Toxicologists Gather to Discuss Autism Spectrum Disorders
Workshops Highlight Environmental Influences, Chelation
The cause and treatment of autism spectrum disorders was the focus of two dedicated sessions at the annual meeting of the Society of Toxicology, held in Charlotte, N.C., in March 2007. More than 6,000 toxicologists convened to interact and present the most recent data in toxicology affecting a wide number of organ systems, including the brain.
The first autism-related session offered an overview of the role of the environment in autism, allowing toxicologists to discuss new avenues of research to study gene–environment interactions in a multidisciplinary setting. The second session focused on the use and efficacy of chelation in heavy metal poisoning and relationship to autism spectrum disorder.
Search for Clues in the Environment
A March 26 workshop, entitled “Environmental Risk Factors for Autism: Search for Clues,” was organized by Autism Speaks/CAN-funded researcher Dr. Ellen Silbergeld from John’s Hopkins University. The workshop presentations spanned multiple disciplines, and highlighted evidence that multiple environmental risk factors may contribute to the development of symptoms of autism.
Dr. Craig Newschaffer started off the workshop by illustrating the “epidemiological triangle,” that is, counting people affected by a disease as a triad across the person, the time, and the place in which they live or are counted. In the case of autism, there is a concern over the change in prevalence over the past 10 years, especially since the recent publication of the MMWR report, which reported an increase in prevalence to 1 in 150 children.
Because of multiple environmental factors (including increased awareness of this disorder) and diagnostic criteria changes, it is hard to parcel out the effect of any one particular exposure using epidemiological data. In fact, it is easy to misinterpret many studies that simply show a correlation of an increased risk of autism due to any one environmental risk factor. Correlation between two variables does not imply causation and studies which do so should be viewed with caution as they can lead to false positives. Newschaffer emphasized that this is a complex disease with a highly heritable component. Therefore, biologically plausible candidates as environmental risk factors should be explored by toxicologists.
Genetic Candidates Provide Scientific Leads
Following that line of reasoning, Pamela Lein from Oregon Health Sciences University, Isaac Pessah from UC Davis (and recipient of the CAN environmental innovator award) and Patricia Rodier identified possible exposures which may interact with known gene candidates.
Lein, an expert in environmental effects on genes that regulate development of the nervous system, hypothesized that genetic factors that interact with environmental exposures lead to a disruption of neurodevelopment. She pointed out several known examples and ideas for future research. For example, gene mutations of proteins MET, Wnt, semaphorin, reelin, neuroligins, engrailed and ephrins, have all been linked to ASD’s through genetic screens and genetic studies.
As they participate in aberrant neuronal connectivity, synaptogenesis and neuronal connectivity, disruption of the normal function of these genes can lead to severe neurological symptoms. Therefore, the effects of environmental toxicants should be studied more closely on the expression of these molecules. Alternatively, the behavioral effects of toxicants or environmental agents in animals which show mutations of these genes should be performed. The abnormal expression of these molecules could help explain the imbalance of inhibition vs. excitation in different brain regions. This imbalance has been observed by other researchers studying the disorder and may serve as one of the mechanisms behind many abnormal behaviors.
Looking specifically into how neurons function on a more basic biological level, Pessah has made important contributions to the understanding of the role of the CaV1.2 receptor in autism. Mutations of this receptor have been reported as the cause of Timothy Syndrome. Around 60 percent of individuals with Timothy Syndrome show symptoms of autism, making this molecular target of interest to many toxicologists and neurobiologists. In addition to this receptor’s role in calcium signaling, which controls cellular processes, it is also present on immune cells. This means that this mutation, along with other mutations that also affect calcium signaling, may contribute to symptoms in ASD via dysfunction in the immune response.
Together, Lein and Pessah presented evidence of specific molecular and genetic targets where environmental exposures may lead to disrupted neurobiological function relevant to understanding ASD.
The Immune System: Target of Toxins or Predisposing Factor?
Both Pessah and Silbergeld emphasized the role of the immune system in ASD, as a potentially important area for evaluating environmental toxicant exposure, as well as interactions between genetic susceptibility and environmental agents at the level of genes which regulate the immune system.
Because of the complexity of ASD, there are likely many different causes of autism and, accordingly, many different risk factors which may contribute. While current diagnostic techniques integrate the range of neurobehavioral deficits and other symptoms in ASD, disaggregation of the many forms of ASD may provide more accurate clues of which genes and which exposures are responsible for autism spectrum disorders.
