308-1311.
  46. Geier DA, Audhya T, Kern JK, Geier MR. Blood mercury levels in autism spectrum disorder: is there a threshold level? Acta Neurobiol Exp (Wars) 2010; 70: 177-186.
  47. Albizzati A, More L, Di Candia D, Saccani M, Lenti C. Normal concentrations of heavy metals in autistic spectrum disorders. Minerva Pediatr 2012; 64: 27-31.
  48. Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E et al. Toxicological status of children with autism vs neurotypical children and the association with autism severity. Biol Trace Elem Res 2013; 151: 171-180.
  49. Rahbar MH, Samms-Vaughan M, Loveland KA, Ardjomand-Hessabi M, Chen Z, Bressler J et al. Seafood consumption and blood mercury concentrations in Jamaican children with and without autism spectrum disorders. Neurotox Res 2013; 23: 22-38.
  50. Stamova B, Green PG, Tian Y, Hertz-Picciotto I, Pessah IN, Hansen R et al. Cor- relations between gene expression and mercury levels in blood of boys with and without autism. Neurotox Res 2011; 19: 31-48.
  51. Hertz-Picciotto I, Green PG, Delwiche L, Hansen R, Walker C, Pessah IN. Blood mercury concentrations in CHARGE Study children with and without autism. Environ Health Perspect 2010; 118: 161-166.
  52. Blaurock-Busch E, Amin OR, Rabah T. Heavy metals and trace elements in hair and urine of a sample of Arab children with autistic spectrum disorder. Maedica (Buchar) 2011; 6: 247-257.
  53. Wright B, Pearce H, Allgar V, Miles J, Whitton C, Leon I et al. A comparison of urinary mercury between children with autism spectrum disorders and control children. PLoS One 2012; 7: e29547.
  54. Bradstreet JJ, Geier DA, Kartzinel JJ, Adams JB, Geier MR. A case-control study of mercury burden in children with autistic spectrum disorders. J Amer Physicians Surg 2003; 8: 76-79.
  55. Soden SE, Lowry JA, Garrison CB, Wasserman GS. 24-hour provoked urine excretion test for heavy metals in children with autism and typically developing controls, a pilot study. Clin Toxicol (Phila) 2007; 45: 476-481.
  56. Blaucok-Busch E, Amin OR, Dessoki HH, Rabah T. Efficacy of DMSA therapy in a sample of Arab children with autistic spectrum disorder. Maedica (Buchar) 2012; 7: 214-221.
  57. Aposhian HV, Maiorino RM, Gonzalez-Ramirez D, Zuniga-Charles M, Xu Z, Hurlbut KM et al. Mobilization of heavy metals by newer, therapeutically useful chelating agents. Toxicology 1995; 97: 23-38.
  58. Fido A, Al-Saad S. Toxic trace elements in the hair of children with autism. Autism 2005; 9: 290-298.
  59. Al-Ayadhi LY. Heavy metals and trace elements in hair samples of autistic chil- dren in central Saudi Arabia. Neurosciences (Riyadh) 2005; 10: 213-218.
  60. El-Baz F, Elhossiny RM, Elsayed AB, Gaber GM. Hair mercury measurement in Egyptian autistic children. Egypt J Med Hum Genet 2010; 11: 135-141.
  61. Elsheshtawy E, Tobar S, Sherra K, Atallah S, Elkasaby R. Study of some biomarkers in hair of children with autism. Middle East Curr Psychiatry 2011; 18: 6-10.
  62. Lakshmi Priya MD, Geetha A. Level of trace elements (copper, zinc, magnesium and selenium) and toxic elements (lead and mercury) in the hair and nail of children with autism. Biol Trace Elem Res 2011; 142: 148-158.
  63. Blaurock-Busch E, Amin OR, Dessoki HH, Rabah T. Toxic metals and essential elements in hair and severity of symptoms among children with autism. Maedica (Buchar) 2012; 7: 38-48.
