The brain pathology in autism spectrum disorders (ASD) indicates marked and ongoing inflammatory reactivity with concomitant neuronal damage. These findings are suggestive of neuronal insult as a result of external factors, rather than some type of developmental mishap. Various xenobiotics have been suggested as possible causes of this pathology. In a recent review, the top ten environmental compounds suspected of causing autism and learning disabilities were listed and they included: lead, methyl-mercury, polychorinated biphenyls, organophosphate pesticides, organochlorine pesticides, endocrine disruptors, automotive exhaust, polycyclic aromatic hydrocarbons, polybrominated diphenyl ethers, and perfluorinated compounds. This current review, however, will focus specifically on mercury exposure and ASD by conducting a comprehensive literature search of original studies in humans that examine the potential relationship between mercury and ASD, categorizing, summarizing, and discussing the published research that addresses this topic. This review found 91 studies that examine the potential relationship between mercury and ASD from 1999 to February 2016. Of these studies, the vast majority (74%) suggest that mercury is a risk factor for ASD, revealing both direct and indirect effects. The preponderance of the evidence indicates that mercury exposure is causal and/or contributory in ASD.
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Blood Levels of Mercury Are Related to Diagnosis of Autism: A Reanalysis of an Important Data Set
Article (PDF Available)inJournal of Child Neurology 22(11):1308-11 · December 2007 with 965 Reads DOI: 10.1177/0883073807307111 · Source: PubMedCite this publication
AbstractThe 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.
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Download full-text PDFContent uploaded by Mary Catherine DesotoAuthor contentContent may be subject to copyright.http://jcn.sagepub.comJournal of Child Neurology DOI: 10.1177/0883073807307111 2007; 22; 1308 J Child NeurolM. Catherine DeSoto and Robert T. Hitlan SetBlood Levels of Mercury Are Related to Diagnosis of Autism: A Reanalysis of an Important Datahttp://jcn.sagepub.com/cgi/content/abstract/22/11/1308 The online version of this article can be found at: Published by:http://www.sagepublications.com can be found at:Journal of Child Neurology Additional services and information for http://jcn.sagepub.com/cgi/alerts Email Alerts: http://jcn.sagepub.com/subscriptions Subscriptions: http://www.sagepub.com/journalsReprints.navReprints: http://www.sagepub.com/journalsPermissions.navPermissions: http://jcn.sagepub.com/cgi/content/refs/22/11/1308SAGE Journals Online and HighWire Press platforms): (this article cites 10 articles hosted on the Citations © 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution. by guest on November 17, 2007 http://jcn.sagepub.comDownloaded from 1308exposed to relatively high mercury would not be affected if,for example, their bodies were very efficient eliminators ofsuch toxins. Only if an exposed infant or fetus also had agenetic susceptibility that makes one less able to removemercury (or other heavy metals) would normal levels of mer-cury exposure lead to problems. Alternatively, it could be thatgenes that help detoxify get switched on and start to expressthemselves a little later than normal in those genetically pre-disposed to autism; or perhaps, autism results from somecombination of these theories.Nevertheless, if mercury does play any causal role infacilitating a diagnosis of autism, there would likely be atleast some relation between high mercury measured in theblood and symptoms of autism even if ability to metabolizemediates the relationship between exposure and neural tox-icity. This is because even if exposure is identical, those whoremove mercury less effectively should still have higher lev-els in the blood. Interestingly, results of hair samples couldbe expected to be somewhat mixed. The level of mercury inhair may be better understood as an indication of how muchmercury has been removed by the body as opposed to thelevel in the body.6If people are approximately equal in theirability to remove circulating mercury from the bloodstream,then these 2 indicators should match up closely, but if a person’s ability to excrete is low, their hair samples mightnot be elevated even when their blood levels are high. Fido and Al-Saad found that mercury levels in hair sam-ples were higher in children diagnosed with autism.8Thesechildren were aged 4 to 7. In contrast, Kern et al. reportedthat mercury hair levels were not significantly different, butwere lower at a marginally significant level.9Kern et al. usedyounger children, ages 1 to 6. Holmes et al. performed theThere is a marked increase in the diagnosis of autism.The question of what is (and is not) related to thisincrease is crucial to millions of persons affected bythe disorder. This article reanalyzes an original data setregarding the relation between blood levels of mercury anddiagnosis of an autism spectrum disorder (ASD) by Ip et al.based on our finding of discrepancies in the original article.1A review of what is known about the