Improbable Causes & Extravagant Claims (Excerpts from Dwyer v. HHS) · 2010-03-15 06:30

The following excerpts are drawn from Special Master Denise Vowell’s 310-page decision in Dwyer v. Secretary of HHS (Case No. 03-1202V), one of the three “thimerosal theory” test cases presented in the Omnibus Autism Proceeding. The claim was dismissed on March 12, 2010, for failure to prove that thimerosal-containing vaccines can cause autism, or that they did so in this instance.

For links to case filings, rulings, expert witness biographies, and other autism and vaccine injury litigation resources, see Neurodiversity Weblog’s newly-updated Omnibus Autism Proceeding: Resources & Documents directory.


Introduction (p. 3)

Colin’s case was heard as part of the largest omnibus proceeding in the history of the Vaccine Act. It was one of three test cases on the second of two theories of causation [“Theory 2”] advanced by petitioners in the Omnibus Autism Proceeding [“OAP”]. Theory 2 is that the mercury in TCVs can cause at least some forms of ASD, and that it did so in the three Theory 2 test cases, including Colin’s. After considering the record as a whole, I find that petitioners have failed to establish by preponderant evidence that Colin’s condition was caused or significantly aggravated by TCVs. They failed to demonstrate either that the mercury component of TCVs can cause ASD or that it did so in Colin’s case. None of the causation hypotheses advanced were reliable as medical or scientific theories. In essence, petitioners propose effects from mercury in TCVs that do not resemble mercury’s known effects on the brain, either behaviorally or at the cellular level. To prevail, they must show that the exquisitely small amounts of mercury in TCVs that reach the brain can produce devastating effects that far larger amounts experienced prenatally or postnatally from other sources do not. In order to account for this dichotomy, they posit a group of children hypersensitive to mercury’s effects, but the only evidence that these children are unusually sensitive is the fact of their ASD itself. In an effort to render irrelevant the numerous epidemiological studies of ASD and TCVs that show no connection between the two, they contend that their children have a form of ASD involving regression that differs from all other forms biologically and behaviorally. World-class experts in the field testified that the distinctions they drew between forms of ASD were artificial, and that they had never heard of the “clearly regressive” form of autism about which petitioners’ epidemiologist testified. Finally, the causal mechanism petitioners proposed would produce, not ASD, but neuronal death, and eventually patient death as well. The witnesses setting forth this improbable sequence of cause and effect were outclassed in every respect by the impressive assembly of true experts in their respective fields who testified on behalf of respondent. Therefore, I hold that petitioners have failed to establish their entitlement to compensation, and their petition is denied.


On the qualifications of expert witnesses (p. 13-15, 44)

Witness qualifications are an important, and a largely objective, basis upon which to assess and weigh expert opinions. In virtually every area of specialization in science and medicine about which testimony was offered, respondent’s experts were far more qualified to opine than those of petitioners. Speaking generally, the qualifications of the experts proffered by respondent, the relationship of those qualifications to the subject matter of their testimony, and the quality of their testimony far exceeded those of petitioners’ experts.

In terms of research, clinical experience, and publications in the subject matter of the testimony proffered, respondent’s witnesses were truly experts, and some were world-class experts, in their fields. In contrast, most of petitioners’ experts had few publications relating to the subject matter of their testimony and far less experience in the subject matter of their proffered opinions. Respondent’s experts were practicing physicians or research scientists (and sometimes both) who have taught and written extensively on the specific subject matter about which they testified. Although most of petitioners’ witnesses had adequate, and occasionally excellent, qualifications as physicians and scientists, most were either not engaged in research and treatment, or were engaged in research that was, at best, tangential to the subject matter of their testimony. One of petitioners’ expert witnesses had testified very frequently in Vaccine Act cases, and thus appeared to derive substantial income from expert witness fees.

In terms of clinical experience in diagnosing and treating children with ASD, every one of respondent’s experts who treated children with ASD had more academic training and clinical and research experience than petitioners’ experts. None of Colin’s own treating physicians testified in this case, and to the extent that any of his medical records reflect any opinions on causation, they focused on a temporal connection between onset of his symptoms and a purported second MMR vaccination. Thus, there are no opinions of treating physicians to be considered on the causation issue. Of the three witnesses who specifically opined on the cause of Colin’s condition, two were engaged in treating children with ASD, but respondent’s expert had far more years of experience in such treatment, more advanced training, and a record of research and publication in the field not possessed by petitioners’ expert. The third expert filed a very generic expert report, and did not testify.

The responses of witnesses to questions, whether from opposing counsel or from the special masters themselves, was also a factor in weighing and evaluating testimony. In general, respondent’s experts provided more responsive answers to such questions. Respondent’s experts were generally more careful and nuanced in their expert reports and testimony. In contrast, petitioners’ experts were more likely to offer opinions that exceeded their areas of expertise, to “cherry-pick” data from articles that were otherwise unsupportive of their position, or to draw conclusions unsupported by the data cited. When an expert relied on a specific medical or scientific journal article in testimony or referenced it in his or her report, I carefully compared the testimony or report to the article cited. Drs. [Marcel] Kinsbourne and [H. Vasken] Aposhian, in particular, on several occasions cited articles for propositions not contained in the publication. Several of these instances are set forth in greater detail in the sections dealing with their testimony.

…Two of petitioners’ experts, Drs. Kinsbourne and [Elizabeth] Mumper, had qualifications that warranted consideration of their testimony about autism’s symptoms, diagnosis, treatments, and causes, but their testimony was not particularly helpful in providing the background information in this section. Although qualified to testify about autism by virtue of his general training and experience in pediatric neurology, Dr. Kinsbourne’s practice never focused on children with ASDs. He no longer sees or treats patients and has conducted no research into autism’s causes, diagnosis, or treatment, other than a review of medical literature. In many cases, his expert report lacked citations for the statements he made and, in some cases, his citations were simply incorrect.

Dr. [Elizabeth] Mumper is a pediatrician, not a neurologist, psychiatrist, or psychologist, and has had only the standard training provided to pediatricians in these disciplines. Although she has considerable experience in treating children with autism, her testimony was largely anecdotal, rather than based on systematic research, and was thus less helpful in terms of input to this section.


On “regressive autism,” “clearly regressive autism,” and the relationship between regression and genetics (pp. 86-87, 95, 98-99)

I conclude that the preponderance of the evidence demonstrates that regressive autism is not a distinct phenotype, and overwhelmingly demonstrates that “clearly regressive autism” is, at best, only a hypothetical construct, unsupported by any credible evidence. I likewise conclude that opinions, such as Dr. [Sander] Greenland’s, that are based on the existence of this subtype lack the factual underpinnings to be considered reliable evidence. Thus, I conclude that the impressive body of epidemiological evidence that TCVs are not causally associated with ASD is relevant and should be considered in determining whether TCVs do indeed cause or substantially contribute to ASDs…

Not surprisingly, respondent’s experts had sharp disagreements with the assertions of Drs. Kinsbourne and Greenland. Those assertions and the criticisms thereof are set forth below.

With respect to Dr. Kinsbourne, respondent’s experts noted that some of his assertions were made without any reference to supportive medical literature, were based on “cherry-picked” data, and conflicted with the weight of scientific and medical authority. Other aspects of Dr. Kinsbourne’s testimony made analysis of his assertions difficult. For example, he declined to define regressive autism. In view of the numerous definitions discussed, Dr. Kinsbourne’s reluctance to specify what he considered to be regressive autism was troublesome. He could not state whether regressive autism was considered a separate diagnostic category by either the DSM-IVTR or the ICD-10.

…The evidence was overwhelming that genetics alone can account for regression, as regression is present in a number of entirely genetic conditions, some with striking similarities to autism. A postnatal environmental cause for regression is highly unlikely, but not impossible. The lack of 100% concordance in identical twins indicates that something other than genetics alone affects who develops ASD, but the “something else” is more likely epigenetic influences, rather than a postnatal toxic insult.

…The evidence for regressive autism constituting a separate phenotype was singularly unpersuasive. The evidence for an even smaller subtype of regression, “clearly regressive autism,” was non-existent. Dr. Greenland lacked the professional qualifications to opine that autism has distinct “clinically recognizable subtypes with distinct development[al] trajectories and possibly different etiologies.” Unlike Drs. [Eric] Fombonne, [Michael] Rutter, and [Steven] Goodman, Dr. Greenland is not a medical doctor and his CV does not reflect any education, training, or experience in diagnosing or treating autism. Dr. Greenland is thus not qualified to opine on subtypes of autism or whether subtypes of autism have distinct causes. He acknowledged this lack of expertise himself.