  64. Majewska MD, Urbanowicz E, Rok-Bujko P, Namyslowska I, Mierzejewski P. Age- dependent lower or higher levels of hair mercury in autistic children than in healthy controls. Acta Neurobiol Exp (Wars) 2010; 70: 196-208.
  65. Adams JB, Holloway CE, George F, Quig D. Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers. Biol Trace Elem Res 2006; 110: 193-209.
  66. Williams PG, Hersh JH, Allard A, Sears LL. A controlled study of mercury levels in hair samples of children with autism as compared to their typically developing siblings. Res Autism Spect Disord 2008; 2: 170-175.
  67. De Palma G, Catalani S, Franco A, Brighenti M, Apostoli P. Lack of correlation between metallic elements analyzed in hair by ICP-MS and autism. J Autism Dev Disord 2012; 42: 342-353.
  68. Kern JK, Grannemann BD, Trivedi MH, Adams JB. Sulfhydryl-reactive metals in autism. J Toxicol Environ Health A 2007; 70: 715-721.
  69. Obrenovich ME, Shamberger RJ, Lonsdale D. Altered heavy metals and trans- ketolase found in autistic spectrum disorder. Biol Trace Elem Res 2011; 144: 475-486.
  70. Holmes AS, Blaxill MF, Haley BE. Reduced levels of mercury in first baby haircuts of autistic children. Int J Toxicol 2003; 22: 277-285.
  71. Canuel R, de Grosbois SB, Atikesse L, Lucotte M, Arp P, Ritchie C et al. New evidence on variations of human body burden of methylmercury from fish consumption. Environ Health Perspect 2006; 114: 302-306.
  72. Adams JB, Romdalvik J, Ramanujam VM, Legator MS. Mercury, lead, and zinc in baby teeth of children with autism versus controls. J Toxicol Environ Health A 2007; 70: 1046-1051.
  73. Rinderknecht AL, Kleinman MT, Ericson JE. Pb enamel biomarker: deposition of pre-and postnatal Pb isotope injection in reconstructed time points along rat enamel transect. Environ Res 2005; 99: 169-176.
  74. Abdullah MM, Ly AR, Goldberg WA, Clarke-Stewart KA, Dudgeon JV, Mull CG et al. Heavy metal in children's tooth enamel: related to autism and disruptive behaviors? J Autism Dev Disord 2012; 42: 929-936.
  75. Sajdel-Sulkowska EM, Lipinski B, Windom H, Audhya T, McGinnis WR. Oxidative stress in autism: elevated cerebellar 3-nitrotyrosine levels. Am J Biochem Biotech 2008; 4: 73-84.
  76. Shandley K, Austin DW. Ancestry of pink disease (infantile acrodynia) identified as a risk factor for autism spectrum disorders. J Toxicol Environ Health A 2011; 74: 1185-1194.
  77. Accardo P, Whitman B, Caul J, Rolfe U. Autism and plumbism. A possible asso- ciation. Clin Pediatr (Phila) 1988; 27: 41-44.
  78. Eppright TD, Sanfacon JA, Horwitz EA. Attention deficit hyperactivity disorder, infantile autism, and elevated blood-lead: a possible relationship. Mo Med 1996; 93: 136-138.
  79. Lidsky TI, Schneider JS. Autism and autistic symptoms associated with childhood lead poisoning. J Appl Res 2005; 5: 80-87.
  80. Newton KE, Leonard M, Delves HT, Bowen-Jones D. A problem with her lead weight. Ann Clin Biochem 2005; 42: 145-148.
  81. Shannon M, Graef JW. Lead intoxication in children with pervasive develop- mental disorders. J Toxicol Clin Toxicol 1996; 34: 177-181.
  82. George M, Heeney MM, Woolf AD. Encephalopathy from lead poisoning mas- querading as a flu-like syndrome in an autistic child. Pediatr Emerg Care 2010; 26: 370-373.
  83. Hallaway N. From autistic to lead toxic. Can Nurse 1993; 89: 53-54.
  84. Campbell M, Petti TA, Green WH, Cohen IL, Genieser NB, David R. Some physical parameters of young autistic children. J Am Acad Child Psychiatry 1980; 19: 193-212.