neurotoxic effects of mercury is beyond the scope of this paper,2but theobservable symptoms of acute mercury poisoning have beenreported to match up with many of the problems observed inautism.3 Furthermore, mercury poisoning has sometimesbeen presumptively diagnosed as autism of unknown etiol-ogy until the mercury poisoning has been uncovered.4Because there has been a several-fold increase in environ-mental mercury exposure, the hypothesis that the rise inautism could be related to an environmental increase in mer-cury levels is a reasonable one to pursue. Autism may resultfrom a combination of genetic susceptibility (perhaps in theform of reduced ability to remove mercury or other neuro-toxins from the system) and environmental exposure at keytimes in development.5-7This would mean a generalizedincrease in mercury levels would be expected to co-occurwith a generalized increase in autism, but some peopleSpecial ArticleBlood Levels of Mercury Are Related to Diagnosis of Autism: A Reanalysis of an Important Data SetM. Catherine DeSoto, PhD, and Robert T. Hitlan, PhDThe question of what is leading to the apparent increase inautism is of great importance. Like the link between aspirinand heart attack, even a small effect can have major healthimplications. If there is any link between autism and mercury,it is absolutely crucial that the first reports of the question arenot falsely stating that no link occurs. We have reanalyzed thedata set originally reported by Ip et al. in 2004 and have foundthat the original p value was in error and that a significantrelation does exist between the blood levels of mercury anddiagnosis of an autism spectrum disorder. Moreover, the hairsample analysis results offer some support for the idea thatpersons with autism may be less efficient and more variable ateliminating mercury from the blood.Keywords: autism; mercury; environmental health; neuro-toxin; neurodevelopment; bloodFrom the Department of Psychology, University of Northern Iowa,Cedar Falls, Iowa.Address correspondence to: M. Catherine DeSoto, Department ofPsychology, University of Northern Iowa, Cedar Falls, IA 50614; e-mail:cathy.desoto@uni.edu.DeSoto, CM, Hitlan RT. Blood levels of mercury are related to diagno-sis of autism: a reanalysis of an important data set. J Child Neurol.2007;22:1308-1311.Journal of Child NeurologyVolume 22 Number 11November 2007 1308-1311© 2007 Sage Publications10.1177/0883073807307111http://jcn.sagepub.comhosted athttp://online.sagepub.com © 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution. by guest on November 17, 2007 http://jcn.sagepub.comDownloaded from Mercury and Autism Reanalysis / DeSoto, Hitlan 1309most direct test of the hypothesis that autistic children maybe deficient in terms of ability to remove mercury from cir-culation.6This study estimated mercury exposure of themothers via a mercury exposure survey questionnaire. Theythen analyzed the first haircuts of the autistic children and agroup of controls (the first haircuts would reflect mercuryexcretion in utero and very early life). In the autistic group,severity of autism was inversely related to hair mercury lev-els. This means that the more severe autistic cases actuallyhad less excretion of mercury. Furthermore, among the nor-mal children, hair levels of mercury were correlated to themother’s mercury exposure (as would of course be expected).But among the autistic children, there was no linear relationbetween the mother’s mercury exposure and excretion ofmercury in the hair. As the authors state, this pattern ofresults is easily understood if one considers “detoxificationcapacity of a subset of infants,”6(p 6) such that the bodies ofthose diagnosed with autism appeared to be less able toexcrete and/or metabolize the mercury they were exposed to. As the rise in autism is relatively recent, it is not sur-prising that research into the etiology has not kept pace.Indeed, there are few published articles that considerblood levels of children with mercury that utilize a controlgroup; a psycInfo search using the words “autism,” “mer-cury,” and “blood” yields only one hit.1Given the highstakes involved, it is crucial that early reports of the con-nection between blood mercury levels and autism not bemisstated. Even a small effect size would be of great the-oretical and practical consequence. In 2004, Ip et al. reported that no relationship existedbetween mercury blood levels and diagnosis of autistic spec-trum disorder among a group of children with an averageage of approximately 7 years. While attempting to estimatethe effect size based on the Ip et al. statistics, we realizedthat the numbers reported by Ip et al could not be correct.The means and standard deviations reported in the 2004article yielded an easily significant t value (autism mean =19.53 nmol/L, SD = 5.6, n = 82; control mean = 17.68nmol/L, SD = 2.48, n = 55 gives a t = 2.283, two-tailed P =.024 or one-tailed P = .012). Ip et al. wrote that the P valuewas “(P) = .15,”1(p432)and that their data indicate “there isno causal relationship between mercury and as an environ-mental neurotoxin and autism.”1(p431)After the error wasbrought to the attention of the authors, a new analysis wasconducted