Is Chelation Harmful to Children with Autism?

Recently, national news agencies reported that the National Institutes of Mental Health (NIMH) have decided to cancel plans for a proposed research study looking at the efficacy of chelation therapy in children with autism. Chelation is the process of using medication, such as dimercaptosuccinic acid (DMSA), to remove heavy metals like lead and mercury from body tissues. It is well-documented that lead and mercury have both neurotoxic and immunotoxic effects. There is also published evidence that suggests children with autism have impaired detoxification capacity and higher levels of heavy-metal body burdens compared to neurotypical children [1-5]. In light of this, chelation is frequently used as a treatment modality for children with autism. Although there are anecdotal reports that these children have improved through chelation therapy[6], there are no published controlled efficacy or safety studies specific to autism. Under pressure from autism advocacy parent organizations, the NIMH agreed to study chelation therapy in autism, but recently reversed their decision, stating, “The money would be better used testing other potential therapies for autism and related disorders.” As a reason for this reversal, they cited a study published in 2007 [7] as cause for concern about the safety of chelation therapy in children with autism, although chelation is FDA-approved for non-autistic children with high blood levels of lead. [8]

Since this study by Stangle et al. seems to be the major factor in the NIMH decision to not study chelation in autism, it is important to review the study. The stated purpose of the study was two-fold: 1) to determine whether treatment with a DMSA regimen that has been shown to decrease blood- and brain-lead levels in exposed rats would also result in lasting cognitive and affective changes caused by a “short” period of lead exposure during early development; and 2) to determine whether DMSA produces lasting cognitive and/or affective impairment when administered in the absence of lead exposure. To this end, a group of 120 rats was divided into three exposure groups: no lead exposure, moderate lead exposure and high lead exposure. They subsequently divided each of those groups into two treatment sub-groups, a DMSA-treated group and a no-treatment group. The exposure groups were then fed lead-contaminated water at different concentrations starting at day one of post-natal life (Day 1). For 17 days, the contaminated water was fed to the mothers, and the rat pups were exposed through the maternal milk. From Day 17 to Day 30, the pups were weaned and given the lead-tainted solution directly. On Day 30, the lead exposure was discontinued. DMSA was started the following day in the treatment group, given in a solution twice a day at a dose of 50 mg/kg/day for the first week and then 25 mg/kg/day for two more weeks. The non-treatment group was given apple juice. Chelation treatment ended on Day 52, and testing started on Day 62 and continued until 15 weeks of age.

The rats were tested in a variety of tasks that measured learning, attention, inhibitory control and arousal regulation, as these are areas that are impaired in lead-exposed children. Contrary to the cautions voiced by the NIMH, the results document a significant improvement in cognitive function in the lead-exposed individuals after chelation therapy. Both the moderate-exposure group and the high-exposure group showed improvement, although to differing degrees and in different areas of function. Prior to therapy, the moderate-exposure group demonstrated significant impairments in learning ability compared with controls. With chelation, the impairments disappeared and the group became indistinguishable from the controls. The high-exposure group had significant impairments in learning, attention and arousal-regulation. After treatment, they showed improvements in attention and arousal-regulation, but not in learning. Their post-treatment cognitive testing was similar to the untreated moderate-exposure group, and interestingly, their post-treatment brain-tissue lead concentrations were about the same as the pre-treatment moderate-exposure group. The authors speculated that a longer duration of chelation might have resulted in further cognitive improvement in this high-exposure group as the brain levels of lead continued to decrease.

The concerning finding in the study was that the group not exposed to lead but given DMSA showed lasting cognitive impairments resembling those of the high-exposure group before treatment. The authors cautioned that DMSA treatment might therefore be harmful in children who did not have elevated tissue-lead levels, perhaps by altering levels of beneficial metals in the body (such as zinc or copper). The authors ended the study report with the statement, “It is of significant concern that this type of therapy is being widely advocated as safe and effective for treating autism.”