  85. Clark B, Vandermeer B, Simonetti A, Buka I. Is lead a concern in Canadian autistic children? Paediatr Child Health 2010; 15: 17-22. 100
  86. Cohen DJ, Johnson WT, Caparulo BK. Pica and elevated blood lead level in autistic and atypical children. Am J Dis Child 1976; 130: 47-48. 101
  87. El-Ansary A, Al-Daihan S, Al-Dbass A, Al-Ayadhi L. Measurement of selected ions related to oxidative stress and energy metabolism in Saudi autistic children. Clin Biochem 2010; 43: 63-70. 102
  88. El-Ansary AK, Bacha AB, Ayahdi LY. Relationship between chronic lead toxicity and plasma neurotransmitters in autistic patients from Saudi Arabia. Clin Bio- chem 2011; 44: 1116-1120. 103
  89. Cohen DJ, Paul R, Anderson GM, Harcherik DF. Blood lead in autistic children. Lancet 1982; 2: 94-95. 104
  90. Tian Y, Green PG, Stamova B, Hertz-Picciotto I, Pessah IN, Hansen R et al. Cor- relations of gene expression with blood lead levels in children with autism compared to typically developing controls. Neurotox Res 2011; 19: 1-13. 105
  91. Vergani L, Cristina L, Paola R, Luisa AM, Shyti G, Edvige V et al. Metals, metal- lothioneins and oxidative stress in blood of autistic children. Res Autism Spect Disord 2011; 5: 286-293. 106
  92. Yorbik O, Kurt I, Hasimi A, Ozturk O. Chromium, cadmium, and lead levels in urine of children with autism and typically developing controls. Biol Trace Elem Res 2010; 135: 10-15. 107
  93. Al-Farsi YM, Waly MI, Al-Sharbati MM, Al-Shafaee MA, Al-Farsi OA, Al-Khaduri MM et al. Levels of heavy metals and essential minerals in hair samples of children with autism in Oman: a case-control study. Biol Trace Elem Res 2012; 151: 181-186. 108
  94. Gentile PS, Trentalange MJ, Zamichek W, Coleman M. Brief report: trace elements in the hair of autistic and control children. J Autism Dev Disord 1983; 13: 205-206. 109
  95. Shearer TR, Larson K, Neuschwander J, Gedney B. Minerals in the hair and nutrient intake of autistic children. J Autism Dev Disord 1982; 12: 25-34. 110
  96. Rahbar MH, Samms-Vaughan M, Ardjomand-Hessabi M, Loveland KA, Dickerson AS, Chen Z et al. The role of drinking water sources, consumption of vegetables and seafood in relation to blood arsenic concentrations of Jamaican children with and without autism spectrum disorders. Sci Total Environ 2012; 433: 362-370. 111
  97. Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A et al. The severity of autism is associated with toxic metal body burden and red blood cell glutathione levels. J Toxicol 2009; 2009: 1-7. 112
  98. Geier DA, Kern JK, King PG, Sykes LK, Geier MR. Hair toxic metal concentrations and autism spectrum disorder severity in young children. Int J Environ Res Public Health 2012; 9: 4486-4497. 113
  99. Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A et al. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: part A--medical results. BMC Clin Pharmacol 2009; 9: 16. 114
  100. Nataf R, Skorupka C, Amet L, Lam A, Springbett A, Lathe R. Porphyrinuria in childhood autistic disorder: implications for environmental toxicity. Toxicol Appl Pharmacol 2006; 214: 99-108. 115
  101. Goin-Kochel RP, Mackintosh VH, Myers BJ. Parental reports on the efficacy of treatments and therapies for their children with autism spectrum disorders. Res Autism Spect Disord 2009; 3: 528-537. 116
  102. Patel K, Curtis LT. A comprehensive approach to treating autism and attention- deficit hyperactivity disorder: a prepilot study. J Altern Complement Med 2007; 13: 1091-1097. 117
