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Monday, January 3, 2011
Updated: Friday, April 18, 2014
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by John C. Pittman, MD, and Mark N. Mead, MSc
Are mercury, lead, and other toxic metals likely culprits in classic autism, ADHD, Asperger Syndrome, and other Autism Spectrum Disorders (ASDs)? Can yeast overgrowth and intestinal imbalances have a substantial impact on many ASDs? Do kids with ASDs often suffer from an inability to detoxify toxic compounds? Can these children benefit from therapies aimed at removing these toxic factors and correcting the underlying biological problems?
The answer to all these questions, based on our clinical experiences and training at the Autism Research Institute, is a resounding yes. But if this is the case, why is there so much disagreement among pediatricians and public health scientists? The reason: Much of the population-based research to date has focused on the more superficial aspects of ASDs, and in doing so has helped engender the misunderstanding that such toxic factors as mercury and fungal toxins are of little relevance to the child with autism.
Of Detox Defects and Vulnerable Brains
A recent study, published in a 2010 issue of Acta Neurobiologiae Experimentalis, found that individuals diagnosed with ASD had blood mercury levels that were approximately double those observed in non-ASD individuals. However, closer examination of the data revealed a threshold blood mercury level below which no autism was seen. Specifically, the total blood mercury level did not increase the odds of having autism until it was greater than 26 nmol/L (>5.2 μg/L). Individuals with a blood level higher than 26 nmol/L were three times more likely to be diagnosed with autism than individuals whose blood level was lower than 26 nmol/L.
These findings, which come from the Institute of Chronic Illnesses, Inc., in Silver Spring, Maryland, are consistent with multiple studies showing increased levels of mercury in the teeth and brains of children diagnosed with an ASD relative to non-ASD kids. Several studies also found increased mercury in the urine and fecal samples following chelation therapy, as well as associated urinary porphyrins among ASD individuals relative to the control groups. Moreover, a 2009 report in the Journal of Toxicology demonstrated a strong relationship between the severity of autism and the relative body burden of toxic metals.
Now, some scientists may reasonably argue that blood mercury levels are not consistently linked with ASDs, and they would be correct. However, blood mercury levels do not reflect chronic exposures or tissue levels—only acute exposures, for example, from industrial accidents, eating mercury-laden fish, or off-gassing from dental amalgams. The metals that accumulate from pre- and post-natal exposure are not reliably detected by a blood test, only by a combination of urinary porphyrins and urinary mercury following administration of metal-binding agents. Doctors who have studied heavy metal toxicology understand this.
Also seemingly paradoxical is the finding of lower hair levels of mercury in very young children with ASDs. This suggests that ASD kids are unable to excrete the mercury that has accumulated in their bodies. Indeed, we find that virtually all children with autism show measurable defects in their detoxifying capacity. These defects render the children unable to eliminate or neutralize many brain-toxic factors such as lead, mercury, and pesticides—and more prone to the brain-injuring effects of inflammation and oxidative stress. Many of these kids also have immune system imbalances that keep ther brains inflammed as well as rendering them even more susceptible to harmful bacteria and other microbes and their toxins.
The implications of this complex profile of susceptibility are profound. These children are like the proverbial “canaries in the coal mine”—far more vulnerable to the pollutants that other children’s bodies handle with ease. If you’re not taking into account the detoxification and immunologic problems commonly found in autistic children, then population-based comparisons of exposure levels have less relevance.
Deficiencies in key nutrients and metabolites that support detoxification pathways also are extremely common among children with ASDs. For example, many of these kids show low glutathione or its metabolites in their blood and urine. Since glutathione is the core detoxifying molecule in our cells, this deficiency greatly limits the child’s ability to process and eliminate mercury and other toxicants from the blood. Those children who are genetically less capable of detoxification, or whose detox mechanisms are overwhelmed with other toxins, are far more prone to toxic overload—and thus to the neurologic and behavioral problems linked with ASDs.
Developmental Delay or True Treatment Effect?
Another common criticism you will hear of doctors who are using this innovative approach is that autism is a condition of developmental delay, and that at least some of these children—possibly 5 to 19 percent—will go on to develop and function fairly well. Without conducting randomized controlled trials, these critics say, you never can know whether the development and improvement of symptoms would have occurred anyway with time, or whether the improvement could simply be attributed to behavioral and occupational therapy.
Going further, the critics contend that the single-person level of observation can be very deceiving, and that you can easily be fooled into believing that what you are observing is a real benefit versus something that might have happened by chance.
Here’s the main problem with this view, and perhaps the most profound myth-busting truth of all. You cannot be fooled by what you’re seeing when improvements occur on the integrative treatment program, and then those same improvements vanish if the child goes off the program. If your child quickly gets worse every time they go off their program, and then improves again every time they go back on, this is clearly due to the treatment. This is what separates clinical trials from case-by-case observations in the clinical setting, and it is incredibly important in the context of ASDs, since every case is so different and requires a high degree of individual tailoring based on testing results.
Let’s take the example of intestinal candidiasis, or yeast overgrowth. When children with ASDs are treated for an obvious yeast overgrowth, at some point they begin to show a dramatic improvement in their behavior—showing great eye contact, communicating well or even animatedly, becoming more peaceful and attentive. When they go off the anti-yeast treatment, their behavior can spin wildly out of control again.
Another example: Many children are sensitive to gluten. Take them off gluten-containing foods for three weeks, then reintroduce those foods and watch what happens. Very often there will be some improvement in behavior during the time off gluten, but if the child has an underlying intestinal infection or yeast overgrowth situation, that must be resolved first.
Our approach at the Carolina Center for Integrative Medicine addresses the problems that are common to virtually all children with ASDs, including detoxification weaknesses, toxic overload, nutritional deficiencies, and intestinal imbalances such as yeast overgrowth. Various nutrient deficiencies have been documented in children with ASDs, and targeted nutritional strategies are often very helpful and again make other strategies more effective. In addition, we help identify certain “trigger” foods, such as casein-containing dairy products, wheat and other gluten sources, sugar, chocolate, preservatives, and food colorings.
