Autism: A Unique Type of Mercury Poisoning
Copyright (c) 2000 by ARC Research
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April 3, 2000
Revision of April 21, 2000
Autism is a syndrome characterized by impairments in social relatedness, language and communication, a need for routine and sameness, abnormal movements, and sensory dysfunction. Mercury (Hg) is a toxic metal that can exist as a pure element or in a variety of inorganic and organic forms and can cause immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with autism. Thimerosal, a preservative frequently added to childhood vaccines, has become a major source of Hg in human infants and toddlers. According to the FDA and the American Academy of Pediatricians, fully vaccinated children now receive, within their first two years, Hg levels that exceed safety limits established by the FDA and other supervisory agencies. A thorough review of medical literature and U.S. government data indicates (i) that many and perhaps most cases of idiopathic autism, in which an extended period of developmental normalcy is followed by an emergence of symptoms, are induced by early exposure to Hg; (ii) that this type of autism represents a unique form of Hg poisoning (HgP); (iii) that excessive Hg exposure from thimerosal in vaccine injections is an etiological mechanism for causing the traits of autism; (iv) that certain genetic and non-genetic factors establish a predisposition whereby thimerosal's adverse effects occur only in some children; and (v) that vaccinal Hg in thimerosal is causing a heretofore unrecognized mercurial syndrome.
A review of medical literature indicates that the characteristics of autism and of mercury poisoning (HgP) are strikingly similar. Traits defining or associated with both disorders are summarized in Table A immediately following the Table of Contents and are discussed and cited in the body of this document. The parallels between the two diseases are so thorough as to suggest, based on total Hg injected into U.S. children, that many cases of autism are a form of mercury poisoning.
For these children, the exposure route is childhood vaccines, most of which contain thimerosal, a preservative which is 49.6% ethylmercury by weight. The amount of mercury a typical child under two years receives from vaccinations equates to 237.5 micrograms, or 3.53 x 1017 molecules (353,000,000,000,000,000 molecules). Most such vaccinal Hg may not be excreted and instead migrates to the brain.
The total amount injected into infants and toddlers (i) is known to exceed Federal safety standards, (ii) is officially considered to be a “low” level; whereby (iii) only a small percentage of exposed individuals exhibit symptoms of toxicity. In fact, children who develop Hg-related autism are likely to have had a predisposition derived from genetic and non-genetic factors.
Importantly, the timings of vaccinal Hg-exposure and its latency period coincide with the emergence of autistic-symptoms in specific children. Moreover, excessive mercury has been detected in urine, hair, and blood samples from autistic children; and parental reports, though limited at this date, indicate significant improvement in symptoms subsequent to heavy-metal chelation therapy.
The HgP phenotype is diverse and depends upon a number of factors - including type of Hg, route of entry into the body, rate and level of dose, individual genotype, and the age and immune status of the patient. Historically, variation among these factors has caused slightly different manifestations of mercurialism; Mad Hatter’s disease, Minamata disease, acrodynia, and industrial exposures provide examples.
The pathology arising from the mercury-related variables involved in autism - intermittent bolus doses of ethylmercury injected into susceptible infants and toddlers - is heretofore undescribed in medical literature. Therefore, in accord with existing HgP data and HgP’s ability to induce virtually all the traits defining or associated with autism spectrum disorders, we hypothesize that many and perhaps most cases of autism represent a unique form of mercury poisoning.
This conclusion and its supporting data have important implications for the affected population of autistic individuals and their families, for other unexplained disorders with symptoms similar to those of heavy metal intoxication, for vaccine content, and for childhood vaccination programs. Due to its high potential for neurotoxicity, thimerosal should be removed immediately from all vaccine products designated for infants and toddlers.
Table of Contents
I. Symptom Comparisona. Affect/Psychological Presentation
b. Language & Hearing
c. Sensory Perception
d. Movement/Motor Function
e. Cognition/Mental Function
h. Physical Presentations
j. Gastrointestinal Function
II. Comparison of Biological Abnormalities
III. Mechanisms, Sources & Epidemiology of Exposurea. Exposure Mechanism
b. Population Susceptibility
c. Sex Ratio
d. Exposure Levels & Autism Prevalence
e. Genetic Factors
f. Course of Disease
g. Thimerosal Interaction with Vaccines
IV. Detection of Mercury in Autistic Children
Diagnostic Criteria Are Met
Unique Form Would be Expected, Implicates Vaccinal Thimerosal
Historical Precedent Exists
Barriers Preventing Earlier Discovery Are Removed
Medical & Societal Implications
Summary Comparison of Characteristics
of Autism & Mercury Poisoning
|Social deficits, shyness, social withdrawal||Social deficits, social withdrawal, shyness|
|Depression, mood swings; mask face||Depressive traits, mood swings; flat affect|
|Schizoid tendencies, OCD traits||Schizophrenic & OCD traits; repetitiveness|
|Lacks eye contact, hesitant to engage others||Lack of eye contact, avoids conversation|
|Irrational fears||Irrational fears|
|Irritability, aggression, temper tantrums||Irritability, aggression, temper tantrums|
|Impaired face recognition||Impaired face recognition|
|Speech, Language & Hearing Deficits|
|Loss of speech, failure to develop speech||Delayed language, failure to develop speech|
|Dysarthria; articulation problems||Dysarthria; articulation problems|
|Speech comprehension deficits||Speech comprehension deficits|
|Verbalizing & word retrieval problems||Echolalia; word use & pragmatic errors|
|Sound sensitivity||Sound sensitivity|
|Hearing loss; deafness in very high doses||Mild to profound hearing loss|
|Poor performance on language IQ tests||Poor performance on verbal IQ tests|
|Sensory Abnormalities< tr>|
|Abnormal sensation in mouth & extremities||Abnormal sensation in mouth & extremities|
|Sound sensitivity||Sound sensitivity|
|Abnormal touch sensations; touch aversion||Abnormal touch sensations; touch aversion|
|Vestibular abnormalities||Vestibular abnormalities|
|Involuntary jerking movements - arm flapping, ankle jerks, myoclonal jerks, choreiform movements, circling, rocking||Stereotyped movements - arm flapping, jumping, circling, spinning, rocking; myoclonal jerks; choreiform movements|
|Deficits in eye-hand coordination; limb apraxia; intention tremors||Poor eye-hand coordination; limb apraxia; problems with intentional movements|
|Gait impairment; ataxia - from incoordination & clumsiness to inability to walk, stand, or sit; loss of motor control||Abnormal gait and posture, clumsiness and incoordination; difficulties sitting, lying, crawling, and walking|
|Difficulty in chewing or swallowing||Difficulty chewing or swallowing|
|Unusual postures; toe walking||Unusual postures; toe walking|
|Borderline intelligence, mental retardation - some cases reversible||Borderline intelligence, mental retardation - sometimes "recovered"|
|Poor concentration, attention, response inhibition||Poor concentration, attention, shifting attention|
|Uneven performance on IQ subtests||Uneven performance on IQ subtests|
|Verbal IQ higher than performance IQ||Verbal IQ higher than performance IQ|
|Poor short term, verbal, & auditory memory||Poor short term, auditory & verbal memory|
|Poor visual and perceptual motor skills, impairment in simple reaction time||Poor visual and perceptual motor skills, lower performance on timed tests|
|Difficulty carrying out complex commands||Difficulty carrying out multiple commands|
|Word-comprehension difficulties||Word-comprehension difficulties|
|Deficits in understanding abstract ideas & symbolism; degeneration of higher mental powers||Deficits in abstract thinking & symbolism, understanding other’s mental states, sequencing, planning & organizing|
|Stereotyped sniffing (rats)||Stereotyped, repetitive behaviors|
|ADHD traits||ADHD traits|
|Agitation, unprovoked crying, grimacing, staring spells||Agitation, unprovoked crying, grimacing, staring spells|
|Sleep difficulties||Sleep difficulties|
|Eating disorders, feeding problems||Eating disorders, feeding problems|
|Self injurious behavior, e.g. head banging||Self injurious behavior, e.g. head banging|
|Poor eye contact, impaired visual fixation||Poor eye contact, problems in joint attention|
|“Visual impairments,” blindness, near-sightedness, decreased visual acuity||“Visual impairments”; inaccurate/slow saccades; decreased rod functioning|
|Light sensitivity, photophobia||Over-sensitivity to light|
|Blurred or hazy vision||Blurred vision|
|Constricted visual fields||Not described|
|Increase in cerebral palsy; hyper- or hypo-tonia; abnormal reflexes; decreased muscle strength, especially upper body; incontinence; problems chewing, swallowing, salivating||Increase in cerebral palsy; hyper- or hypotonia; decreased muscle strength, especially upper body; incontinence; problems chewing and swallowing|
|Rashes, dermatitis/dry skin, itching; burning||Rashes, dermatitis, eczema, itching|
|Autonomic disturbance: excessive sweating, poor circulation, elevated heart rate||Autonomic disturbance: unusual sweating, poor circulation, elevated heart rate|
|Gastro-intestinal Disturbances< tr>|
|Gastroenteritis, diarrhea; abdominal pain, constipation, “colitis”||Diarrhea, constipation, gaseousness, abdominal discomfort, colitis|
|Anorexia, weight loss, nausea, poor appetite||Anorexia; feeding problems/vomiting|
|Lesions of ileum & colon; increased gut permeability||Leaky gut syndrome|
|Inhibits dipeptidyl peptidase IV, which cleaves casomorphin||Inadequate endopeptidase enzymes needed for breakdown of casein & gluten|
|Binds -SH groups; blocks sulfate transporter in intestines, kidneys||Low sulfate levels|
|Has special affinity for purines & pyrimidines||Purine & pyrimidine metabolism errors lead to autistic features|
|Reduces availability of glutathione, needed in neurons, cells & liver to detoxify heavy metals||Low levels of glutathione; decreased ability of liver to detoxify heavy metals|
|Causes significant reduction in glutathione peroxidase and glutathione reductase||Abnormal glutathione peroxidase activities in erythrocytes|
|Disrupts mitochondrial activities, especially in brain||Mitochondrial dysfunction, especially in brain|
|Sensitivity due to allergic or autoimmune reactions; sensitive individuals more likely to have allergies, asthma, autoimmune-like symptoms, especially rheumatoid-like ones||More likely to have allergies and asthma; familial presence of autoimmune diseases, especially rheumatoid arthritis; IgA deficiencies|
|Can produce an immune response in CNS||On-going immune response in CNS|
|Causes brain/MBP autoantibodies||Brain/MBP autoantibodies present|
|Causes overproduction of Th2 subset; kills/inhibits lymphocytes, T-cells, and monocytes; decreases NK T-cell activity; induces or suppresses IFNg & IL-2||Skewed immune-cell subset in the Th2 direction; decreased responses to T-cell mitogens; reduced NK T-cell function; increased IFNg & IL-12|
|CNS Structural Pathology|
|Selectively targets brain areas unable to detoxify or reduce Hg-induced oxidative stress||Specific areas of brain pathology; many functions spared|
|Damage to Purkinje and granular cells||Damage to Purkinje and granular cells|
|Accummulates in amygdala and hippocampus||Pathology in amygdala and hippocampus|
|Causes abnormal neuronal cytoarchitecture; disrupts neuronal migration & cell division; reduces NCAMs||Neuronal disorganization; increased neuronal cell replication, increased glial cells; depressed expression of NCAMs|
|Progressive microcephaly||Progressive microcephaly and macrocephaly|
|Brain stem defects in some cases||Brain stem defects in some cases|
|Abnormalities in Neuro-chemistry|
|Prevents presynaptic serotonin release & inhibits serotonin transport; causes calcium disruptions||Decreased serotonin synthesis in children; abnormal calcium metabolism|
|Alters dopamine systems; peroxidine deficiency in rats resembles mercurialism in humans||Possibly high or low dopamine levels; positive response to peroxidine (lowers dopamine levels)|
|Elevates epinephrine & norepinephrine levels by blocking enzyme that degrades epinephrine||Elevated norepinephrine and epinephrine|
|Elevates glutamate||Elevated glutamate and aspartate|
|Leads to cortical acetylcholine deficiency; increases muscarinic receptor density in hippocampus & cerebellum||Cortical acetylcholine deficiency; reduced muscarinic receptor binding in hippocampus|
|Causes demyelinating neuropathy||Demyelination in brain|
|EEG Abnormalities / Epilepsy|
|Causes abnormal EEGs, epileptiform activity||Abnormal EEGs, epileptiform activity|
|Causes seizures, convulsions||Seizures; epilepsy|
|Causes subtle, low amplitude seizure activity||Subtle, low amplitude seizure activities|
|Effects more males than females||Male:female ratio estimated at 4:1|
|At low doses, only affects those geneticially susceptible||High heritability - concordance for MZ twins is 90%|
|First added to childhood vaccines in 1930s||First "discovered" among children born in 1930s|
|Exposure levels steadily increased since 1930s with rate of vaccination, number of vaccines||Prevalence of autism has steadily increased from 1 in 2000 (pre1970) to 1 in 500 (early 1990s), higher in 2000.|
|Exposure occurs at 0 - 15 months; clinical silent stage means symptom emergence delayed; symptoms emerge gradually, starting with movement & sensation||Symptoms emerge from 4 months to 2 years old; symptoms emerge gradually, starting with movement & sensation|
Autism, or Autistic Spectrum Disorder (ASD), is considered a neurodevelopmental syndrome, emerging early in life and exhibiting a constellation of seemingly unrelated features and a wide variation in symptom expression and level of severity by individual (Filipek et al, 1999; Bailey et al, 1996). The diagnostic criteria for autism are qualitative impairments in social relatedness, deficits in verbal and nonverbal communication, and the presence of repetitive and restricted behaviors or interests (APA, 1994). As will be cited below, other traits associated with autism are movement disorder, sensory dysfunction, and cognitive impairments as well as gastrointestinal difficulties and immune abnormalities (Gillberg & Coleman, 1992; Warren et al, 1990; Horvath et al, 1999). Onset must occur before age 36 months (APA, 1994); although in some instances deficits are apparent at birth, in the great majority of cases there are at least several months of normal development followed by clear regression or failure to progress normally (Gillberg & Coleman, 1992; Filipek et al, 1999; Bailey et al, 1996). Formerly regarded as a rare disease, autism is now said to affect one in 500 children (Bristol et al, 1996), with some estimates suggesting one in 100 for a broader phenotype often labeled as the "autism-spectrum" of disorders and which includes both higher and lower functioning individuals (Arvidsson et al, 1997; Wing, 1996).
Autism and autistic symptoms can arise from a number of known disorders, most notably tuberous sclerosis, Rhett syndrome, Landau-Kleffner syndrome, Fragile X, Phenylketonuria, purine autism, and other purine metabolic diseases such as PRPP synthetase defects and 5'-nucleotidase superactivity. The etiology and pathogenesis of the vast majority of autism cases - 70% - 90% (Gillberg and Coleman, 1992; Bailey et al, 1996) - remain unexplained, however, despite ASD being "one of the most extensively studied disorders in child psychiatry today" (Malhotra and Gupta, 1999). Nevertheless, there is general agreement that most cases of autism arise "from the interaction of an early environmental insult and a genetic predisposition" (Trottier et al, 1999; Bristol et al, 1996).
A heavy metal, mercury (Hg) is widely considered one of the most toxic substances on earth (Clarkson, 1997). Instances of Hg poisoning or "mercurialism" have been described since Roman times. The Mad Hatter in Alice in Wonderland was a victim of occupational exposure to mercury vapor, referred to as "Mad Hatter's Disease." Further human data has been derived from instances of widespread poisonings during the 20th Century. These misfortunes include an outbreak in Minamata, Japan, caused by consumption of contaminated fish and resulting in "Minamata Disease;" outbreaks in Iraq, Guatemala and Russia due to ingestion of contaminated seed grains; and, in the first half of the century, poisoning of infants and toddlers by mercury in teething powders, leading to acrodynia or Pink Disease. Besides these epidemics, numerous instances of individual or small group cases of Hg intoxication and subsequent phenotype are described in the literature.
The constellation of mercury-induced symptoms varies enormously from individual to individual. The diversity of disease manifestations derives from a number of interacting variables which are summarized in Table I. The variables which affect phenotype include an individual's age, the total dosage, dose rate, duration of exposure, type of mercury, routes of exposure such as inhaled, subcutaneous, oral, or intramuscular, and, most importantly, by individual sensitivity arising from immune and genetic factors (Dales, 1972; Koos and Longo, 1976; Matheson et al, 1980; Eto et al, 1999; Feldman, 1982; Warkany and Hubbard, 1953).
Leading to Diverse & Non-Specific Symptomatology
|Variable||Level of Variable|
|Exposure Amount||Ranges from high doses, leading to death or near death with severe impairments, to low "safe" doses, leading to subtle neurological and other physical impairments|
|Duration of exposure||One time vs. multiple times over the course of weeks, months, or years|
|Dose rate||Bolus dose, daily dose|
|Individual sensitivity||A function of (a) the age at which exposure occurs, that is, prenatal, infant, child, adolescent, or adult, (b) genetically determined reactivity to mercury, and (c) gender|
|Common types of mercury||The organic alkyl forms - methylmercury and ethylmercury; and inorganic forms - metallic mercury, elemental (liquid) mercury, and ionic mercury/mercuric salt|
|Primary routes of exposure||Inhalation of mercury vapors, orally through the intestinal tract, subcutaneous and intramuscular injections, topically through ear drops, teething powders, skin creams and ointments, and intravenously during medical treatments|
While these variations in exposure, individual status, and genotype give rise to a diverse clinical phenotype, there are nevertheless obvious commonalities across all mercury-caused disorders. Thus, for example, victims will almost always develop a movement disorder, but in some individuals this may manifest as mere clumsiness, while others will develop severe involuntary jerking movements. Likewise, psychological disturbances are usually present, but in some individuals these might manifest as anxiety while in others it might present as aggression or irritability.
Diagnosing Mercury Poisoning in Autism
Mercury poisoning can be difficult to diagnose and is often interpreted by clinicians as a psychiatric disorder, especially if exposure is not suspected (Diner and Brenner, 1998; Frackelton and Christensen, 1998). The difficulty in diagnosis derives primarily from two notable characteristics of this heavy metal. First, there can be a long latent period between time of exposure and onset of overt symptoms, so that the connection between the two events is often overlooked. The latency period is discussed in more detail below. Second, the diverse manifestations of the disease make it difficult for the clinician to find a precise match of his particular patient's symptoms with those described in other case reports (Adams et al, 1983, Kark et al, 1971; Florentine and Sanfilippo, 1991; Matheson et al, 1980; Frackelton and Christensen, 1998; Warkany & Hubbard, 1953).
Due to the difficulty of diagnosing mercurialism based on presentation of non-specific symptoms alone, clinicians have come to rely on the following criteria (Warkany & Hubbard, 1953; Vroom and Greer, 1972).
- Observation of impairments in many but not all of the following
domains: (a) movement/motor disorder, (b) sensory abnormalities, (c)
psychological and behavioral disturbances, (d) neurological and cognitive
deficits, (e) impairments in language, hearing, and vision, and (f)
miscellaneous physical presentations such as rashes or unusual reflexes (Adams
et al, 1983; Snyder, 1972; Vroom & Greer, 1972).
- Known exposure to Hg (a) at a level that has been documenting as causing
impairment in similar individuals under similar circumstances, and (b) at
approximately the same time as the symptoms emerge, with allowances given for
the latency period (Ross et al, 1977; Amin-Zaki et al, 1978). It should be
noted that the dose which is considered "toxic" vs. "safe" is unresolved among
toxicologists; some researchers feel that any amount of exposure is "unsafe"
(see EPA, 1997, pp.6-47 to 6-59, for dose discussion).
- Detectable levels of mercury in urine, blood, or hair (Florentine and
Sanfilippo, 1991; Frackelton and Christensen, 1998; EPA, 1997, p.ES-2).
Importantly, because mercury can clear from biologic samples before the
patient feels symptoms or is tested, the lack of detectable mercury is not
cause for ruling out mercury poisoning; and conversely, detectable levels have
been observed in unaffected individuals (Adams et al, 1983; Warkany &
Hubbard, 1953; Cloarec, 1995).
- Improvement in symptoms after chelation. While many patients' symptoms
resolve with chelation, some clearly poisoned individuals do not improve.
Other exposed subjects have also been known to improve without intervention
(Vroom & Greer, 1972; Warkany & Hubbard, 1953).