Other than Dr. Greenland’s assertions, petitioners offered absolutely no evidence that “clearly regressive autism” is considered a separate diagnostic category by anyone with expertise in diagnosing autism. The medical literature does not use the term. Dr. Greenland was unable to present any evidence indicating that regressive autism is biologically distinct from nonregressive autism.

Most of Dr. Kinsbourne’s assertions about regressive autism were simply wrong. He failed to demonstrate that regression is a separate phenotype. In Dr. [Robert] Rust’s words, his assertion that regressive and classic autism are different conditions is an artificial one. There are a very small number of children with apparently normal development who suffer “sudden and even shocking” regression in their second year of life. Aside from this regression, which is not unique to autism, there is nothing else that sets them apart from children whose regression manifests more slowly or who have sudden regression after some slow or abnormal development.

His assertion that regression is caused by a disease process rather than genetics does not follow logically from what is known about regression in other conditions. Brain development in human infants occurs in phases. At each phase of brain development, genetic signals turn on processes that result in elaborations, development, and eliminations of brain structures. These changes in the brain result in behavioral changes as well. The evidence establishes that whatever sets the development of the brain of an autistic child apart from a typically developing peer likely occurs early in gestation. On a theoretical basis, some changes might be postnatally influenced, but the evidence for such postnatal events is scant. Even when disease processes such as herpes encephalitis postnatally induce autistic-like symptoms, the behaviors induced are similar to, but qualitatively different from, those seen in most children with autism.

Regressive autism cannot be distinguished biologically from other forms of ASD. There is no evidence of any brain abnormality that sets those with regression apart from those with classic or early onset ASD. With regard to “clearly regressive autism,” it was petitioners’ burden to demonstrate its existence as a separate phenotype. I find that petitioners failed to do so. Because the facts that formed the basis for his opinion were not satisfactorily established, Dr. Greenland’s opinion that the existing studies cannot rule out a substantial causal role for TCVs in one form of autism is not relevant or persuasive.


Conclusions regarding epidemiology (p. 120)

Epidemiological evidence has limitations. It cannot speak to causation in an individual case. It can, however, sufficiently undermine a hypothesis or theory regarding causation, making reliance on such a theory unreasonable under all the facts and circumstances of an individual case.

To use Althen’s terms, epidemiological studies point out possible logical connections between two events; further scientific effort must ensue to establish whether the connections are biologically plausible and therefore truly logical. After studying the evidence available, the IOM concluded that the evidence favored rejection of the TCV-ASD hypothesis. Since that 2004 conclusion, all of the reliable epidemiological studies have buttressed the finding of no relationship.

Each epidemiological study filed has limitations that affect the data acquired and may affect the conclusions drawn. However, when numerous well-designed studies have looked at a particular issue and arrived at the same or similar conclusions, the likelihood that the studies’ limitations have caused the negative results becomes vanishingly small. Epidemiology can never be direct proof that vaccines do not cause ASD, but it can be strong circumstantial evidence that causation is improbable. In this case, the epidemiological studies furnish powerful evidence refuting a causal association between TCVs and ASD.


On Dr. H. Vasken Aposhian’s testimony (p. 121)

Some aspects of Dr. Aposhian’s testimony were troubling. He occasionally cited studies in support of his testimony, that, when examined, did not support that testimony. In spite of his acknowledgment that the various species of mercury had different toxicokinetics, he often attributed the effects of one species to another. Much of his direct testimony appeared scripted, consisting of reading his slides verbatim. On cross-examination, he provided wandering, anecdotal, and nonresponsive answers. He avoided responding to cross-examination questions with comments such as “it depends on how you define…” or “this is a court of law and I must tell the truth.”


Factual conclusions regarding mercury and “hypersusceptibility” (p. 172)

Dr. Brent referred to a scientific methodology for determining if a given substance was responsible for a particular toxic effect, in which four questions must be answered: (1) to what chemical was the patient exposed; (2) how much of the substance was involved; (3) what conditions is the chemical known to cause; and (4) did this exposure cause the condition from which the patient suffers? Essentially, this methodology asks: what, how much, can it, and did it?

Applying Dr. [Jeffrey] Brent’s methodology, I conclude that it is undisputed that human beings are born with some amount of mercury present in their brains. Throughout the first year of life, U.S. children have additional mercury exposure from diet, environment (air and water), and, prior to the removal of most TCVs from the U.S. market, TCVs. Mercury exposure continues throughout life, and some portion of the mercury to which human beings are exposed adds to brain mercury levels.

Petitioners have contended that inorganic mercury in the brain is responsible for at least some cases of ASD. However, the amount of inorganic mercury produced in the brains of infants who received TCVs is extremely low. Dr. Aposhian’s calculations of the contribution of TCVs to brain inorganic mercury levels were incorrect, but even if I use his figures, TCVs produced far less than the amount of inorganic mercury in the brain that produced inflammatory responses in adult primates. The actual TCV contribution was undoubtedly much smaller than Dr. Aposhian postulated. The evidence is clear that ethylmercury, in sufficient doses, is neurotoxic. The brain levels at which toxic effects have been observed are not well-established for ethylmercury, but total brain mercury levels associated with toxic effects are thousands of times higher than the levels produced by TCVs, and hundreds of times higher than baseline measurements in autopsies of human neonates.

Through a series of accidental poisonings, toxicologists have determined the neurotoxic effects from prenatal and early postnatal mercury exposure. Those effects are not ASDs. Through sophisticated tests administered to children in populations exposed pre- and postnatally to levels insufficient to produce toxicity, but sufficient to produce measurable cognitive effects, effects of lower dose exposure have been described. Once again, those effects are not ASDs.

The levels of inorganic and total brain mercury at which widespread evidence of neuroinflammation was observed in the adult monkeys were far higher than the levels found in human neonates (baseline exposure) plus any amount attributable to vaccines. Even in the adult primates, the cellular changes in the brain produced no observable neurological effects after months of daily exposure. Every two days, the adult primates received approximately as much mercury as is contained in all the mercury in the first six months of TCVs, calculated at a dose per kilogram.

Methylmercury has an affinity for certain areas of the brain. The brain areas most affected by mercury are not the areas affected in ASD patients. The brain cells most vulnerable to mercury’s effects are largely unaffected in ASD patients. Conversely, the loss of Purkinje cells is the most consistent pathological finding in the ASD autopsy studies, but mercury exposure spares Purkinje cells while damaging others. The neurological symptoms caused by mercury exposure do not resemble ASD’s symptoms and behaviors.

The evidence that some individuals are hypersusceptible to mercury’s effects is singularly unconvincing. There is no reliable evidence that mercury levels in children with ASD, with or without regression, differ from those in the general population. There is no reliable evidence that children with ASD respond differently to mercury than neurotypical children do. The studies upon which Dr. Aposhian relied were, in general, poorly performed, and in all cases, their results either had not been or could not be duplicated.

Through Dr. Aposhian, petitioners attempted to demonstrate mercury’s probable causal role in ASD. Similarly, through Dr. Aposhian, petitioners attempted to demonstrate that vaccine levels of TCVs, alone or in combination with other sources of mercury exposure, would produce brain levels of mercury sufficient to provoke oxidative stress, oxidative injury, and neuroinflammation. The evidence presented by Dr. Aposhian failed to do either.


On Dr. Richard Deth’s testimony regarding mercury, oxidative stress and sulfur metabolism (pp. 176, 185, 192, 208, 224)

Summarizing Dr. Deth’s opinions on the causal role of mercury in autism is difficult. Not only were the biochemical processes allegedly affected very complex, his explanations of those processes lacked coherence. He opined that very small amounts of mercury had a scattershot effect on a number of biochemical processes, inducing systemic metabolic abnormalities and oxidative stress. He also opined that these metabolic abnormalities resulted in interference with neuronal functioning in attention and cognition, causing the major symptoms of autism. His entire hypothesis rested on a speculative “genetic susceptibility” to environmental toxins, such as heavy metals in general, and mercury in particular. He asserted that children with autism have polymorphisms – variations in genes that are not considered mutations—that render them more sensitive to mercury’s effects by impairing their ability to eliminate ethylmercury, maintain normal oxidative and methylation balance, and maintain synchronization in neuronal signaling. The scientific studies upon which he relied provided, at best, only tangential support for his hypothesis. His own research, most of which was unpublished, unduplicated, or mentioned for the first time during the Theory 2 general causation hearing, was poorly performed and scientifically implausible. Based on in vitro effects of mercury on “neuronal cells,” he claimed that mercury had the same effects on human brain cells.