As implied in the mention of gluten and yeast (see above), proper sequencing of the treatments is part of the art of medicine when it comes to helping kids with ASDs. For example, the full benefits from heavy metal detoxification and hyperbaric therapy (pressurized oxygen) are only likely to occur when the GI tract problems are addressed first. Children undergoing this integrative approach may show rapid improvement in language and social skills, as well as better sleep, moods, and overall disposition.
The medical-scientific community is beginning to wake up to the power of this perspective. In November 2009, the American Academy of Pediatrics, Autism Speaks, and the North America Society for Pediatric Gastroenterology, Hepatology and Nutrition, hosted a symposium of researchers and physicians to address GI problems seen in children with ASDs. The symposium was intended to raise awareness among specialists about GI disorders in autism and to educate doctors about new treatment strategies for ASDs.
Overcoming Autism: A Success Story
When it comes to harnessing the power of this integrative approach, one of the keys to therapeutic success is catching ASDs at an early age, when there is still sufficient neuro-plasticity or brain plasticity. The term plasticity refers to the central nervous system’s ability to change neurons and neuronal pathways, and ultimately to re-organize entire neural networks. A good example of this early-life therapeutic advantage is the story Mike Simpson, now age 5, who was diagnosed in November 2006 with autism. At the time of his diagnosis, several physicians had told Mike’s parents, John and Suki Simpson, that no treatment options existed and that recovery was impossible.
Mike’s pediatrician referred the parents to the state’s behavioral intervention program. Although they found the program somewhat helpful, it clearly was only a start, and his behavior remained that of a child with classic autistic disorder. “At the time, Mike did not respond to his own name,” Suki Simpson recalls. “He was unable to sit in a chair or by a table, and he could not focus on any activity for any extended period of time.” Due to these limitations, it seemed unlikely that he could reasonably benefit from the behavioral program.
In his first year of life, Mike appeared to be deaf because he would not respond to his name, nor did he react to loud noises, such as the doorbell ringing or a car horn honking. Testing revealed that his hearing was fine. In fact, as the parents later learned, Mike was quite sensitive to sound—but was not responding because he was tuning the sound out due to the pain it caused. This phenomenon is fairly typical among children with autism.
One glance at Mike’s diet at the time might have provided some insight into his behavioral issues. From the moment he began eating solid foods, according to the Simpson parents, he seemed to constantly crave carbohydrate items such as crackers, pizza, chicken nuggets and Cheerios. His diet as a whole was quite limited, and he invariably shunned new foods. The parents began to wonder whether his diet might have something to do with the abnormal behaviors he was exhibiting.
“We began to speculate about how nutrition could be impacting Mike’s body and mind,” says John Simpson. “Perhaps his limited diet was giving him headaches, or perhaps he lacked the nutrition needed for normal brain function. Perhaps he was unable to sleep because his stomach was upset, or he was not eating well because the food did not taste good to him. These kinds of questions prompted us to begin looking into alternative approaches to autism.” As the parents looked further, they came to believe that a “leaky gut” and possibly other digestive problems, along with poor nutrition, could be fueling Mike’s abnormal behaviors.
When Mike turned age two in the spring of 2007, the parents placed him on a gluten-free, casein-free (GFCF) diet—a diet free of cow’s milk, wheat and most other grain products. “Immediately, we saw several of his behaviors improve,” Suki Simpson says. “Soon afterward, we added digestive enzymes as supplements to his diet six months later. This led to small but continual improvements in his focus and communication, including his very first ‘Mama.’ That was immensely exciting. We realized then that there had to be an underlying biological reason for his behavioral symptoms.”
In December 2007, after an Internet search of physicians listed in the Defeat Autism Now! (DAN!) directory, the parents sought my expertise and scheduled an office visit with me at the Raleigh-based Carolina Center for Integrative Medicine. (Much of the Carolina Center’s approach to autism is adapted from the DAN! program. To help decide which supplements and which parts of the program to emphasize, we recommend individualized, in-depth clinical and laboratory testing.)
After an extensive evaluation that included laboratory testing to look for signs or markers of hidden infection, I determined that Mike had an overgrowth of Candida yeast and bacteria in his intestines. The first treatment priority was to reduce the yeast levels in order to improve his digestive function health. In addition to pharmaceutical and herbal anti-fungals, Mike received specific supplements aimed at killing disease-causing organisms, as well as replacing those microbes with beneficial bacteria.
Our second effort was targeted towards vitamins and other nutrients his body lacked, and were intended to help him feel and function normally. At the same time, the parents also elected to have him start hyperbaric therapy, involving the use of pressurized oxygen to activate neurons in his brain. Children undergoing hyperbaric therapy often show rapid progression in language skills and the expansion of their vocabulary, as well as a range of behavioral improvements. Later in his treatment, Mike received an antiviral medication called Valtrex, which is thought to work as a brain anti-inflammatory agent. Recent research, all published in peer-review medical journals, has highlighted the benefits of this integrative medical approach. For some excellent summaries of this research, see the August and December 2002 issues of Alternative Medicine Review, as well as the February 2008 Journal of Alternative & Complementary Medicine.
The multi-pronged treatment—including anti-microbial therapy, physiological rehabilitation, and nutritional and behavioral interventions—led to rapid and dramatic improvements. Within four months, Mike not only knew his own name and made good eye contact, he also began speaking the name of everyone with whom he was coming into contact on a daily basis. He could speak in full sentences and quickly developed a huge vocabulary. He could count to 40, and his ability to recite the alphabet, identify letters, and put letters together was that of a first grader. To his parents’ delight, Mike became very sociable, talkative and interactive, singing songs and playing games like tag and Hide-and-Seek. He made friends easily at school, and it was very clear to his teachers that he had a keen ability to learn.