Thus, none of these criteria is sufficient on its own for a certain diagnosis. Rather, observed effects within two or three domains are generally required. This paper, which reviews and compares the extensive literature available on both ASD and mercury, provides citations documenting that, based on these four diagnostic criteria, many if not most cases of autism meet the requirements for mercury poisoning. In fact, this review and its citations (i) delineate a single mechanism for inducing all of the primary domains of impairment and biological abnormalities in autism, including its genetic component, prevalence levels, and sex ratios; and (ii) identify that mechanism as arising from the "environmental insult" of early childhood exposure to mercury. Furthermore, the route of exposure is thimerosal, which is 50% ethylmercury by weight and which is a preservative used in many childhood vaccines.
We are not suggesting that the previous reports of mercurialism described in the literature are in fact cases of autism; rather, we claim that autism represents its own unique form of Hg poisoning, just like acrodynia, Minamata disease, and Mad Hatter's disease represent distinct yet closely related presentations of mercurialism. A unique expression would be expected in cases of autism, given that the effects of repeated vaccinal administration of ethylmercury to infants and toddlers have never been described before in mercury-related literature. We maintain that the diverse phenotype that is autism matches the diverse phenotype that is mercurialism to a far greater degree that could reasonably be expected to occur by chance. Given the known exposure to mercury via vaccination of autistic children and the presence of mercury found in biologic samples from a number of autistic subjects, also described here, we are confident that our claim is substantiated. Our paper discusses some important medical and societal ramifications of this conclusion.
I. Symptom Comparison
The overt symptoms of ASD and mercury poisoning, described in the literature and presented here, are strikingly similar. Summary tables have been provided after each section to aid in symptom comparisons.
a. Affect/Psychological Presentation
Since its initial description in 1943 by Leo Kanner, a psychiatrist, autism has been defined primarily as a psychiatric condition. One of the three requirements for diagnosis is a severe deficit in social interactions (APA, 1994). Self and parental reports describe children and adults who prefer to be alone and who will withdraw to their rooms if given the chance (MAAP, 1996-1999). Even high functioning autistics tend to be aloof, have poor social skills, are unable to make friends, and find conversation difficult (Tonge et al, 1999; Capps et al, 1998). Face recognition and what psychologists call "theory of mind" are impaired (Klin et al, 1999, Baron-Cohen et al, 1993). Poor eye contact or gaze avoidance is present in most cases, especially in infancy and childhood (Bernabei et al, 1998).
The second psychobehavioral diagnostic characteristic of autism is the presence of repetitive, stereotyped activities and the need for sameness (APA, 1994). Traits in this domain strongly resemble obsessive-compulsive tendencies in both thought and behavior (Lewis, 1996; Gillberg & Coleman, 1992, p.27), especially as the individual becomes more high functioning (Roux et al, 1998): "it [is] very difficult.to distinguish between obsessive ideation and the bizarre preoccupations so commonly seen in autistic individuals" (Howlin, 2000). Serotonin uptake inhibitors known to be effective for OCD also reduce repetitive behaviors in some autistic patients (Lewis, 1996). Most autistic subjects - 84% in one study - show high levels of anxiety and meet diagnostic criteria for anxiety disorder (Muris et al, 1998).
ASD has been linked to depression, based on symptoms, familial history of depression and the positive response to SSRIs among many autistics (Clarke et al, 1999; DeLong, 1999; Piven and Palmer, 1999). One subset of autistics has been described as "passive", with flat affect, "absence of facial expression," lack of initiative, and diminished outward emotional reactions. Some autistics have a strong family history of manic depression and mood swings, and, among those who are verbal, psychotic talk is frequently observed (Plioplys, 1989). Autism is also said to strongly resemble childhood schizophrenia. In the past it was often misdiagnosed as such (Gillberg & Coleman, 1992, p.100), and there are a number of instances of dual ASD-schizophrenia diagnoses in the literature (Clarke et al, 1999). Furthermore, irrational fears, aggressive behaviors, and severe temper tantrums are common (Muris et al, 1998; McDougle et al, 1994), as are chronic hyperarousal and irritability (Jaselskis et al, 1992). "Inexplicable changes of mood can occur, with giggling and laughing or crying for no apparent reason" (Wing & Attwood, 1987).
Mercury poisoning, when undetected, is often initially diagnosed as a psychiatric disorder in both children and adults (Fagala and Wigg, 1992). Common psychiatric symptoms are (a) depression, including "lack of interest" and "mental confusion;" (b) "extreme shyness," indifference to others, active avoidance of others or "a desire to be alone"; (c) irritability in adults and tantrums in children; and (d) anxiety and fearfulness. Neurosis, including schizoid and obsessive-compulsive traits, has been reported in a number of cases (Fagala and Wigg, 1992; Kark et al, 1971; O'Carroll et al, 1995; Florentine and Sanfilippo, 1991; Amin-Zaki, 1974 and 1979; Matheson et al, 1980; Joselow et al, 1972; Smith, 1972; Lowell, 1996; Tuthill, 1899; Clarkson, 1997; Camerino et al, 1981; Grandjean et al, 1997; Piikivi et al, 1984; Rice, 1996; Vroom & Greer, 1972; Adams et al, 1973; Hua et al, 1996).
Juvenile monkeys prenatally exposed to mercury exhibit decreased social play and increased passive behavior (Gunderson et al, 1986, 1988), as well as impaired face recognition (Rice, 1996). Humans exposed to mercury vapor also perform poorly on face recognition tests and may present with a "mask face" (Vroom & Greer, 1972); emotional instability can occur in children and adults exposed to Hg. For instance, Iraqi children poisoned by methylmercury had a tendency "to cry, laugh, or smile without obvious provocation" (Amin-Zaki et al, 1974 & 1979), like the autistic group described by Wing and Attwood (1987).
Found in Autism & Mercury Poisoning
|Extreme shyness, social withdrawal, feeling overly sensitive, introversion||Social deficits, social withdrawal, self reports of extreme shyness, aloofness|
|Mood swings; flat affect; mask face; laughing or crying without provocation; episodes of hysteria||Mood swings; flat affect in some; no facial expression; laughing or crying without reason|
|Anxiety; nervousness; tremulousness; somatization of anxious feelings||Anxiety, nervousness; anxiety disorder|
|Schizoid tendencies, neurosis, obsessive-compulsive traits, repetitive dreams||Schizophrenic traits; OCD traits; repetitive behaviors and thoughts|
|Lack of eye contact; being less talkative; hesitancy to engage others||Lack of eye contact, gaze avoidance; avoids conversation|
|Depression, lack of interest in life, lassitude, fatigue, apathy; feelings of hopelessness; melancholy||Association with depression; lack of initiative, diminished outward emotions|
|On the one hand, less overtly active, unwilling to go outside or be with others; on the other hand, increased restlessness||Tendency to withdraw, especially to own rooms, prefer to be alone; hyperactivity|
|Irrational fears||Irrational fears|
|Irritability, anger, and aggression; in children this may manifest as frequent and severe temper tantrums||Irritability and aggression; severe temper tantrums in children|
|Psychotic episodes; hallucinations, hearing voices; paranoid thoughts||Psychotic talk, paranoid thoughts|
|Impaired face recognition||Impaired face recognition|
Since traditionally autism has been characterized and studied by researchers primarily in psychiatric terms, providing case studies illustrating the psychiatric aspects of ASD and of mercurialism are necessary in establishing the similarities of the two disorders on this critical domain. Also included is a comparison of "Lenny," an autistic adult described by Rhea Paul (1987), and the Mad Hatter from Alice in Wonderland, considered to be an accurate portrayal of victims of the disease. Of particular relevance in all these cases are social withdrawal and deficits in social communication, traits (i) always prominent in autism and (ii) clearly associated with mercurialism.
Case Studies: Autism
"I am 18 years old. My parents found out I was autistic when I was 18 months old. My parents said I banged my head a lot when I got frustrated when I was young. Head banging motions help me deal with nervousness. I also take 2 medications to help me cope with stress. I have very few friends. It is also somewhat painful for me to look people in the eye. This sometimes makes people think I am not paying attention" (The MAAP, Vol. II, 1997).
"I have a high-functioning autistic eight-year-old boy. My mistake was putting him in the second grade with a teacher who was determined to 'socialize' him. After three months, the anxiety proved to be too great for him. He spent a lot of time crying, withdrawing to his room, becoming compulsive and belligerent. In another era, he would have been seen as having a 'nervous breakdown'" (The MAAP, Vol. II, 1997).
"I am writing regarding our 25 year old son who was diagnosed only a few months ago as having Asperger's Syndrome. All his life he displayed the 'classic' symptoms of Asperger's (lack of social skills, disorganization, anxiety, etc.). A few months ago, he became clinically depressed, phobic about being around people for fear of more rejection or being laughed at. He now has obsessive thoughts that our home is electronically 'bugged' and all his actions are being observed and belittled" (The MAAP, Vol. II, 1997).
"Several people have asked me what it's like to have Asperger's Syndrome. Today, I still prefer to work on my computer or with electronics rather than socialize. I've never been able to tolerate any kind of physical contact or intimacy. I like wrestling and rough-housing, but I hate being caressed or held." (The MAAP, Vol. II, 1997).
"My son Brian is a 6-year-old with high functioning autism. Our main problem now is his rigidity and obsessive/compulsive behaviors. He gets extremely upset when activities don't go as he thinks they should. He first gets mad, screaming and yelling, then begins to obsessively talk about how he can remedy the situation, then often begins to cry uncontrollably. These tantrums can go on for hours" (The MAAP, Vol. IV, 1996).
"[I'm] age 12r. I have Autism/PDD. I don't really know any real social skills, though my brother Isaiah says I am a social outcast. I do have trouble making new friends because I get real shy and nervous" (The MAAP, Vol. IV, 1997).
"I am the mother of three autistic boys. Nate was considered very shy. Poor eye contact but very smart and doing well in school. Nate was also diagnosed with Hypotonia of the face (which answered all the mumbling he did wasn't just shyness) and extremities" (The MAAP, Vol. III, 1999)
"I spent many hours sitting in the trees or under the bed or in a dark closet. I had a loud flat voice. Socialization has always been beyond me" (The MAAP, Vol. II, 1998).
"I sit in my room a prisoner to my autism. Mom and sis doing their loving best to get me out. I wanted to get out - really get out. I wanted to love, to feel, to connect. But, I couldn't. I was stuck. I was slowly dying. There were days I truly wanted to end it all. If any days were good, I didn't deserve it. I shouldn't be happy. Autism teaches you that - because it's a life sentence" (The MAAP, Vol. VI, 1996).
Case Studies: Mercury Poisoning
A 12 year old girl with recent mercury vapor poisoning was initially diagnosed as having a psychiatric disturbance. Her behavior was more normal when she was unaware of being watched. She became upset when people were around, was reluctant to speak when others were present, spoke in a soft, mumbling voice, lacked eye contact, had a flat affect, was sometimes tearful, experienced auditory hallucinations of voices laughing at her, wished to stay alone in her room with the lights off and her head covered, and had frequent temper tantrums (Fagala and Wigg, 1992).
Sufferers of Mad Hatter's disease, arising from prolonged mercury vapor exposure, were known to suffer from depression, lassitude, acute anxiety, and irrational fears. They also became nervous, timid, and shy. They blushed readily, were embarrassed in social situations, objected to being watched, and sought to avoid people. They felt a constant impulse to return home. They were easily upset, and were prone to agitation, irritability, anger, and aggressive behavior (O'Carroll et al, 1995).
A survey on an Internet site of adult acrodynia victims, which compared the symptoms of adults who suffered from acrodynia as children with controls, reported the following symptoms as seen to a greater degree in acrodynia sufferers than in controls: dislikes being touched or hugged, is a loner, lacks self confidence, feels nervousness and has a racing heart, has depression and suicidal feelings (Farnesworth, 1997). One acrodynia victim described his own situation: "not having learnt normal social skills I spent a lot of my time alone.Gradually by age 11 or so, I was becoming 'normal'.But, I have never overcome the headache problem, irritability, shyness with real people, not wanting to be touched, depression, fear of doctors, great anxiety." (Neville's Recollection, Pink Disease site)
A doctor from the 19th century described several cases of mercury poisoning from dental amalgams: "There is mental excitability as well as mental depression; perplexing events cause the highest degree of excitement, ordinary conversation sometimes causes complete confusion, headache, palpitation, intense solicitude, and anxiety, without reason for it. Such are some of the symptoms attending these cases." As an example he cites the case of a young woman who "had come to be melancholic and to withdraw herself from her family and friends, seeking the seclusion of her room -- refusing to go out or to associate with others, or even with the members of her own household." (Tuthill, 1899)
Nearly a century later, initial questioning of a 28 year old woman, subsequently found to have mercury vapor poisoning, "elicited the fact that she had become increasingly withdrawn from social activities and had felt most uncomfortable when with strangers. She also felt that her friends had turned against her. She had a repetitive disturbing dream of electric fire around the frames of the windows in her bedroom." (Ross et al, 1977)
Lenny and The Mad Hatter
(a) Rigid literal interpretation of word meaning; word meaning and pragmatic errors which interfere with social communication
Lenny - "He was very literal minded, and words spoken to him became matters of immutable fact. For example, he was trying on new shoes. His mother asked him if they slipped up and down. He said they didn't, and when asked again if he were sure, he replied, 'No, they don't slip up and down; they slip down and then they slip up.' "
The Mad Hatter - "Take some more tea," the March Hare said to Alice, very earnestly.
"I've had nothing yet," Alice replied in an offended tone: "so I ca'n't take more."
"You mean you ca'n't take less," said the Hatter: "It's very easy to take more than nothing."
(b) Social deficits, inability to interpret social rules, leading to perceived rude behavior
Lenny - "Although he tried working in his father's business for a time, his immaturity, self-centered behavior, and lack of social judgment required his return to a sheltered setting."
The Mad Hatter - "Your hair wants cutting," said the Hatter. He had been looking at Alice for some time with great curiosity, and this was his first speech.
"You should learn not to make personal remarks," Alice said with some severity: "it's very rude."
The Hatter opened his eyes wide upon hearing this; but all he said was "Why is a raven like a writing desk?"
(c) Inability to engage in meaningful social conversation; poor conversational interpretation skills; perseverative thoughts
Lenny - "During one interview he engaged in a 20 minute monologue about a broken washing mashine. The interviewer momentarily dozed off. Upon rousing, the interviewer exclaimed, 'Oh, Lenny, I'm sorry!' 'It's all right,' Lenny replied calmly, 'the washing machine got fixed."
The Mad Hatter (who talks obsessively/perseveratively about Time for a good portion of the chapter) - "What a funny watch!" she remarked. "It tells the day of the month, and doesn't tell what o'clock it is!"
"Why should it?" muttered the Hatter. "Does your watch tell you what year it is?"
"Of course not, " Alice replied very readily: "but that's because it stays the same year for such a long time altogether."
"Which is just the case with mine," said the Hatter.
Alice felt dreadfully puzzled. The Hatter's remark seemed to her to have no sort of meaning in it, and yet it was certainly plain English.
b. Language and Hearing
The third diagnostic criterion for autism is a qualitative impairment in communication (APA, 1994), and such impairment is a primary feature of mercury poisoning.
Delayed language onset is often among the first overt signs of ASD (Eisenmajer et al, 1998). Historically, half of those with classic autism failed to develop meaningful speech (Gillberg & Coleman, 1992; Prizant, 1996); and oral-motor deficits (e.g. chewing, swallowing) are often present (Filipek et al, 1999). When speech develops, there may be "specific neuromotor speech disorders," including verbal dyspraxia, a dysfunction in the ability to plan the coordinated movements to produce intelligible sequences of speech sounds, or dysarthria, a weakness or lack of control of the oral musculature" leading to articulation problems (Filipek et al, 1999). Echolalic speech and pronoun reversals are typically found in younger children. Many ASD subjects show poorer performance on tests of verbal IQ relative to performance IQ (Dawson, 1996; Filipek at al, 1999). Higher functioning individuals, such as those with Asperger's Syndrome, may have language fluency but still exhibit semantic (word meaning) and pragmatic (use of language to communicate) errors (Filipek et al, 1999).
Auditory impairment is also common. Two separate studies, for example, both found that 24% of autistic subjects have a hearing deficit (Gillberg & Coleman, 1992). More recently Rosenhall et al (1999) have diagnosed hearing loss ranging from mild to profound, as well as hyperacusis, otitis media, and conductive hearing loss, in a minority of ASD subjects, and these traits were independent of IQ status. Among the earliest signs of autism noted by mothers were strange reactions to sound and abnormal babble (Gillberg & Coleman, 1992), and many ASD children are tested for deafness before receiving a formal autism diagnosis (Vostanis et al, 1998). "Delayed or prompted response to name" differentiates 9-12 months old toddlers, later diagnosed with autism, from mentally retarded and typical controls (Baranek, 1999). In fact, "bizarre responses" to auditory stimuli are nearly universal in autism and may present as "either a lack of responsiveness or an exaggerated reaction to auditory stimuli" (Roux et al, 1998), possibly due to sound sensitivity (Grandin, 1996). Kanner noted an aversion to certain types of sounds, such as vacuum cleaners (Kanner, 1943). Severe deficits in language comprehension are often present (Filipek et al, 1999). Difficulties in picking out conversational speech from background noise are commonly reported by high functioning ASD individuals (Grandin, 1995; MAAP, 1997-1998).
In regard to language and auditory phenomena, autism's parallels to mercurialism are striking. Emerging signs of mercury poisoning are dysarthria (defective articulation in speech due to CNS dysfunction) and then auditory disturbance, leading to deafness in very high doses (Clarkson, 1992). In some cases, hearing impairment manifests as an inability to comprehend speech rather than an inability to hear sound (Dales, 1972). Hg poisoning can also result in aphasia, the inability to understand and/or physically express words (Kark et al, 1971). Speech difficulties may arise from "intention tremor, which can be noticeable about the mouth, tongue, face, and head, as well as in the extremities" (Adams et al, 1983).
Mercury-exposed children especially show a marked difficulty with speech (Pierce et al, 1972; Snyder, 1972; Kark et al, 1971). Even children exposed prenatally to "safe" levels of methylmercury performed less well on standardized language tests than did unexposed controls (Grandjean et al, 1998). Iraqi babies exposed prenatally either failed to develop language or presented with severe language deficits in childhood. They exhibited "exaggerated reaction" to sudden noise and some had reduced hearing (Amin-Zaki, 1974 and 1979). Iraqi children who were postnatally poisoned from bread containing either methyl or ethylmercury developed articulation problems, from slow, slurred word production to the inability to generate meaningful speech. Most had impaired hearing and a few became deaf (Amin-Zaki, 1978). In acrodynia, symptoms of sufferers (vs. controls) include noise sensitivity and hearing problems (Farnesworth, 1997).
Adults also exhibit these same Hg-induced impairments. There is slurred or explosive speech (Dales, 1972), as well as difficulty in picking out one voice from a group (Joselow et al, 1972). Poisoned Iraqi adults developed articulation problems (Amin-Zaki, 1974). A 25 year old man with elemental mercury poisoning had reduced hearing at all frequencies (Kark et al, 1971). Thimerosal injected into a 44 year old man initially led to difficulty verbalizing, even though his abilities in written expression were uncompromised; he then progressed to slow and slurred speech, although he could still comprehend verbal language; and he finally lost speech altogether (Lowell et al, 1996). In Mad Hatter's disease, there were word retrieval and articulation difficulties (O'Carroll et al, 1995). A scientist who recently died from dimethylmercury poisoning demonstrated an inability to understand speech despite having good hearing sensitivity for pure tones (Musiek and Hanlon, 1999). Workers exposed to mercury vapor showed decreased verbal intelligence relative to performance IQ (Piikivi et al, 1984; Vroom and Greer, 1972).