In addition to his own unpublished research, Dr. Deth relied heavily on his one article on mercury, the Waly study. He relied on two studies conducted by Dr. S. Jill James, calling them the strongest evidence in support of his hypothesis. He also claimed that the “strongest evidence” in favor of his hypothesis derived from his own unpublished work on post-mortem brain samples from individuals with ASD.

Perhaps his most extravagant claim involved the quantity of mercury required to induce the claimed effects. He claimed the ability to detect the effects of mercury on cells at levels 100-1000 times lower than levels used by other researchers. He testified that mercury, in amounts at or well below the amounts contained in TCVs, could induce some individuals to enter into and remain in a state of oxidative stress.

In the course of the hearing, nearly every premise of his causation theory, other than that of the ubiquity of mercury exposure in children (with or without autism), was seriously undermined, where not completely demolished. Mercury, and a number of other heavy metals, can affect cellular metabolism, but Dr. Deth’s assertions that mercury does so in the manner and at the levels of exposure postulated and with the effects claimed were not scientifically supported. His assertion that oxidative stress in children with autism is causal of their autism was pure speculation.

…Although Dr. Deth’s testimony was superficially coherent, the defects pointed out by true experts revealed the critical flaws in Dr. Deth’s presentation, and, ultimately established that his hypothesis of causation was not reliable.

…The discovery of an extracellular methylation cycle, when all other methylation cycles take place inside cells, is so highly unusual that it warrants independent confirmation. That confirmation is lacking. The assertion in the Waly study that the D4 receptor was the site of the methylation activity was based on gel electrophoresis, but a critical failure in that process was noted by Dr. [Richard] Mailman. In view of Dr. Mailman’s many publications on dopamine receptors, his testimony regarding them carries exceptional weight.

As Dr. Deth had not conducted studies on human brain cells, other than his unpublished work discussed below, his testimony that human neurons lack the ability to use SAM to reactivate methionine synthase lacks scientific support. He based his findings on experiments conducted on cells with a known methionine synthase mutation. In summary, Dr. Deth and his colleagues designed an experiment around two faulty premises: the existence of the only extracellular methylation cycle, and a purported defect in human neuronal cells. In view of these problems, and the other issues noted by Drs. Jones and Mailman, any conclusions drawn from the first part of the Waly study are so unreliable as to render its evidentiary value virtually nil.

…Dr. Deth’s late-in-the-game switch from mercury’s impact on glutathione to its binding to otherwise unidentified “regulatory proteins” was unpersuasive. After considerable testimony about mercury’s effects on transsulfuration and the methionine methylation cycle and his many experiments that purported to measure these effects, Dr. Deth’s new focus on “regulatory proteins” was disingenuous at best. Given the ubiquity of thiols and sulfur in the brain and elsewhere in the body, the tiny amounts of mercury administered through TCVs, and the even smaller amounts that will reach and remain in the brain, are unlikely to deplete the thiols available. Most mercury in the brain is already bound, and only the small amount not already bound to thiols would be available to react with these “regulatory proteins.”

…Initially, to someone unacquainted with mercury’s toxicology, ASD, or biochemistry, Dr. Deth’s opinions on mercury, oxidative stress, and sulfur metabolism might appear to be solidly based and plausible. After all, mercury can be toxic to cells and is known to produce neurological injuries. Mercury does bind to glutathione, the body’s primary antioxidant molecule, and thus might be expected to affect adversely the body’s oxidative status. Mercury is known to bind to cysteine transporters, and thus might be expected to affect cysteine levels in cells, and thus adversely affect cells that cannot manufacture their own cysteine, such as neurons. There is evidence to indicate that mercury can cause proliferation of microglia and reductions in astrocyte numbers in at least some areas of the brain, which Dr. Deth equated to the neuroinflammation found in the brains of individuals with ASD. There is some evidence that children with ASD display biomarkers of oxidative stress in peripheral blood, and may even have some polymorphisms associated with higher levels of oxidative stress.

However, when critically examined, Dr. Deth’s causal assertions fall apart. Mercury, at sufficient doses, is toxic to cells, but humans are born with mercury in their brains, blood, and hair as a result of maternal exposures. Humans continue to be exposed to mercury throughout their lives, and methods for detoxifying and eliminating mercury have evolved to account for this exposure. In populations with high mercury exposure, there is no increased incidence of ASD, and thus the low levels once found in vaccines are unlikely to be a cause or a substantial contributor to the condition. Mercury, at sufficient doses, can produce neurological injuries, but not at the levels of mercury found in vaccines. The neurological injuries it produces are well established and do not resemble ASD. A comparison of autopsy findings in mercury’s victims and autopsy findings from individuals with ASD do not show the same patterns of damage or injury.

Dr. Deth attempted to demonstrate that vaccine levels of mercury could adversely affect sulfur metabolism and produce oxidative injury in the human brain through a series of experiments on cells in culture. He represented the cells as “neuronal,” although they were not neurons and had defects affecting the processes he attempted to measure. His laboratory experiments, funded largely by contributions from groups associated with the belief that vaccines cause ASD (ARI [Autism Research Institute] and SafeMinds), found adverse effects from doses of mercury between 100-10,000 times lower than those used by other researchers. Assuming, arguendo, that these experiments were properly performed and produced correct results (both points about which I am unconvinced), the experiments contribute little to nothing to the causation hypothesis. In vitro experiments on cells in culture may suggest likely avenues for further research, but the complexity of sulfur metabolism presented in Dr. Deth’s testimony and report demonstrates the robust systems in place in human beings to handle oxidative stress and produce the methylated products needed for cellular functioning, including DNA expression. I note that Dr. Deth heavily relied on mercury’s effects on glutathione, but the evidence overwhelmingly illustrated that glutathione levels in the body would be unaffected by vaccine level doses.

Dr. Deth also relied heavily on evidence indicating that children with ASD display peripheral markers of oxidative stress, and that brains of those with ASD have evidence of neuroinflammation, which he equated to oxidative damage. He failed to mention that oxidative stress in the periphery is associated with many different diseases, but that peripheral levels do not represent brain redox status. He likewise failed to point out that neuroinflammation is found in many brain disorders and injuries, including those produced by trauma. Thus, a finding of oxidative stress or even oxidative injury says little about mercury as a probable cause of the stress or injury because there are so many other possible causes, including neuroinflammation as a response to the other pathophysiological findings in the brains of those with ASD. Since ASD is a highly genetic disorder, it is unsurprising that preliminary studies have found some polymorphisms exist in children with ASD in higher numbers than in neurotypical individuals. It is equally unsurprising that some of these polymorphisms are associated with problems in oxidation or sulfur metabolism. Children with Down syndrome, an entirely genetic disorder involving mental retardation, also have oxidative stress levels higher than neurotypical children. Children with Rett’s disorder, another entirely genetic condition, have impairments in DNA methylation, a sulfur metabolism problem. The preliminary findings in children with ASD say nothing about a genetic susceptibility to mercury or even that the oxidative stress levels found actually affect mercury detoxification.

Dr. Deth’s own experiments were based on faulty premises regarding methylation of the D4 receptor and defects in methionine synthase activity in human neurons. His experiments detecting effects of nanomolar levels of mercury on glutathione, cysteine, methylcobalamin, and methionine synthase had so many flaws that they cannot be considered reliable as evidence. Respondent’s experts in oxidative stress, sulfur metabolism, neurodegenerative disorders, and mercury pointed out the serious deficiencies in Dr. Deth’s hypothesis, experiments, and conclusions. Their criticisms, coupled with the flaws in Dr. Deth’s logic, his own acknowledgment that eliminating TCVs has not produced any decline in ASD rates, and the conflicts between his testimony and what is well established about mercury’s toxicology, all convince me that Dr. Deth’s hypothesis is not reliable, and cause me to accord his testimony and report little weight.