While observational and biological markers of immune dysfunction have been observed in some children with autism, these markers have not been organized into different subsets of clinical symptoms. Silbergeld pointed out some convergent mechanisms by which mercury exposures could contribute to ASD. She concluded by pointing out that genotype, which might contribute to immune system changes, can serve as an underlying susceptibility for which different triggers produce disease. In this way, environmental triggers or exposures have different effects based on a predisposing susceptibility. While some individuals are vulnerable based on genetics or early exposure, others are not affected by these same environmental risk factors.
Risk Factors Previously Identified:
In addition to unknown environmental factors, Rodier at the University of Rochester reported her findings on five known pharmaceutical and environmental factors which result in higher odds ratios for developing autism after exposures. These include: valproic acid, thalidomide, rubella, misoprostol and ethanol.
She pointed out that in addition to their teratogenic effects, exposure to these agents led to some symptoms and features that resembeled autism when administered during specific critical times in gestation. Together with colleagues at the University of Rochester, she also demonstrated that both children and animals exposed to valproic acid in utero demonstrated similar responding on a learning task which is dependent on normal functioning of a brain region called the cerebellum. This parallel in behavioral functioning may be due to alterations in expression of a gene called HOX1A, or it may be the result of more subtle “epigenetic” changes which affect gene expression.
Role of Epigenetics
Epigenetics refers to mutations that can be passed on from generation to generation without modifications of the DNA sequence. This can be done by chemically modifying different parts of the DNA code, which either turns on or turns off gene expression. Of interest, instead of observing changes in the DNA code, chemical modifications can be made to the DNA, or to the proteins which pack DNA.
Importantly, these epigenetic modifications can be inherited, occur spontaneously, or they can be targets of environmental factors. These sorts of “epigenetic” changes have been studied in autism spectrum disorder and may not only be the target of pharmacological agents, but other non-toxic environmental exposures including diet and social experiences. This means that environmental exposures may include neurotoxic agents, but should not be restrictive in definition.
Summary and Conclusions
Together, the speakers urged the over 150 toxicologists who attended this workshop to consider studying autism as a multifactorial disease, incorporating genetic and environmental influences and requiring multidisciplinary research teams. In addition, the immune system should be considered as target or a predisposing factor to a number of environmental exposures in autism. Finally, environmental exposures and toxins for study should be carefully chosen based on their biological plausibility in producing neurobiological and behavioral symptoms characteristic of ASD.
Utility of Chelation Therapy Highlighted
In the March 27 workshop, Donald Smith from the University of California Santa Cruz and Barbara Sturpp from Cornell University organized a symposium on “Advances in the Efficacy of Chelation Treatment to Alleviate Neurocognitive Effects of Lead and Autistic Spectrum Disorders.”
Smith pointed out that the use of the chelating agent succimer (otherwise known as Chemet®, or meso 2, 3-dimercaptosuccinic acid, DMSA) is FDA-approved for use in cases of lead poisoning only. However, this treatment is being used in a variety of neurological disorders, including autism.
While the practice of using chelation therapy is becoming more common, the benefits and risks of this treatment are not well studied. Therefore, the purpose of this workshop was to highlight recent clinical and animal model studies to address the possible risks and benefits of chelation treatment for metal poisoning.
Lessons for the “TLC” Study
The benefits of chelation to treat individuals with severe lead poisoning have been well established. However, prior to the mid-1990s there was little evidence to demonstrate the benefits and possible risks of chelating children with mild to moderate, or ‘subclinical’ lead poisoning. Cognitive impairments including behavioral, attention, memory, and IQ deficts can occur at lead levels lower than what has historically been considered “toxic”.
In order to determine the beneficial effects of succimer chelation at these lower exposure levels, a NIH-funded multicenter, placebo-controlled randomized clinical trial in children with moderate (below 45 micrograms/deciliter) blood lead levels was conducted. Kim Dietrich from the University of Cincinnati, an investigator in this study (termed the Treatment of Lead Poisoned Children, or “TLC” study) presented his findings, which were originally published in 2004.
This study investigated the effects of chelation or placebo in lead-exposed children who were chelated as toddlers and followed them up at 7 1/2 years of age. Children were administered a battery of tests which examined cognitive, learning, memory and behavioral domains. Their results showed that children receiving succimer chelation did not perform any differently on these measures compared to those receiving a placebo.
The authors concluded that because chelation showed no beneficial effects on cognitive performance, this study reinforces the importance of preventing or limiting exposure to lead in the environment to eliminate childhood lead poisoning.
Recent Evidence to Suggest Caution
Lead exposure in animal models and humans has been shown to produce cognitive deficits, and these cognitive deficits have been alleviated by succimer chelation treatment in animals. Recent studies published in Environmental Health Perspectives and Neurotoxicology and Teratology examined the effects of chelation in animals treated during development with differing lead levels (no lead, moderate, and high lead).