So, what does this study teach us regarding chelation therapy in lead-exposed individuals, and is the strong caution about its use as a treatment modality for autistic children warranted?

In my opinion, the most important finding in this study is that lead induces significant cognitive impairments at relatively low blood levels after early developmental lead-exposure, and that chelation therapy resulted in significant improvements, including complete reversal of the impairments in the moderate-exposure group. According to the authors, very few studies have looked at cognitive measures when studying the effects of DMSA and lead exposure. Only one study has been done in human children, and it showed no detectable effect. [9] Stangle et al suggest that it was differences in design and duration of therapy that account for the discrepancy between their study and the human study. To the extent that we can extrapolate the findings of this rat study to humans, the outcome is very exciting. The authors state, “The present findings thus suggest that if a succimer (DMSA) treatment protocol that produced a substantial removal of lead from the brain could be identified for humans, a functional benefit might be derived.”

It is important to note that although the period of exposure of the rats to lead was only 3 weeks, this is equivalent to a period in humans extending from the third trimester of pregnancy to late childhood/early adolescence. This means that treatment didn’t start until adolescence, and yet they still showed dramatic improvement. It is also important to note that neither the moderate-exposure group nor the high-exposure group showed any outward evidence of lead toxicity, and the subtle cognitive effects were only detectable with behavior testing. Therefore, these rats would be representative of subclinical or asymptomatic lead toxicity in humans. Furthermore, similar to previous studies including one by the same authors, the blood level was not an accurate predictor of the brain tissue levels of lead [10-12]. Even the high-exposure group had a blood level that was lower than the recommended level for chelation under current CDC guidelines, in spite of a very high brain concentration of lead, and cognitive impairments across multiple areas. The authors also state that rats typically require much higher levels of lead exposure to show negative effects compared to humans, so theoretically, humans would have higher levels of cognitive impairment at even lower levels of lead exposure.

How does the protocol used in this study differ from the DMSA protocols commonly used in autism? The rats were given oral DMSA twice daily for 21 days straight (using a commonly prescribed regimen for non-autistic children with high blood lead levels)[13]. Because rats develop at a much faster rate than humans, one would need to project that a 21-day treatment in rats would represent many years of daily treatment in humans. The rats were given 50 mg/kg/day for the first week and then 25 mg/kg/day for the next two weeks. Most doctors treating children with autism use a 3-day-on, 11-day-off protocol at a concentration of 30 mg/kg/day (divided every 8 hours, if given orally), with treatment lengths varying from several months to a couple of years, depending on metal excretion results. Therefore, the cumulative levels of DMSA exposure in the rats were many orders of magnitude higher than in common chelation regimens used in autism. When chelating children, it is imperative that minerals and antioxidants are supplemented to prevent mineral depletion or oxidative stress. These supportive measures were not given to the rats in any of the treatment groups, and this is likely the reason for the worsening of the group of rats that were never exposed to lead and given the DMSA.

This study does underscore the importance of appropriate patient selection when deciding whether or not to chelate. Because blood metal levels are not accurate predictors of tissue levels, you cannot use them as a screening measure (as is the current standard practice recommended by the CDC and the AAP). I use a surrogate marker of tissue levels, such as a urinary porphyrin test or a urinary DMSA challenge test with a pre- and post-medication urine collection. If there is no evidence of elevated tissue levels of heavy metals, I agree with the precautions as presented in this study and would refrain from chelating. However, unlike the controlled laboratory situation of the rats in this study, heavy metal exposure to the human population is ubiquitous, and autistic children in particular seem to be at risk of injury from environmental toxicants. [14-19] It is unlikely that if the patients are adequately supported with minerals and antioxidants, the negative outcome of the study would be duplicated in real-life clinical practice.