  103. Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A et al. Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: part B-behavioral results. BMC Clin Pharmacol 2009; 9: 17. 118
  104. Geier DA, Geier MR. A clinical trial of combined anti-androgen and anti-heavy metal therapy in autistic disorders. Neuro Endocrinol Lett 2006; 27: 833-838. 119
  105. Kidd PM. Autism, an extreme challenge to integrative medicine. Part II: Medical management. Alternat Med Rev 2002; 7: 472-499. 120
  106. Lonsdale D, Shamberger RJ, Audhya T. Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study. Neuro Endocrinol Lett 2002; 23: 303-308. 121
  107. Lofthouse N, Hendren R, Hurt E, Arnold LE, Butter E. A review of complementary and alternative treatments for autism spectrum disorders. Autism Res Treat 2012; 2012: 870391. 122
  108. Woods JS. Porphyrin Metabolism as Indicator of Metal Exposure and Toxicity. vol. 115. Springer-Verlag: Berlin, 1995. 123
  109. Heyer NJ, Bittner AC Jr, Echeverria D, Woods JS. A cascade analysis of the interaction of mercury and coproporphyrinogen oxidase (CPOX) polymorphism on the heme biosynthetic pathway and porphyrin production. Toxicol Lett 2006; 161: 159-166. 124
  110. Pingree SD, Simmonds PL, Rummel KT, Woods JS. Quantitative evaluation of urinary porphyrins as a measure of kidney mercury content and mercury body burden during prolonged methylmercury exposure in rats. Toxicol Sci 2001; 61: 234-240. 125
  111. Gonzalez-Ramirez D, Maiorino RM, Zuniga-Charles M, Xu Z, Hurlbut KM, Junco- Munoz P et al. Sodium 2,3-dimercaptopropane-1-sulfonate challenge test for mercury in humans: II. Urinary mercury, porphyrins and neurobehavioral chan- ges of dental workers in Monterrey, Mexico. J Pharmacol Exp Ther 1995; 272: 264-274. 126
  112. Austin DW, Shandley K. An investigation of porphyrinuria in Australian children with autism. J Toxicol Environ Health A 2008; 71: 1349-1351. 127
  113. Geier DA, Kern JK, Garver CR, Adams JB, Audhya T, Nataf R et al. Biomarkers of environmental toxicity and susceptibility in autism. J Neurol Sci 2009; 280: 101-108. 128
  114. Geier DA, Kern JK, Geier MR. A prospective blinded evaluation of urinary por- phyrins verses the clinical severity of autism spectrum disorders. J Toxicol Environ Health A 2009; 72: 1585-1591. 129
  115. Kern JK, Geier DA, Adams JB, Geier MR. A biomarker of mercury body-burden correlated with diagnostic domain specific clinical symptoms of autism spec- trum disorder. Biometals 2010; 23: 1043-1051. 130
  116. Geier DA, Geier MR. A prospective assessment of porphyrins in autistic disorders: a potential marker for heavy metal exposure. Neurotox Res 2006; 10: 57-64. 131
  117. Geier DA, Geier MR. A prospective study of mercury toxicity biomarkers in autistic spectrum disorders. J Toxicol Environ Health A 2007; 70: 1723-1730. 132
  118. Heyer NJ, Echeverria D, Woods JS. Disordered porphyrin metabolism: a potential biological marker for autism risk assessment. Autism Res 2012; 5: 84-92. 133
  119. Kern JK, Geier DA, Adams JB, Mehta JA, Grannemann BD, Geier MR. Toxicity biomarkers in autism spectrum disorder: a blinded study of urinary porphyrins. Pediatr Int 2011; 53: 147-153. 134
  120. Woods JS, Armel SE, Fulton DI, Allen J, Wessels K, Simmonds PL et al. Urinary porphyrin excretion in neurotypical and autistic children. Environ Health Perspect 2010; 118: 1450-1457. 135
  121. Youn SI, Jin SH, Kim SH, Lim S. Porphyrinuria in Korean children with autism: correlation with oxidative stress. J Toxicol Environ Health A 2010; 73: 701-710. 136