These studies also examined succimer chelation therapy in animals that had not been exposed to lead. The authors report that while the succimer treatment was beneficial in lead exposed animals, it appeared to produce some long-term detrimental effects in those who were not exposed. While chelation treatment paradigms differ in animals and in clinical practice, the authors of this report urge caution in administering chelating agents to individuals who do have not show evidence of heavy metal exposure.
Chelators help remove heavy metals from the body by forming chemical bonds with metals (such as lead and mercury), which facilitates excretion of these chelator/metal complexes through the urine or feces. Therefore, individuals undergoing chelation may show a reduction in blood levels of these toxic metals accompanied by an increase in their urinary excretion. However, in animal studies of lead poisoning, these changes were not well-associated with reductions in brain lead levels, leading researchers conclude that the use of blood lead levels as a marker of metal reductions in other tissues such as the brain may overestimate the potential benefits of chelation.
This suggests that clincial chelation as currently practiced may reduce uptake of heavy metals into the brain but may not sufficiently remove what is already there. Therefore, the mechanism by which chelation alters cognitive performance in individuals with mild to moderate metal exposure needs further study.
Chelation Use in Autism Spectrum Disorders
The role of heavy metals such as mercury in autism has been heavily debated, and many parents are turning to chelation as a potential treatment. Dr. Elizabeth Mumper presented her findings from treating children at the Advocates for Children Pediatric Clinic in Virginia.
She reports that she has treated 280 children with autism who showed altered metabolism of porphyrins in blood and urine. She uses this disruption in porphyrin levels as an indirect marker for heavy metal exposure, and in addition noted that these patients show a disruption in the methionine synthase pathway, also measured in urine and blood. In addition to chelation therapy, children receive vitamin supplementation to compensate for possible loss of essential metals lost during succimer treatment.
Although no statistical analyses were conducted on the effectiveness of chelation therapy in children with autism, Dr. Mumper has cited positive responses from parents who report an improvement of symptoms following oral succimer chelation therapy as part of the
Summary and Conclusions
The panel of experts convened to discuss and present this topic emphasized the need for studies which show the molecular actions of chelation for efficacy and adverse events. In addition, research needs to be conducted to resolve inconsistencies between animal models and human data. In order to protect against depletion of essential minerals during chelation, studies need to evaluate the mobilization and excretion of essential trace elements during long-term chelation to determine whether vitamin and mineral supplementation offers protection against possible adverse effects of chelation.
More With DAN!
Autistic people have fought the inclusion of ABA in therapy for us since before Autism Speaks, and other non-Autistic-led autism organizations, started lobbying legislation to get it covered by insurances and Medicaid.
ABA is a myth originally sold to parents that it would keep their Autistic child out of an institution. Today, parents are told that with early intervention therapy their child will either be less Autistic or no longer Autistic by elementary school, and can be mainstreamed in typical education classes. ABA is very expensive to pay out of pocket. Essentially, Autism Speaks has justified the big price tag up front will offset the overall burden on resources for an Autistic’s lifetime. The recommendation for this therapy is 40 hours a week for children and toddlers.
The original study that showed the success rate of ABA to be at 50% has never been replicated. In fact, the study of ABA by United States Department of Defense was denounced as a failure. Not just once, but multiple times. Simply stated: ABA doesn’t work. In study after repeated study: ABA (conversion therapy) doesn’t work.
What more recent studies do show: Autistics who experienced ABA therapy are at high risk to develop PTSD and other lifelong trauma-related conditions. Historically, the autism organizations promoting ABA as a cure or solution have silenced Autistic advocates’ opposition. ABA is also known as gay conversion therapy.
The ‘cure’ for Autistics not born yet is the prevention of birth.
The ‘cure’ is a choice to terminate a pregnancy based on ‘autism risk.’ The cure is abortion. This is the same ‘cure’ society has for Down Syndrome.
This is eugenics 2021. Instead of killing Autistics and disabled children in gas chambers or ‘mercy killings’ like in Aktion T4, it’ll happen at the doctor’s office, quietly, one Autistic baby at a time. Different approaches yes, but still eugenics and the extinction of an entire minority group of people.
Fact: You can’t cure Autistics from being Autistic.
Fact: You can’t recover an Autistic from being Autistic.
Fact: You can groom an Autistic to mask and hide their traits. Somewhat. … however, this comes at the expense of the Autistic child, promotes Autistic Burnout (this should not be confused with typical burnout, Autistic Burnout can kill Autistics), and places the Autistic child at high risk for PTSD and other lifelong trauma-related conditions.
[Note: Autism is NOT a disease, but a neurodevelopmental difference and disability.]
Fact: Vaccines Do Not Cause Autism.