& Hearing Deficits in Autism & Mercury Poisoning
|Complete loss of speech in adults or children; failure to develop speech in infants||Delayed language onset; failure to develop speech|
|Dysarthria; speech difficulties from intention tremor; slow and slurred speech||Dysarthria; dyspraxia and oral-motor planning difficulties; unintelligible speech|
|Aphasia, the inability to use or understand words, inability to comprehend speech although ability to hear sound is intact||Speech comprehension deficits, although ability to hear sound is intact|
|Difficulties verbalizing; word retrieval problems||Echolalia; pronoun reversals, word meaning and pragmatic errors; limited speech production|
|Auditory disturbance; difficulties differentiating voices in a crowd||Difficulties following conversational speech with background noise|
|Sound sensitivity||Sound sensitivity|
|Hearing loss; deafness in very high doses||Mild to profound hearing loss|
|Poor performance on standardized language tests||Poor performance on verbal IQ tests|
c. Sensory Perception
Sensory impairment is considered by many researchers to be a defining characteristic of autism (Gillberg and Coleman, 1992; Williams, 1996). Baranek (1999) detected sensory-motor problems - touch aversion, poor non-social visual attention, excessive mouthing of objects, and delayed response to name - in 9-12 month old infants later diagnosed with autism, and suggests that these impairments both underlie later social deficits and serve to differentiate ASD from mental retardation and typical controls. Besides sensitivity to sound, as previously noted, ASD often involves insensitivity to pain, even to a burning stove (Gillberg & Coleman, 1992), while on the other hand there may be an overreaction to stimuli, so that even light to moderate touches are painful. Pinprick tests are usually normal. Children with autism have been described as "stiff to hold," and one of the earliest signs reported by mothers is an aversion to being touched (Gillberg & Coleman, 1992). Abnormal sensation in the extremities and mouth are common. Toe-walking is frequently seen. Oral sensitivity often results in feeding difficulties (Gillberg & Coleman, 1992, p.31). Autistic children frequently have vestibular impairments and difficulty orienting themselves in space (Grandin, 1996; Ornitz, 1987).
As in ASD, sensory issues are reported in nearly all cases of mercury toxicity, and serve to demonstrate the similarities between the two conditions. Paresthesia, or abnormal sensation, tingling, and numbness around the mouth and in the extremities, is the most common sensory disturbance in Hg poisoning, and is usually the first sign of toxicity (Fagala and Wigg, 1992; Joselow et al, 1972; Matheson et al, 1980; Amin-Zaki, 1979). In Japanese who ate contaminated fish, there was numbness in the extremities, face and tongue (Snyder, 1972; Tokuomi et al, 1982). Iraqi children who ate bread experienced sensory changes including numbness in the mouth, hands and feet, and a feeling that there were "ants crawling under the skin." These children could still feel a pinprick (Amin-Zaki, 1978). Loss of position in space has also been noted (Dales, 1972). Acrodynia sufferers describe excessive pain when bumping limbs, numbness, and poor circulation (Farnesworth, 1997). One adult acrodynia victim described himself as a boy as "shying away from people wanting to touch me" due to extreme touch sensitivity (Neville Recollection, Pink Disease Support Group). Iraqi babies exposed to mercury prenatally showed excessive crying, irritability, and exaggerated reaction to stimulation such as sudden noise or when touched (Amin-Zaki et al, 1974 and 1979).
in Mercury Poisoning & Autism
|Abnormal sensation or numbness around mouth and extremities (paresthesia); burning feet||Abnormal sensation in mouth and extremities; excessive mouthing of objects (infants); toe walking; difficulty grasping objects|
|Sound sensitivity||Sound sensitivity|
|Excessive pain when bumping; abnormal touch sensations; touch aversion||Insensitivity or overreaction to pain and touch; touch aversion; stiff to hold|
|Loss of position in space||Vestibular system abnormalities; difficulty orienting self in space|
|Normal pinprick tests||Normal pinprick tests|
d. Movement/Motor Function
Nearly all cases of autism include disorders of physical movement. Movement disturbances have been detected in infants as young as four to six months old who were later diagnosed as autistic: Teitelbaum et al (1998) have observed that these children do not lie, roll over, sit up or crawl like normal infants; impairment in motor control sometimes caused these babies to fall over while sitting, consistently to avoid using one of their arms, or to rest on their elbows for stability while crawling. Later, when trying to walk their gait was abnormal, and some degree of asymmetry, mostly right-sided, was present in all cases studied. Kanner noted in several of his subjects the absence of crawling and a failure to assume an anticipatory posture preparatory to being picked up in infancy (Kanner, 1943). Arm flapping, abnormal posture, jumping, and hand-finger mannerisms (choreiform movements) are common (Tsai, 1996). Many individuals with Asperger's syndrome are typically characterized as uncoordinated or clumsy (Kugler, 1998). Other autism movement disorders include praxis (problems with intentional movement), stereotypies, circling or spinning, rocking, toe walking, myoclonal jerks, difficulty swallowing and chewing, difficulty writing with or even holding a pen, limb apraxia, and poor eye-hand coordination (Caesaroni and Garber, 1991; Gillberg and Coleman, 1992; Filipek et al, 1999).
Like ASD, movement disorders have been a feature of virtually all descriptions of mercury poisoning in humans (Snyder, 1972). Even children prenatally exposed to "safe" levels of methylmercury had deficits in motor function (Grandjean et al, 1998). The movement-related behaviors are extremely diverse: Iraqi infants and children exposed postnatally, for example, developed ataxia that ranged from clumsiness and gait disturbances to an "inability to stand or even sit" (Amin-Zaki et al, 1978). The various movement behaviors are listed more fully in Table V (Adams et al, 1983; Kark et al, 1971; Pierce et al, 1972; Snyder, 1972; O'Carroll et al, 1995; Tokuomi et al, 1982; Amin-Zaki, 1979; Florentine and Sanfilippo, 1991; Rohyans et al, 1984; Fagala and Wigg, 1992; Smith, 1977; Grandjean et al, 1998; Farnesworth, 1997; Dales, 1972; Matheson et al, 1980; Lowell et al, 1996; O'Kusky et al, 1988; Vroom and Greer, 1972; Warkany and Hubbard, 1953).
Noteworthy because of similarities to movement disorders in autism are reports in the Hg literature of (a) an infant with "peculiar tremulous movements of the extremities which were principally proximal and can best be described as flapping in nature" (Pierce et al, 1972; Snyder, 1972); (b) "jerking movements of the upper extremities" in a man injected with thimerosal (Lowell et al, 1996); (c) "constant choreiform movements affecting the fingers and face" in mercury vapor intoxication (Kark et al, 1971); (d) myoclonal jerks, associated with epilepsy among Iraqi subjects (Amin-Zaki et al, 1978); (e) poor coordination and clumsiness among victims of acrodynia (Farnesworth, 1997); (f) rocking among infants with acrodynia (Warkany and Hubbard, 1953); (g) "unusual postures" observed in both acrodynia and mercury vapor poisoning (Vroom and Greer, 1972; Warkany and Hubbard, 1953); and (h) toe walking among less severely poisoned children in the Minamata epidemic (Minamata Disease, 1973). In animal studies, cats exposed to mercury by eating fish developed "circling movements" (Snyder, 1972), and subcutaneous administration of methylmercury to rats during postnatal development has resulted in postural disorders (O'Kusky et al, 1988).
As summarized in Table V, movement similarities in autism and Hg poisoning are clear.
in Mercury Poisoning & Autism
|Involuntary jerking movements, e.g., arm flapping, ankle jerks, myoclonal jerks; choreiform movements; circling (cats); rocking; purposeless movement of extremities; twitching, shaking; muscular spasticity||Stereotyped movements such as arm flapping, jumping, circling, spinning, rocking; myoclonal jerks; choreiform movements|
|Unsteadiness in handwriting or an inability to hold a pen; deficits in eye-hand coordination; limb apraxia; intention tremors; loss of fine motor skills||Difficulty in writing with or holding a pen; poor eye-hand coordination; limb apraxia; problems carrying out intentional movements (praxia)|
|Ataxia: gait impairment; severity ranging from mild incoordination, clumsiness to complete inability to walk, stand, or sit; staggering, stumbling; loss of motor control||Abnormal gait and posture, clumsiness and incoordination; difficulties sitting, lying, crawling, and walking in infants and toddlers|
|Toe walking||Toe walking|
|Difficulty in chewing or swallowing||Difficulty chewing or swallowing|
|Unusual postures||Unusual postures|
|Tremors in general, tremors of the face and tongue, hand tremors||None described|
e. Cognition/Mental Function
Nearly all autistic individuals show impairment in some aspects of mental function, even as other cognitive abilities remain intact. Most individuals may test in the retarded range, while others have normal to above average IQs. These characteristics are true in mercurialism. Moreover, the specific areas of impairment are similar in the two disorders.
The impaired areas in autism are generally in (a) short term or working memory and auditory and verbal memory; (b) concentration and attention, particularly attention shifting; (c) visual motor and perceptual motor skills, including eye-hand coordination; (d) language/verbal expression and comprehension; and (e) using visually presented information when constraints are placed on processing time. Relatively unimpaired areas include rote memory skills, pattern recognition, matching, perceptual organization, and stimuli discrimination. Higher level mental skills requiring complex processing are typically deficient; these include (a) processing and filtering of multiple stimuli; (b) following multiple step commands; (c) sequencing, planning and organizing; and (d) abstract/conceptual thinking and symbolic understanding (Rumsey & Hamburger, 1988; Plioplys, 1989; Bailey et al, 1996; Filipek et al, 1999; Rumsey, 1985; Dawson, 1996; Schuler, 1995; Grandin, 1995; Sigman et al, 1987). Younger or more mentally impaired children may have difficulties with symbolic play and understanding object permanence or the mental state of others (Bailey et al, 1996). Some autistic children are hyperlexic, showing superior decoding skills while lacking comprehension of the words being read (Prizant, 1996). As mentioned before, for most autistic individuals verbal IQ is lower than performance IQ.
As in autism, Hg exposure causes some level of impairment primarily in (a) short term memory and auditory and verbal memory; (b) concentration and attention, including response inhibition; (c) visual motor and perceptual motor skills, including eye-hand coordination; (d) language/verbal expression and comprehension; and (e) simple reaction time. Hg-affected individuals may present as "forgetful" or "confused." Performance IQ may be higher than verbal IQ. "Degeneration of higher mental powers" has resulted in (a) difficulty carrying out complex commands; (b) impairment in abstract and symbolic thinking; and (c) deficits in constructional skills and conceptual abstraction. One study mentions alexia, the inability to comprehend the meaning of words, although reading of the words is intact (Yeates & Mortensen, 1994; O'Carroll et al, 1995; Pierce et al, 1972; Snyder, 1972; Adams et al, 1983; Kark et al, 1971; Amin-Zaki, 1974 and 1979; Davis et al, 1994; Grandjean et al, 1997 & 1998; Myers & Davidson, 1998; Gilbert & Grant-Webster 1995; Dales, 1972; Fagala and Wigg, 1992; Farnesworth, 1997; Tuthill, 1899; Joselow et al, 1972; Rice, 1997; Piikivi et al, 1984; Vroom and Greer, 1972). Even children exposed prenatally to "safe" levels of methylmercury show lower scores on selective subtests of cognition, especially in the domains of memory and attention, relative to unexposed controls (Grandjean et al, 1998). In exposed juvenile monkeys, tests have revealed delays in the development of object permanence, or the ability to conceptualize the existence of a hidden object (Rice, 1996).
Research on mental retardation in autism is contradictory (Schuler, 1995). The finding that "mental retardation or borderline intelligence often co-exists with autism" (Filipek et al, 1999) is based on using standard measures of intelligence (Gillberg & Coleman, 1992, p.32; Bryson, 1996); other intelligence tests, designed to circumvent the language and attentional deficits of autistic children, show significantly higher intelligence test scores (Koegel et al, 1997; Russell et al, 1999). One study using such a modified rating instrument has found 20% of autistic children to be mentally retarded (Edelson et al, 1998), rather than the 70%-80% so scored on standard tests. ASD individuals also show "strikingly uneven scores" on IQ subtests, "unlike other disorders involving mental retardation, in which subtest scores seem to be more or less even" (Bailey et al, 1996). Also unlike typical cases of mental retardation, which is nearly always noted in the peri- or neonatal periods, most parents of ASD children report infants of seemingly normal appearance and development who were later characterized as mentally retarded on tests. For example, one study compared early developmental aberrations in mentally retarded children with and without autism. Findings indicated that, whereas nearly all parents of the non-autistic mentally retarded study group were aware of their child's impairment by age 3 months, nearly all parents of the autistic children failed to notice any developmental delays or issues until after 12 months of age (Baranek, 1999). Finally, there are several case reports of autistic adults who were labeled mentally retarded as children based on tests, who later "emerged" from their autism and had normal IQs (ARI Newsletter, 1993, review).
As in autism, symptomatic mercury-poisoned victims can present with normal IQs, borderline intelligence, or mental retardation; some may be so impaired as to be untestable (Vroom and Greer, 1972; Davis et al, 1994). When lowered intelligence is found, it is always reported as an obvious deterioration among previously normally functioning people; this includes children exposed as infants or toddlers (Dale, 1972; Vroom and Greer, 1972; Amin-Zaki, 1978). Once the Hg-exposure source is removed, many (although not all) of these patients "recover" their normal IQ, suggesting that "real" IQ was not affected (Vroom and Greer, 1972; Davis et al, 1994). Infant monkeys given low doses of Hg, while clearly impaired in visual, auditory, and sensory functions, had intact central processing speed, which has been shown to correlate with IQ in humans (Rice, 1997).
in Mercury Poisoning & Autism
|Some aspect of mental impairment in all symptomatic cases||Some aspect of mental impairment in all cases|
|Borderline intelligence on testing among previously normal individuals; mental retardation occurring in severe cases of pre-/postnatal exposure; some cases of MR reversible; primate studies indicate core intelligence spared with low exposures||Borderline intelligence or mental retardation on standard tests among previously normally appearing infants; some cases of MR "reversible"; indications that normal IQ might be present in MR-labeled individuals|
|Uneven performance on subtests of intelligence||Uneven performance on subtests of intelligence|
|Verbal IQ higher than performance IQ; compromised language/verbal expression and comprehension||Verbal IQ higher than performance IQ; compromised language/verbal expression and comprehension|
|Poor concentration, shortened attention span, general lack of attention; poor response inhibition||Lack of concentration, short attention span, lack of attention, difficulty shifting attention|
|Forgetfulness, loss of memory, particularly short term, verbal and auditory memory; mental confusion||Poor short term/working memory; poor auditory and verbal memory; lower verbal encoding abilities|
|Poor visual and perceptual motor skills, poor eye-hand coordination; impairment in simple reaction time||Poor visual and perceptual motor skills, poor eye-hand coordination; lowered performance on timed tests|
|Not reported as being tested||Difficulty processing multiple stimuli|
|Difficulty carrying out complex commands||Difficulty carrying out multiple commands|
|Alexia (inability to comprehend the meaning of written words)||Hyperlexia (ability to decode words while lacking word comprehension)|
|Deficits in constructional skills, conceptual abstraction, understanding abstract ideas and symbolism; degeneration of higher mental powers||Deficits in abstract/conceptual thinking, symbolism, understanding other's mental states; impairment in sequencing, planning, organizing|
|Lack of understanding of object permanence (primates)||Deficient understanding of object permanence (children)|
Autism is associated with difficulties initiating and/or maintaining sleep; hyperactivity and other ADHD traits; and self injurious behavior such as head banging, even in the absence of mental retardation. Agitation, screaming, crying, staring spells, stereotypical behaviors, and grimacing are common (Gaedye, 1992; Gillberg and Coleman, 1992; Plioplys, 1989; Kanner, 1943; Richdale, 1999; Stores & Wiggs, 1998). Kanner (1943) made a point of noting excessive and open masturbation in two of the eleven young children comprising his initial cases. Feeding and suckling problems are typical (Wing, 1980), and restricted diets and narrow food preferences "are the rule rather than the exception" (Gillberg and Coleman, 1992; Clark et al, 1993); some autistics show a preference for salty foods (Shattock, 1997). Kanner, in his 1943 article, noted feeding problems from infancy, including vomiting and a refusal to eat, in six of the eleven autistic children he described. There are case studies of anorexia nervosa occurring in ASD patients, as well as an increased likelihood of this eating disorder in families with ASD (Gillberg & Coleman, 1992, p.99).
Humans and animals exposed to mercury develop unusual, abnormal, and "inappropriate" behaviors (Florentine and Sanfilippo, 1991). Rats exposed to mercury during gestation have exhibited stereotyped sniffing (Cuomo et al, 1984) and hyperactivity (Fredriksson et al, 1996). "Restlessness" has already been noted, and Davis et al (1994) found poor response inhibition in their human subjects; both of these behaviors are closely associated with ADHD in children. Babies and children with Hg poisoning exhibit agitation, crying for no observable reason, grimacing, and insomnia (Pierce et al, 1972; Snyder, 1972; Kark et al, 1971; Amin-Zaki, 1979; Florentine and Sanfilippo, 1991; Aronow and Fleischmann, 1976). An 18 month old toddler with otitis media, exposed to thimerosal in ear drops, had staring spells and unprovoked screaming episodes (Rohyans et al, 1984). Symptoms of acrodynia in babies and toddlers include continuous crying, anorexia and insomnia (Matheson et al, 1980; Aronow and Fleischmann, 1976). These children were said to bang their heads, have difficulty falling asleep, be irritable, and either refuse to eat or only eat a few foods (Neville Recollection, Pink Disease Support Group Site; Farnesworth, 1997). The frequent temper tantrums of a previously normal 12 year old, poisoned by mercury vapor, included hitting herself on the head and screaming; furthermore, she had extreme genital burning and was observed to masturbate even in front of others (Fagala and Wigg, 1992). Similarly, priapism, persistent erection of the penis due to a pathologic condition resulting in pain and tenderness, has been noted in boys with mercury poisoning (Amin-Zaki et al, 1978).
Adults with mercury poisoning present with insomnia, agitation, and poor appetite (Tuthill, 1899; Adams et al, 1983; Fagala and Wigg, 1992). Relative to controls, more adults who had acrodynia in childhood have eating idiosyncrasies, particularly a preference for salty foods to sweet ones (Farnesworth, 1997), possibly because mercury causes excessive sodium excretion, as shown in studies of dental amalgam placed in monkeys and sheep (Lorscheider et al, 1995).
in Mercury-Poisoned Animals and Humans & in Autism
|Stereotyped sniffing (rats)||Stereotyped, repetitive behaviors|
|Hyperactivity (rats); poor response inhibition (humans), restlessness||Hyperactivity; ADHD-traits|
|Insomnia; difficulty falling asleep (humans)||Insomnia; difficulty falling or staying asleep|
|Eating disorders: anorexia, poor appetite, food aversion, narrow food preferences, decided food preferences (salty food) (humans)||Eating disorders: anorexia; restricted diet/narrow food preferences; feeding and suckling problems|
|Masturbation, priapism (children)||Masturbatory tendencies|
|Unintelligible cries; continuous crying; unprovoked crying (infants and children)||Unprovoked crying|
|Self injurious behavior, including head banging and hitting the head (toddlers and children)||Self injurious behavior, including head banging and hitting the head|
|Staring spells (infants and children)||Staring spells|
In autism, one of the earliest signs detected by mothers is a lack of eye contact (Gillberg & Coleman, 1992), and an early diagnostic behavior is failure to engage in joint attention based on the ability to "look where you are pointing" (CHAT, Baron-Cohen et al, 1992). Of 11 autistic children studied, ten had inaccurate or slow visual saccades (Rosenhall et al, 1988). Although some adults with ASD report exceptional visual acuity, visual problems are common, with two separate studies reporting 50% of ASD subjects having some type of unusual visual impairment (Steffenburg, in Gillberg & Coleman, 1992). Ritvo et al (1986) and Creel et al (1989) found decreased function of the rods in a study of autistic people, including a retinal sheen, and noted that many such individuals tend to use peripheral vision because of this. A number of case reports describe over-sensitivity to light and blurred vision (Sperry, 1998; Gillberg & Coleman, 1992, p.29; O'Neill & Jones, 1997).
Mercury can lead to a variety of vision problems, especially in children (Pierce et al, 1972; Snyder, 1972). Children who ate high doses of mercury from contaminated pork developed blindness (Snyder, 1972). In Iraqi babies exposed prenatally there was blindness or impaired vision (Amin-Zaki, 1974 and 1979). Iraqi children exposed postnatally developed visual disturbances, which ranged from blurred or hazy vision to constriction of the visual fields to complete blindness (Amin-Zaki et al, 1978). Two girls with mercury vapor poisoning were found to have visual field defects (Snyder, 1972), and, as previously noted, one child with Hg poisoning developed gaze avoidance (Fagala & Wigg, 1992). Acrodynia sufferers report vision problems, including near-sightedness and light sensitivity or photophobia (Diner and Brenner, 1998; Neville Recollection, Pink Disease site; Farnesworth, 1997; Matheson et al, 1980; Aronow and Fleischmann, 1976). A 25 year old man with elemental mercury poisoning exhibited decreased visual acuity, difficulty with visual fixation, and constricted visual fields (Kark et al, 1971). In Japanese victims, there was blurred vision as well as constriction of visual fields (Snyder, 1972; Tokuomi et al, 1982). Iraqi mothers exposed to Hg had visual disturbance (Amin-Zaki, 1979).