On Dr. Richard Deth’s and Dr. Marcel Kinsbourne’s neuroinflammation hypothesis (p. 226)

Drs. Deth and Kinsbourne presented hypotheses that involved persistent inorganic mercury in the brain causing neuroinflammation, leading to autism. The majority of Dr. Deth’s testimony focused on the effects of mercury on sulfur metabolism, leading to a state of oxidative stress in the brain, manifesting with the neuroinflammatory findings reported by the Vargas study. His neuroinflammation hypothesis was similar, but not identical, to that of Dr. Kinsbourne, and he was less clear about how the neuroinflammation resulted in ASD. Dr. Kinsbourne’s hypothesis attempted to fill that gap. Dr. Kinsbourne asserted that mercury-induced neuroinflammation caused excitotoxicity, which manifested as overarousal of individuals with ASD, causing autistic behaviors. Dr. Kinsbourne made it clear that his opinion did not depend on that of Dr. Deth, who “was studying at the molecular level a particular component of the broader process that I was invoking.” However, Dr. Kinsbourne did not tie his neuroinflammation process specifically to Dr. Deth’s oxidative stress model. For purposes of his hypothesis, it did not matter how the neuroinflammation was produced. However, Dr. Kinsbourne’s hypothesis was based on Dr. Aposhian’s opinions about the amount of mercury required to cause the excitotoxic process he proposed. As indicated in Section VI, I did not find Dr. Aposhian’s calculations regarding the amount of mercury in the brain generated from vaccines to be correct. I did not credit Dr. Aposhian’s testimony that TCVs could produce enough mercury to cause the widespread glial activation necessary to Dr. Kinsbourne’s hypothesis. Nevertheless, because of the role of Dr. Kinsbourne’s testimony in the general causation test case, I evaluate his general causation hypothesis as if these evidentiary prerequisites had been met. I conclude that there are other fatal flaws in his hypothesis. The method of injury he proposed would lead to neuronal death, and eventually patient death, not ASD. The brain cell interactions he proposed are not consistent with the complex interactions that actually occur in human brains. Mercury’s effects on the brain and the symptoms it produces do not resemble those of ASD. Dr. Kinsbourne’s overarousal model of ASD is not new, but it has never been widely accepted because there is no evidence linking the behaviors Dr. Kinsbourne attributed to overarousal to physiological measurements of hyperexcitability.


On Dr. Marcel Kinsbourne’s methodology (pp. 235-238, 248, 253-255)

… Although Dr. Kinsbourne cited a number of studies as supporting his model of autism as a consequence of an excitatory-inhibitory imbalance, many either do not support the points for which he cited them or the points he made were taken out of context. Dr. Rust generally characterized Dr. Kinsbourne as overstating the support found in these studies. What emerges when these studies are critically examined is validation for Dr. Rust’s characterization. The data Dr. Kinsbourne cited are not representative of the studies’ findings, and much of the data contained in the studies do not support Dr. Kinsbourne’s hypothesis. As Dr. Rust further observed: “Prominent countervailing data and theories are not considered.” An occasional misstatement of a study might be expected in any expert’s analysis of such complex issues. However, the pattern that emerges in Dr. Kinsbourne’s citations is not that of an occasional misstatement. A scientist might well pick data from many different sources to serve as circumstantial evidence for a particular hypothesis, but a reliable expert would not ignore contrary data, misstate the findings of others, make sweeping statements without support, and cite papers that do not provide the support asserted.

When confronted with evidence that one of the studies upon which he relied stated that Purkinje cells were not damaged by methylmercury exposure, Dr. Kinsbourne’s response was more than a little illogical. He testified that he was not attributing the loss of Purkinje cells directly to mercury poisoning, but rather to the excitotoxic effects of mercury. That is, he was saying that high doses of methylmercury (which converts to inorganic mercury) will spare Purkinje cells, but low-dose exposure will kill them through excitotoxicity caused by inorganic mercury. The evidence established that doses of mercury sufficient to cause harm spared Purkinje cells, while damaging other cell types… Dr. Kinsbourne could not explain why high-dose exposure would spare cells, but low-dose mercury exposure would damage them or impair their function.

A careful examination of his cited references reflected Dr. Kinsbourne’s penchant for extracting data and out-of-context references to support his position, while ignoring contrary data or remarks in the same study or article. Although some studies contained support for specific aspects of his hypothesis, the studies Dr. Kinsbourne cited were not supportive of glutamate excess as a cause of ASD.

Dr. Kinsbourne’s proposed mechanisms of injury from TCVs (or mercury in general) do not account for any of the development anomalies Dr. [Thomas] Kemper and others have found in autistic brains. Dr. Kemper provided a list of clinical features and neuropathological findings in autism compared to those of mercury toxicity. The clinical features and neuropathology of the two conditions do not overlap; in many cases, the findings in autistic brains are the opposite of those caused by mercury.

Dr. Rust commented that if inorganic mercury causes overexcitation, and the amount of mercury increases over time, patients with autism would get progressively worse over time. Because human beings are continually exposed to various sources of mercury, brain inorganic mercury levels increase over time, even in the absence of TCV exposure. Dr. Kinsbourne’s report indicated both that autistic symptoms plateau, but may also become more severe if epilepsy ensues. Although he distinguished ASD from metabolic brain degeneration, the implication of a steadily increasing toxic element causing a reaction is that there would be a steady deterioration in function. That is not what is seen in autism; individuals with autism improve over time. This is inconsistent with Dr. Kinbourne’s hypothesis.

…In his Theory 2 general causation hypothesis, Dr. Kinsbourne added a new coat of paint to an old building, but failed to shore up the building’s basic structural failings. As Dr. Rust characterized it, Dr. Kinsbourne’s hypothesis has “lethal problems in terms of scientific support.” Rather than producing ASD, the excitotoxic state Dr. Kinsbourne’s hypothesis envisioned would produce neuronal death, followed by patient death. That is not descriptive of the natural history of ASD. His whole hypothesis relied on “a toxicologist” (presumably Dr. Aposhian) to establish that exposure to TCVs could produce enough mercury in the brain, either alone or in conjunction with other environmental mercury exposure, to cause neuroinflammation. For reasons detailed at length in Section VI, Dr. Aposhian’s opinion that TCVs would produce enough mercury to cause the effects postulated was not reliable.

Even if, arguendo, sufficient brain mercury is produced by TCVs, Dr. Kinsbourne’s hypothesis cannot explain why most children with ASD improve over time, while the mercury levels in their brains are likely increasing over the same time frame from diet and other sources. His assertion that brain protective measures kick in at some point to ameliorate the effects of additional mercury was sheer speculation. Dr. Kinsbourne opined that neuroinflammation produces ASD through a glutamate excess. None of the studies he cited measured glutamate levels in the brains of those with ASD. The evidence of neuroinflammation does not establish a cause for neuroinflammation, and there was ample evidence that it is a nonspecific finding with many possible causes, including a response to injury.

Witnesses with far better qualifications in research into neurodegenerative diseases and oxidative stress established that the cellular processes Dr. Kinsbourne described do not work the way he asserted. Dr. Kinsbourne’s testimony about what happened to astrocytes in his model was inconsistent. He relied on the Lopez-Hurtado study’s findings of gliosis, which he erroneously equated to astrocytic death. He relied on damage to astrocytes as an essential component of his theory of a glutamate imbalance, and indicated that astrocytic death was not required. Then, he postulated an increase in astrocyte numbers as responsible for causing ASD. He was not only inconsistent, he was wrong.

Although, on a theoretical level, other physicians and scientists have considered Dr. Kinsbourne’s overarousal model as an explanation for autism’s behavior, a mercury-produced glutamate excess is not a probable explanation for overarousal. As Dr. Kinsbourne conceded, glutamate has never been identified as a cause of ASD. What mercury does in the brain is well-known. In sufficient doses, it is a potent neurotoxin, but not one that has ever been shown to cause autism or autistic symptoms. To properly place a factor on a list of differential causes for a disease or disorder requires some evidence that it is capable of causing that disease or disorder. To prevail, petitioners must establish by preponderant evidence that TCV exposure belongs “on the differential” as a cause for ASD. Even by this standard, which is much lower than that of “scientific certainty,” petitioners’ case falls well short.


Conclusion regarding general causation (pp. 256-263)

A. Conclusions in General

A diagnosis of ASD can be heartbreaking. Although most children improve, few ever lose the diagnosis. Most children with ASD will never live independently as adults. The true cost of ASD is borne by those who live daily with the condition and contend with its financial and emotional tolls. In the caring and compassionate words of Dr. Rust during the general causation hearing, those of us on the outside looking in “do not understand.”