“If we had not seen it happen before our own eyes, we would not have believed it to be possible,” says Suki Simpson. “Recovery from autism is possible. In the beginning, teaching Mike was like driving down a dead end street. Today, we are cruising along a highway with interaction in both directions.” Suki adds that Mike has been thriving both socially and intellectually in a mainstream classroom at their local elementary school. “He has lots of friends,” she says. “And he talks with them and us all the time. We couldn’t be happier with his complete turnaround, and for that, we give credit to the Carolina Center’s approach.”
In short, there is now light at the end of the tunnel. At this writing, we have seen hundreds of children with ASDs go from having all types of aberrant behaviors to becoming playful, sociable, and communicative. Many of them have gone from extreme isolation to being mainstreamed in a normal school, performing just as well as their peers, sometimes even ending up at the top of their class. Yes, behavioral interventions such as speech therapy, occupational therapy, and Applied Behavior Analysis still have an integral role to play, but very often the results they achieve are limited. By addressing the underlying biological issues, autism and other ASDs can be greatly improved. And in some cases, as we saw with young Mike Simpson, autism and ASD symptoms may disappear altogether.
John C. Pittman, MD, is the Medical Director of the Carolina Center for Integrative Medicine in Raleigh, NC, and is certified by the American Board of Clinical Metal Toxicology. Mark N. Mead, MSc, serves as the Center’s Nutrition Educator and Integrative Medicine Research Consultant.
For more information, please visit our website: www.carolinacenter.com
Key scientific references:
Rossignol DA. Novel and emerging treatments for autism spectrum disorders: a systematic review. Ann Clin Psychiatry. 2009;21(4):213-36.
Bradstreet JJ, Smith S, Baral M, Rossignol DA. Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder. Altern Med Rev. 2010;15(1):15-32.
Landrigan PJ. What causes autism? Exploring the environmental contribution. Curr Opin Pediatr. 2010; 22(2):219-25.
Adams JB, Baral M, Geis E, Mitchell J, et al. The severity of autism is associated with toxic metal body burden and red blood cell glutathione levels. J Toxicol. 2009;2009:532640.
Adams JB, Baral M, Geis E, Mitchell J, 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.
O'Hara NH, Szakacs GM. The recovery of a child with autism spectrum disorder through biomedical interventions. Altern Ther Health Med. 2008;14(6):42-4.
Kidd PM. An approach to the nutritional management of autism.
Altern Ther Health Med. 2003;9(5):22-31
Kidd PM. Autism, an extreme challenge to integrative medicine. Part 2: medical management. Altern Med Rev. 2002;7(6):472-99.
Kidd PM. Autism, an extreme challenge to integrative medicine. Part: 1: The knowledge base. Altern Med Rev. 2002;7(4):292-316.
Posted By Administration,
Friday, October 1, 2010
Updated: Friday, April 18, 2014
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This study investigated the relationship of children's autism symptoms with their toxic metal body burden and red blood cell (RBC) glutathione levels. In children ages 3–8 years, the severity of autism was assessed using four tools: ADOS, PDD-BI, ATEC, and SAS. Toxic metal body burden was assessed by measuring urinary excretion of toxic metals, both before and after oral dimercaptosuccinic acid (DMSA). Multiple positive correlations were found between the severity of autism and the urinary excretion of toxic metals. Variations in the severity of autism measurements could be explained, in part, by regression analyses of urinary excretion of toxic metals before and after DMSA and the level of RBC glutathione (adjusted R2 of 0.22–0.45, P < .005 in all cases). This study demonstrates a significant positive association between the severity of autism and the relative body burden of toxic metals.
Autism is a severe developmental disorder which involves social withdrawal, communication deficits, and stereotypic/repetitive behaviour. The pathophysiological etiologies which precipitate autism symptoms remain elusive and controversial in many cases, but both genetic and environmental factors (and their interactions) have been implicated. One environmental factor that has received significant attention is the body burden of mercury, lead, and other toxic metals [1-5].
Bernard et al.  discussed the many similarities between the symptoms of children with autism and children poisoned by mercury. An epidemiology study by Windham et al.  found that the amount of airborne pollutants, and especially mercury, correlated with an increased risk for autism. A study by DeSoto and Hitlan  found that blood levels of mercury did significantly correlate with the diagnosis of autism. A small study by Adams et al.  found that children with autism had a 2-time higher level of mercury in their baby teeth than typical children. A study by Bradstreet et al.  investigated the body burden of toxic metals by giving dimercaptosuccinic acid (DMSA), an oral chelation medication approved by the FDA for treating infantile lead poisoning. They found that the children with autism excreted 3.1 times as much mercury into their urine (which is where DMSA is excreted), P < .0002, but lead and cadmium levels were not significantly different. Overall there is some evidence to suggest that mercury and possibly other toxic metals are related to the etiology of autism.
This study investigates the possible relationship of the severity of autism to the relative body burden of toxic metals. The severity of autism was assessed using four tools, a professional evaluation based on the Autism Diagnostic Observation Schedule , and parental evaluations based on the Pervasive Developmental Disorders Behaviour Inventory (PDD-BI) , the Autism Treatment Evaluation Checklist (ATEC) , and the Severity of Autism Scale (SAS). The individual burden of toxic metals was assessed based on urinary excretion, both before and after taking oral dimercaptosuccinic acid (DMSA). DMSA is a licensed medication for treating lead poisoning and indicated in cases meeting toxic criteria. DMSA is, however, widely used off-label for other metal exposures, for example, mercury. It acts by forming sulfhydryl linkages to divalent metal cations, forming a chelated metal complex which is then excreted in the urine . Urine measurements before and after taking DMSA provide an indication of both ongoing environmental exposures (before DMSA provocation) and the accumulated or relative body burden (postprovocation with DMSA). Red blood cell (RBC) glutathione was measured because it is one of the body's primary means for excretion of toxic metals.