In dogs exposed to daily doses of methylmercury, distortion of the visual evoked response from the visual cortex was the first sign. Damage occurred in the preclinical silent stage, demonstrating that CNS damage is occurring before overt symptoms appear (Mattsson et al, 1981). Monkeys treated at birth with low level methylmercury exhibited impaired spatial vision and visual acuity at age 3 and 4 years (Rice and Gilbert, 1982). Disturbances caused by methylmercury in rat optic nerves were observed (Kinoshita et al, 1999).
Seen in Mercury Poisoning & Autism
|Lack of eye contact; difficulties with visual fixation||Lack of eye contact; gaze abnormalities; problems in joint attention|
|"Visual impairments," blindness, near-sightedness, decreased visual acuity||"Visual impairments"; inaccurate or slow saccades; decreased functioning of the rods; retinal sheen|
|Light sensitivity, photophobia||Over-sensitivity to light|
|Blurred or hazy vision||Blurred vision|
|Constricted visual fields||Not described|
h. Physical Presentations
There is a much higher rate of autism among children with cerebral palsy than would be expected by chance (Nordin and Gillberg, 1996). Many autistic children have abnormal muscle tone including hyper- and hypotonia, and many are incontinent or have difficulty being toilet trained (Filipek et al, 1999; Church and Coplan, 1995). Several of the infants which Teitelbaum and colleagues (1998) observed showed decreased arm strength, and Schuler (1995) describes greater muscle weakness in the upper than the lower body. Impairments in oral-motor function, including problems chewing and swallowing, are common, as noted previously.
These impairments are seen in mercurialism as well. In the Iraqi and Japanese epidemics, many children developed clinical cerebral palsy (Amin-Zaki, 1979; Myers & Davidson, 1998; Gilbert & Grant-Webster 1995; Dale, 1972). Amin-Zaki et al (1978) reported muscle wasting and lack of motor power and control in most cases, complete paralysis in several cases, and athetotic movements in 2 cases, of postnatally exposed children. In the Iraqi babies and children, some had increased muscle tone, while others had decreased muscle tone. Abnormal reflexes, spasticity, and weakness were common. One child said "my hands are weak and do not obey me" (Amin-Zaki et al, 1974 and 1978). The 12 year old who inhaled mercury vapor exhibited weakness and decreased muscle strength (Fagala and Wigg, 1992). As in autism, muscle weakness from mercury poisoning is most prominent in the upper body (Adams et al, 1983). Acrodynia, for example, is marked by poor muscle tone in general and loss of arm strength in particular (Farnesworth, 1997). Finally, difficulty in chewing and swallowing, salivation, and drooling are common in children as well as adults; incontinence was observed in children in the Iraqi Hg-crisis (Amin-Zaki, 1974 and 1978; Pierce et al, 1972; Snyder, 1972; Joselow et al, 1972; Smith, 1977).
The presence of rashes and dermatitis is sometimes reported in descriptions of ASD subjects. Whiteley et al (1998) found that 63% of the ASD children had a history of eczema or other skin complaints. "Some children with autism are frequent scratchers. Gentle rubbing and scratching can become a calming self-stimulation; but when it becomes clawing, and there are rashes and open scrapes on the skin, a tactile intolerance can be responsible" (O'Neill, 1999).
Rashes and itching are common disturbances in mercury toxicity as well (Kark et al, 1971). A 4 year old with Hg poisoning developed an itchy, peeling rash on the extremities (Florentine and Sanfilippo, 1991). Mercury vapor inhalation caused a rash and peeling on the palms and soles of a pre-adolescent (Fagala and Wigg, 1992). An acrodynia victim described himself as a child as having severe itching and a constant burning sensation at the extremities, resulting in him rubbing his hands and feet raw (Neville Recollection, Pink Disease Support Group). Acrodynia symptoms in an adult poisoned by ethylmercury injection included pink scaling palms and soles, flushed cheeks, and itching (Matheson et al, 1980). In acrodynia the skin may be rough and dry, and the soles and palms are usually but not necessarily red (Aronow and Fleischmann, 1976). Thimerosal ingested by 44 year old man led to dermatitis (Pfab et al, 1996).
In autism, "signs of autonomic disturbance may be noticed at times, including sweating, irregular breathing, and rapid pulse" (Wing and Attwood, 1987). There may be elevated blood flow and heart rate (Ornitz, 1987). An increased incidence of acrocyanosis has been observed in Asperger's syndrome. Acrocyanosis is an uncommon disorder of poor circulation in which skin on the hands and feet turn red and blue; there is profuse sweating; and the fingers and toes are persistently cold (Carpenter and Morris, 1991).
Sweating and circulatory abnormalities are also common in some forms of mercury poisoning. Acrodynia in adults and children results in excessive sweating, poor circulation, and rapid heart rate (Farnesworth, 1997; Matheson et al, 1980; Cloarec et al, 1995; Warkany and Hubbard, 1953). The 12 year old with mercury vapor poisoning sweated profusely, especially at night (Fagala and Wigg, 1992), and elevated blood pressure has been reported in exposed workers (Vroom and Greer, 1972). Autonomic system abnormalities can be caused by disturbances in acetylcholine levels, known to be deficient in both autism and Hg poisoning (see neurotransmitter section below).
in Mercury Poisoning & Autism
|Increase in cerebral palsy; hyper- or hypotonia; paralysis, abnormal reflexes; spasticity; decreased muscle strength and motor power, especially in the upper body; incontinence; problems chewing, swallowing, and salivating||Increase in cerebral palsy; hyper- or hypotonia; decreased muscle strength, especially in the upper body; incontinence/toilet training difficulties; problems chewing and swallowing|
|Rashes, dermatitis, dry skin, itching; burning sensation||Rashes, dermatitis, eczema; itching|
|Autonomic disturbances: excessive sweating; poor circulation; elevated heart rate||Autonomic disturbances: sweating abnormalities; poor circulation; elevated heart rate|
j. Gastrointestinal Function
Many if not most autistic individuals have gastrointestinal problems, the most common complaints being chronic diarrhea, constipation, gaseousness, and abdominal discomfort and distention (D'Eufemia et al, 1996; Horvath et al, 1999; Whitely et al, 1998). Colitis is not uncommon (Wakefield et al, 1998). As noted previously, anorexia is sometimes associated with ASD (Gillberg & Coleman, 1992). Kanner noted that over half his initial cases had feeding difficulties and excessive vomiting as infants (1943). O'Reilly and Waring (1993) have described sulfur deficiencies in autism, an effect of which can be clumping of proteins on the gut wall, which is lined with sulfated proteins. The clumping can lead to increased intestinal permeability, or leaky gut syndrome (Shattock, 1997), found in many autistic individuals (D'Eufemia, 1996). Some ASD individuals have unusual opioid peptide fragments in urine; these peptides are believed to enter the bloodstream due to a leaky gut and to result from an incomplete breakdown of gluten and casein in the diet possibly arising from "inadequacy of the [endopeptidase] enzyme systems which are responsible for their breakdown" (Shattock, 1997).
Mercury, which binds to sulfur groups (Clarkson, 1992), is known to cause gastroenteritis (Kark et al, 1971). For example, a four year old with diarrhea was initially diagnosed with gastroenteritis (Florentine and Sanfilippo, 1991). A pre-adolescent with mercury vapor poisoning developed nausea, abdominal pain, poor appetite, rectal itching, and diarrhea; she frequently strained to have a bowel movement, and was at one point diagnosed with colitis (Fagala and Wigg, 1992). Acrodynia is marked by both constipation and diarrhea (Diner and Brenner, 1998). Incontinence of urine and stool are observed in infants and children exposed pre- and postnatally in Iraq (Amin-Zaki, 1974 and 1978). In another case, a 28 year old woman with occupational exposure to mercury vapor developed watery stools (Ross et al, 1977). Diarrhea and digestive disturbance were seen in a dentist with measurable mercury levels; there was obesity in another dentist (Smith, 1977). A 44 year old man poisoned with thimerosal given intramuscularly developed gastrointestinal bleeding, which looked like hemorrhaging colitis (Lowell et al, 1996). Intense exposure to mercury vapor can cause abdominal pain, nausea, and vomiting (Feldman, 1982). Severe constipation, anorexia, weight loss, and other "disturbances of gastrointestinal function" have been noted in other cases (Adams et al, 1983; Joselow et al, 1972). Rats tested with mercuric chloride were observed with "lesions of the ileum and colon with abnormal deposits of IgA in the basement membranes of the intestinal glands and of IgG in the basement membranes of the lamina propria" (Andres, 1984, reviewed in EPA, 1997, p.3-36). In another rat experiment, Hg was found to increase the permeability of intestinal epithelial tissues (Watzl et al, 1999). Mercury also inhibits the peptidase - dipeptidyl peptidase IV - which cleaves, among other substances, casomorphin during the digestive process (Puschel et al, 1982).
There is no reported increase in incidence in kidney problems in autism. Although renal function is commonly impaired from Hg exposure, such impairment would not be expected if the mercury exposure occurred from thimerosal injections, since kidney function may be unaffected when mercury is injected or inhaled (Davis et al, 1994; Fagala and Wigg, 1992). For example, although thimerosal ingested orally by a 44 year old man resulted in renal tubular failure and gingivitis (Pfab et al, 1996), renal function was normal in another 44 year old man injected intramuscularly with thimerosal (Lowell et al, 1996).
in Mercury Poisoning & Autism
|Gastroenteritis, diarrhea; abdominal pain, rectal itching, constipation, "colitis"||Diarrhea, constipation, gaseousness, abdominal discomfort, colitis|
|Anorexia, weight loss, nausea, poor appetite||Anorexia; feeding difficulties, vomiting as infants|
|Lesions of the ileum and colon; increased intestinal permeability||Leaky gut syndrome from sulfur deficiency|
|Inhibits dipeptidyl peptidase IV, which cleaves casomorphin||Inadequate endopeptidase enzymes responsible for breakdown of casein and gluten|
II. Comparison of Biological Abnormalities
Like the similarities seen in observable symptoms, parallels between autism and mercury poisoning clearly exist even at cellular and subcellular levels. These similarities are summarized in tables after each individual section.
Sulfur: Studies of autistic children with known chemical or food intolerances show a low capacity to oxidize sulfur compounds and low levels of sulfate (O'Reilly & Waring, 1993; Alberti et al, 1999). These findings were interpreted as suggesting that "there may be a fault either in the manufacture of sulfate or that sulfate is being used up dramatically on an unknown toxic substance these children may be producing" (O'Reilly and Waring, 1993). Alternatively, these observations may be linked to mercury, since mercury preferentially forms compounds with molecules rich in sulfhydryl groups (--SH), such as cysteine and glutathione, making them unavailable for normal cellular and enzymatic functions (Clarkson, 1992). Relatedly, mercury may cause low sulfate by its ability to irreversibly inhibit the sulfate transporter Na-Si cotransporter NaSi-1 present in kidneys and intestines, thus preventing sulfate absorption (Markovitch and Knight, 1998).
Among the sulfhydryl groups, or thiols, mercury has special affinity for purines and pyrimidines, as well as other subcellular substances (Clarkson, 1992; Koos and Longo, 1976). Errors in purine or pyrimidine metabolism are known to result in classical autism or autistic features in some cases (Gillberg and Coleman, 1992, p.209; Page et al, 1997; Page & Coleman, 2000; The Purine Research Society), thereby suggesting that mercury's disruption of this pathway might also lead to autistic traits.
Likewise, yeast strains sensitive to Hg are those which have innately low levels of tyrosine synthesis. Mercury can deplete cellular tyrosine by binding to the SH-groups of the tyrosine uptake system, preventing colony growth (Ono et al, 1987), and Hg-depleted tyrosine would be particularly significant in cells known to accumulate mercury (e.g., neurons of the CNS, see below). Similarly, disruptions in tyrosine production in hepatic cells, arising from a genetic condition called Phenylketonuria (PKU), also results in autism (Gillberg & Coleman, 1992, p.203).
Glutathione: Glutathione is one of the primary means through which the cells detoxify heavy metals (Fuchs et al, 1997), and glutathione in the liver is a primary substrate by which body clearance of organic mercury takes place (Clarkson, 1992). Mercury, by preferentially binding with glutathione and/or preventing absorption of sulfate, reduces glutathione bioavailability. Many autistic subjects have low levels of glutathione. O'Reilly and Waring (1993) suggest this is due to an "exotoxin" binding glutathione so it is unavailable for normal biological processes. Edelson and Cantor (1998) have found a decreased ability of the liver in autistic subjects to detoxify heavy metals. Alternatively, low glutathione can be a manifestation of chronic infection (Aukrust et al, 1996, 1995; Jaffe et al, 1993), and infection-induced glutathione deficiency would be more likely in the presence of immune impairments derived from mercury (Shenkar et al, 1998).
Glutathione peroxidase activities were reported to be abnormal in the erythrocytes of autistic children (Golse et al, 1978). Mercury generates reactive oxygen species (ROS) levels in cells, which increases ROS scavenger enzyme content and thus glutathione, to relieve oxidative stress (Hussain et al, 1999). At high enough levels, mercury depletes rat hepatocytes of glutathione (GSH) and causes significant reduction in glutathione peroxidase and glutathione reductase (Ashour et al, 1993).
Mitochondria: Disturbances of brain energy metabolism have prompted autism to be hypothesized as a mitochondrial disorder (Lombard, 1998). There is a frequent association of lactic acidosis and carnitine deficiency in autistic patients, which suggests excessive nitric oxide production in mitochondria (Lombard, 1998; Chugani et al, 1999), and again, mercury may be a participant. Methylmercury accumulates in mitochondria, where it inhibits several mitochondrial enzymes, reduces ATP production and Ca2+ buffering capacity, and disrupts mitochondrial respiration and oxidative phosphorylation (Atchison & Hare, 1994; Rajanna and Hobson, 1985; Faro et al, 1998). Neurons have increased numbers of mitochondria (Fuchs et al, 1997), and since Hg accumulates in neurons of the CNS, an Hg effect upon neuronal mitochondria function seems likely - especially in children having substandard mercury detoxification.
Arising from Hg Exposure & Present in Autism
|Ties up sulfur groups; prevents sulfate absorption||Low sulfate levels|
|Has special affinity for purines and pyrimidines||Errors in purine and pyrimidine metabolism can lead to autistic features|
|Depletes cellular tyrosine in yeast||PKU, arising from disruption in tyrosine production, results in autism|
|Reduces bioavailability of glutathione, necessary in cells and liver for heavy metal detoxification||Low levels of glutathione; decreased ability of liver to detoxify heavy metals|
|Can cause significant reduction in glutathione peroxidase and glutathione reductase||Abnormal glutathione peroxidase activities in erythrocytes|
|Disrupts mitochondrial activities, especially in brain||Mitochondrial dysfunction, especially in brain|
b. Immune System
A variety of immune alterations are found in autism-spectrum children (Singh et al, 1993; Gupta et al, 1996; Warren et al, 1986 & 1996; Plioplys et al, 1994), and these appear to be etiologically significant in a variety of ways, ranging from autoimmunity to infections and vaccination responses (e.g., Fudenberg, 1996; Stubbs, 1976). Mercury's effects upon immune cell function are well documented and may be due in part to the ability of Hg to reduce the bioavailability of sulfur compounds:
"It has been known for a long time that thiols are required for optimal primary in vitro antibody response, cytotoxicity, and proliferative response to T-cell mitogens of murine lymphoid cell cultures. Glutathione and cysteine are essential components of lymphocyte activation, and their depletion may result in lymphocyte dysfunction. Decreasing glutathione levels profoundly affects early signal transduction events in human T-cells" (Fuchs & Sch"fer, 1997).
Allergy, asthma, and arthritis: Individuals with autism are more likely to have allergies and asthma, and autism occurs at a higher than expected rate in families with a history of autoimmune diseases such as rheumatoid arthritis and hypothyroidism (Comi and Zimmerman, 1999; Whitely et al, 1998). Relative to the general population, prevalence of selective IgA deficiency has been found in autism (Warren et al); individuals with selective IgA deficiency are more prone to allergies and autoimmunity (Gupta et al, 1996). Furthermore, lymphocyte subsets of autistic subjects show enhanced expression of HLA-DR antigens and an absence of interleuken-2 receptors, and these findings are associated with autoimmune diseases like rheumatoid arthritis (Warren et al). These observations suggest autoimmune processes are present in ASD (Plioplys, 1989; Warren et al); and this possibility is reinforced by Singh's findings of elevated antibodies against myelin-basic protein (Singh et al, 1993).
Atypical responses to mercury have been ascribed to allergic or autoimmune reactions (Gosselin et al, 1984; Fournier et al, 1988), and a genetic predisposition for Hg reaction may explain why sensitivity to this metal varies so widely by individual (Rohyans et al, 1984; Nielsen & Hultman, 1999). Acrodynia can present as a hypersensitivity reaction (Pfab et al, 1996), or it may arise from immune over-reactivity, and "children who incline to allergic reactions have an increased tendency to develop acrodynia" (Warkany & Hubbard, 1953). Those with acrodynia are also more likely to suffer from asthma, to have poor immune system function (Farnesworth, 1997), and to experience intense joint pains suggestive of rheumatism (Clarkson, 1997). Methylmercury has altered thyroid function in rats (Kabuto, 1991).
Rheumatoid arthritis with joint pain has been observed as a familial trait in autism (Zimmerman et al, 1993). A subset of autistic subjects had a higher rate of strep throat and elevated levels of B lymphocyte antigen D8/17, which has expanded expression in rheumatic fever and may be implicated in obsessive-compulsive behaviors (DelGiudice-Asch & Hollander, 1997).
Mercury exposure frequently results in rheumatoid-like symptoms. Iraqi mothers and children developed muscle and joint pain (Amin-Zaki, 1979), and acrodynia is marked by joint pain (Farnesworth, 1997). Sore throat is occasionally a presenting sign in mercury poisoning (Vroom and Greer, 1972). A 12 year old with mercury vapor poisoning, for example, had joint pains as well as a sore throat; she was positive on a streptozyme test, and a diagnosis of rheumatic fever was made; she improved on penicillin (Fagala and Wigg, 1992). Acrodynia, which is almost never seen in adults, was also observed in a 20 year old male with a history of sensitivity reactions and rheumatoid-like arthritis, who received ethylmercury via injection in gammaglobulin (Matheson et al, 1980). One effective chelating agent, penicillamine, is also effective for rheumatoid arthritis (Florentine and Sanfilippo, 1991).
Mercury can induce an autoimmune response in mice and rats, and the response is both dose-dependent and genetically determined. Mice "genetically prone to develop spontaneous autoimmune diseases [are] highly susceptible to mercury-induced immunopathological alterations" (al-Balaghi, 1996). The autoimmune response depends on the H-2 haplotype: if the strain of mice does not have the susceptibility haplotype, there is no autoimmune response; the most sensitive strains show elevated antibody titres at the lowest dose; and the less susceptible strain responds only at a medium dose (Nielsen & Hultman, 1999). Interestingly, Hu et al (1997) were able to induce a high proliferative response in lymphocytes from even low responder mouse strains by washing away excess mercury after pre-treatment, while chronic exposure to mercury induced a response only in high-responder strains.
Autoimmunity and neuronal proteins: Based upon research and clinical findings, Singh has been suggesting for some time an autoimmune component in autism (Singh, Fudenberg et al, 1988). The presence of elevated serum IgG "may suggest the presence of persistent antigenic stimulation" (Gupta et al, 1996). Connolly and colleagues (1999) report higher rates in autistic vs. control groups of elevated antinuclear antibody (ANA) titers, as well as presence of IgG and IgM antibodies to brain endothelial cells. On the one hand, since mercury remains in the brain for years after exposure, autism's persistent symptoms may be due to an on-going autoimmune response to mercury remaining in the brain; on the other hand, activation and continuation of an autoimmune response does not require the continuous presence of mercury ions: in fact, once induced, autoimmune processes in the CNS might remain exacerbated because removal of mercury after an initial exposure can induce a greater proliferative response in lymphocytes than can persistent Hg exposure (Hu et al, 1997).