  122. Frye RE, Rossignol DA. Mitochondrial physiology and autism spectrum disorder. OA Autism 2013; 1: 5. 137
  123. Edelson SB, Cantor DS. Autism: xenobiotic influences. Toxicol Ind Health 1998; 14: 553-563. 138
  124. Edelson SB, Cantor DS. The neurotoxic etiology of the autistic spectrum dis- orders: a replication study. Toxicol Ind Health 2000; 16: 239-247. 139
  125. Otake T, Yoshinaga J, Seki Y, Matsumura T, Watanabe K, Ishijima M et al. Ret- rospective in utero exposure assessment of PCBs using preserved umbilical cords and its application to case-control comparison. Environ Health Prev Med 2006; 11: 65-68. 140
  126. Mitchell MM, Woods R, Chi LH, Schmidt RJ, Pessah IN, Kostyniak PJ et al. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environ Mol Mutagen 2012; 53: 589-598. 141
  127. Testa C, Nuti F, Hayek J, De Felice C, Chelli M, Rovero P et al. Di-(2-ethylhexyl) phthalate and autism spectrum disorders. ASN Neuro 2012; 4: 223-229. 142
  128. Stein TP, Schluter MD, Steer RA, Ming X. Autism and phthalate metabolite glu- curonidation. J Autism Dev Disord 2013; 43: 2677-2685. 143
  129. Ashwood P, Schauer J, Pessah IN, Van de Water J. Preliminary evidence of the in vitro effects of BDE-47 on innate immune responses in children with autism spectrum disorders. J Neuroimmunol 2009; 208: 130-135. 144
  130. Archibeque-Engle SL, Tessari JD, Winn DT, Keefe TJ, Nett TM, Zheng T. Com- parison of organochlorine pesticide and polychlorinated biphenyl residues in human breast adipose tissue and serum. J Toxicol Environ Health 1997; 52: 285-293. 145
  131. Jandacek RJ, Anderson N, Liu M, Zheng S, Yang Q, Tso P. Effects of yo-yo diet, caloric restriction, and olestra on tissue distribution of hexachlorobenzene. Am J Physiol Gastrointest Liver Physiol 2005; 288: G292-G299. 146
  132. Yu GW, Laseter J, Mylander C. Persistent organic pollutants in serum and several different fat compartments in humans. J Environ Public Health 2011; 2011: 417980. 147
  133. Rusiecki JA, Matthews A, Sturgeon S, Sinha R, Pellizzari E, Zheng T et al. A correlation study of organochlorine levels in serum, breast adipose tissue, and gluteal adipose tissue among breast cancer cases in India. Cancer Epidemiol Biomarkers Prev 2005; 14: 1113-1124. 148
  134. Ruggeri B, Sarkans U, Schumann G, Persico AM. Biomarkers in autism spectrum disorder: the old and the new. Psychopharmacology (Berl) 2013; 151: 181-186. 149
  135. Eskenazi B, Huen K, Marks A, Harley KG, Bradman A, Barr DB et al. PON1 and neurodevelopment in children from the CHAMACOS study exposed to orga- nophosphate pesticides in utero. Environ Health Perspect 2010; 118: 1775-1781. 150
  136. Pasca SP, Nemes B, Vlase L, Gagyi CE, Dronca E, Miu AC et al. High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism. Life Sci 2006; 78: 2244-2248. 151
  137. Pasca SP, Dronca E, Nemes B, Kaucsar T, Endreffy E, Iftene F et al. Paraoxonase 1 activities and polymorphisms in autism spectrum disorders. J Cell Mol Med 2010; 14: 600-607. 152
  138. Serajee FJ, Nabi R, Zhong H, Huq M. Polymorphisms in xenobiotic metabolism genes and autism. J Child Neurol 2004; 19: 413-417. 155
  139. Al-Yafee YA, Al-Ayadhi LY, Haq SH, El-Ansary AK. Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia. BMC Neurol 2011; 11: 139. 156
  140. Buyske S, Williams TA, Mars AE, Stenroos ES, Ming SX, Wang R et al. Analysis of case-parent trios at a locus with a deletion allele: association of GSTM1 with autism. BMC Genet 2006; 7: 8. 157