This paper investigates the possible relationship of the severity of autism to the body burden of toxic metals and RBC glutathione levels. This paper is part of a larger study which investigates the safety and efficacy of DMSA therapy, including both the biological consequences  and the DMSA associated behavioural effects . The larger study involves a 3-day round of DMSA, to screen for admission into a 3-month DMSA treatment study; only children with high levels of urinary toxic metals were admitted into the long-term 3-month treatment study.
The methodology is discussed in detail in the companion paper . Briefly, this study was conducted with the approval of the Human Subjects Institutional Review Board of Southwest College of Naturopathic Medicine. All parents and (where possible) children signed informed consent/assent forms. The study participants were recruited in Arizona, with the help of the Autism Society of America—Greater Phoenix Chapter and the Arizona Division of Developmental Disabilities.
The entry criteria were the following.
- Children with autism spectrum disorder, diagnosed by a psychiatrist, psychologist, or developmental pediatrician.
- Age 3–8 years.
- No mercury amalgam dental fillings (due to a concern of their interaction with DMSA).
- No previous use of DMSA or other prescription chelators.
- No anemia or currently being treated for anemia due to low iron.
- No known allergies to DMSA.
- No liver or kidney disease.
- Children are well hydrated (receiving adequate daily intake of water).
Four metrics were employed to assess the severity of autism: the PDD-BI, ATEC, SAS, and ADOS. Multiple assessment instruments were selected because they each provide insights into various aspects of autism. The ATEC was completed approximately 2-3 weeks prior to taking the DMSA, and the other three instruments were completed approximately 2–4 weeks after the initial 3-day round of DMSA, for children whose excretion of toxic metals was deemed high enough to warrant continuation in the long-term treatment study. The ATEC, PDD-BI, and SAS were assessed by the participant's parents, and the ADOS evaluation was performed by a certified ADOS evaluator. It should be noted that the ADOS was developed primarily for diagnosing autism, whereas the other tools were developed for assessing changes in autistic symptoms during treatment studies.
DMSA was administered orally in 9 doses of 10 mg/kg, 3 times daily, over 3 days. Urine was collected for approximately 8 hours prior to taking the DMSA, and for approximately 8 hours immediately after the 9th dose, in a process similar to a previous retrospective study of relative body burden of heavy metals . RBC glutathione was measured approximately 1-2 weeks prior to taking the DMSA. The details of measuring the urinary metals and RBC glutathione are given in .
The PDD-BI is composed of many subscales. One of the subscales, the Semantic/Pragmatic Problems (SPPs), was difficult to interpret, since children with no spoken language inappropriately scored as less severely affected than those with limited language. Therefore, we exclude the SPP subscale in the Autism Composite score, resulting in a modified Autism Composite score consisting of Sensory/Perceptual Approach, Ritualisms/Resistance to Change, Social Pragmatic Problems, Social Approach Behaviors, Phonological and Semantic Pragmatic subscales. This modified Autism Composite score was discussed with I. Cohen, the developer of the PDD-BI. We believe that this modified subscale is more useful because several children initially without speech began talking after DMSA treatment in the study. The development of speech led to a worsening of their score on the SPP, because a nonverbal child is given a score of zero (indicating no semantic/pragmatic problems, which is the same score a typically developed child would receive) compared to a child with limited speech but major semantic/pragmatic problems who would receive a high score on the SPP. Thus, we think the modified Autism subscale (without the SPP) is more useful for children with very limited or no language.
In order to assess global changes in autism severity, a new metric was developed for this study. The Severity of Autism Scale (SAS) is introduced for the first time in this series of papers. It is essentially a Clinical Global Impression scale using a 0–10 severity scale, with the difference being that the scale was made specific to autism by defining the numeric values (see below). The purpose of the tool is to provide a simple, overall assessment of the severity of the symptoms of autism. In this study we will analyze the correlation of this scale with the other more established assessment tools.
Severity of Autism Scale:
- 0: normal,
- 1: slight symptoms of autism,
- 2–4, mild symptoms of autism,
- 5–7, moderate symptoms of autism,
- 8–10, severe symptoms of autism.
63 participants were assessed with the ATEC, and 49 participants were assessed with the PDD-BI, SAS, and ADOS. Fewer participants were assessed for the latter three tests because some participants had low urinary excretion of toxic metals and were not eligible to continue, and some participants dropped out. Table 1 lists the characteristics of the participants.
Characteristics of participants. The second number is the standard deviation.
||5.6 ± 1.6
||62 autism, 1 Asperger's
||62 ± 28
||5.1 ± 2.2
|ADOS (communication + social)
||15.8 ± 6.5
|PDD-BI (modified autism score)
||−54.3 ± 62
|RBC glutathione (pre-DMSA)
||501 ± 246 micromolar
Table 2 lists their average urinary excretion of toxic metals before and after taking DMSA.
Urinary excretion of toxic metals in Phase 1, at baseline and after 9th dose of DMSA, in mcg/g creatinine. Creatinine values have units of mg/dL. N = 63. The metals are listed in approximate order of effect of DMSA on excretion. Significant results are highlighted in bold font.
|Element||Baseline||After 9th dose||After 9th dose versus baseline|
||1.3 ± 2.3
||9.2 ± 7.8
||2.3 ± 3.4
||9.7 ± 24
||0.18 ± 0.45
||0.41 ± 1.0
||0.015 ± .04
||0.031 ± .1
||0.86 ± .92
||0.97 ± 0.88
||0.15 ± 0.12
||0.21 ± 0.19
||0.10 ± 0.10
||0.14 ± 0.20
||0.3 ± 0.29
||0.46 ± 0.50
||16 ± 21
||19 ± 33
||6.7 ± 5.1
||7.6 ± 4.3
||0.38 ± 0.24
||0.3 ± 0.23
||32 ± 20
||25 ± 18
||94 ± 52
||80 ± 43
*P < .1, **P < .05, ***P < .01, ****P < .001
2.1. Regression Analysis
Regression analysis was employed to examine the relationship between the severity of autism (assessed by the ATEC, PDD-BI, SAS, and ADOS) and the urinary excretion of toxic metals, (both before and after taking DMSA), and further with the initial glutathione (in the red blood cells). For the selected dependent and independent variables, stepwise linear regression analyses were conducted: initially all independent variables were included in the regression; then at each step, the variable with the highest P-value was eliminated, and this process was continued until the adjusted R2 value began declining. Thus, the goal was to determine the best fit to the sample data for the selected model, taking into account the correlation among the independent variables. Since the data had several missing values (due to missing lab or behavioural data), the regression analyses were conducted in two slightly different ways which generally yielded very similar results: ( 1) eliminate all participants with missing data for any of the variables in the model at the beginning of the analysis, and ( 2) eliminate participants on an as-needed basis (i.e., only where there is missing data for any variable in the current step in the analysis). Since these two methods yielded very similar results, for brevity we only report the results for method 1.