In sera of male workers exposed to mercury, autoantibodies (primarily IgG) to neuronal cytoskeletal proteins, neurofilaments (NFs), and myelin basic protein (MBP) were prevalent. These findings were confirmed in rats and mice, and there were significant correlations between IgG titers and subclinical deficits in sensorimotor function. These findings suggest that peripheral autoantibodies to neuronal proteins are predictive of neurotoxicity, since histopathological findings were associated with CNS and PNS damage. There was also evidence of astrogliosis (indicative of neuronal CNS damage) and the presence of IgG concentrated along the bbb (El-Fawal et al, 1999). Autoimmune response to mercury has also been shown by the transient presence of antinuclear antibodies (ANA) and antinucleolar antibodies (ANolA) (Nielsen & Hultman, 1999; Hu et al, 1997; Fagala and Wigg, 1992).
A high incidence of anti-cerebellar immunoreactivity which was both IgG and IgM in nature has been found in autism, and there is a higher frequency of circulating antibodies directed against neuronal antigens in autism as compared to controls (Plioplys, 1989; Connolly et al, 1999). Furthermore, Singh and colleagues have found that 50% to 60% of autistic subjects tested positive for the myelin basic protein antibodies (1993) and have hypothesized that autoimmune responses are related to an increase in select cytokines and to elevated serotonin levels in the blood (Singh, 1996; Singh, 1997). Weitzman et al (1982) have also found evidence of reactivity to MBP in autistic subjects but none in controls.
Since anti-cerebellar antibodies have been detected in autistic blood samples, ongoing damage may arise as these antibodies find and react with neural antigens, thus creating autoimmune processes possibly producing symptoms such as ataxia and tremor. Relatedly, the cellular damage to Purkinje and granule cells noted in autism (see below) may be mediated or exacerbated by antibodies formed in response to neuronal injury (Zimmerman et al, 1993).
T-cells, monocytes, and natural killer cells: Many autistics have skewed immune-cell subsets and abnormal T-cell function, including decreased responses to T-cell mitogins (Warren et al, 1986; Gupta et al, 1996). One recent study reported increased neopterin levels in urine of autistic children, indicating activation of the cellular immune system (Messahel et al, 1998).
Workers exposed to Hgo exhibit diminished capacity to produce the cytokines TNF (alpha) and IL-1 released by monocytes and macrophages (Shenkar et al, 1998). Both high dose and chronic low-level mercury exposure kills lymphocytes, T-cells, and monocytes in humans. This occurs by apoptosis due to perturbation of mitochondrial dysfunction. At low, chronic doses, the depressed immune function may appear asymptomatic, without overt signs of immunotoxicity. Methylmercury exposure would be especially harmful in individuals with already suppressed immune systems (Shenker et al, 1998). Mercury increases cytosolic free calcium levels [Ca2+]i in T lymphocytes, and can cause membrane damage at longer incubation times (Tan et al, 1993). Hg has also been found to cause chromosomal aberrations in human lymphocytes, even at concentrations below those causing overt poisoning (Shenkar et al, 1998; Joselow et al, 1972), and to inhibit rodent lymphocyte proliferation and function in vitro.
Depending on genetic predisposition, mercury causes activation of the immune system, especially Th2 subsets, in susceptible mouse strains (Johansson et al, 1998; Bagenstose et al, 1999; Hu et al, 1999). Many autistic children have an immune portrait shifted in the Th2 direction and have abnormal CD4/CD8 ratios (Gupta et al, 1998; Plioplys, 1989). This may contribute to the fact that many ASD children have persistent or recurrent fungal infections (Romani, 1999).
Many autistic children have reduced natural killer cell function (Warren et al, 1987; Gupta et al, 1996), and many have a sulfation deficiency (Alberti, 1999). Mercury reduces --SH group/sulfate availability, and this has immunological ramifications. As noted previously, decreased levels of glutathione, observed in autistic and mercury poisoned populations, are associated with impaired immunity (Aukrust et al, 1995 and 1996; Fuchs and Sch"fer, 1997). Decreases in NK T-cell activity have in fact been detected in animals after methylmercury exposure (Ilback, 1991).
Singh detected elevated IL-12 and IFNg in the plasma of autistic subjects (1996). Chronic mercury exposure induces IFNg and IL-2 production in mice, while intermittent presence of mercury suppresses IFNg and enhances IL-4 production (Hu et al, 1997). Interferon gamma (IFNg) is crucial to many immune processes and is released by T lymphocytes and NK cells, for example, in response to chemical mitogens and infection; sulfate participates in IFNg release, and "the effector phase of cytotoxic T-cell response and IL-2-dependent functions is inhibited by even a partial depletion of the intracellular glutathione pool" (Fuchs & Sch"fer, 1997). A mercury-induced sulfation problem might, therefore, impair responses to viral (and other) infections - via disrupting cell-mediated immunity as well as by impairing NK function (Benito et al, 1998). In animals, Hg exposure has led to decreases in production of antibody-producing cells and in antibody titres in response to inoculation with immune-stimulating agents (EPA, 1997, review, p.3-84).
in Mercury Exposure & Autism
|Individual sensitivity due to allergic or autoimmune reactions; sensitive individuals more likely to have allergies and asthma, autoimmune-like symptoms, especially rheumatoid-like ones||More likely to have allergies and asthma; familial presence of autoimmune diseases, especially rheumatoid arthritis; IgA deficiencies|
|Can produce an immune response, even at low levels; can remain in CNS for years||Indications of on-going immune response in CNS|
|Presence of autoantibodies (IgG) to neuronal cytoskeletal proteins, neurofilaments, and myelin basic protein; astrogliosis; transient ANA and AnolA||Presence of autoantibodies (IgG and IgM) to cerebellar cells, myelin basis protein|
|Causes overproduction of Th2 subset; diminishes capacity to produce TNF(alpha) and IL-1; kills lymphocytes, T-cells, and monocytes; inhibits lymphocyte production; decreases NK T-cell activity; may induce or suppress IFN(gamma) and IL-2 production||Skewed immune-cell subset in the Th2 direction and abnormal CD4/CD8 ratios; decreased responses to T-cell mitogens; increased neopterin; reduced NK T-cell function; increased IFN(gamma) and IL-12|
c. CNS Structure
Autism is primarily a neurological disorder (Minshew, 1996), and mercury preferentially targets nerve cells and nerve fibers (Koos and Longo, 1976). Experimentally, primates have the highest levels in the brain relative to other organs (Clarkson, 1992). Methylmercury easily crosses the blood-brain barrier by binding with cysteine to form a molecule that is nearly identical to methionine. This molecule - methylmercury cysteine - is transported on the Large Neutral Amino Acid across the bbb (Clarkson, 1992).
Once in the CNS, organic mercury is converted to the inorganic form (Vahter et al, 1994). Inorganic mercury is unable to cross back out of the bbb (Pedersen et al, 1999) and is more likely than the organic form to induce an autoimmune response (Hultman and Hansson-Georgiadis, 1999). Furthermore, although most cells respond to mercurial injury by modulating levels of glutathione, metallothionein, hemoxygenase, and other stress proteins, "with few exceptions, neurons appear to be markedly deficient in these responses" and thus more prone to injury and less able to remove the metal (Sarafian et al, 1996).
While damage has been observed in a number of brain areas in autism, many functions are spared (Dawson, 1996). In mercury exposure, damage is also selective (Ikeda et al, 1999; Clarkson, 1992), and the list of Hg-affected areas is remarkably similar to the neuroanatomy of autism.
Cerebellum, Cerebral Cortex, & Brainstem: Autopsy studies of carefully selected autistic individuals revealed cellular changes in cerebellar Purkinje and granule cells (Bauman and Kemper, 1988; Ritvo et al, 1986). MRI studies by Courchesne and colleagues (1988; reviewed in ARI Newslett, 1994) described cerebellar defects in autistic subjects, including smaller vermal lobules VI and VII and volume loss in the parietal lobes. The defects were present independently of IQ. "No other part of the nervous system has been shown to be so consistently abnormal in autism." Courchesne (1989) notes that the only neurobiological abnormality known to precede the onset of autistic symptomatology is Purkinje neuron loss in the cerebellum. Piven found abnormalities in the cerebral cortex in seven of 13 high-functioning autistic adults using MRI (1990). Although more recent studies have called attention to amygdaloid and temporal lobe irregularities in autism (see below), and cerebellar defects have not been found in all ASD subjects studied (Bailey et al, 1996), the fact remains that many and perhaps most autistic children have structural irregularities within the cerebellum.
Mercury can induce cellular degeneration within the cerebral cortex and leads to similar processes within granule and Purkinje cells of the cerebellum (Koos and Longo, 1976; Faro et al, 1998; Clarkson, 1992; see also Anuradha, 1998; Magos et al, 1985). Furthermore, cerebellar damage is implicated in alterations of coordination, balance, tremors, and sensations (Davis et al, 1994; Tokuomi et al, 1982), and these findings are consistent with Hg-induced disruption in cerebellar synaptic transmission between parallel fibers or climbing fibers and Purkinje cells (Yuan & Atchison, 1999).
MRI studies have documented Hg-effects within visual and sensory cortices, and these findings too are consistent with the observed sensory impairments in victims of mercury poisoning (Clarkson, 1992; Tokuomi et al, 1982). Acrodynia, a syndrome with symptoms similar to autistic traits, is considered a pathology mainly of the CNS arising from degeneration of the cerebral and cerebellar cortex (Matheson et al, 1980). In monkeys, mercury preferentially accumulated in the deepest pyramidal cells and fiber systems.
Mercury causes oxidative stress in neurons. The CNS cells primarily affected are those which are unable to produce high levels of protective metallothionein and glutathione. These substances tend to inhibit lipid peroxidation and thereby suppress mercury toxicity (Fukino et al, 1984). Importantly, granule and Purkinje cells have increased risk for mercury toxicity because they produce low levels of these protective substances (Ikeda et al, 1999; Li et al, 1996). Naturally low production of glutathione, when combined with mercury's ability to deplete usable glutathione reserves, provides a mechanism whereby mercury is difficult to clear from the cerebellum -- and this is all the more significant because glutathione is a primary detoxicant in brain (Fuchs et al, 1997).
Mercury's induction of cerebellar deterioration is not restricted to high-doses. Micromolar doses of methylmercury cause apoptosis of developing cerebellar granule cells by antagonizing insulin-like growth factor (IGF-I) and increasing expression of the transcription factor c-Jun (Bulleit and Cui, 1998).
Several researchers have found evidence of a brainstem defect in a subset of autistic subjects (Hashimoto et al, 1992 and 1995; McClelland et al, 1985); and MRI studies have revealed brainstem damage in a few cases of mercury poisoning (Davis et al, 1994). The peripheral polyneuropathy examined in Iraqi victims was believed to have resulted from brain stem damage (Von Burg and Rustam, 1974).
Amygdala & Hippocampus: Atypicalities in other brain areas are remarkably similar in ASD and mercury poisoning. Pathology affecting the temporal lobe, particularly the amygdala, hippocampus, and connected areas, is seen in autistic patients and is characterized by increased cell density and reduced neuronal size (Abell et al, 1999; Hoon and Riess, 1992; Otsuka, 1999; Kates et al, 1998; Bauman and Kemper, 1985). The basal ganglia also show lesions in some cases (Sears, 1999), including decreased blood flow (Ryu et al, 1999).
Mercury can accumulate in the hippocampus and amygdala, as well as the striatum and spinal chord (Faro et al, 1998; Lorscheider et al, 1995; Larkfors et al, 1991). One study has shown that areas of hippocampal damage from Hg were those which were unable to synthesize glutathione (Li et al, 1996). A 1994 study in primates found that mercury accumulates in the hippocampus and amygdala, particularly the pyramidal cells, of adults and offspring exposed prenatally (Warfvinge et al, 1994).
The documenting of temporal lobe mercury provides a direct link between autism and mercury because, as cited previously, (i) mercury alters neuronal function, and (ii) the temporal lobe, and the amygdala in particular, are strongly implicated in autism (e.g., Aylward et al, 1999; Bachevalier, 1994; Baron-Cohen, 1999; Bauman & Kemper, 1985; Kates et al, 1998; Nowell et al, 1990; Warfvinge et al, 1994). Bachevalier (1996) has shown that infant monkeys with early damage to the amygdaloid complex exhibit many autistic behaviors, including social avoidance, blank expression, lack of eye contact and play posturing, and motor stereotypies. Hippocampal lesions, when combined with amygdaloid damage, increases the severity of symptoms.
Also noteworthy is the fact that amygdala findings in autism and mercury literatures are paralleled in fragile X syndrome, a genetic disorder wherein many affected individuals have traits worthy of an autism diagnosis. These traits include sensory alterations, emotional lability, appetite dysregulation, social deficits, and eye-contact aversion (Hagerman). Not only are fraX-related proteins (FRM1, FMR2) implicated in amygdaloid function (Binstock, 1995; Yamagata, 1999), but neurons involved in gaze- and eye-contact-aversion have been identified within the primate temporal lobe and amygdaloid subareas (Rolls 1992, reviewed in Binstock 1995). These various findings in ASD, mercury poisoning, and fragile X suggest that amygdaloid mercury is a mechanism for inducing traits central to or associated with autism and the autism-spectrum of disorders.
Neuronal Organization & Head Circumference: Several autism brain studies have found evidence of increased neuronal cell replication, a lowered ratio of glia to neurons, and an increased number of glial cells (Bailey et al, 1996). Based on these and other neuropathological findings, autism can be characterized as "a disorder of neuronal organization, that is, the development of the dendritic tree, synaptogenesis, and the development of the complex connectivity within and between brain regions" (Minshew, 1996).
Mercury can interfere with neuronal migration and depress cell division in the developing brain. Post-mortem brain tissue studies of exposed Japanese and Iraqi infants revealed "abnormal neuronal cytoarchitecture characterized by ectopic cells and disorganization of cellular layers" (EPA, 1997, p.3-86; Clarkson, 1997). Developmental neurtoxicity of Hg may also be due to binding of mercury to sulfhydryl-rich tubulin, a component of microtubules (Pendergrass et al, 1997). Intact microtubules are necessary for proper cell migration and cell division (EPA, review, 1997, p.32-88).
Rat pups dosed postnatally with methylmercury had significant reductions in neural cell adhesion molecules (NCAMs), which are critical during neurodevelopment for proper synaptic structuring. Sensitivity of NCAMs to methylmercury decreased as the developmental age of the rats increased. "Toxic perturbation of the developmentally-regulated expression of NCAMs during brain formation may disturb the stereotypic formation of neuronal contacts and could contribute to the behavioral and morphological disturbances observed following methylmercury poisoning" (Deyab et al, 1999). Plioplys et al (1990) have found depressed expression of NCAM serum fragments in autism.
Abnormalities in neuronal growth during development are implicated in head size differences found in both autism and mercury poisoning. In autism, Fombonne and colleagues (1999) have found a subset of subjects with macrocephaly and a subset with microcephaly. The circumference abnormalities were progressive, so that, while micro- and macrocephaly were present in 6% and 9% respectively of children under 5 years, among those age 10-16 years, the rates had increased to 39% and 24% respectively. Another study, by Stevenson et al (1997), had found just one subject out of 18 with macrocephaly who had this abnormality present at birth. The macrocephaly in autism is generally believed to result from "increased neuronal growth or decreased neuronal pruning." The cause of microcephaly has not been investigated.
The most detailed study of head size in mercury poisoning, by Amin-Zaki et al (1979), involved 32 Iraqi children exposed prenatally and followed up to age 5 years. Eight (25%) had progressive microcephaly, i.e., the condition was not present at birth. None had developed macrocephaly, at least at the time of the study. The microcephaly has been ascribed to neuronal death or apoptosis from Hg intoxication.
in Mercury Poisoning & Autism
|Primarily impacts CNS||Neurological impairments primary|
|Selectively targets brain areas - those unable to detoxify heavy metals or reduce Hg-induced oxidative stress||Specific areas of brain pathology; many functions spared|
|Damage to Purkinje and granular cells||Damage to Purkinje and granular cells|
|Accummulates in amygdala and hippocampus||Pathology in amygdala and hippocampus|
|Causes abnormal neuronal cytoarchitecture; interferes with neuronal migration and depresses cell division in developing brains; reduces NCAMs||Neuronal disorganization; increased neuronal cell replication, small glia to neuron ration, increased glial cells; depressed expression of NCAMs|
|Head size differences: progressive microcephaly||Head size differences: progressive microcephaly and macrocephaly|
|Brain stem defects in some cases||Brain stem defects in some cases|
d. Neurons & Neurochemicals
The brains of autistic subjects show disturbances in many neurotransmitters, primarily serotonin, catecholamines, the amino acid neurotransmitters, and acetylcholine. Mercury poisoning causes disturbances in these same neurotransmitters: primarily serotonin, the catecholamines, glutamate, and acetlycholine.
Serotonin: Serotonin synthesis is decreased in the brains of autistic children and increased in autistic adults, relative to age-matched controls (Chugani et al, 1999), while whole blood serotonin in platelets is elevated regardless of age (Leboyer; Cook, 1990). Autistic patients frequently respond well to SSRIs as well as Risperidone (McDougal; 1997; Zimmerman et al, 1996). Likewise, a number of animal studies have found serotonin abnormalities from mercury exposure. For example, subcutaneous administration of methylmercury to rats during postnatal development increases tissue concentration of 5-HT and HIAA in cerebral cortex (O'Kusky et al, 1988).
Findings about serotonin abnormalities in mercury literature implicate interactions between mercury and intracellular calcium as well as mercury and sulfhydral groups:
Many researchers have documented disruptions of intra- and extra-cellular calcium in neurons from mercury exposure (Atchison & Hare, 1994), including thimerosal (Elferink, 1999), and calcium metabolism abnormalities have been identified in autism (Plioplys, 1989; Coleman, 1989).
Intracellular concentrations of Ca2+ are critical for controlling gene expression in neurons and mediating neurotransmitter release from presynaptic vesicles (Sutton, McRory et al, 1999). 5-HT re-uptake activity and intrasynaptic concentration of 5-HT are regulated by Ca2+ in nerve terminals. Methylmercury causes a rapid, irreversible block of synaptic transmission by suppression of calcium entry into nerve terminal channels (Atchison et al, 1986). Thimerosal inhibits 5-HT transport activity in particular through interaction with intracellular sulfhydryl groups associated with Ca2+ pump ATPase (Nishio et al, 1996), for example, by modifying cysteine residues of the Ca(2+)-ATPase (Sayers et al, 1993; Thrower et al, 1996).
Dopamine: Studies have found indications both of abnormally high and low levels of dopamine in autistic subjects (Gillberg & Coleman, 1992, p288-9). For example, Ernst et al (1997) reported low prefrontal dopaminergic activity in ASD children, while Gillberg and Svennerholm (1987) reported high concentrations of homovanillic acid (HVA), a dopamine metabolite, in cerebro-spinal fluid of autistic children, suggesting greater dopamine synthesis. Pyridoxine (vitamin B6) has been found to improve function in some autistic patients by lowering dopamine levels through enhanced DBH function (Gillberg & Coleman, 1992, p289; Moreno et al, 1992; Rimland & Baker, 1996). Dopamine antagonists such as haloperidol improve some antipsychotic symptoms in ASD subjects, including motor stereotypies (Lewis, 1996).
Rats exposed to mercury during gestation show major alterations in synaptic dynamics of brain dopamine systems. The effects were not apparent immediately after birth but showed a delayed onset beginning at the time of weaning (Bartolome et al, 1984). A variety of mercuric compounds increase the release of [3H]dopamine, possibly by disrupting calcium homeostasis or calcium-dependent processes (McKay et al, 1986). Minnema et al (1989) found that methylmercury increases spontaneous release of [3H]dopamine from rat brain striatum mainly due to transmitter leakage caused by Hg-induced synaptosomal membrane permeability. SH groups may also be involved in the inhibition of dopamine binding in rat striatum (Bonnet et al, 1994). Pyridoxine deficiency in rats causes acrodynia, with features similar to human acrodynia (Gosselin et al, 1984).