  141. Williams TA, Mars AE, Buyske SG, Stenroos ES, Wang R, Factura-Santiago MF et al. Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype. Arch Pediatr Adolesc Med 2007; 161: 356-361. 159
  142. Gundacker C, Komarnicki G, Jagiello P, Gencikova A, Dahmen N, Wittmann KJ et al. Glutathione-S-transferase polymorphism, metallothionein expression, and mercury levels among students in Austria. Sci Total Environ 2007; 385: 37-47. 160
  143. Klautau-Guimarães MN, D'Ascenção R, Caldart FA, Grisolia CK, Souza JR, Barbosa AC et al. Analysis of genetic susceptibility to mercury contamination evaluated through molecular biomarkers in at-risk Amazon Amerindian populations. Genet Mol Biol 2005; 28: 827-832. 161
  144. Westphal GA, Schnuch A, Schulz TG, Reich K, Aberer W, Brasch J et al. Homo- zygous gene deletions of the glutathione S-transferases M1 and T1 are asso- ciated with thimerosal sensitization. Int Arch Occup Environ Health 2000; 73: 384-388. 162
  145. Tsai PC, Huang W, Lee YC, Chan SH, Guo YL. Genetic polymorphisms in CYP1A1 and GSTM1 predispose humans to PCBs/PCDFs-induced skin lesions. Chemo- sphere 2006; 63: 1410-1418. 163
  146. Hung RJ, Boffetta P, Brennan P, Malaveille C, Hautefeuille A, Donato F et al. GST, NAT, SULT1A1, CYP1B1 genetic polymorphisms, interactions with environmental exposures and bladder cancer risk in a high-risk population. Int J Cancer 2004; 110: 598-604. 164
  147. Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Dalla Bernardina B et al. Oxidative stress-related biomarkers in autism: systematic review and meta-a- nalyses. Free Radic Biol Med 2012; 52: 2128-2141. 165
  148. Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tancredi DJ et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology 2011; 22: 476-485. 166
  149. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 2004; 80: 1611-1617. 167
  150. James SJ, Rose S, Melnyk S, Jernigan S, Blossom S, Pavliv O et al. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. FASEB J 2009; 23: 2374-2383. 168
  151. Melnyk S, Fuchs GJ, Schulz E, Lopez M, Kahler SG, Fussell JJ et al. Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism. J Autism Dev Disord 2012; 42: 367-377. 169
  152. Rose S, Melnyk S, Savenka A, Hubanks A, Jernigan S, Cleves MA et al. The frequency of polymorphisms affecting lead and mercury toxicity among children with autism. Am J Biochem Biotech 2008; 4: 85-94. 170
  153. Montenegro MF, Barbosa FJr, Sandrim VC, Gerlach RF, Tanus-Santos JE. A polymorphism in the delta-aminolevulinic acid dehydratase gene modifies plasma/whole blood lead ratio. Arch Toxicol 2006; 80: 394-398. 171
  154. Weuve J, Kelsey KT, Schwartz J, Bellinger D, Wright RO, Rajan P et al. Delta- aminolevulinic acid dehydratase polymorphism and the relation between low level lead exposure and the Mini-Mental Status Examination in older men: the Normative Aging Study. Occup Environ Med 2006; 63: 746-753. 172
  155. Owens SE, Summar ML, Ryckman KK, Haines JL, Reiss S, Summar SR et al. Lack of association between autism and four heavy metal regulatory genes. Neurotox- icology 2011; 32: 769-775. 173
  156. O'Reilly BA, Waring RH. Enzyme and sulphur oxidation deficiencies in autistic children with known food/chemical intolerances. J Orthomol Med 1993; 8: 198-200. 174
  157. Waring RH, Ngong JM, Klovrza L, Green S, Sharp H. Biochemical parameters in autistic children. Dev Brain Dysfunct 1997; 10: 40-43. 175
  158. Li Z, Dong T, Proschel C, Noble M. Chemically diverse toxicants converge on Fyn and c-Cbl to disrupt precursor cell function. PLoS Biol 2007; 5: e35. 176