3.1. Correlations of Severity Scales
Table 3 shows the correlations among the assessment scales. There is a high correlation between the ATEC and the PDD-BI (r = 0.87), and a good correlation of the SAS with the ATEC (r = 0.70) and the PDD-BI (r = 0.72). The correlation of the ADOS with the other scales is somewhat lower (r
= 0.60–0.67), probably since the ADOS evaluation was done by a professional evaluator, whereas the other assessments were done by the same parent.
Correlation of autism severity scores.
| ||ATEC total||SAS||ADOS (social + communication)||PDD-BI (modified autism score)|
3.2. Correlation Analysis
Table 4 shows the results of a simple correlation analysis of severity of autism versus toxic metal levels. Correlations with a P-value of less than .05 are shown in bold. Baseline excretion of antimony (Sb) and excretion of lead (Pb) after the 9th dose of DMSA are the two most consistent factors, although other metals also haveP < .05 for some of the severity scales. In all cases for P < .05, the correlations are positive, so that high levels of toxic metals correlate with higher severity of autism, as expected. Also, the initial glutathione correlates positively with two of the severity scales at P
Correlation analyses of initial autism severity versus urinary metal excretion and initial glutathione. The metal excretion is measured both at Baseline (before DMSA) and after the 9th dose of DMSA. The first number in each cell is the correlation coefficient (r) and the second number is the P-value. Correlation coefficients with P < .05 are in bold. The last 2 rows list the total number of positive and negative correlation coefficients, respectively.
| ||ATEC total||ADOS (social + communication)||SAS||PDD-BI (modified autism score)|
|Number of positive coefficients
|Number of negative coefficients
However, because we are analyzing many correlations, a traditional
P-value of < .05 is not a rigorous guide. Since we are analyzing 76 possible correlations, random chance alone would result in approximately 4 results at P < .05. We found 13 instances of P < .05 for toxic metals, and the probability of that occurring randomly is 7 × 10−5, so it is very likely that most, but probably not all, of the correlations represent actual relationships.
One way to deal with the problem of multiple correlation analyses is the Bonferroni approach. Using this approach involves dividing the nominal P-value by the number of tests, so that for 95% confidence one needs a P-value less than .05/76, or P < .0007. Using the Bonferroni approach, the correlations between initial Severity of Autism Scale (SAS) and baseline excretion of lead (Pb) and antimony (Sb) are significantly different from 0 at the 95% confidence level, and these are the only pairs that meet the Bonferroni criterion for the 5% significance threshold. Again, it should be noted that this is a conservative approach, designed to ensure that very few nonsignificant correlations are misrepresented as significant.
False discovery rate (FDR) is a less conservative method for performing multiple hypothesis tests, based on controlling the expected number of false positives among the cases declared significant. If we use FDR on the summary severity scores, then in addition to the results obtained from the Bonferroni analysis, the correlation between Initial ATEC Total and baseline excretion of antimony (Sb), and the correlations between Initial PDD-BI Autism Total and baseline excretion of antimony (Sb) and 9th dose excretion of lead (Pb) are significantly different from 0; we will term these findings “marginally significant.”
Next, consider the numbers of positive and negative sample correlation coefficients in the table. If there were no statistically significant correlations between autism severity and biological measures then we would expect on average about equal numbers of positive and negative sample correlation coefficients. For the summary severity measures, we observed 63 positive sample correlation coefficients (r's) and 13 negative r's. This corresponds to a P-value of 3 × 10−9 for the hypothesis that there is no correlation between the severity measures and biological measures. Thus it is extremely likely that there is a high overall positive correlation between the severity measures as a group and the biological measures taken as a group.
Finally, the average of all of the 76 sample correlation coefficients is 0.14. If there were no statistically significant correlations between autism severity and the biological measures, the average of 76 sample correlation coefficients (each of which was taken form a sample of size 40 or more) would come from a distribution with mean 0 and standard deviation equal to 0.02. Under those conditions, the P-value for a mean correlation coefficient of 0.14 is less that 10−10, so again it is extremely likely that there is a high overall positive correlation between the severity measures as a group and the biological measures taken as a group.
Since multiple correlations were obtained, it was decided to conduct regression analyses, which are discussed in the next section. Basically, a regression analysis allows for the simultaneous consideration of multiple factors, such as how well certain combinations of different toxic metal excretions can predict values of a specific autism severity measure.
3.3. Regression Analyses of Initial Severity of Autism
Tale 5 shows the results of stepwise linear regression analyses for the various autism severity scales as a function of urinary excretion of toxic metals (at baseline and after the 9th dose of DMSA) and initial glutathione. All of the analyses found that the variations in the severity of autism could be partially explained by the urinary excretion of toxic metals and initial glutathione, with adjusted R2 values ranging from 0.22 to 0.45, and P-values all below .005. For the ADOS (which had the highest adjusted R2), the most significant variables were mercury (Hg) and antimony (Sb) at baseline and mercury and tungsten (W) at the 9th dose.