Epinephrine and norepinephrine: Studies on autistic subjects have consistently found elevated norepinephrine and epinephrine in plasma, which suggests elevated levels of these transmitters in brain, as plasma and CSF norepinephrine are closely correlated (Gillberg and Coleman, 1992, p.121-122). Recently, Hollander et al (2000) have noted improvement in function in about half of their ASD subjects with administration of venlafaxine, a norepinephrine reuptake inhibitor. Mercury also disrupts norepinephrine levels by inhibiting sulfhydryl groups and thus blocking the function of O-methyltransferase, the enzyme that degrades epinephrine (Rajanna and Hobson, 1985). In acrodynia, blocking this enzyme resulted in high levels of epinephrine and norepinephrine in plasma (Cheek, Pink Disease Website). In rats, chronic exposure to low doses of methylmercury increased brain-stem norepinephrine concentration (Hrdina et al, 1976).
Glutamate: It has been observed that many autistics have irregularities related to glutamate (Carlsson ML, 1998). In autism, glutamate and aspartate have been found to be significantly elevated relative to controls (Moreno et al, 1992); and in a more recent study of ASD subjects, plasma levels of glutamic acid and aspartic acid were elevated even as levels of glutamine and asparagine were low (Moreno-Fuenmayor et al, 1996).
Mercury inhibits the uptake of glutamate, with consequent elevation of glutamate levels in the extracellular space (O'Carroll et al, 1995). Prenatal exposure to methylmercury of rats induced permanent disturbances in learning and memory which could be partially related to a reduced functional activity of the glutamatergic system (Cagiano et al, 1990). Thimerosal enhances extracellular free arachidonate and reduces glutamate uptake (Volterra et al, 1992). Excessive glutamate is implicated in epileptiform activities (Scheyer, 1998; Chapman et al, 1996), frequently present in both ASD and mercurialism (see below).
Acetylcholine: Abnormalities in the cortical cholinergic neurotransmitter system have recently been reported in a post mortem brain study of adult autistic subjects (Perry et al, 2000). The problem was one of acetylcholine deficiency and reduced muscarinic receptor binding, which Perry suggests may reflect intrinsic neuronal loss in hippocampus due to temporal lobe epilepsy (see section below for discussions of epilepsy and ASD/Hg). Mercury alters enzyme activities (Koos and Longo, 1976, p.400), including choline acetyltransferase, which may lead to acetylcholine deficiency (Diner and Brenner, 1998), or Hg may inhibit acetylcholine release due to its effects on Ca2 homeostasis and ion channel function (EPA, 1997, p.3-79). In rats, chronic exposure to low doses of methylmercury decreased cortical acetylcholine levels (Hrdina et al, 1976). Methylmercury has also been found to increase spontaneous release of [3H]acetylcholine from rat brain hippocampus (Minnema et al, 1989) and to increase muscarinic cholinergic receptor density in both rat hippocampus and cerebellum, suggesting upregulation of these receptors in these selected brain regions (Coccini, 2000).
Demyelination: Evidence of demyelination has been observed in the majority of autistic brains (Singh, 1992). This is true of mercury poisoning as well. Mild demyelinating neuropathy was detected in two girls (Florentine and Sanfilippo, 1991), and an adult showed axonal degeneration with Hg-related demyelination (Chu et al, 1998). Methylmercury can alter the fatty acid composition of myelin cerebrosides in suckling rats (Grundt et al, 1980).
from Mercury & in Autism
|Can increase tissue concentration of serotonin in newborn rats; causes calcium disruptions in neurons, preventing presynaptic serotonin release and inhibiting serotonin transport activities||Serotonin abnormalities: decreased serotonin synthesis in children; over-synthesis in adults; elevated serotonin in platelets; positive response to SSRIs; calcium metabolism abnormalities present|
|Alters dopamine systems; disrupts calcium and increases synaptosome membrane permeability, which affect dopamine activities; peroxidine deficiency in rats results in acrodynia||Indications of either high or low dopamine levels; positive response to peroxidine by lowering dopamine levels; positive response to dopamine antagonists|
|Increases epinephrine and norepinephrine levels by blocking the enzyme which degrades epinephrine||Elevated norepinephrine and epinephrine; positive response to norepinephrine reuptake inhibitors|
|Elevates glutamate; decreases glutamate uptake; reduces functional activity of glutamatergic system||Elevated glutamate and aspartate|
|Alters choline acetyltransferase, leading to acetylcholine deficiency; inhibits acetylcholine neurotransmitter release via impact on calcium homeostasis; causes cortical acetylcholine deficiency; increases muscarinic receptor density in hippocampus and cerebellum||Abnormalities in cholinergic neurotransmitter system: cortical acetylcholine deficiency and reduced muscarinic receptor binding in hippocampus|
|Causes demyelating neuropathy||Demyelation in brain|
e. EEG Activity/Epilepsy
Abnormal EEGs are common in mercury poisoning as well as autism. In one study, half the autistic children expressed abnormal EEG activity during sleep (reviewed in LeWine, 1999). Gillberg and Coleman (1992) estimate that 35%-45% of autistics eventually develop epilepsy. A recent study by LeWine and colleagues (1999) using MEG found epileptiform activity in 82% of 50 regressive-autistic children. EEG abnormalities in autistic populations tend to be non-specific and consist of a variety of epileptiform discharge patterns (Nass, Gross, and Devinsky, 1998).
Unusual epileptiform activity has been found in a variety of mercury poisoning cases (Brenner & Snyder, 1980). These include (i) the Minamata outbreak - generalized convulsions and abnormal EEGs (Snyder, 1972); (ii) methylmercury ingestion through contaminated pork - all four affected children had epileptiform features and disturbances of background rhythms; two had seizures (Brenner & Snyder, 1980); (iii) mercury vapor poisoning - abnormal EEG in a 12 year old girl (Fagala and Wigg, 1992) and slower and attenuated EEGs in chloralkali workers with long term exposure (Piikivi & Tolonen, 1989); and (iv) exposure from thimerosal in ear drops and through IVIG - EEG with generalized slowing in an 18 month old girl with otitis media (Rohyans et al, 1984) and a 44 year old man (Lowell et al, 1996). More recently, Szasz and colleagues (1999), in a study of early Hg-exposure, described methylmercury's ability to enhance tendencies toward epileptiform activity and reported a reduced level of seizure-discharge amplitude, a finding which is at least consistent with the subtlety of seizures in many autism spectrum children (LeWine, 1999; Nass, Gross, and Devinsky, 1998).
Processes whereby neuronal damage is induced by epileptiform discharges are elucidated in a number of studies, many of which focus upon brain regions affected in autism. Importantly, neuronal damage in the amygdala can be an "ongoing delayed process," even after the cessation of seizures (Tuunanen et al, 1996, 1997, 1999). Alterations of cerebral metabolic function last long after seizures have occurred. In a model of seizure-induced hippocampal sclerosis, Astrid Nehlig's group describes hypometabolism having its regional boundaries "directly connected" to seizure-damaged locus (Bouilleret et al, 2000). That Hg increases extracellular glutamate would also contribute to epileptiform activity (Scheyer, 1998; Chapman et al, 1996).
These findings support a rationale:
In susceptible individuals, mercury can potentiate or induce Hg-related epileptiform activity, which can have lower amplitude and be harder to identify. Furthermore, this low-level but persisting epileptiform activity would gradually induce cell death in the seizure foci and in brain nuclei neuroanatomically related to the seizure foci.
These studies have a more direct relevance to the possibility of Hg-induced cases of autism (i) because the amygdala are implicated in regard to core traits in autism, as described above, and (ii) because mercury finds its way into the amygdala (see above). Furthermore, these theoretical relationships are consistent with SPECT imaging studies by Mena, Goldberg, and Miller, who have demonstrated areas of regional hypoperfusion neuroanatomically associated with trait deficits in autism-spectrum children (Goldberg et al, 1999).
in Mercury Poisoning & Autism
|Causes abnormal EEGs and unusual epileptiform activity||Abnormal EEG activity; epileptiform activity|
|Causes seizures, convulsions||Seizures; epilepsy|
|Causes subtle, low amplitude seizure activity||Subtle, low amplitude seizure activities|
III. Mechanisms, Sources & Epidemiology of Exposure
a. Exposure Mechanism
Vaccine injections are a known source of mercury (Plotkin and Orenstein, 1999), and the typical amount of mercury given to infants and toddlers in this manner exceeds government safety limits, according to Neal Halsey of the American Academy of Pediatrics (1999) and William Egan of the Biologics Division of the FDA (1999).
Most vaccines given to children 2 years and under are stored in a solution containing thimerosal, which is 49.6% mercury by weight. Once inside humans, thimerosal (sodium ethylmercurrithio-salicylate) is metabolized to ethylmercury and thiosalicylate (Gosselin et al, 1984). The vaccines mixed with this solution are DTaP, HIB, and Hepatitis B (Egan, 1999). Thimerosal is not an integral component of vaccines, but is a preservative added to prevent bacterial contamination. Many vaccine products are available without the thimerosal preservative; however, these alternatives have not been widely used (Egan, 1999). In addition, thimerosal is used during the manufacturing process for a number of vaccines, from which trace amounts are still present in the final injected product (FDA, personal communication; Smith-Kline press release on Hepatitis B, March 31, 2000).
Since at least 1977 clinicians have recognized thimerosal as being potentially dangerous, especially in situations of long term exposure (Haeney et al, 1979; Rohyans et al, 1984; Fagan et al, 1977; Matheson et al, 1980). For nearly twenty years the US government has also singled out thimerosal as a potential toxin (FDA, 1982). In response to the Food and Drug Administration (FDA) Modernization Act of 1997, which called for the FDA to review and assess the risk of all mercury containing food and drugs (MMWR, 1999, July 9), the FDA issued a final rule in 1998 stating that over-the-counter drug products containing thimerosal and other mercury forms "are not generally recognized as safe and effective" (FDA, 1998). In December 1998 and April 1999, the FDA requested US vaccine manufacturers to provide more information about the thimerosal content in vaccines (MMWR, 1999, July 9); and in July 1999, the CDC asked manufacturers to start removing thimerosal from vaccines and rescheduled the Hepatitus B vaccine so it is given at 9 months of age instead of at birth (CDC, July 1999). In November 1999, the CDC repeated its recommendation that vaccine manufacturers move to thimerosal-free products (CDC, November 1999).
Importantly, based on the CDC's own recommended childhood immunization schedule (and excluding any trace amounts), the amount of mercury a typically vaccinated two year old child born in the 1990s would receive is 237.5 micrograms; and a typical six month old might receive 187.5 micrograms (Egan, 1999). These amounts equate to 3.53 x 1017 molecules and 2.79 x 1017 molecules of mercury respectively (353,000,000,000,000,000 and 279,000,000,000,000,000 molecules). Since thimerosal is injected during vaccinations, the mercury is given intermittently in large, or 'bolus', doses: at birth and at 2, 4, 6, and approximately 15 months (Egan, 1999). The amount of mercury injected at birth is 12.5 micrograms, followed by 62.5 micrograms at 2 months, 50 micrograms at 4 months, another 62.5 micrograms during the infant's 6-month immunizations, and a final 50 micrograms at about 15 months (Halsey, 1999).
Although infancy is recognized as a time of rapid neurological development, to the best of our belief and knowledge, there are no published studies on the effect of injected ethylmercury in intermittent bolus doses in infants from birth to six months or to 2 years (Hepatitis Control Report, 1999; Pediatrics, 1999; EPA, 1997, p.6-56). In contrast, four government agencies have set safety thresholds for daily mercury exposure based on ingested fish or whale meat containing methylmercury. Two of these guidelines are based on adult values and two are for pregnant women/fetuses (Egan, 1999). Applying these guidelines to a bolus dose scenario (see Halsey, 1999 for bolus vs. daily dose discussion), the sum of Hg-doses given at 6 months of age or younger, correlated to infant weights, exceed all of the Hg-total guidelines for all infants. The 2 month dose is especially high relative to the typical infant body weight. Halsey (1999) has calculated the 2 month dose to be over 30 times the recommended daily maximum exposure, with babies of the smallest weight category receiving almost three months worth of daily exposures on a single day.
Halsey's observation is all the more important because even at doses which were not previously thought to be associated with adverse affects, mercury has resulted in some damage to humans (Grandjean et al, 1998). Given that ethylmercury is equally neurotoxic as methylmercury (Magos et al, 1985), and that injected mercury is more harmful than ingested mercury (EPA, 1997, p.3-55; Diner and Brenner, 1998), the amount of injected ethylmercury given to young children is cause for concern. The potential for Hg-induced harm is compounded by the special vulnerability of infants (Gosselin et al, 1984). Mercury, which primarily affects the central nervous system, is most toxic to the developing brain (Davis et al, 1994; Grandjean et al, 1999; Yeates and Mortensen, 1994), and neonates exposed to methyl (organic) mercury have been shown to accumulate significantly more Hg in the brain relative to other tissues than do adults ( EPA, 1997, p.4-1). Mercury may also be more likely to enter the infant brain because the blood-brain barrier has not fully closed (Wild & Benzel, 1994). In addition, infants under 6 months are unable to excrete mercury, most likely due to their inability to produce bile, the main excretion route for organic mercury (Koos and Longo, 1976; Clarkson, 1993). Bakir et al (1973) have shown that those with the longest half-time of clearance are most likely to experience adverse sequelae, while Aschner and Aschner (1990) have demonstrated that the longer that organic mercury remains in neurons, the more it is converted to its inorganic irreversibly-bound form, which has greater neurotoxicity.
b. Population Susceptibility
Nearly all children in the United States are immunized, yet only a small proportion of children develop autism. The NIH (Bristol et al, 1996) estimates the current prevalence of autism to be 1 in 500. A pertinent characteristic of mercury is the great variability in its effects by individual. At the same exposure level of mercury, some will be affected severely, while others will be asymptomatic or only mildly impaired (Dale, 1972; Warkany and Hubbard, 1953; Clarkson, 1997). A ten-fold difference in sensitivity to the same exposure level has been reported (Koos and Longo, 1976; Davis et al, 1994; Pierce et al, 1972; Amin-Zaki, 1979). An example of variability in children is the mercury-induced disease called acrodynia. In the earlier half of this century, from one in 500 to one in 1000 children exposed to the same chronic, low-dose of mercury in teething powders developed this disorder (Matheson et al, 1980; Clarkson, 1997), and the likelihood of developing the disease "appears to be dominated more by individual susceptibility and possibly age rather than the dose of the mercury" (Clarkson, 1992). Given the documented inter-individual variability of responses to Hg, and the young age at which exposure occurs, the doses of mercury given concurrently with vaccines are such that only a certain percentage of children will develop overt symptoms, even as other children might have trait irregularities sufficiently mild as to remain unrecognized as having been induced by mercury.
c. Sex Ratio
Autism is more prevalent among boys than girls, with the ratio generally recognized as approximately 4:1 (Gillberg & Coleman, 1992, p.90). Mercury studies have consistently shown a greater effect on males than females, except in instances of kidney damage (EPA, 1997). At the highest doses, both sexes are affected equally, but at lower doses only males are affected. This is true of mice as well as humans (Sager et al, 1984; Rossi et al, 1997; Clarkson, 1992; Grandjean et al, 1998; McKeown-Eyssen et al, 1983; see also review in EPA, 1997, p.6-50).
d. Exposure Levels & Autism Prevalence
Perhaps not coincidentally, autism's initial description and subsequent epidemiological increase mirror the introduction and use of thimerosal as a vaccine preservative. In the late 1930s, Leo Kanner, an experienced child psychologist and the "discoverer" of autism, first began to notice the type of child he would later label "autistic." In his initial paper, published in 1943, he remarked that this type of child had never been described previously: "Since 1938, there have come to our attention a number of children whose condition differs so markedly and uniquely from anything reported so far, that each case merits.a detailed consideration of its fascinating peculiarities." All these patients were born in the 1930s. Thimerosal was introduced as a component of vaccine solutions in the 1930s (Egan, 1999).
Not only does the effect of mercury vary by individual, as noted above, it also varies in a dose-dependent manner, so that the higher the exposure level, the more individuals that are affected. At higher dose levels, the most sensitive individuals will be more severely impaired, and the less sensitive individuals will be only moderately impaired, and the majority of individuals may still show no overt symptoms (Nielson and Hultman, 1999). The vaccination rate, and hence the rate of mercury exposure via thimerosal, has steadily increased since the 1930s. In 1999 it was the highest ever, at close to 90% or above, depending on the vaccine (CDC, 1999, press release). The rate of autism has increased dramatically since its discovery by Kanner: prior to 1970, studies showed an average prevalence of 1 in 2000; for studies after 1970, the average rate had doubled to 1 in 1000 (Gillberg and Wing, 1999). In 1996, the NIH estimated occurrence to be 1 in 500 (Bristol et al, 1996). A large increase in prevalence, yet to be confirmed by stricter epidemiological analysis, appears to be occurring since the mid-1990s, as evidenced by several state departments of education statistics reflecting substantial rises in enrolment of ASD children (California, Florida, Maryland, Illinois, summarized by Yazbak, 1999). These increases have paralleled the increased mercury intake induced by mandatory innoculations: in 1991, two vaccines, HIB and Hepatitis B, both of which generally include thimerosal as a preservative, were added to the recommended vaccine schedule (Egan, 1999).
e. Genetic Factors
ASD is one of the most heritable of developmental and psychiatric disorders (Bailey et al, 1996). There is 90% concordance in monozygotic twins and a 3-5% risk of autism in siblings of affected probands (Rogers et al, 1999), a rate 50 to 100 times higher than would be expected in the general population (Smalley & Collins, 1996; Rutter, 1996). From 2 to 10 genes are believed to be involved (Bailey et al, 1996).
Individual differences in susceptibility to mercury are said to arise from genetic factors and these too may be multiple in nature (Pierce et al, 1972; Amin-Zaki, 1979). They include innate differences in (i) the ability to detoxify heavy metals, (ii) the ability to maintain balanced gut microflora, which can impair detoxification processes, and (iii) immune over-reactivity to mercury (Nielson and Hultman, 1999; Hultman and Nielson, 199; Johansson et al, 1998; Clarkson, 1992; EPA, review 1997, p.3-26). Many autistic children are described as having (i) difficulties with detoxification of heavy metals (Edelson & Cantor, 1998), possibly due to low glutathione levels (O'Reilly and Waring, 1993), (ii) intestinal microflora imbalances that can impede excretion (Shattock, 1997), and (iii) autoimmune dysfunction (Zimmerman et al, 1993). These characteristics might be reflective of the underlying "susceptibility genes" that predispose to mercury-induced sequelae and hence to autism.
As noted above, autism family studies show an exceptionally high concordance rate of 90% for identical twins. Most environmental factors, such as a postnatal viral infection, tend not to be present at exactly the same time or at the same level or rate for each twin. This would cause a difference in phenotype expression, and thus postnatal environmental influences in general reduce the concordance rate for identical twins. However, given the extremely high vaccination rate and the high likelihood of vaccination of one twin at the same time and with the same vaccines as the other twin, mercury-induced autism via vaccination injection, even though it is an environmental factor, would still lead to the high concordance rate seen in twins.
Furthermore, among identical twin pairs, the 90% concordance rate is for the milder phenotype: if one twin has pure classic autism, there is (i) a 60% chance that the other twin will have pure classic autism; (ii) a 30% chance that the other twin will exhibit some type of impairment falling on the autism spectrum, but with less severe symptoms; and (iii) a 10% chance the other twin will be unimpaired. The difference in symptom severity among the 40% of monozygotic pairs who do not exhibit classic autism may arise from either (i) a different vaccination history within pairs, or (ii) the tendency of thimerosal to "clump" or be unevenly distributed in solution, so that one twin might receive more or less mercury than the other. One study found a 62% difference in the mercury concentration of ampoules drawn from the same container of immunoglabulin batches containing thimerosal (Roberts and Roberts, 1979).
f. Course of Disease
Age of onset: Autism emerges during the same time period as infant and toddler thimerosal injections during vaccinations. As noted above, the recommended childhood vaccination schedule from 1991 to 1999 has called for injections of thimerosal starting at birth and continuing at 2, 4, 6, and approximately 15 months (Halsey, 1999); a similar schedule occurred prior to this time but for DTP alone. In the great majority of cases, the more noticeable symptoms of autism emerge between 6 and 20 months old - and mostly between 12 and 18 months (Gillberg & Coleman, 1992). Teitelbaum et al (1998), who have claimed the ability to detect subtle abnormalities at the youngest age so far, have observed these abnormalities at 4 months old at the earliest, the exception being a "Moebius mouth" seen at birth in a small number of subjects.