When petitions for compensation alleging that ASD was the result of childhood vaccinations were filed in mounting numbers, the OAP was created to help resolve the factual and legal questions the petitions presented. The Vaccine Program exists to compensate victims of vaccine injuries easily, quickly, and with generosity, but entitlement to compensation requires more than a sincere and honest belief that a vaccine is responsible for causing ASD. In these cases, as in all other off-Table cases, petitioners must establish by preponderant evidence that a vaccine can cause ASD, and that it did so in their children’s cases. The evidence produced in the Theory 2 cases alone was voluminous and highly technical, and the hypotheses presented were very complex. This illustrates not only the difficulty of making factual conclusions regarding that evidence, but also the utility of an omnibus hearing to produce and evaluate it. However, nearly a decade after the OAP was created, all of the evidence produced to date is inadequate to demonstrate any causal connection between vaccines and ASD.

The TCV causation hypothesis emerged from a combination of mercury’s long-established role as a neurotoxin, ASD’s status as a neurological disorder, and the ubiquity of exposure to TCVs prior to the perceived emergence of ASD’s symptoms. The Faroe Islands studies suggested that maternal methylmercury exposure during gestation was a statistically significant predictor of poorer performance on some neurological tests. Although the Seychelles Island studies did not make the same findings, the Faroe Islands studies were some evidence that smaller doses of methylmercury than previously thought could cause neurological harm. The Internet likely played a role as well, according to at least one commentator.

The focus on TCV causation of regressive ASD emerged in the Theory 2 cases as a consequence of what Dr. Kinsbourne called the “striking” and “shocking” presentation in some cases of regression, in which apparently normal toddlers lost skills and sociability. Without an understanding of how behavior at age two could be caused by some brain systems coming on line while others were disconnected, it made sense for parents and others to look for a more recent triggering event. Most children with ASD had received vaccines containing “a known neurotoxin” and, equating the reference dose for methylmercury to ethylmercury, parents voiced concerns about the amount of mercury children received in vaccines. Even the prestigious IOM called the mercury hypothesis “biologically plausible” in 2001, although what the IOM meant by that term was not what the parents perceived.

However, over the following three years, more scientific studies were published. The toxicokinetics of ethylmercury were studied in primates and human infants, and every reputable study confirmed that methylmercury studies were not a good predictor of ethylmercury’s effects. Well-conducted epidemiological studies found no connection between TCVs and ASD. In 2004, the IOM reexamined the TCV-ASD hypothesis and concluded, in the strongest terms available to it, that the evidence favored rejection of any causal connection. Since 2004, every epidemiological study except one has continued to find no connection between TCVs and ASD. The one study that found a connection was funded by the Petitioners’ Steering Committee representing the OAP petitioners in this omnibus proceeding.

The Theory 2 cases may have continued to press the TCV-ASD hypothesis because some of the factual predicates for the hypothesis are well established. The strong beliefs of many parents (and a small group of physicians and scientists) that vaccines are causal undoubtedly played a role as well. Vaccines received by most U.S. children in the 1990s through the 2001-2003 time frame contained more than trace amounts of thimerosal. When injected, thimerosal is metabolized into ethylmercury. A small portion of this ethylmercury reaches the brain, where an even smaller amount is converted to inorganic (mercuric) mercury. Once converted to inorganic mercury in the brain, it is virtually immobile. At certain brain levels in primates, organic mercury has been shown to cause fairly widespread activation of microglial cells and some reduction in astrocytic cells. Activated microglia have been found in autopsies of the brains of patients with ASD in greater numbers than in the brains of neurotypical individuals.

In spite of these widely-accepted factual predicates, the TCV-ASD causation hypothesis has been rejected by the general scientific community for many cogent reasons. However, it continues to be pressed by a small group of physicians and scientists associated with groups such as SafeMinds, DAN [Defeat Autism Now!], and ARI. Most of petitioners’ experts were drawn from this group. Dr. Deth’s research has been funded by them; Dr. Mumper is the medical director of ARI, and Dr. Aposhian has participated in ARI’s “think tanks.” Many of the published studies relied upon by the testifying experts, including nearly all of those relied upon by Dr. Aposhian in his “six pillars,” were written by individuals associated with ARI and other similar groups. As discussed in Sections VI-VIII above, the conclusions of this group are not grounded on reputable and reliable scientific foundations.

The view that ASD is caused by mercury may have persisted because it provides some hope that ASD can be treated, and even cured. The general scientific consensus is that ASD is the result of prenatal developmental problems shaped largely by genetic and epigenetic contributions. This consensus provides little hope for parents of children with ASD. Mainstream science does not, at present, offer many effective therapies, much less offer hope of a cure. Mainstream science tells us that some manifestations of autistic behavior can be treated with drugs, behavioral therapy, and speech and language therapy, but that few children will lose the diagnosis or live independently in adulthood. Understandably, many parents have looked to practitioners who offer hope of improvement, and even a cure.

After extensively reviewing the testimony, expert reports, and other evidence, I have concluded that petitioners have failed in the general causation case to demonstrate that TCVs cause or substantially contribute to ASD. Their experts proffered hypotheses that were illogical, contrary to the weight of the evidence, and, ultimately, unpersuasive.

B. Qualifications of the Experts

The quality of the expert opinions proffered in this case was heavily influenced by the expertise of the scientists and physicians offering them. Respondent produced an impressive group of physicians and scientists who were truly experts in the fields about which they testified. They had garnered awards from both peers and autism advocacy groups. Many had published hundreds of peer reviewed articles and book chapters pertaining to the subjects about which they testified. Dr. Rutter has been researching ASD for more than four decades, and Drs. Lord, Kemper, Rodier, Leventhal, and Rust have been involved in such research for nearly as long. Doctors [Jeff] Johnson, Mailman, [Dean] Jones, and [L. Jackson] Roberts each had extraordinarily impressive qualifications in the highly technical subject matter about which they testified. Dr. Brent brought both a treating physician’s perspective and a toxicologist’s background to the discussion of mercury’s effects on human beings, and clearly and carefully explained the significance of the science about which he testified. Only in epidemiology did the qualifications of petitioners’ expert even approach those of respondent’s, and even there, Drs. Fombonne and Rutter brought the additional expertise from their own research and publications in the epidemiology of ASDs. Dr. Goodman offered much-needed insight into the IOM reports on TCVs and expertise on the issues of “subgroups” and biological plausibility.

In contrast, petitioners produced a very well-qualified epidemiologist, Dr. Greenland, whose opinion was so limited as to be essentially useless as part of a causation hypothesis. Because the factual predicates for his opinion on “clearly regressive autism” were not established, Dr. Greenland’s primary contribution was pointing out the generally acknowledged weaknesses in the epidemiological studies of ASD and TCVs. Dr. Aposhian was qualified to opine on mercury, but lacked the qualifications in medical toxicology that Dr. Brent possessed. Dr. Deth’s experience in mercury, sulfur metabolism, oxidative stress, and ASD was minimal and recently acquired, and paled in comparison to that of respondent’s experts in academic background, teaching experience, research focus, publications, and awards and recognitions. Dr. Kinsbourne has not had a clinical practice in nearly two decades, and, in comparison to respondent’s experts, relatively little experience before that in diagnosing and treating children with ASD.

I emphasize that the qualifications of the experts were not, standing alone, determinative in my conclusion that petitioners have failed to make a prima facie case for mercury’s causal role in ASD. Not only were respondent’s experts far better qualified to opine, the evidentiary quality of their opinions exceeded that of petitioners’ witnesses. With very few exceptions, when one of respondent’s witnesses cited a medical or scientific study for a point, the study fully supported that point. Their opinions were well supported by other evidence, and, when contrary studies existed, they were careful to explain why they found them unpersuasive or unreliable. In contrast, on many occasions when I read a study that one of petitioners’ experts cited, I found that it did not provide substantial support for the point for which it was cited, or did so only in part, with the study as a whole being unsupportive of the proposition advanced by the expert. The studies that were supportive often had problems of their own in that they could not be duplicated by other researchers. Many of Dr. Aposhian’s conclusions were drawn from studies that could not be duplicated. Most of Dr. Deth’s opinions were based on his own unpublished work, certain aspects of which were, according to experts in the field, poorly performed and unlikely to be correct. Although peer review and publication are not necessary conditions for consideration in Vaccine Act cases, the problems with Dr. Deth’s own work cast substantial doubt on the conclusions he drew from it. As respondent’s experts correctly noted, Dr. Kinsbourne sometimes cited studies for unsupported propositions, misstated the degree of support found, and “cherry-picked” data from studies, while ignoring contrary data in the same study.