In summary, Stangle et al. show that cognitive symptoms in subclinical lead toxicity can be reversed by DMSA chelation therapy, and that it is effective at removing lead from the blood and the brain in rats. It also shows that blood levels are not accurate predictors of tissue (brain) levels, and should not be used as a screening mechanism. It shows that chelation therapy done with no concurrent mineral or antioxidant support might be harmful in situations where there is no previous exposure to heavy metals. What it does not show is whether chelation is safe or effective in autistic children with documented elevated tissue levels of heavy metals. The suggestion by these authors that chelation is dangerous to these children is premature and is not supported by their study. It shows an obvious bias on the part of the authors and a lack of understanding about the detoxification impairments in children with autism. It is too bad that the NIMH have decided that in spite of widespread positive anecdotal reports and studies showing biological plausibility, chelation therapy in autism is not deemed worthy of further study. Perhaps it is for the best, however, since the study design that they were considering, like the rat study, did not include supportive mineral or antioxidant therapy. It is possible that they would have seen some negative effects related to mineral depletion, which would have further prevented a promising therapy from receiving the attention that it deserves. Hopefully, others will take up the charge and fund an appropriately-designed chelation study to finally answer this controversial, but important question.

Bryan Jepson MD

References:

1. Adams, J.B., et al., Mercury, lead, and zinc in baby teeth of children with autism versus controls. J Toxicol Environ Health A, 2007. 70(12): p. 1046-51.
2. Fido, A. and S. Al-Saad, Toxic trace elements in the hair of children with autism. Autism, 2005. 9(3): p. 290-8.
3. Holmes, A.S., M.F. Blaxill, and B.E. Haley, Reduced levels of mercury in first baby haircuts of autistic children. Int J Toxicol, 2003. 22(4): p. 277-85.
4. Desoto, M.C. and R.T. Hitlan, Blood levels of mercury are related to diagnosis of autism: a reanalysis of an important data set. J Child Neurol, 2007. 22(11): p. 1308-11.
5. Geier, D.A., et al., Biomarkers of environmental toxicity and susceptibility in autism. J Neurol Sci, 2008.
6. ARI. Parent Ratings of behavioral effects of biomedical interventions. 2008 [cited.
7. Stangle, D.E., et al., Succimer chelation improves learning, attention, and arousal regulation in lead-exposed rats but produces lasting cognitive impairment in the absence of lead exposure. Environ Health Perspect, 2007. 115(2): p. 201-9.
8. Volume, DOI: http://www.fda.gov/cder/foi/label/2007/019998s013lbl.pdf
9. Dietrich, K.N., et al., Effect of chelation therapy on the neuropsychological and behavioral development of lead-exposed children after school entry. Pediatrics, 2004. 114(1): p. 19-26.
10. Cremin, J.D., Jr., et al., Efficacy of succimer chelation for reducing brain lead in a primate model of human lead exposure. Toxicol Appl Pharmacol, 1999. 161(3): p. 283-93.
11. Stangle, D.E., et al., Reductions in blood lead overestimate reductions in brain lead following repeated succimer regimens in a rodent model of childhood lead exposure. Environ Health Perspect, 2004. 112(3): p. 302-8.
12. Smith, D., L. Bayer, and B.J. Strupp, Efficacy of succimer chelation for reducing brain Pb levels in a rodent model. Environ Res, 1998. 78(2): p. 168-76.
13. Rogan, W.J., et al., The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead. N Engl J Med, 2001. 344(19): p. 1421-6.
14. James, S.J., et al., Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr, 2004. 80(6): p. 1611-7.
15. James, S.J., et al., Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet, 2006. 141B(8): p. 947-56.
16. Palmer, R.F., et al., Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas. Health Place, 2006. 12(2): p. 203-9.
17. Palmer, R.F., S. Blanchard, and R. Wood, Proximity to point sources of environmental mercury release as a predictor of autism prevalence. Health Place, 2008.
18. Windham, G.C., et al., Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay area. Environ Health Perspect, 2006. 114(9): p. 1438-44.
19. Roberts, E.M., et al., Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environ Health Perspect, 2007. 115(10): p. 1482-9.

Return to Press Releases