by the original authors and they found the originalt test to be in error and the P value to be a mistake (refer to Erratum, p.1324). Based on their corrected analysis, theauthors report the revised P value for their t test to actuallybe P = .056. We disagree on several grounds that these dataindicate no significant effect exists, and report on a com-pletely new reanalysis of the original data set.MethodsOutliers were removed prior to statistical analysis. Anoutlier is defined as a score that is “substantially greateror less than the values obtained from any other individ-ual.”10(p521)Outliers have an unduly large influence on theoutcome of a statistical test. What actually qualifies as anoutlier differs depending on the research question andthe statistician analyzing the results; however, valuesgreater than 3 standard deviations either above or belowthe mean generally qualify as extreme cases.11Within theIp et al. data, there were 2 such values that were notremoved prior to our reanalysis. These 2 values were morethan 3 standard deviations above the mean, and both ofthese values were far from any other score. (Other scoreswere within 3 points of the next individual; these 2 scoreswere each 15 or more points away from any other scorein the distribution.) To avoid the appearance that these 2outliers were removed to influence the statistical out-come as opposed to objective criteria for cleaning a dataset, it should be noted that the biggest outlier of the 2 wasan unusually high blood mercury level of 98, which wasin the autistic group. To be clear⎯if anything, removal ofthe outliers resulted in a more conservative test as it actu-ally decreased the mean difference between the 2 groups.ResultsLogistic regression was performed using blood mercurylevel as the predictor and the autistic/control group as thecriterion. Results of this reanalysis indicate that bloodmercury level can be used to predict autism diagnosis.Data included: r = .20, r2= .04, F(1,133) = 5.76, P = .017.This finding indicates that there is a statistically signifi-cant relationship between mercury levels in the blood anddiagnosis of an autism spectrum disorder.There was no difference in the mean hair levels wheret(135) = .24 and one-tailed P = .40; this is essentially thesame result reported in the original article. However,given that hair levels would normally be expected to behighly correlated to blood levels, it might be surprisingthat blood levels could predict an autism spectrum diag-nosis, but that hair mercury levels could not. Indeed, hairand mercury levels for the full sample were correlated (r = .86, P < .001) indicating that about 75% of the vari-ance in hair levels was accounted for by the mercury levelin the blood. To us, the question turned to what the other25% of the variance might be due, and whether theassumptions of the t test were violated. Although not thecentral focus of this report, these results could certainlyhelp to inform future researchers of the nature of therelation between autism and mercury, and we include thisinformation for completeness. Exploratory Analysis. If one hypothesizes that personswith autism are less able to excrete mercury, especiallywhen their blood levels get in the higher range, one mightexpect that the correlation between blood and hair levelswould break down at the higher blood levels among theautism spectrum group (a type of heteroscedasticity).5 © 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution. by guest on November 17, 2007 http://jcn.sagepub.comDownloaded from 1310 Journal of Child Neurology / Vol. 22, No. 11, November 2007Another way of looking at it, the relationship between bloodlevel and hair excretion may be different for persons withautism than those without autism. Levine’s test of equalityof variance indicated the variance in hair mercury was notevenly distributed between the autism and control groups (F =5.98, P = .017). We calculated the correlation for personswhose circulating levels of mercury were in the top quartileseparately for the autism and control groups. The correla-tion between blood and hair levels of mercury was r = .91for the control group (accounting for 84% of the variance).For the autistic group, the correlation was r = .73, meaningonly about 55% of the variance in the hair mercury levelswas attributable to the blood mercury level differences. To check the hypothesis that hair excretion was over-all lower than would otherwise be predicted based on acertain blood level in the autistic group, a best fit regres-sion line was calculated (y = 10.3, x =−2.48) indictingthat for each unit increase in hair level, blood levelincreased by 10.3 units. A t test on the residuals showedthat autistic participants were significantly more likely tohave lower hair mercury levels than would be predicted asa function of their blood levels, t(133) =−2.92, P < .005;see Figure 1). It should also be noted that the presence ofunequal variances or nonrandom residuals (in this case,autistic persons are both more likely to have greater vari-ability at high levels of circulating mercury and a lowerhair value for a given blood level) are both violations ofimportant assumptions of the t test; a t test of hair