Regression analyses of initial autism severity versus urinary metal excretion and initial glutathione. In the regression equation, the suffixes for the metals refer to the value at Baseline (B) and after the 9th ( 9) dose of DMSA in Phase 1.
| ||AdjustedR2||P-value||Equation||Most significant variables|
||24.1–6.17 HgB + 76.6 SbB + 0.593 Pb9 + 3.97 Hg9 + 0.27 As9
||4.81 + 1.70 PbB + 4.87 TlB − 0.640 HgB + 5.48 SbB − 1.87 CdB − 0.0237 AlB − 0.114 Pb9 − 3.14 Tl9 + 6.07 Sb9
|ADOS (comm. + social)
||13.19–4.29 HgB + 24.1 SbB − 3.67 WB − 0.0673 AlB + 2.75 Hg9 + 6.60 W9 − 0.0539 As9 + 0.0054 Glut
||HgB**, SbB*, Hg9*, W9*
|PDD-BI (modified autism score)
||−131.8 + 70.4 WB − 0.789 Sn9 + 18.8 Hg9 + 255 Sb9 + 21.8 W9
||Sb9**, WB*, Sn9*
Since the ADOS score had the highest adjusted R2 values, we also conducted a similar regression analysis on the subscales—(a) language and communication; (b) reciprocal social interaction; (c) play; (d) stereotyped behaviors and restricted interests (SBRIs). Those results are show in Table 6. The variation in all four of the ADOS subscales could also be partially explained by urinary excretion of toxic metals and RBC glutathione (adjusted R2 of 0.21–0.41, P < .02 in all cases). The ADOS Sociability and the ADOS Communication subscales had the highest adjustedR2 (0.41 and 0.37, resp.). For the ADOS Sociability subscale, the most significant variable was tungsten at the 9th dose, followed by tungsten, aluminum, and thallium at baseline and lead and thallium at the 9th dose. For the ADOS Communication subscale, the most significant variables were mercury (at baseline and 9th dose) and antimony (Sb) at baseline.
Regression analyses of initial ados subscales versus urinary metal excretion and initial glutathione. In the regression equation, the suffixes for the metals refer to the value at Baseline (B) and after the 9th ( 9) dose of DMSA in Phase 1.
| ||AdjustedR2||P-value||Equation||Most significant variables|
||8.70 + 1.20 PbB + 0.217 SnB + 12.7 TlB − 1.64 HgB − 10.2 SbB − 2.61 CdB − 0.631 AlB − 0.186 Pb9 − 7.13 Tl9 + 6.27 Sb9 +6.15 W9 +3.62 Cd9
||W9***, AlB**, TlB*, HgB*, Pb9*, Tl9*
||2.39–2.57 HgB + 23.1 SbB + 2.32 Hg9 + .0048 Glut
||HgB**, Hg9**, SbB**
||1.20 + 0.540 PbB + 4.23 Sb9 + 0.0017 Glut
||4.64–0.897 HgB − 2.63 CdB − 0.26 AlB + 0.050 Pb9 + 0.730 Hg9
***P < .001, **P < .01, *P < .05
Since the toxic metal excretions exhibit considerable correlation amongst themselves , one should refrain from reading too much into the relationships between specific metals and severity of autism and instead should interpret the results as indicating a general relationship between autism severity and urinary excretion of toxic metals.
The different assessment tools were found to be highly correlated, which generally supports the validity of each of the assessment tools. The correlations were the highest between the modified PDD-BI and the ATEC, suggesting that those scales are very consistent. The ADOS had a lower correlation with the other scales; this at least partly due to different evaluator for the ADOS (assessed by a professional certified in the ADOS) versus the ATEC, modified PDD-BI, and SAS which were assessed by the same person (the parent who was the primary care giver).
The various correlation analyses found that overall there were multiple positive correlations between the severity of autism and the urinary excretion of some toxic metals (both before and after taking DMSA). Lead (after DMSA) and antimony (at baseline) had the most consistent effect, but other metals were also important. The existence of multiple positive correlations suggested that a regression analysis was appropriate.
The regression analysis found that the body burden of toxic metals (as assessed by urinary excretion before and after DMSA) was significantly related to the variations in the severity of autism, for each of the four scales. The metals of greatest influence were lead (Pb), antimony (Sb), mercury (Hg), tin (Sn), and aluminum (Al). Different metals are significant for the different scales, and this partial disagreement is probably due to two factors. First, the severity scales are not identical, having somewhat different questions and evaluating symptoms somewhat differently; as pointed out in Table 3, the correlations between the scales are good but not identical. Second, it should be noted that the high correlation between urinary excretion of many of the metals (see Adams et al. ) makes it difficult to separate the effect of one metal from another. This makes it improper to assign too much meaning to specific regression variables and their coefficients. Thus, it is probably best to not overinterpret the results in terms of a particular metal, but to instead interpret them as evidence of the general role of toxic metals in relation to the severity of autism. Since oxidative stress and thiol metabolic disturbances have both been described in the autism population [12, 13], it is likely that these play a role in both relative burden and susceptibility to heavy metals. And since heavy metal exposure generates oxidative stress and thiol depletion, the potential etiological role of metal cations in generating autism symptoms should be further studied. Similarly, prior depletion of thiols and increased oxidative stress makes it more likely the individual will accumulate metals.
It should also be noted that each severity scale assesses a somewhat different aspect of autism; for example, the ATEC has a major section on physical health, which is not assessed by the other scales. So, that may also explain why the different scales have somewhat different relationships with different metals.
The ADOS had the highest adjusted R2 value, suggesting that it is a very useful scale for assessing the severity of autism and for inclusion in correlation and regression analyses with biological factors. This may be due to the fact that, of the four tools we used, only the ADOS involves a trained professional making a quantitative assessment of many children, whereas the other tools are assessments by parents of only their child.
The strong correlation of the SAS with the other scales, and the high adjusted R2value (0.36), suggests that the SAS is a useful tool for simple assessment of the severity of autism.