C. A Failure of Proof

As Dr. Rust stated, a hypothesis that is so broad that anything from measles virus to an environmental toxin could cause ASD is unlikely to be correct. Where the evidence was in conflict, the great weight of the evidence favored respondent. Thus, I have resolved most of the factual disputes against petitioners. With regard to ASD itself, I concluded that there is no reliable evidence that regressive autism is a disorder distinct from that of classic or early onset ASD. The evidence for any postnatal causal factors, including environmental toxins, is very weak. The weight of the evidence is that ASD originates prenatally, with genetics playing a very strong role in its origin and manifestations.

1. TCVs Do Not Substantially Contribute to Brain Mercury Levels.

Humans are born with some mercury present in their brain as the result of maternal exposure to various sources of mercury. Inorganic mercury continues to accumulate in the brain over a lifetime from sources ranging from food products and dental amalgams to air and water. Mercury is considered a neurotoxin, and its neurotoxic effects are more pronounced when the exposure occurs in utero. Harmful effects are a function of dose and other factors, including the method of administration, the species of mercury involved, and the time period over which exposure occurs.

However, there is no reliable evidence that TCVs produced anything more than minuscule levels of inorganic mercury in the brain of infant monkeys exposed to approximately 2.5 times as much mercury as human infants received in TCVs. In contrast, autopsy studies of U.S. infants who died within a few days of birth demonstrated mercury levels much higher than those of the infant monkeys, likely a result of prenatal exposure. A number of studies established that at birth, human infants have blood mercury levels strikingly similar to those of their mothers.

Dr. Aposhian’s contrary testimony and calculations were based on faulty premises. Although the widespread use of TCVs contributed some amount to the level of inorganic mercury in the brain, the amount contributed was very small in comparison to amounts that accrue from environmental exposures over time. The levels of mercury that have produced toxic symptoms, including the subtle neurodevelopmental testing abnormalities observed in children from areas with high levels of dietary exposure, have all been much higher than those produced by TCVs.

2. Evidence that TCVs Produce Neuroinflammation is Lacking.

Although exposure to far higher doses of methylmercury has been observed to produce neuroinflammatory responses in the brains of adult primates, there is no direct evidence that the ethylmercury from TCVs produces the same effects. The circumstantial evidence that vaccine level doses can do so, even in conjunction with other mercury exposure, is likewise lacking. Microglial activation is not specific to mercury, other heavy metals, or ASD; it occurs in many brain disorders, and may represent a response to injury, rather than its cause. An author of the Vargas study, one of the papers on which petitioners primarily relied, wrote that the neuroinflammatory responses observed in the brains of autism patients were not consistent with a response to a toxic exposure.

3. Mercury’s Known Biological Effects in the Brain Do Not Resemble Those of ASD.

What mercury exposure does to the brain is well established, and neither the structures nor the cell types principally injured by mercury exposure are those that are malpositioned, damaged, missing, or destroyed in ASD. Petitioners’ hypothesis requires that high level doses of mercury spare Purkinje cells, while low level doses damage them. The pathophysiological changes in the brain in ASD largely occur prenatally; prenatal exposure to high enough doses of mercury to cause observable neurological symptoms produces cerebral palsy and developmental delays, but has not been observed to produce anything resembling ASD’s core symptoms. Mercury causes damage to discrete anatomical regions of the brain associated with motor coordination; motor skills are largely unaffected in ASD.

4. The Symptoms of ASD Do Not Resemble Symptoms Produced by Mercury Exposure.

Dr. Rodier, the one witness with considerable expertise in both mercury exposure and ASD, testified that there are no similarities between ASD and either ethylmercury poisoning or mercury poisoning in general. If ASD results from a hypersusceptibility to mercury in a small group of children, one would expect the symptoms of this group to resemble closely those of mercury poisoning victims, with a lower dose producing similar effects in those genetically hypersusceptible. It does not. Sensory and motor disturbances are the first effects observed in mercury poisoning; language, communication, and social skills losses are among the first symptoms observed in ASD.

5. There is No Evidence of Hypersusceptibility to Mercury in Individuals with ASD.

Although both Drs. Aposhian and Deth testified about a hypersusceptibility to mercury, or mercury efflux disorder, there is no reliable evidence that one exists. The studies on which Dr. Aposhian relied could not be duplicated by other researchers. At best, preliminary evidence that children with ASD have higher biomarkers of oxidative stress suggests that they may be more affected by administration of substances that produce oxidative stress, but there is no evidence that they respond differently to vaccine level doses of thimerosal. To point to the existence of ASD as validation of that aberrant response is simply circular reasoning.

6. Postnatal Causes for ASD Are Unlikely.

The pathophysiological findings from the autopsy studies strongly point to a prenatal origin for nearly all the abnormal findings observed. The co-occurrence of dysmorphology in substantial numbers of those with ASD, and the dating of the origin of the dysmorphology to points in early gestation, buttresses the autopsy studies. ASD is strongly genetic, and although there is not a 100% concordance rate for ASD diagnoses in monozygotic twins, epigenetics may account for the discordance. Dr. Rutter explained that the development of human beings is designed to work in a particular way, but genes do not tell each cell what to do. Genetics specifies a pattern, but the pattern may be altered by many factors.

Injuries early in the prenatal period produce, as Dr. [Patricia] Rodier remarked, a cascade of further injuries in the nervous system. As the authors of the Connors study, relied upon by Dr. Aposhian, noted: “The neurobiologic mechanisms underlying autism are in place before birth.”

7. There is Insufficient Evidence that Regression or “Clear Regression” in ASD has a Separate Biological Basis.

Dr. Kinsbourne was unpersuasive in his attempts to establish that regression in ASD has a separate biological basis or even that it should be considered a separate type of ASD. His opinions were contradicted by several witnesses, each of whom had far more experience in diagnosis of ASD and research into how ASD presents. They described some loss of skills occurring in many, if not most, children with ASD, and rarely constituting the first sign or symptom of the disorder. Loss of skills is something apparent to parents; failure to meet milestones may or may not be. ASD may present in any number of subtle ways not readily apparent to untrained observers. Regression occurs in several genetically-caused disorders, clearly indicating that it need not be the result of a triggering postnatal event.

8. Neither Excitotoxicity nor Oxidative Injury is Likely as a Cause of ASD.

Glutamate may well play a role in ASD’s symptomology, but a general level of excitotoxicity caused by mercury damage is unlikely as a cause for ASD. Dr. Kinsbourne hypothesized that mercury causes neuroinflammation, which causes damage to astrocytes, leading to overexcited neurons firing too frequently. This scenario, in the opinion of several of respondent’s experts who have researched brain disorders, would lead to neurodegeneration and neuronal death. There is little evidence of neuronal death in ASD; neurons are frequently smaller and more numerous in ASD patients. Neuronal death progresses to patient death in other neurological disorders, most of which occur later in life. There is no evidence of progressive neurological injury in ASD.

9. Epidemiology Has Failed to Detect Any Connection Between TCV Exposure and ASD.

The epidemiological evidence presented was strong, but not dispositive, on the issue of general causation. These studies indicated that a causal connection between TCVs and ASD is unlikely, but not impossible. Because I have concluded that there is no evidence to show that “clearly regressive” autism exists as a separate phenotype of the disorder, and have likewise concluded that there is virtually no evidence suggesting that regression in general constitutes a separate phenotype with a distinct etiology, I consider the epidemiology relevant to my ultimate conclusion on general causation. Strong epidemiological evidence indicates that TCVs are unlikely to play a causal role. Although most U.S. vaccines manufactured after 2001 contained no more than trace amounts of thimerosal, its removal had no effect on the prevalence of ASD rates, even considering that stockpiles of TCVs may have been used for a year or two after manufacturing ceased.

D. Conclusion

The Theory 2 hypotheses have fared no better than the Theory 1 hypotheses. The evidence in favor of TCV causation of ASD is weak and singularly unpersuasive. Two processes that are not pathognomonic of any disorder, neuroinflammation and oxidative stress, were assigned a causal role in the development of ASD, but the presence of either or both in ASD patients says little to nothing about ASD’s potential causes. If ASD can be caused by neuroinflammation and/or oxidative stress, then anything that can cause either of those conditions belongs, according to Dr. Kinsbourne’s reasoning, “on the differential” for ASD causation. Petitioners have failed to demonstrate why TCVs – among all the possible causes of neuroinflammation and oxidative stress – are a probable cause of, or a substantial contributor to, ASD.