mer-cury is therefore probably not a valid means to predictautism diagnosis as a function of mercury exposure. Weperformed an analysis of covariance (ANCOVA) withautism diagnosis as the independent variable and hairmercury level as the dependent predictor using blood lev-els as a covariate. Results indicate that hair level may berelated to diagnosis of autism, not as a predictor in termsof absolute value, but such that for equivalent circulatinglevels of mercury in the body, those with ASD excretedless than normal such that F(1,134) = 3.9 and P = .05. Tosum, the relationship between blood levels of mercuryand mercury excreted in the hair is reduced for those withautism compared with nonautistic persons; furthermore,the difference between autistic and nonautistic persons ismost pronounced at high levels of mercury.DiscussionIn statistics, obtaining a probability value of P < .05 indi-cates that the obtained test statistic (based on one’s sam-ple) is extremely unlikely (less then 5% chance) to havebeen obtained by chance alone. By convention, this valueis usually set at .05 (as a balance of type 1 and type 2errors); however, this value is, in fact, arbitrary and sta-tistical probability tables for hypothesis testing alwaysinclude a range of probability values⎯not only probabil-ity at the .05 level. Given that this is the first direct testof this hypothesis and considering the potential impor-tance of finding a relation between mercury blood levelsand autism, it is just as important to avoid a false negativeas a false positive. As the original authors have now cur-rently calculated, the obtained difference suggests thatthere is probably a real difference (specifically that thechance that a real effect exists is about 94%, or, con-versely, that the chance the null effect is true is less thanFigure 1. More variability is seen in the relation between circulating levels of mercury and hair levels (a mark of excretion) among those diagnosedwith an autism spectrum disorder than among control group participants. Autistic participants are also significantly more likely to have lower hairexcretion for the same blood levels. This is consistent with the idea that autism may be partly related to a lesser ability to rid the body of neurotox-ins such as mercury. © 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution. by guest on November 17, 2007 http://jcn.sagepub.comDownloaded from Mercury and Autism Reanalysis / DeSoto, Hitlan 13116%, which misses the conventional .05⎯or 5%⎯mark ofstatistical significance). Given the close value to conven-tional significance, most researchers would not call this afirm rejection of the hypothesis, but might say it was mar-ginally significant. Most researchers facing a P value of.056 would not want to categorically state that results“indicate that there is no casual relation between mercurylevel . . . and autism.”1It concerns us that the originalauthors would want to let this conclusion stand in light ofthe new P value (which differs markedly from the .15 pre-viously reported in 2004). Another issue to consider is the question of a one-tailedor a two-tailed hypothesis test. Usually, researchers use atwo-tailed test, which tests if there is a “difference” between2 groups. However, when the literature leads a researcher topropose a specific direction of the difference, a one-tailedtest is called for, “Often a researcher begins an experimentwith a specific prediction about the treatment effect. Forexample, a special training program is expected to increasestudent performance, or alcohol consumption is expected toslow reaction times . . . The result is a directional test, orwhat is commonly called a one-tailed test.”10(p246)Whether to use a one-tailed test or a two-tailed testcan be decided based on considering what would happenif the results ended up in the opposite direction of whatone suspects. In this case, it would mean that the bloodmercury levels were lower in the autistic group. Wouldthis support the original hypothesis? (No!) However, ifthis were to happen, that is, if the autistic group were sig-nificantly lower in their blood mercury levels than thenormal group, the researchers would find themselves inthe incongruous position of having to accept theirhypothesis that autism is related to elevated levels ofmercury in the blood! The key point here is that theirhypothesis was directional, and a one-tailed test shouldhave been used. In this case, the just missed significanceof their new analysis using a two-tailed t-test (P = .056)would have reached a conventional level of statistical sig-nificance (with P < .03). Although the statistics can be tedious, the bottom line isthat only by an apparent error in the original data analysiswas the original lack of effect found. The authors’ revisedcalculation (t test) still has problems (two-tailed test for adirectional hypothesis, not removing clear outliers). Andfinally, the willingness to characterize a t test with a .056level of statistical significance as no effect is questionable,especially in this particular case.Of utmost importance (which outweighs the discomfortof writing about an error made by colleagues whom weknow are generally competent researchers) is that