We are aware of two other studies which found a relationship between the severity of autism and a biomarker related to heavy metal toxicity. One study by Geier et al.  found that elevations in urinary porphyrins (associated with mercury or lead and mercury toxicity) were significantly associated with Childhood Autism Rating (CARS) scores. A second paper to report a relationship of the severity of autism with a biomarker was a study which found a strong inverse relationship of the severity of autism with the amount of mercury in the baby hair of the subjects . However, a replication study  did not reproduce that correlation with severity. So, while two studies [14, 15] do support a possible relationship of variations in the severity of autism with body burden of toxic metals, as was found in this paper, additional research is needed to confirm this finding.
This paper has focused on the possible relationship between toxic metals and the severity of autism. It has not included an examination of the source of those metals. Mercury, lead, and other toxic metals come from many sources. There has been particular interest in the possible relationship of autism and thimerosal (a mercury-based preservative once used in many childhood vaccines, but removed from most vaccines after 2003). However, this study was not designed to determine the sources of the toxic metals found in children with autism.
4.1. Limitations of this Study
The original study was designed primarily for evaluating the safety and efficacy of DMSA therapy. It was not primarily designed for investigating the relationship of the severity of autism to toxic metals, but that was an interesting outcome, so we felt it worthwhile to report it. Some limitations of the study design include the following.
- The PDD-BI, SAS, and ADOS were assessed 2–4 weeks after the first round of DMSA, whereas the ATEC was assessed before. However, the strong correlation of the ATEC and PDD-BI suggests that this was a minor issue, and that the initial round of DMSA did not significantly affect the assessment.
- The ATEC involved the largest number of participants (n = 63), whereas the other assessments involved somewhat smaller numbers (n = 49).
Overall, the correlation analysis found multiple significant correlations of severity of autism and the urinary excretion of toxic metals, such that a higher body burden of toxic metals was associated with more severe autistic symptoms. The results of the regression analyses (P < .005 in all cases) indicate that variations in the severity of autism may be partially explained in terms of toxic metal body burden. However, the finding of a relationship does not establish causality.
First and foremost, the authors thank the many autism families and their friends who volunteered as participants in this research study. They thank the Wallace Foundation and the Autism Research Institute for financial support of this study. They thank Nellie Foster of SCNM for help with blood draws. They thank Women's International Pharmacy for assistance with compounding the DMSA individually for each child. They thank Spectrum Chemicals for providing the DMSA. They thank Doctor's Data and Immunosciences for providing testing at reduced cost. They thank the Autism Society of America—Greater Phoenix Chapter and the Arizona Division of Developmental Disabilities for their help with advertising the study.
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Source: J Toxicol. 2009; 2009: 532640. Published online 2009 August 26. doi: 10.1155/2009/532640. The Severity of Autism Is Associated with Toxic Metal Body Burden and Red Blood Cell Glutathione Levels. J. B. Adams,1* M. Baral,2 E. Geis,3 J. Mitchell,1 J. Ingram,3 A. Hensley,3I. Zappia,3 S. Newmark,4 E. Gehn,3 R. A. Rubin,5 K. Mitchell,3 J. Bradstreet,2, 6 and J. M. El-Dahr7
1Division of Basic Medical Sciences, Southwest College of Naturopathic Medicine, Tempe, AZ 85282, USA
2Department of Pediatric Medicine, Southwest College of Naturopathic Medicine, Tempe, AZ 85282, USA
3Autism Research Institute, San Diego, CA 92116-2599, USA
4Center for Integrative Pediatric Medicine, Tucson, AZ 85711, USA
5Department of Mathematics, Whittier College, Whittier, CA 90601-4413, USA
6International Child Development Resource Center, Phoenix, AZ, USA
7Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA
Posted By Administration,
Thursday, September 17, 2009
Updated: Friday, April 18, 2014
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by John C. Pittman, MD
Back in February of this year, the Associated Press released an article titled “Officials say 'bad science' links vaccines, autism.” The article, which was picked up by newspapers across the country, proclaimed that the U.S. Court of Claims had found little if any evidence to support a connection between vaccine use and autism risk, and that overall the evidence was evidence "weak, contradictory and unpersuasive." The ruling was in response to some 5,500 claims filed by families who were seeking compensation through the government’s Vaccine Injury Compensation Program.
In 1998, considerable media attention in the United States and Europe followed the publication of a controversial report on autism in the esteemed medical journal, The Lancet. In that report, British researchers documented the emergence of autistic behaviors and intestinal problems, which in several cases closely followed vaccination for measles, mumps and rubella (MMR). The study found measles virus antigens in the intestinal linings of many autistic children—antigens presumably linked with MMR vaccination. The Lancet’s publication of this issue sparked a torrent of media attention because of the fact that Thimerosal, an antiseptic containing ethyl mercury, was being used as a preservative of vaccines distributed and administered worldwide.
As documented in the 12 March 2009 issue of the American Journal of Perinatology, “There are studies that point to a significant link between exposure to TCVs [Thimerosal-containing vaccines] and neurodevelopmental delays.” Direct intramuscular injection of Thimerosal results in the rapid release of mercury into the blood stream, and this mercury can eventually accumulate in the tissues of the brain. In animal experiments, vaccination was shown to result in autistic symptoms.
Some evidence has begun to link Thimerosal-containing vaccines to the onset of autistic behaviors. In 2001, researchers at the Institute of Medicine published an analysis of autism rates and mercury exposure and found an association between rising autism rates in California and mercury exposure in childhood vaccines. This preliminary report, though heavily criticized at the time, was followed by a more rigorous report published in the August 2006 issue of Neuro Endocrinology Letters—a meta-analysis of autism and other neurodevelopmental disorders following vaccines administered in the United States from 1994 through 2000. Pooling together data from many studies at once, the researchers found a statistically significant association between the development of autism and early exposure to Thimerosal-containing vaccines.