On Dr. Mumper’s clinical judgment (pp. 303-304)

Dr. Mumper’s willingness to rely on testing she considered of dubious reliability gave me pause, in addition to her willingness to make causal determinations based on laboratory testing not specific for ASD. Many of the test results she relied upon could be attributed to nutritional problems in a child with an extremely restricted diet. Others focused on peripheral markers that could not reflect what was happening in the brain. She proffered opinions on Colin’s mercury levels based on tests showing an absence of mercury in the presence of chelation, and opined that the one positive test result was extremely elevated without any reliable basis to do so.

…Having conducted little to no research herself, Dr. Mumper relied on the opinion of Dr. Aposhian regarding mercury efflux disorders in ASD. I rejected that opinion in Section VI. She relied on Dr. Deth’s opinions regarding sulfur metabolism and oxidative stress. However, even if the test results upon which she based her opinion regarding Colin’s sulfur metabolism and level of oxidative stress are accurate and reliable, they say little about mercury as a causal factor. Children with many diseases and disorders display markers of oxidative stress. Diet alone is a significant confounder of plasma levels of the oxidative biomarkers upon which Dr. Mumper relied, and she acknowledged that diet could skew these results. She relied on Dr. Kinsbourne’s opinion about neuroinflammation in ASD, and tried to tie Colin’s neurofilament test results to that opinion, but those results were performed by an unreliable laboratory. Furthermore, Dr. Kinsbourne did not suggest that neurofilament testing would be helpful or useful in detecting neuroinflammation. Most significantly, even if Colin had some degree of neuroinflammation, which the Vargas study would suggest is likely in those with ASD, neuroinflammation is so nonspecific that it would be of little evidentiary value to establish that mercury was its cause.

Dr. Mumper’s willingness to rely on Colin’s mercury test results as evidence of high levels of mercury in his body was particularly troubling. She admitted that his results were not typical of those she saw in other autistic children. She admitted that she knew of no research into normal mercury excretion levels after chelation against which Colin’s one positive mercury test could be measured. It appeared that regardless of the results for mercury levels, Dr. Mumper was willing to opine that they reflected mercury’s role in ASD. If levels were low, it was because the child had excretion difficulties even in response to chelation or was hypersusceptible to the low level of mercury present. If the levels were high, then the child was retaining mercury, demonstrating excretion difficulties, and thus had more mercury available to cause neuroinflammation. Thus, either the presence or the absence of mercury in test results in a child with ASD could be interpreted as “proof” of a mercury excretion problem. Finally, because Colin did not appear to be exposed to mercury on any continuing basis from diet and was not breast fed, he likely had a lower level of mercury in his system than other children. Thus, his TCV exposure would not be likely to “tip him over the edge.”


On the standard of proof in Vaccine Court: Applying Althen (pp. 304-310)

The burden on the petitioners in Colin’s specific case is to demonstrate by preponderant evidence that Colin’s ASD was caused by his vaccines. They asserted that the thimerosal component of those vaccines either caused or substantially contributed to his ASD. To meet their burden under Althen, petitioners must demonstrate by preponderant evidence “(1) a medical theory causally connecting the vaccination and the injury; (2) a logical sequence of cause and effect showing that the vaccination was the reason for the injury; and (3) a showing of a proximate temporal relationship between vaccination and injury.” Althen v. Sec’y, HHS, 418 F.3d 1274, 1278 (Fed. Cir. 2005).

In their post-hearing brief, petitioners acknowledged their burden to establish each of Althen’s three factors by a preponderance of the evidence. Petitioners correctly noted that scientific certainty regarding causation is not required by the Vaccine Act, and that circumstantial evidence showing that a vaccine was a preponderant cause is sufficient. Petitioners framed Althen’s first prong as requiring them to demonstrate that the immunizations in question can cause the type of injury at issue, and the second prong as “addressing the question of whether the particular vaccines did cause the particular condition at issue.”

1. Medical Theory

Evaluating petitioners’ medical theory is complicated by the many links in the chain of causation hypothesized. Some of the links are not reasonably subject to dispute, others are partially correct, and still others are just plain wrong. Concisely stated, their hypothesis is that Colin’s “neurodevelopmental injuries are the result of a neuroinflammatory process triggered by inorganic mercury…deposited in [his] brain[] as a byproduct of exposure to TCVs in the first two years months [sic] of life.” The inorganic mercury triggered neuroinflammation, characterized by the activation of the brain’s innate immune system. This neuroinflammation produced two interrelated effects. First, it created an environment of oxidative stress in the brain, “with a complex cycle of impaired and disrupted biochemical processes that interfered with brain function.” Second, it produced an excess of glutamate, the primary excitatory neurotransmitter in the brain, leading to a persistent state of overexcitation or overarousal.

Petitioners asserted that exposure to vaccines leads to an accumulation of “toxic” mercury in the brain. They asserted that inorganic mercury can cause neuroinflammation, which can disrupt neuronal functioning, leading to an excitatory-inhibitory imbalance, which is amplified by mercury-induced oxidative stress. This imbalance manifested in the development of other symptoms of ASD in a genetically susceptible child.

As the recitation and discussion of the evidence in Sections VI-VIII above demonstrate, petitioners failed to establish that their medical theory was probable, plausible, or reliable. They failed to produce sufficient reliable evidence to show that TCVs, either alone or in combination with other environmental mercury exposure, were a cause of ASD in children susceptible or vulnerable to such exposure. They failed to produce sufficient reliable evidence to demonstrate that TCVs, either alone or in combination with other environmental mercury exposure, can produce mercury levels capable of causing neuroinflammation. Thus, they failed to show that TCVs belong on the list of potential causes of ASD.

They framed the general causation question in terms of regression. “Can TCVs in general be a substantial factor in causing autistic regression in some susceptible or vulnerable number of children?” Petitioners relied on the general causation evidence “to establish by a preponderance of the evidence that TCVs could have been substantial contributing causes of [the] autistic regression[]” in Colin’s case. In making this argument, they appeared to distinguish Colin from other autistic children without loss of skills. Although they claimed that they were not seeking to show that regression is a separate diagnostic category or syndrome, they relied on Colin’s regression as a evidence of an environmental trigger or “second hit” demonstrating the effect of TCVs on a genetically susceptible child. Although petitioners argued that “none of the epidemiology addresses autistic regression of the sort these three boys experienced,” they did not explicitly state that Colin experienced the “clearly regressive autism” about which Dr. Greenland testified.

Petitioners correctly asserted that they have no burden to present epidemiologic evidence demonstrating an association between ASD and TCVs, calling such evidence “scant, at best.” The testimony of their own epidemiologist was even stronger. Dr. Greenland testified that he did not find the only studies purporting to show an increased risk of autism associated with TCVs – studies by Dr. [Mark Geier] and Mr. [David] Geier – to be of evidentiary value.

While certain subpoints of their causation hypothesis – their medical theory – were clearly established or uncontested, most were not. Although they called their evidence “robust and reliable” and claimed that a prima facie case for causation in general had been established, I have concluded otherwise.

Althen requires more than merely asserting a medical theory. Petitioners must offer a reputable medical theory, and inherent in that standard is a requirement that the theory be biologically plausible. See Walther, 485 F.3d at 1148 and Pafford, 451 F.3d at 1355-56 (petitioner’s theory must be reputable). The theory of TCV causation is simply not reliable, and can no longer be considered “biologically plausible,” in view of all that is known about mercury in the brain.

2. Logical Sequence of Cause and Effect

Petitioners equated Althen’s second prong to establishing whether causation had been shown in Colin’s specific case. They argued that “ample indirect and circumstantial evidence” established that Colin’s TCVs caused neuroinflammation that caused his ASD. Even if Dr. [Bennett] Leventhal applied a heightened evidentiary standard to determining causation in Colin’s specific case, I have not. At best, the evidence established that Colin received vaccines that probably contained thimerosal and that he had a diagnosis of ASD. No sequence of cause and effect between the two can be logical, in view of the conclusion that petitioners have failed to establish a causal connection in general between ASD and TCVs.

Furthermore, Dr. Mumper’s causal opinion is based, in large part if not in its entirety, on the opinions of Drs. Kinsbourne, Deth, and Aposhian, whose opinions I have rejected as scientifically implausible and unsound. Notwithstanding this defect, the specific factors she cited as important in Colin’s case largely concerned testing performed by laboratories with questionable reliability. Many of the laboratory tests upon which she relied are not tests appearing in standard laboratory manuals or tests that would even be ordered by most practitioners, and the data they provide are not diagnostic of ASD. Treatments designed to target the “problems” noted in Colin’s test results were not efficacious, either in the view of Colin’s parents or in the view of Colin’s subsequent treating physician.