  159. Shelton JF, Hertz-Picciotto I, Pessah IN. Tipping the balance of autism risk: potential mechanisms linking pesticides and autism. Environ Health Perspect 2012; 120: 944-951. 177
  160. Vahter M, Akesson A, Liden C, Ceccatelli S, Berglund M. Gender differences in the disposition and toxicity of metals. Environ Res 2007; 104: 85-95. 178
  161. Mocarelli P, Gerthoux PM, Ferrari E, Patterson DG Jr, Kieszak SM, Brambilla P et al. Paternal concentrations of dioxin and sex ratio of offspring. Lancet 2000; 355: 1858-1863. 179
  162. Hertz-Picciotto I, Jusko TA, Willman EJ, Baker RJ, Keller JA, Teplin SW et al. A cohort study of in utero polychlorinated biphenyl (PCB) exposures in relation to secondary sex ratio. Environ Health 2008; 7: 37. 180
  163. Borras C, Gambini J, Vina J. Mitochondrial oxidant generation is involved in determining why females live longer than males. Front Biosci 2007; 12: 1008-1013. 181
  164. Lavoie JC, Chessex P. Gender and maturation affect glutathione status in human neonatal tissues. Free Radic Biol Med 1997; 23: 648-657. 182
  165. Ballatori N, Clarkson TW. Dependence of biliary secretion of inorganic mercury on the biliary transport of glutathione. Biochem Pharmacol 1984; 33: 1093-1098. 183
  166. Thomas DJ, Fisher HL, Sumler MR, Mushak P, Hall LL. Sexual differences in the excretion of organic and inorganic mercury by methyl mercury-treated rats. Environ Res 1987; 43: 203-216. 184
  167. Muraoka Y, Itoh F. Sex difference of mercuric chloride-induced renal tubular necrosis in rats--from the aspect of sex differences in renal mercury con- centration and sulfhydryl levels. J Toxicol Sci 1980; 5: 203-214. 185
  168. Oliveira FR, Ferreira JR, dos Santos CM, Macedo LE, de Oliveira RB, Rodrigues JA et al. Estradiol reduces cumulative mercury and associated disturbances in the hypothalamus-pituitary axis of ovariectomized rats. Ecotoxicol Environ Saf 2006; 63: 488-493. 186
  169. Llop S, Lopez-Espinosa MJ, Rebagliato M, Ballester F. Gender differences in the neurotoxicity of metals in children. Toxicology 2013; 311: 3-12. 187
  170. Ballatori N, Clarkson TW. Biliary transport of glutathione and methylmercury. Am J Physiol 1983; 244: G435-G441. 189
  171. Serajee FJ, Zhong H, Mahbubul Huq AH. Association of Reelin gene poly- morphisms with autism. Genomics 2006; 87: 75-83. 192
  172. Fatemi SH, Stary JM, Halt AR, Realmuto GR. Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord 2001; 31: 529-535. 193
  173. Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 2006; 29: 349-358. 194
  174. Rubenstein JL, Merzenich MM. Model of autism: increased ratio of excitation/ inhibition in key neural systems. Genes Brain Behav 2003; 2: 255-267. 195
  175. Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 2001; 57: 1618-1628. 196
  176. Kenet T, Froemke RC, Schreiner CE, Pessah IN, Merzenich MM. Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortex. Proc Natl Acad Sci USA 2007; 104: 7646-7651. 197
  177. Xu F, Farkas S, Kortbeek S, Zhang FX, Chen L, Zamponi GW et al. Mercury- induced toxicity of rat cortical neurons is mediated through N-Methyl-D- Aspartate receptors. Mol Brain 2012; 5: 30. 198
  178. Juarez BI, Martinez ML, Montante M, Dufour L, Garcia E, Jimenez-Capdeville ME. Methylmercury increases glutamate extracellular levels in frontal cortex of awake rats. Neurotoxicol Teratol 2002; 24: 767-771. 199
  179. Gafni J, Wong PW, Pessah IN. Non-coplanar 2,2′,3,5′,6-pentachlorobiphenyl (PCB 95) amplifies ionotropic glutamate receptor signaling in embryonic cerebellar granule neurons by a mechanism involving ryanodine receptors. Toxicol Sci 2004; 77: 72-82. 200