Symptoms of mercury poisoning do not usually appear immediately upon exposure, although in especially sensitive individuals or in cases of excessive exposure they can (Warkany and Hubbard, 1953; Amin-Zaki, 1978). Rather, there is generally a preclinical "silent stage," seen in both animals and humans, during which subtle neurological changes are occurring (Mattsson et al, 1981). The delayed reaction between exposure and overt signs can last from weeks to months to years (Adams et al, 1983; Clarkson, 1992; Fagala & Wigg, 1992; Davis et al, 1994; Kark et al, 1971). Consequently, mercury given in vaccines before age 6 months would not in most individuals lead to an observable or recognizable disorder, except for subtle signs, prior to age 6-12 months, and for some individuals, symptoms induced by early vaccinal Hg might not emerge until the infant had become a toddler (Joselow et al, 1972).
A few autism researchers have suggested a prenatal onset for autism (Rodier et al, 1997; Bauman & Kemper, 1994), which would preclude a vaccinal-mercury etiology. Others, however, have evidence that suggest post-natal timings (Bailey, 1998; Courchesne, 1999; Bristol Power, NICHD, Dateline Interview, 1999). The general consensus at this point is that the timing cannot be determined (Bailey et al, 1996; Bristol et al, 1996); and, further, that there is "little evidence" that prenatal or perinatal events "predict to later autism" (Bristol et al, 1996), even though clustering of adverse effects (suboptimality factors) are associated with autism (Prechtel, 1968; Bryson et al, 1988; Finegan and Quarrington, 1979). There is also a general agreement that, in the great majority of cases, autistic signs emerge among infants and toddlers who had looked "normal", developed normally, met major milestones, and had unremarkable pediatric evaluations (Gillberg & Coleman, 1992; Filipek et al, 1999; Bailey et al, 1996), so that autism presents as an obvious deterioration or regression, either before age two or before age three (Baranek, 1999; Bristol Power, NICHD, Dateline Interview, 1999; LeWine, 1999).
It is worthwhile to note that early and intensive educational and behavioral intervention can produce dramatic gains in function, and the gains made by these children "may be somewhat unique among the more severe developmental disabilities" (Rogers, 1996). This phenomenon further suggests that autism arises from an environmental overlay rather than being purely an organic disease. Additionally, at least one study has reported that "re-education and physical treatment" can improve outcomes in mercurialism (Amin-zaki, 1978).
Emergence of symptoms: The manner in which symptoms emerge in many cases of autism is consistent with a multiple low-dose vaccinal exposure model of mercury poisoning. From a parent's and pediatrician's perspective, such an individual is a "normal" looking child who regresses or fails to develop after thimerosal administration. Clinically relevant symptoms generally emerge gradually over many months, although there have been scattered parental reports of sudden onset (Filipek, et al, 1999). The initial signs, occurring shortly after the first injections, are subtle, suggesting disease emergence, and consist of abnormalities in motor behavior and in sensory systems, particularly touch sensitivity, vision, and numbness in the mouth (excessive mouthing of objects) (Teitelbaum et al, 1998; Baranek, 1999). These signs persist and are followed by parental reports of speech and hearing abnormalities appearing before the child's second birthday (Prizant, 1996; Gillberg & Coleman, 1992), that is, within several months of when additional and final injections are given. Finally, in year two, there is a full blossoming of ASD traits and a continuing regression or lack of development, so that the most severe expression of symptoms occurs at approximately 3-5 years of age. These symptoms then begin to ameliorate (Church & Coplan, 1995; Wing & Attwood, 1987; Paul, 1987). The exceptions are the subset of those with regression during adolescence or early adulthood, which may involve onset of seizures and associated neurodegeneration (Howlin, 2000; Paul, 1987; Tuunanen et al, 1996, 1997, 1999).
As in autism, onset of Hg toxicity symptoms is gradual in some cases, sudden in others (Amin-Zaki et al, 1979 & 1978; Joselow et al, 1972; Warkany and Hubbard, 1953). In the case of organic poisoning, the first signs to emerge are abnormal sensation and motor disturbances; as exposure levels increase, these signs are followed by speech and articulation problems and then hearing deficits (Clarkson, 1992), just like autism. Once the mercury source is removed symptoms tend to ameliorate (though not necessarily disappear) except in instances of severe poisoning, which may lead to a progressive course or death (Amin-Zaki et al, 1978). As in autism, epilepsy in Hg exposure also predicts a poorer outcome (Brenner & Snyder, 1980).
Long term prognosis: The long term outcomes of ASD and mercury poisoning show the same wide variation. Autism is viewed as a lifelong condition for most; historically, three-fourths of autistic individuals become either institutionalized as adults or are unable to live independently (Paul, 1987). There are, however, many instances of partial to full recovery, in which autistic traits persist in a much milder form or, in some individuals, disappear altogether once adulthood is reached (Rogers, 1996; Church & Coplan, 1994; Szatmari et al, 1989; Rimland 1994; Wing & Attwood, 1987).
Upon exposure, mercury entering the bloodstream tends to accumulate in tissues and organs, primarily the brain (Koos and Long, 1976; Lorscheider et al, 1995). Once inside tissues, and particularly the brain, mercury will linger for years, as shown on X rays of a poisoned man 22 years after exposure (Gosselin et al, 1984), as well as autopsies of humans with known mercury exposure (Pedersen et al, 1999; Joselow et al, 1972) and primate studies (Vahter et al, 1994). The continued presence of mercury in organs and the CNS in particualr would explain why autistic symptoms might persist, why researchers such as Zimmerman or Singh would detect an on-going immune reaction, why epilepsy might not emerge until adolescence, or why sulfate transporters in the intestine or kidney might continue to be blocked.
Nevertheless, despite the continued presence of Hg in tissue, the degree of recovery from mercurialism varies greatly. Even in severe cases, there are reports of full or partial recovery (e.g., Adams et al, 1983; Vroom & Greer, 1972; Amin-Zaki et al, 1978). In less severe cases, especially those in which exposure occurs early in life, the more severe symptoms may ameliorate over time, but milder impairments remain, especially neurological ones (Feldman, 1982; Yeates & Mortensen, 1994; Amin-Zaki, 1974 & 1978; Mathiesin et al, 1999; Vroom and Greer, 1972; EPA 1997, pp.3-10, 3-14, and 3-75). The wide variation in outcome is believed to be due, again, to individual sensitivity to mercury, in this case, the ability of some victims to develop "immunity" or a "tolerance" to Hg even when the metal is still present in tissue (Warkany & Hubbard, 1953).
Typical Autism & Ingested Organic Mercury
Typical Autism Progression & Thimerosal Administration
|Birth||2 mos||4 mos||6 mos||15 mos||2 yrs||3-5 yrs||6-18 yrs||Adults|
|Hg dose||Hg dose||Hg dose||Hg dose||Hg dose|
|Delay (no signs)||Delay (no signs)||subtle signs - movement||subtle signs - sensory||definite signs- hearing & speech||full array of symptoms||Height of symptom severity||Symptom amelioration||Occasional full or partial recovery|
|Hg dose||Delay (no signs)||1st sign - sensory||2nd sign - movement||3rd sign - speech/ articulation||4th sign - hearing||full array of symptoms||Symptom amelioration (or death)||full or partial recovery|
g. Thimerosal Interaction with Vaccines
As noted above, for most ASD children symptom onset is gradual, but for a significant minority it is sudden. Additionally, many parents believe there is a connection between their child's autism and his or her immunizations. The Cure Autism Now Foundation, for example, reports that many parents who contact it mention such a connection (Portia Iversen, CAN president, personal communication). The association extends not only to the mercury-containing vaccines - DTP/DTaP, HIB, and Hepatitis B - but also to those without thimerosal, particularly the MMR (Bernard Rimland, president, Autism Research Institute, personal communication). Parents may describe a variety of post-vaccine scenarios: a fever followed by a short recovery period and then a more gradual symptom onset; onset of symptoms immediately and suddenly after inoculation with or without fever; or even a mildly impaired child whose condition worsened after vaccination (CAN Parent Advisory Board Internet list; St. John's Autism Internet list).
While it is possible that any temporal association between vaccination and emergence of autism is due to chance, Warkany and Hubbard, who successfully proved the connection between acrodynia and mercury poisoning to the medical community 50 years ago, offer alternate explanations. In their 1953 article in Pediatrics, they made the following points:
- They noted that high fever accompanied by a rash after mercury
administration can be signs of a "typical, acute, mercurial reaction," and
"acrodynia may follow, immediately or after short intervals, acute
idiosyncratic reactions to mercury." This reaction was independent of
hypersensitivity to mercury, as detected from skin tests, as they reported
that only 10% of acrodynia victims responded positively to Hg on patch tests.
Thus in ASD, the fevers and deteriorations seen by parents immediately after a thimerosal-containing vaccine injection may be a systemic reaction (and not a hypersensitivity response) to the mercury content, and this reaction may subsequently progress to the emergence of autism, just as topical mercury administration produced fever and then acrodynia over 50 years ago.
Warkany and Hubbard provided some tentative observations that the administration of a vaccine, irrespective of whether or not it contains thimerosal, can set off a reaction to any mercuric compound that may also be given to a child, which in the case of acrodynia, would be topical mercury in powders or rinses. This inter-reactivity might explain the pronounced effects from the MMR among subsequently-diagnosed autistic children:
"[One patient] underwent a fourteen day course of antirabies injections six weeks before outbreak of acrodynia. Ten days after completion of the therapy she was treated with ammoniated mercury ointment and subsequently acrodynia developed...[In another case] antirabies treatment preceded the disease by three months. In several children various immunization procedures preceded the onset of acrodynia in addition to [topical] mercurial exposure. This could be purely coincidental or the vaccination material may play a role as an accessory factor. It is noteworthy that many vaccines and sera contain small amounts of mercury as preservatives which are injected together with the biologic material. These small amounts of mercurial compounds could act as sensitizing substances. In several instances vaccination against smallpox preceded the development of acrodynic symptoms, and some patients were exposed to bismuth, arsenic, lead, and antimony in addition to mercury. Such observations deserve attention."
Finally, these two researchers observed that some individuals would react to mercury and then, upon re-exposure, not show any effects, i.e., they had acquired an unexplained tolerance to it. In other cases, Hg sensitivity would be maintained. Rarely, though, would reactivity occur with the first dose: "more often the patient tolerates several" before the reaction occurs.
"The organism can harbor appreciable amounts of mercury while remaining in perfect health, and then, for unknown reasons, these innocuous stores of mercury become toxic. It seems in such cases as if the barriers which held the mercury in check break down without provocation, or as if the mercury had been converted from a nontoxic to a toxic form..."
In ASD, this delayed sensitivity would explain why some might develop autism later, not after the first few vaccines, and it would also explain in part why the more vaccines that are given, the more likely it is that a given individual will develop a reaction since there are more "sensitizing" opportunities. Importantly, in susceptible individuals, the reactions described by Warkany and Hubbard are likely to occur if mercury's presence occurred via injected thimerosal.
IV. Detection of Mercury in Autistic Children
In the past, hair, urine, or blood tests from autistic subjects have mostly found lead rather than mercury (Wecker et al, 1985), but this is likely due (i) to lead's pervasiveness in our environment, coupled with autistic children's pica tendencies and general inability to detoxify any heavy metal (LaCamera and LaCamera, 1987; Edelson & Cantor, 1998); (ii) to the difficulty in detecting Hg, especially in older children exposed early in life, since remaining mercury is sequestered in tissue; and (iii) to the greater affinity of standard chelators used in challenge tests (e.g., DMSA) for lead over mercury, making lead more readily detectable in such exams (Frackelton and Christenson, 1998).
More recently, a number of parents of younger autistic children, in whom mercury is more likely to be detectable, have reported higher than expected levels of mercury in hair, blood, and urine samples. Cases studies are listed below, and more are in the process of documentation. Several parents have also noted improved function after chelation.
The Case Studies
We are providing data from several retrospective case studies of autistic children with associated tissue mercury burdens. In each case we have tried to identify potential sources of exposure, although we have not been able to identify the exact amounts in some cases due to inadequate documentation. This information does not purport to be a rigid scientific study, but rather an initial effort to demonstrate that there may be a problem with mercury toxicity in children with autism. Our primary objective is to show that considerable amounts of mercury are found in the bodies of some autistic children. The data we present were derived from many sources: hair, urine and blood. Some of the samples were baseline and others were obtained utilizing a provocative agent, either DMPS or DMSA. Typically a single dose of DMPS will provoke more mercury from the tissue than a single oral dose of DMSA. Excretion levels will also vary depending on the amount of DMPS or DMSA given. There are also variations among these factors in the case studies.
In addition to the above case studies, we have collected preliminary data on three autistic children who have not undergone chelation. These children also exhibit elevated levels of mercury.
|Age||Sex||Mercury level and source of sample|
|2 r yrs.||Female||Heavy metal hair analysis 5.6ppm (ref.range 0-2)|
|4 r yrs.||Male||Hair analysis 1.2ug/g (ref. <0.4) PRBC 18.4 (ref <9)|
|5 yrs.||Male||Hair analysis 1.8 ppm PRBC 18.3 (ref.<9)|
Several observations from these case studies deserve mention. One is that all of the children experienced a regressive form of autism. Other findings are that (i) low levels of mercury in hair may be associated with large amounts of mercury excretion on provocation and (ii) initial levels of provoked mercury may not be as high as subsequent ones. Mercury in the hair will only reflect a current or recent exposure of approximately one year or the body's active detoxification of mercury. This was evident in a child with non-detectable levels of mercury in the hair and positive levels on provocation.
In the case studies there is also a trend of higher numbers for mercury in younger children (20 month hair sample of 4.8 ppm and 2 r year hair sample of 5.6 ppm). This may be related to the fact that the testing was performed closer to the time of exposure. Hair levels of mercury greater than 5.0 ppm are considered diagnostic for mercury poisoning (Applied Toxicology, 1992). Among the majority of these case studies much moremodest elevations of mercury, if detected at all, were associated with high levels of provoked mercury.
There are no standards for provoked levels of mercury in children in the context of behavioral disorders. Therefore, we surveyed a large number of physicians treating adults with chronic health problems diagnosed as secondary to mercury. These clinicians advise that tolerable limits may vary according to the general health of the patient and associated health problems. All consulted agreed that in adults excretion of 50 mcg of mercury per gm creatine after intravenous DMPS challenge is worrisome. We submit that the concern level for children should be even more stringent. High levels of mercury are demonstrated in some children without a history of fish consumption, amalgam burden, or known environmental exposure, suggesting the role of vaccines as a contribution to body burden.
The families who submitted these case histories wanted to tell their stories because their children are noticeably improved after treatment for mercury. Whether this improvement was sudden or gradual, the parents are convinced that lessening the mercury and heavy metal burden has helped their child. They ask us to request support for much needed research in this area.
How reasonable is it to claim that the most common form of autism, where there is normal development and then regression, could be caused by mercury poisoning? There are several reasons to believe that this process has indeed occurred.
Diagnostic Criteria Are Met
Medical literature demonstrates that mercury can induce autism-spectrum traits, and this association extends to mercury's localization within specific brain nuclei. In attempting to address "the totality of the syndrome" (Bailey et al, 1996), we have shown that every major characteristic of autism has been exhibited in at least several cases of documented mercury poisoning, and that every major area of biological and neurological impairment implicated in ASD has been observed with Hg exposure. Recently, government-directed studies have revealed that the amount of mercury given to infants receiving vaccinations exceeds safety levels. The timing of mercury administration via vaccines coincides with the onset of autistic symptoms. Case reports of autistic children with measurable mercury levels in hair, blood, and urine indicate a history of mercury exposure along with inadequate detoxification. Thus the standard criteria for a diagnosis of mercury poisoning in autism, as outlined at the beginning of this paper, are met. In other words, mercury toxicity is a significant contributing factor or primary etiological factor in many or most cases of autism.
Unique Form Would be Expected, Implicates Vaccinal Thimerosal
Symptoms manifested in mercury poisoning are diverse and vary by the interaction of variables such as type of mercury, age of patient, method of exposure, and so forth. Thus, although it could be argued that in all the thousands of cases of past Hg poisonings, no instance of autism could be found, such an argument fails to take into account the possibility of unique expression. It would be comparable to saying that, because in all the cases of Minamata disease no instance of acrodynia could be found, then acrodynia could not be caused by mercury poisoning. Since there are no case reports or systematic studies in the literature of the effects of intermittent bolus doses of injected ethylmercury on "susceptible" infants and toddlers, it would be reasonable to expect that symptoms arising from this form of mercury poisoning would present as a novel disease. In fact, given the high neurotoxicity of organic mercury, its known psychological effects, and the age at which it has been given in vaccines, it would almost be a given that the "novel disease" would present as a neurodevelopmental disorder like autism.
Conversely, the fact that autism meets the diagnostic criteria for mercury poisoning, yet has never been described as a mercury-induced disease, requires that the disorder must arise from a mode of mercury administration which has not been studied before. This would rule out other known sources of Hg like fish consumption or occupational mercury hazards, as these have been well characterized. It is possible that another under-investigated mercury route, such as maternal Hg exposures (e.g., from vaccinations, thimerosal-containing RhoGam injections during pregnancy, or dental fillings) or infant exposures to thimerosal-containing eardrops or eyedrops, might be a factor, and this cannot be ruled out.
Historical Precedent Exists
There is a precedent for large scale, undetected mercury poisoning of infants and toddlers in the syndrome that came to be known as acrodynia or pink disease. For over 50 years, tens of thousands of children suffered the bewildering, debilitating, and often life-long effects of this disease before its mercury etiology was established, as Ann Dally relates in The Rise and Fall of Pink Disease (1997, excerpts):
"Acrodynia is a serious disease that was common, at least in children's clinics, during the first half of the present (20th) century. Reports abound of children too miserable to acknowledge their mothers, such as the child who kept repeating, "I am so sad." One unhappy mother was quoted as saying, "My child behaves like a mad dog." In most cases the condition improved spontaneously, but was often regarded as chronic. Mortality varied from 5.5% to 33.3% and was usually about 7%. Most physicians who speculated on the causes of pink disease believed in either the infective or the nutritional theory. No one seems to have suggested that it might be due to poisoning. It was a tradition to advise student doctors to treat cases of difficult teething with the mercury powders that were eventually to be revealed as the cause of the disease. The ill-effects of mercury on the mouth had been known at least since the time of Paraclesus, but it was not until 1922 that the pediatrician, John Zahorsky, commented on the similarity between pink disease and mercury poisoning. He dismissed rather than pursued his new idea of possible mercury poisoning and suggested a theory that was more in tune with current fashion. Most doctors, even those skilled in the use of calomel, associated mercury poisoning with adults (syphilis, industrial poisoning, hatters shakes) rather than with infants. By 1935 the disease was seen in every children's out-patient clinic.
The mystery began to be solved in 1945 by Dr. Josef Warkany, of the Cincinnati Children's Hospital. He and his assistant found large amounts of mercury in the urine of a child with pink disease. They did not publish their findings until 1948, but it is noteworthy that the news seems not to have spread through the small and tightly knit pediatric world, where everyone knew everyone else. It was probably because the idea was unfashionable and contrary to the conventional wisdom. The theory that mercury poisoning caused pink disease was gradually accepted, but against resistance, particularly by older men and those in powerful positions. Mercury was withdrawn from most teething powders after 1954, initially through voluntary action by the manufacturers because of adverse publicity and probably in the hope of avoiding statutory prohibition. Pink disease almost disappeared. Later in the decade the theory was widely accepted and soon pink disease was no longer part of the usual pediatric out-patient clinic."
Barriers Preventing Earlier Discovery Are Removed
The priorities and methods of research experts in the autism and mercury fields have prevented the association between mercurialism and ASD to be recognized until recently.
The effects on humans of mercury-containing medicinals and home remedies used to be studied quite regularly by medical researchers (Warkany and Hubbard, 1953); but since, aside from vaccinal thimerosal, such products have declined dramatically in number since the 1950s and 1960s, most mercury researchers today focus on biochemical studies or environmental sources like fish and coal plants. Some mercury experts seem surprised to learn that Hg is present in infant vaccines (authors' personal experience), and as recently as 1997, when the EPA released its massive review of extant mercury research, vaccines were not even mentioned as a potential source. Thus it is not surprising that mercury experts have never investigated thimerosal as they have, say, contaminated whale meat consumption in the Faroes Islands or Hg exposure among Amazonian goldminers.