In their post-hearing brief, petitioners appear to acknowledge the problematic nature of Colin’s test results. Although Dr. Mumper testified about a number of test results that contributed to her opinion that Colin’s ASD was caused by his TCVs, in their post-hearing brief they only mentioned a “latent, genetic inabilit[y] to properly metabolize and excrete mercury.” Colin’s only positive mercury test occurred after chelation, and its results were not measured against any standardized normal values. In spite of numerous other rounds of chelation with a variety of chemical and “natural” chelators, no detectible levels of mercury were ever again excreted. This result is not compatible with a child with problems metabolizing and excreting mercury.

Petitioners’ causation claim is unaffected by Dr. Greenland’s opinion that the existing epidemiological studies of ASD cannot detect a causal connection with TCVs on a small subgroup. The hypothetical subgroup he described involved regression after previously normal development. Contrary to petitioners’ assertions, Colin was not developmentally normal at the time he received his last TCV. Colin’s ASD had already begun to manifest by the time he was 20 months of age. Thus, Dr. Greenland’s opinion that the epidemiological studies of ASD cannot rule out an effect on a small subgroup of children is irrelevant to Colin’s case.

Ruling out known causes of ASD, as Dr. Mumper did in her report and testimony, is not sufficient to put TCVs on the list of possible causes. “Although probative… a simplistic elimination of other potential causes” is insufficient to show actual causation. Moberly 592 F.3d at 1323 (citing Althen, 418 F.3d at 1278); see also Ruggiero v. Warner-Lambert Co., 424 F.3d 249, 254 (2d Cir. 2005) (using differential diagnosis to eliminate other causes is insufficient to demonstrate causation). Thus, the process of differential diagnosis cannot be applied to conclude that Colin’s ASD must have been caused by TCVs, once other causes are ruled out. A differential diagnosis is only as good as the list of possible causes.

3. Proximate Temporal Relationship

Onset after vaccination is not enough, standing alone, to satisfy Althen’s third prong. Petitioners have the burden to demonstrate the existence of a “scientific temporal relationship.” Pafford v. Sec’y, HHS, 64 Fed. Cl. 19, 29-30 (2005), aff’d, 451 F.3d 1352 (Fed. Cir. 2006). The time frame must be medically acceptable. De Bazan 539 at 1352.

Petitioners did not address this prong of the Althen standard in their briefs and this omission is a significant flaw. The failure to show that a disease arose in the time expected by the medical community means a petitioner is not entitled to compensation. Pafford, 451 F.3d at 1358-60. It is clear that Colin’s ASD manifested with speech delay at or before 20 months of age, before he received his last round of vaccinations. At that point in his life, he had already received vaccines containing as much as 212.5 μg of ethylmercury. However, none of petitioners’ experts opined on the time frame in which mercury must be received in order to cause autism in a developing brain. The weight of the evidence was that ASD’s origins are largely prenatal, and thus any environmental insult contributing to its largely genetic cause must have occurred prenatally. Respondent’s experts indicated that if post-natal causes played any role in the many neuropathological differences found in individuals with ASD, they must occur very early in the post-natal period, but the experts did not think postnatal causes were likely or probable.

At best, petitioners have demonstrated that Colin’s ASD manifested after most of his vaccinations. That would be true of any child with this condition who had received vaccines, because ASD cannot be reliably diagnosed until at least one year of age, even if subtle indicators may have existed earlier. Most ASD symptoms become apparent to parents at 18-24 months of age, and thus onset will follow vaccinations in almost every child with ASD.

4. No Burden on Respondent to Establish an Alternate Cause

Petitioners have failed to establish any of Althen’s three factors. Thus, they have failed to establish that Colin’s vaccines were a substantial cause of his injury. Because they have failed to establish causation by a preponderance of the evidence, the burden never shifted to respondent to establish an alternative cause for Colin’s condition. De Bazan, 539 F.3d at 1353-54.

5. Summary

In concluding that petitioners have failed to establish that Colin’s TCVs caused his ASD, I emphasize that I have not applied a heightened evidentiary burden. I did not require scientific certainty, nor direct evidence of causation. Daubert requires that an opinion be supported by something more than subjective belief; it must be grounded in “the methods and procedures of science.” 509 U.S. at 590. There is no evidence that mercury has ever caused an ASD, only speculation that it might. At best, there is some evidence of an ongoing inflammatory process in ASD, but no indication that it is caused by mercury, and many indications that it is not. The excitation-inhibition theory is likewise unsupported in the peer reviewed medical literature; at best, there is some speculation that some ASD symptoms may be a reflection of an excitatory-inhibitory imbalance, but no proof of any biological overarousal when the symptoms are observed.

Scientists use the terms “hypothesis” and “theory” with very specific meanings. A hypothesis is an idea proffered to explain an event. A theory is what is developed after a hypothesis has been subjected to many attempts to disprove it, and thus, it is likely correct. This is an important distinction, because in biology, almost anything is possible. The pertinent question is whether something is probable or likely. Petitioners had several hypotheses but nothing that approached a theory. As Dr. Rust commented: “Hypotheses are a dime a dozen.”

A number of governmental and non-governmental scientific agencies have looked at the issue of a relationship between TCVs and ASD. These agencies include the National Academy of Sciences, Institute of Medicine, American College of Medical Toxicology, American Academy of Pediatrics, World Health Organization, U.S. Center for Disease Control and Prevention, the European Medicine Agency, and the American Academy of Family Practice. They have all concluded that there is no causal connection between the two.

Unfortunately, the Dwyers (and uncounted other parents of children with ASD) have relied upon practitioners and researchers who peddled hope, not opinions grounded in science and medicine. My heart goes out to parents like the Dwyers who struggle daily, emotionally and financially, to care for their children, but I must decide cases based on the law and not sentiment. The law in this case requires preponderant evidence that TCVs caused or substantially contributed to Colin’s ASD, and, by that standard, petitioners are not entitled to compensation.

Conclusion

Petitioners have not demonstrated by a preponderance of the evidence that Colin’s condition was either caused or significantly aggravated by his vaccinations. Thus, they have failed to establish entitlement to compensation and the petition for compensation is therefore DENIED. In the absence of a motion for review filed pursuant to RCFC, Appendix B, the clerk is directed to enter judgment accordingly.

IT IS SO ORDERED.

Denise K. Vowell
Special Master

Comments


  1. A few of my favorites:

    “Dr. Deth’s assertions that mercury does so in the manner and at the levels of exposure postulated and with the effects claimed were not scientifically supported. His assertion that oxidative stress in children with autism is causal of their autism was pure speculation.”

    “Although Dr. Deth’s testimony was superficially coherent, the defects pointed out by true experts revealed the critical flaws in Dr. Deth’s presentation, and, ultimately established that his hypothesis of causation was not reliable.”

    “When confronted with evidence that one of the studies upon which he relied stated that Purkinje cells were not damaged by methylmercury exposure, Dr. Kinsbourne’s response was more than a little illogical.”

    “Dr. Mumper’s willingness to rely on testing she considered of dubious reliability gave me pause, in addition to her willingness to make causal determinations based on laboratory testing not specific for ASD. Many of the test results she relied upon could be attributed to nutritional problems in a child with an extremely restricted diet. Others focused on peripheral markers that could not reflect what was happening in the brain.”

    THAT’S going to leave a mark!

    Prometheus

    — Prometheus    2010-03-15 13:14    #

  2. So it can all be summed up in these immortal words then:

    “It’s all a loada bollox innit”

    — Laurentius Rex    2010-03-16 01:26    #

  3. Thanks for posting these, Kathleen. Haven’t managed to read all of it but the excerpt format is a big step toward accessibility (at least for me).

    — Ralph    2010-03-24 05:49    #

  4. Agreed – it might take me years to get around to reading the entire decision and this summary is incredibly helpful.

    It’s hard to believe any of the folks who are going around crying about how they wuz robbed in Vaccine Court actually read any amount of any of the opinions.

    — isles    2010-03-28 00:02    #

  5. I’m surprised that he couldn’t find an ICD-10 code to diagnose Regressive Autism, or even why he would need to think that Regressive Autism would need its own category outside of autism.

    — Quang    2010-12-09 20:06    #

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