Prior to the hubbub over vaccines and autism, there was a history of toxic effects associated with the use of Thimerosal in topical medicines, such as contact lens solution, eye drops, and other products. Indeed, it was due to this history of documented toxic effects that the Food and Drug Administration (FDA) eventually instituted restrictions on the use of Thimerosal in these medical products in the late 1990s. And in 1999, the United States and the European Union countries took major steps to reduce and even eliminate Thimerosal from most vaccines. Nevertheless, all U.S. pregnant women, infants, and children (until 18 years old) are still advised to receive an annual influenza vaccination, of which more than 90% still contain Thimerosal. In addition, Thimerosal is still found in trace amounts in many vaccines on the market today, according to the FDA.
What worries many integrative physicians and environmental medicine experts is that any mercury at all—whether from vaccines, the diet, or from the silver fillings used in dental work—can be a threat to young brains, which undergo many changes in the early years. Mercury exposure begins in utero, being passed easily from the mother to fetus due to consumption of tuna and other fish, presence of amalgam dental fillings, and sometimes the use of mercury-containing vaccines like Rhogam. Mercury exposure may then continue after birth through fish consumption, dental amalgams (especially with increasing age), and flu vaccines. Both the fetal brain and infant brain are uniquely vulnerable to the effects of even small amounts of mercury, lead, and other neurotoxic factors.
Researchers reported in the October 2007 Journal of Toxicology and Environmental Health that individuals with severe Autistic Spectrum Disorders (ASDs) had significantly increased levels of various indicators of mercury exposure in their urine. These indicators, called “porphyrins”, were much higher in people with severe ASDs compared to those with mild ASDs, whereas other urinary porphyrins—those not linked with mercury exposure—were similar in both groups. At the same time, the individuals with severe ASDs had much lower levels of glutathione, a core antioxidant in healthy cells that is inextricably linked to the body’s detoxifying capacity.
This last point offers us a vital piece to the autism puzzle: Along with the unique developmental vulnerability of the young brain, autistic kids are far less able to process and eliminate mercury from their bodies, often due to having extremely low glutathione levels. Many of these children have a genetic predisposition to low glutathione levels. This means that, even with low-level exposure to mercury and other toxic metals, they may be far more vulnerable than other kids with normal glutathione levels.
At the Raleigh-based Carolina Center for Integrative Medicine, we see the best outcomes when glutathione, intestinal infections and other factors are addressed in a systematic way. The mother’s mercury burden from her diet and from dental amalgams may also contribute substantially to the higher mercury levels that are often seen in autistic children. Ridding the body of mercury and other toxins is most likely to be therapeutically successful in the context of this more comprehensive approach.
Shifting the Focus to the Immune System
If there is an adverse impact of vaccinations, it probably has more to do with disrupting the functioning of the immune system and with "developmental immunotoxicity", as reviewed by Cornell immunologist Rodney Dietert in the October 2008 Journal of Toxicology and Environmental Health. Part B. These days, vaccination programs often entail more than 30 immunizations administered to the child between the ages of 12 and 24 months. This practice introduces a vast number of foreign proteins into the body—sometimes as three different attenuated viruses in one vaccine, as in the case of the MMR. This raises the possibility that there may be insufficient time between vaccinations for the child’s immune system to return to a normal healthy baseline. Side effects of these vaccinations have included allergic reactions, autoimmunity, and on some rare occasions, the full development of viral diseases (ostensibly from infections by the attenuated viral particles of the vaccine).
It is possible that such inflammatory immune reactions to a multi-vaccine program could result in neurobehavioral changes that have been linked with autism and ASDs. This is something we have heard repeatedly from parents who brought their autistic children into our Raleigh-based clinic, the Carolina Center for Integrative Medicine. In some cases, we have been able to document the effects ourselves. Even with contemporary vaccine programs (containing little or no Thimerosal), we still see children who are fine one day and then quit talking or behaving normally the day after they get vaccinated. Some of these children will regress dramatically, so much so that the parents fear they are losing their children before their eyes.
So, the question remains: Are we overvaccinating our children? According to an April 2009 article by Bernadine Healy, M.D. in U.S. News & World Report, the United States “gives more vaccines to all its children, and earlier in life, than the rest of the developed world: some 36 doses before our little ones hit kindergarten, with most crammed into the first 18 months of life. If you look at the best-performing countries in terms of infant and early-childhood mortality, the average number of doses is 18, with most of the Scandinavian countries, Japan, and Israel mandating just 11 to 12.”
Does the simultaneous administration of multiple vaccines overwhelm the immune system and predispose some individuals to autism? Epidemiological studies (which focus on populations, not individuals) have thus far been unable to show a significant link between autism and vaccinations. However, epidemiology is a crude science in some respects, often leading to general conclusions that overlook individual differences or variations. Large population studies may look impressive, but they may totally miss the small and specific subsets of the general population (such as those with glutathione deficiency) that may be at elevated risk of neurodevelopmental problems, possibly including developing autism subsequent to live virus vaccination.
Autism most likely arises from a complex interplay of genes, nutrients, and toxic factors, all affecting the individual during unique windows of developmental vulnerability. Studies are now underway to examine the possible role of environmental risk factors and their interplay with genetic susceptibility during the prenatal, neonatal and early postnatal periods. Let’s hope that some studies will compare groups of vaccinated and unvaccinated children by measuring individual effects on their immune systems while also taking into account their genetics, detoxification capacity (again, many autistic children lack the essential means to detoxify due to low glutathione levels), and exposure to toxic factors such as mercury and intestinal infections.
Until such studies are done, the jury is still out on whether we are overvaccinating our children and fueling the autism epidemic. Multiple vaccinations could certainly play a role, especially given the many immune problems that have been found in autistic children. On a precautionary basis, then, pediatricians should consider spacing out shots that are normally given in one visit—particularly those that contain live viruses like measles, mumps, and chicken pox and tend to deliver strong immune reactions. Some Docs now advocate delaying hepatitis B vaccination until school age. Helping our kids develop strong, healthy bodies and immune systems, and giving parents the tools to support such development, could prove extremely valuable.
To reach Dr. Pittman, or to obtain more information on his integrative pediatrics program, contact the Carolina Center for Integrative Medicine in Raleigh, NC at 919-571-4391, or visit the website at carolinacenter.com.