potentialresearchers who are trying to understand what is and is not behind the rise in autism are not misled by even theslightest misinformation. It is imperative that researchers,medical professionals, and the public at large have the fullset of information. To put it in perspective, the connectionbetween taking aspirin and prevention of heart attack has aneffect size equal to .038 which represents an effect sizeapproximately equal to what we find between circulatinglevels and ASD diagnosis in this age group.12Just as impor-tant is the fact that for those physicians in the aspirin groupwho did have a heart attack, the heart attack was less likelyto be fatal. The effect size for this latter effect was .08 anddid not represent a significant difference from the placebogroup by traditional dichotomous significance testing.13Yet,this does not mean no effect exists or that the effect is not ofpractical importance. We would encourage all researchers tonot only report whether a test of mercury and autism reachessignificance with the sample size used, but to report theexact statistic and also effect sizes to help future researchersresolve all the factors involved in the etiology of autism. References1. Ip P, Wong V, Ho M, Lee J, Wong W. Mercury exposure in childrenwith autistic spectrum disorder. J Child Neuro. 2004;19:431-434. 2. National Academy of Sciences. Toxicological Effects of Methylmer-cury. Washington, DC: National Academy Press; 2000.3. Bernard S, Enayati A, Redwood L, et al. Autism: a novel formof mercury poisoning. Med Hypoth. 2001;56:462-471.4. Chrysochoou C, Rutishauser C, Rauber-Luthy C, et al. An 11-month-old boy with psychomotor-regression and auto-aggressivebehavior. Eur J Pediatr. 2003;162:559-561. 5. Adams JB, Romdalvic J, Sadagopa VH, Legator MS. Mercury,lead, and zinc in baby teeth of children with autism versus con-trols. J Toxicol Environ Health. 2007;70:1046-1051.6. Holmes AS, Blaxill MF, Haley BE. Reduced levels of mercuryin first baby haircuts of autistic children. Int J Toxicol. 2003;22:277-285.7. Walker SJ, Segal J, Aschner M. Cultured lymphocytes from autis-tic children and nonautistic siblings up-regulate heat shock proteinRNA in response to thimerosal challenge. Neurotoxicol. 2006;27:685-692.8. Fido A, Al-Saad S. Toxic race elements in the hair of childrenwith autism. Autism. 2005;9:290-298.9. Kern JK, Grannerman BD, Trivedi MH, Adams J. Sulfhydryl-reactive metals in autism. J Toxicol Environ Health. 2007;70:715-721.10. Gravetter FJ, Wallnau LB. Essentials of Statistics for the BehavioralSciences. 4th ed. Pacific Grove, CA: Wadsworth; 2005.11. Tabachnik B, Fidell LS. Using Multivariate Statistics. New York:Prentice Hall; 2006. 12. Steering Committee of the Physicians’ Health Study ResearchGroup. Preliminary report: findings from the aspirin compo-nent of the ongoing physicians’ health study. N Engl J Med.1988;318:262-264.13. Rosnow RL, Rosenthal R. Statistical procedures and the justi-fication of knowledge in psychological science. Am Psychol.1989;44:1276-1284. © 2007 SAGE Publications. All rights reserved. Not for commercial use or unauthorized distribution. by guest on November 17, 2007 http://jcn.sagepub.comDownloaded from Citations (93)References (17)
- … In 2007, Desoto and Hitlan also reported a significant relationship between higher blood levels of mercury and ASD. This paper also reported reduced excretion of mercury in hair, suggesting impaired mercury excretion in ASD (Desoto and Hitlan, 2007). …Autism spectrum disorder and mercury toxicity: use of genomic and epigenetic methods to solve the etiologic puzzleArticle
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- … Among all reviewed studies, only for a few health conditions the associations with mercury levels were found to be conclusive. For ex- ample, at higher mercury exposure, significant differences in Hg-B le- vels were observed between autistic children (grand mean: 64.6 μg/L) and controls (grand mean: 23.2 μg/L) (DeSoto and Hitlan, 2007;Li et al., 2017;Mostafa et al., 2016;Mostafa and Al-Ayadhi, 2015;Mostafa and Refai, 2007;Yassa, 2014). In agreement with this finding, two earlier reviews suggested that a majority (74%) of the published lit- erature supports a positive association between mercury exposure and autism in children (deSoto and Hitlan, 2010;Kern et al., 2016). …An overview of worldwide and regional time trends in total mercury levels in human blood and breast milk from 1966 to 2015 and their associations with health effectsArticleFull-text available
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- A generalized weighted quantile sum approach for analyzing correlated data in the presence of interactionsArticle
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- Interaction between manganese and GSTP1 in relation to autism spectrum disorder while controlling for exposure to mixture of lead, mercury, arsenic, and cadmiumArticle
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- Systematic Assessment of Research on Autism Spectrum Disorder (ASD) and Mercury Reveals Conflicts of Interest and the Need for Transparency in Autism ResearchArticleFull-text available
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