  180. Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B et al. Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry 2002; 7: 302-310. 201
  181. Serajee FJ, Zhong H, Nabi R, Huq AH. The metabotropic glutamate receptor 8 gene at 7q31: partial duplication and possible association with autism. J Med Genet 2003; 40: e42. 202
  182. Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J et al. Association between a GABRB3 polymorphism and autism. Mol Psychiatry 2002; 7: 311-316. 203
  183. Vincent JB, Horike SI, Choufani S, Paterson AD, Roberts W, Szatmari P et al. An inversion inv(4)(p12-p15.3) in autistic siblings implicates the 4p GABA receptor gene cluster. J Med Genet 2006; 43: 429-434. 204
  184. Graf ER, Zhang X, Jin SX, Linhoff MW, Craig AM. Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 2004; 119: 1013-1026. 206
  185. Lintas C, Persico AM. Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist. J Med Genet 2009; 46: 1-8. 207
  186. Grandjean P. Individual susceptibility in occupational and environmental tox- icology. Toxicol Lett 1995; 77: 105-108. 208
  187. Weiss B, Bellinger DC. Social ecology of children's vulnerability to environmental pollutants. Environ Health Perspect 2006; 114: 1479-1485. 209
  188. Filipek PA, Accardo PJ, Baranek GT, Cook EH Jr, Dawson G, Gordon B et al. The screening and diagnosis of autistic spectrum disorders. J Autism Dev Disord 1999; 29: 439-484. 210
  189. Jones RL, Homa DM, Meyer PA, Brody DJ, Caldwell KL, Pirkle JL et al. Trends in blood lead levels and blood lead testing among US children aged 1 to 5 years, 1988-2004. Pediatrics 2009; 123: e376-e385. 211
  190. Bellinger DC. Very low lead exposures and children's neurodevelopment. Curr Opin Pediatr 2008; 20: 172-177. 212
  191. Braun JM, Kahn RS, Froehlich T, Auinger P, Lanphear BP. Exposures to environ- mental toxicants and attention deficit hyperactivity disorder in US children. Environ Health Perspect 2006; 114: 1904-1909. 213
  192. Seidel S, Kreutzer R, Smith D, McNeel S, Gilliss D. Assessment of commercial laboratories performing hair mineral analysis. JAMA 2001; 285: 67-72.

Cited by

Sorted by citations

Authors
Rossignol, D. A., Genuis, S. J., & Frye, R. E.
Affiliations
  • University of Alberta (CA)
  • Arkansas Children's Hospital (US)
Corresponding author
Rossignol, D A
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2014-02-11
Volume
4
Issue
2
Pages
e360-e360
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/tp.2014.4
PMC
PMC3944636
OpenAlex
W2132957742
Cited by
458
References
16
Citations by year
2026: 21 · 2025: 19 · 2024: 29 · 2023: 40 · 2022: 40 · 2021: 41 · 2020: 54 · 2019: 38 · 2018: 32 · 2017: 44 · 2016: 45 · 2015: 36 · 2014: 17 · 2013: 1
FWCI
4.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Autism Research Institute
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
Keywords
autism spectrum disorder, environmental toxins, prenatal exposure, early childhood exposure, air pollutants, pesticides, phthalates, polychlorinated biphenyls, solvents, heavy metals, genetic susceptibility, genetic polymorphism, autism severity, dose-response relationship, methylmercury, hazardous waste sites, water contaminants, autism risk factors, brain development
MeSH terms
Child Development Disorders, Pervasive, Humans, Hazardous Substances, Gene-Environment Interaction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review