Likewise, it is not surprising that neither mercury experts nor autism professionals have ever investigated autism as a possible disease of mercury exposure. Since its discovery by Kanner, autism has been characterized in almost exclusively psychological terms. The descriptions have been such that the symptoms would be essentially unrecognizable as manifestations of poisoning to any mercury expert not looking closely. A perfect example is Kanner himself, who recorded feeding problems and vomiting in infants and concluded: "Our patients, anxious to keep the outside world away, indicated this by the refusal of food." Bruno Bettleheim, who dominated autism discourse in the 1950s and 1960s and blamed the entire disorder on "refrigerator mothers" who forced the withdrawal of the child, asserted, "the source of the anxiety is not an organic impairment but the child's evaluation of his life as being utterly destructive" (1967, reported in ARI Newsletter). In 1987, Robert Sternberg would propose a "unified theoretical perspective on autism" by defining the disorder in terms of a "triarchic theory of intelligence," and in the same publication Lorna Wing and Anthony Attwood would write:
"Sometimes young autistic children will stand in a dejected posture, with tears streaming down their faces, as if they suddenly felt their helplessness in the face of a world they cannot understand."
Even as recently as 1995, a typical slate of articles in the dominant Journal of Autism and Developmental Disorders (April 1995) would consist of eight psychological pieces (example: "Generativity in the Play of Young People with Autism") and one biomedical one (on biopterin). Thus biomedical research in autism existed, but it was mostly relegated to the margins as psychology held center stage, and the symptomatic characteristics of autism continued to be presented in accord with psychological biases.
In the latter part of the 1990s, the situation on both sides changed. Congressional mandate led to the public quantification of the cumulative amount of mercury in vaccines, raising interest in understanding its effects. Parent organizations like CAN and NAAR, working with the NIH and other researchers, engineered an autism research agenda which is more heavily focused on underlying physiological mechanisms of the disease. With parents already suspecting a vaccine-autism link, the environment was right for investigations focused on the link between vaccinal mercury and autism.
Medical & Societal Implication
The NIH (1999, web site) estimates that there are nearly half a million Americans who suffer from autism, a devastating, debilitating, and lifelong disorder. Given the role of thimerosal as a major contributing factor in ASD, basic and clinical research efforts should be focused on understanding how mercury leads to autism in susceptible individuals and on finding effective methods to address the resulting Hg damage. Such research might focus on the following areas, with others undoubtedly still to be identified:
- Chelation methods which will work across all body tissues and especially the brain. The current standard chelators - DMPS and DMSA - appear unable to cross the blood-brain barrier. Other promising but less studied chelators like alpha lipoic acid can cross the bbb (Fuchs et al, 1997) and should be studied in autism.
- Mechanisms to induce immunity to Hg and which might possibly reverse the Th2 shift or IFNg expression which mercury causes. The work of Hu and colleagues suggests that Hg can cause an immune reaction in any individual, but some are protected by a counteractive immunosuppressive response, and Warkany and Hubbard have pointed out that individuals who are Hg-sensitive can later become "immune". It may be possible to engineer these responses in autistic individuals through careful research.
- Mechanisms which might reverse Na-Si transporter blockage in the intestines and kidney, thereby normalizing sulfate absorption.
- Techniques to eliminate the Hg-induced epileptiform activities found in the majority of autistic children, as outlined by LeWine et al.
- Stem cell applications in autism to repair brain damage that occurred during development.
As pointed out by David Hartman (1998), mercury's ability to cause a wide range of common psychiatric disturbances should be considered in their diagnosis, and it might also be productive in developing hypotheses about and designing research studies for these other disorders. The disorders might include depression, OCD, dementia, anxiety, ADHD/ADD, Tourette's, and schizophrenia. Mercury may play a role in the etiology of some cases of these conditions. Conversely, investigating mercury's wide ranging effects upon neurobiological processes may lead to a quicker understanding of the organic etiologies in these other diseases which are now seen with increasing frequency.
Universal compliance with the recommended vaccine schedule is a governmental, medical, and societal goal, since "vaccines save lives" (CDC). Our goal is not to negatively impact childhood immunization rates. Instead, we have been careful to distinguish between thimerosal and vaccines. Thimerosal is not a vaccine; it is a preservative. Except for trace amounts, vaccines without thimerosal are currently available for all routinely recommended immunizations for children under 6 years (Institute for Vaccine Safety, 1999). Furthermore, it is possible to remove mercury from existing products. Merck, for example, delivered and received FDA approval for a thimerosal-free Hepatitis B vaccine in a record-breaking two months from the time the FDA publicly encouraged manufacturers to develop thimerosal-free alternatives (Pless, 1999; Merck, 1999). Thus, any issues being raised here are related to how vaccine programs are run, not with vaccines themselves.
The issues, of course, are: (i) first, how thimerosal was allowed to remain a component of the immunization program, even after 1953 when Warkany and Hubbard specifically named vaccinal mercury as a possible factor in acrodynia, or 1982 when the FDA issued a notice singling out thimerosal as especially neurotoxic as well as ineffective as a preservative (Federal Register, 1982); and (ii) second, why thimerosal remains in over 30 vaccine products today (FDA, 1999), and why the FDA, as of March 2000, has only "encouraged" rather than required the vaccine manufacturers to remove the thimerosal (William Egan personal communication). Although the CDC has stated that no adverse effects from thimerosal have been found other than hypersensitivity reactions, the sad fact is there have been no direct studies on the long term effects of intermittent bolus doses of ethylmercury injected in infants and toddlers. As Altman and Bland have aptly demonstrated (1995), "absence of evidence is not evidence of absence."
These lapses in vaccine program oversight suggest that vaccine safety studies need to be bolstered. Current practice is to track adverse reactions only if they occur within one month of the vaccination. The experience with mercury clearly shows that an adverse event may not manifest for months if not years. Studies on adverse reactions must involve long term tracking of patients; they should investigate the impact of multiple injections as well as compare reactions to vaccines with and without various additives; and sample sizes need to be large enough to include especially sensitive groups. Finally, the FDA should require manufacturers to remove all remaining thimerosal from their vaccines immediately, so that another child is not lost to this terrible disease.
The authors would like to thank the following people for their important contributions to this article: Amy Rosenberg, Ayda Halker, Andrew Cutler, Edie Davis, Merri Adler-Ross (Bergen County Community Service Program, Hackensack, NJ), Mark Maxon, Thomas Marchie, Ramone Martinas, Michael DiPrete, Nancy Gallo, David Patel and Paramus Library, Reference Desk (Paramus NJ)
Abell F, Krams M, Ashburner J, Passingham R, Friston K, Frackowiak R, Happé F, Frith C, Frith U, ‘The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans’, NeuroReport, June 1999, Vol. 10, No. 8, 1647-1651
Adams CR, Ziegler DK, Lin JT, ‘Mercury intoxication simulating amyotrophic lateral sclerosis’, JAMA 1983; 250:642-643.
Al-Balaghi S, Möller E, Möller G, Abedi-Valugerdi M, ‘Mercury induces polyclonal B cell activation, autoantibody production and renal immune complex deposits in young (NZB x NZW) F1 hybrids’, Eur J Immunol, July 1996, 26(7):1519-1526
Alberti A, Pirrone P, Elia M, Waring RH, Romano C, ‘Sulphation deficit in “low-functioning” autistic children: a pilot study’, Biol Psychiatry 1999 Aug 1; 46(3):420-424
Altman DG, Bland JM, ‘Absence of evidence is not evidence of absence’, Br Med J, 1995;311:485
American Academy of Pediatrics and US Public Health Service, July 8, 1999, Thimerosal, a Mercury-containing Preservative used in Some Vaccines American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Washington D.C., American Psychiatric Association, 1994
Amin-Zaki L, Majeed MA, Clarkson TW, Greenwood MR, ‘Methylmercury poisoning in Iraqi children: clinical observations over two years’, British Medical Journal 1978 March 1, 613-616
Amin-Zaki L, Majeed MA, Elhassani SB, Clarkson TW, Greenwood MR, Doherty RA,
‘Prenatal Methylmercury Poisoning’,
Amin-Zaki, L, Elhassani S, Majeed MA, Clarkson TW, Doherty RA, Greenwood M, ‘Intra-uterine methylmercury poisoning in Iraq’, Pediatrics 1974 Nov 54:5 587-595
Anuradha B, Rajeswari M, Varalakshmi P, ‘Degree of peroxidative status in neuronal tissues by different routes of inorganic mercury administration’, Drug Chem Toxicol 1998 Feb;21(2):47-55
Applied Toxicology, 1992 Apr;12(2):79-84
ARI Newsletter, review, 'Long term follow-up: early intervention effects lasting', 1993 7(1):1&6
Aronow R, Fleischmann L , ‘Mercury Poisoning in Children’ Clinical Pediatrics, 1976 Oct, Vol.15, No.10, 936-945
Arvidsson T, Danielsson B, Forsberg P, Gillberg C, Johansson M, Kjellgren G, ‘ Autism in 3-6 year old children in a suburb in Göteborg, Sweden’, Autism, November 1997, Vol. 1, No. 2, 163-173
Aschner M, Aschner JL, ‘Mercury Neurotoxicity: Mechanisms of Blood-Brain Barrier Transport’, Neuroscience & Behavioral Reviews, 1990, Vol. 14, 169-176
Aschner M, Lorscheider FL, Cowan KS, Conklin DR, Vimy MJ, Lash LH, ‘Methallothionein induction in fetal rat brain and neonatal primary astrocyte cultures by in utero’, Brain Res, Dec 5 Abstract, 778(1):222-232
Aschner M, Sager PR, 1984. Mitotic arrest in the developing CNS after prenatal exposure to methyl mercury. Neurobehav. Toxical. Teratol. 6:379-385.
Ashour H, Abdel-Rahman M, Khodair A., 1993 ‘The mechanism of methyl mercury toxicity in isolated rat hepatocytes’, Toxicology Letters 1993 Jul;69(1):87-96.
Atchison WD and Hare MF, ‘Mechanisms of methylmercury-induced neurotoxicity’, FASEB Journal 1994 Jun;8(9):622-629
Atchison WD, Joshi U, Thornburg JE, ‘Irreversible Suppression of Calcium Entry into Nerve Terminals by Methylmercury’, The Journal of Pharmacology and Experimental Therapeutics, 1986, Vol. 238, No. 2, 618-624
ATSDR, US Department of Health & Human Services, ‘ATSDR/EPA Priority List’, 1995. Aukrust P, et al, ‘Decreased levels of total and reduced glutathione in CD4+ lymphocytes in common variable immunodeficiency are associated with activation of the tumor necrosis factor system: possible immunopathogenic role of oxidative stress’, Blood, 1995, 86.4.1383-1391
Aukrust P, et al, persistent activvation of the tumor necrosis factor system in subgroup of patients with common variable immunodeficiency - possible immunological and clinical consequences’, Blood, 1996, 97.2.674-681
Aylward EH, Minshew NJ, Goldstein G, Honeycutt NA, Augustine AM, Yates KO, Barta PE, Pearlson GD, 'MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults', Neurology1999 Dec 10;53(9):2145-50
Bachevalier J, 'Brief Report: Medial Temporal Lobe and Autism: A Putative Animal Model in Primates', Journal of Autism and Developmental Disorders, 1996;26(2):217-220
Bachevalier J, 'Medial Temporal Lobe Structures: a Review of Clinical and Experimental Findings', Neuropsychologia, 1994;32:627-648
Bagenstose LM, Salgame P, Monestier M, ‘Mercury-induced autoimmunity in the absence of IL-4’, Clin Exp Immunol, Oct 1998, 114(1):9-12
Bagenstose LM, Salgame P, Monestier M, ‘Murine mercury-induced autoimmunity: a model of chemically related autoimmunity in humans’, Immunol Res, 1999, 20(1):67-78
Bailey A, Phillips W, Rutter M, ‘Autism: Towards an Integration of Clinical,
Genetic, Neuro-psychological, and Neurobiological Perspectives’,
Bailey A, Luthert P, Dean A, Harding B, Janota I, Montgomery M, Rutter M, Lantos, 'A clinicopathological study of autism', Brain 1998 May;121 ( Pt 5):889-905
Bakir F, Damluji SF, Amin-Zaki L, Murtadha M, Khalidi A, Al-Rawi NY, Tikrit S, Dhahir HI, Clarkson TW, Smith JC, Doherty RA, ‘Methylmercury poisoning in Iraq’, Science, July 1973, 181;230-241
Baranek G, 'Autism During Infancy: A Retrospective Video Analysis of Sensory-Motor and Social Behaviors and 9-12 Months of Age', Journal of Autism and Developmental Disorders, 1999, Vol. 29, No. 3, pp. 213-224
Baron-Cohen S, Ring HA, Wheelwright S, Bullmore ET, Brammer MJ, Simmons A, Williams SC, 'Social intelligence in the normal and autistic brain: an fMRI study', Eur J Neuroscience 1999 Jun;11(6):1891-8
Baron-Cohen S, Leslie A, Frith U, ‘Does the autistic child have a ‘theory of mind’?’, Cognition, 1985, No. 21, pp. 37-46
Baron-Cohen S, Allen J, Gillberg C, 'Can autism be detected at 18 months: the needle, the haystack, and the CHAT', Br. J. Psychiatry, 1992;161:839-843
Baron-Cohen S, Tager-Flusberg H, Cohen D, Understanding Other Minds: Perspectives from Autism, Oxford: Oxford University Press, 1993
Barregard L, Sallsten G, Conradi N, ‘Tissue levels of mercury determined in a deceased worker after occupational exposure’, Int Arch Occup Environ Health 1999 May;72(3):169-173
Bartolome J, Whitmore WL, Seidler FJ, Slotkin TA 1984 ‘Exposure to methylmercury in utero: effects on biochemical development of catecholamine neurotransmitter systems’, Life Sciences 1984 Aug 6;35(6):657-670
Bauman ML, Kemper TL, 'Neuroanatomical observations of the brain in autism', in Bauman & Kemper, eds, The Neuroanatomy of Autism, The Johns Hopkins University Press
Bauman ML and Kemper TL, Journal of Experimental Neurology, 1988 47:369
Bauman M, Kemper TL, 'Histoanatomic observations of the brain in early infantile autism', Neurology, 1985;35:866-874
Bernabei P, Camaioni L, Levi G, ‘An evaluation of early development in children with autism and pervasive developmental disorders from home movies: preliminary findings’, Autism, September 1999, Vol. 2, No. 3, 243-258
Bettleheim B, 'A letter from Bruno Bettleheim', Autism Research Review International, 1989, Vol 3, No. 3, p. 6
Bidet B, Leboyer M, Descours B, Bouvard MP, Benveniste J, ‘Allergic sensitization in infantile autism’ (letter), Journal of Autism and Developmental Disorders, June 1993, Vol. 23, No. 2, pp. 419-420
Binstock T, 'Fragile X and the amygdala: cognitive, interpersonal, emotional, and neuroendocrine considerations', Dev Brain Dysfunction 1995 8:199-217
Bonnet JJ, Benmansour S, Amejdki-Chab N, Costentin J, ‘Effect of CH3HgCl and several transition metals on the dopamine neuronal carrier; peculiar behaviour of Zn2+’, Eur J Pharmacol 1994 Jan 1;266(1)87-97
Bouilleret V, Boyet S, Marescaux C, Nehlig A, ‘Mapping of the progressive metabolic changes occurring duing the development of hippocampal sclerosis in a model of mesial temporal lobe epilepsy’, Brain Research, 2000, 952:255-262
Brenner RP and Snyder RD, ‘Late EEG finding and clinical status after organic mercury poisoning’, Archives of Neurology 1980 May; 37(5):282-284
Bristol M, Cohen D, Costello E, Denckla M, Eckberg T, Kallen R, Kraemer H, Lord C, Maurer R, McIlvane W, Minshew N, Sigman M, Spence M, 'State of the Science in Autism: Report to the National Institutes of Health' , Journal of Autism and Developmental Disorders, 1996, Vol. 26, No. 2, pp. 121-157
Bryson SE, ‘Brief Report: Epidemiology of Autism’, Journal of Autism and Developmental Disorders, 1996, Vol. 26, No. 2, 165-167
Bryson SE, Smith IM, Eastwood D, 'Obstetrical suboptimality in autistic children', J Am Acad Child Adolesc Psychi, 1988;27(4)418-22
Bulleit RF, Cui H, ‘Methylmercury antagonizes the survival-promoting activity of insulin-like growth factor on developing cerebellar granule neurons’, Toxicol Appl Pharmacol 1998 Dec;153(2):161-168.
Cagiano R, De Salvia MA, Renna G, Tortella E, Braghiroli D, Parenti C, Zanolie P, Baraldi M, Annau Z, Cuomo V, ‘Evidence that exposure to methyl mercury during gestation induces behavioral and neurochemical changes in offspring of rats’, Neurotoxicol Teratol 1990 Jan-Feb;12(1):23-28
Camerino , Cassitto M, 'Behavior of Some Psychological Parameters of a Population of a Hg Extraction Plant', Journal of Clinical Toxicology, 1981, Vol. 18 (11), pp. 1299-1309
Capps L, Kehres J, Sigman M, 'Conversational abilities among children with autism and children with developmental delays', Autism, 1998 Dec;2(4):325-44
Carlsson ML, ‘Hypothesis: is infantile autism a hypoglutamatergic disorder? Relevance of glutamate - serotonin interactions for pharmacotherapy’, Journal of Neural Transmitters 1998 105(4-5):525-535
Carlsson ML, Martin P, Nilsson M, Sorensen SM, Carlsson A, Waters S, Waters N, ‘The 5-HT2A receptor antagonis M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice’, J Neural Transm 1999; 106(2):123-129
Carpenter PK, Morris D, ‘Association of acrocyanosis with Asperger’s syndrome’, Journal of Mental Deficiency Research, 1990, 34, pp. 97-90
Carroll L, Alice in Wonderland, W.W. Norton & Company, 1992, 1971
CDC, ‘Recommendations regarding the Use of Vaccines That Contain Thimerosal as a Preservative’, MMWR November 5, 1999 / 48(43); 996-998
CDC, ‘Thimerosal in vaccines: a joint statement of the Amercian Academy of Pediatrics and the Public Health Service’, MMWR Morb Mortal Wkly Rep 1999 July 9; 48(26):563-565
CDC, 'Record Immunization Rate, 80% of Kids Getting Vaccinated', Associated Press, September 23, 1999 Cesaroni L, Garber M, 'Exploring the experience of autism through firsthand accounts', Journal of Autism and Developmental Disorders, 1991 Sep;21(3):303-13
Chapman AG, Elwes RD, Millan MH, Polkey CE, Meldrum BS, 'Role of Glutamate and Aspartate in Epileptogenesis; Contribution of Microdialysis Studies in Animal and Man', Epilepsy Res Suppl, 1996, Vol. 12, pp. 239-246
Cheek DB, 'Acrodynia', in Brennemann's Practice of Pediatrics, Chapter 17D, from Pink Disease website, www.users.bigpond.com/difarnsworth/pcheek42.htm
Chodorowski Z, Sein Anand J, Nowicki A, Galant K, ‘Subcutaneous self-injection and oral self-administration of metallic mercury - case report’, Przegl Lek 1997;54(10):759-762
Chu CC, Huang CC, Ryu SJ, Wu TN, ‘Chronic inorganic mercury induced peripheral neuropathy’, Acta Neurology Scandanavia 1998 Dec;98(6):461-465
Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT, ‘Developmental Changes in Brain Serotonin Synthesis Capacity in Autistic and Nonautistic Children’, Ann Neurol 1999; 45:
Church C, Coplan J, 'The High Functioning Autistic Experience: Birth to Preteen Years', Journal of Pediatric Health Care, 1995, Vol. 9, pp.22-29
Clarke D, Baxter M, Perry D, Prasher V, 'The diagnosis of affective and psychotic disorders in adults with autism: seven case reports', Autism, 1999 Jun;3(2):149-164
Clarkson TW, ‘Mercury: Major Issues in Environmental Health’, Environmental Health Perspectives vol. 100, pp. 31-38, 1992
Clarkson, T. 1997 ‘The Toxicology of Mercury’, Critical Reviews in Clinical Laboratory Sciences, 34(3): 369-403 (1997)
Clarkson, TW, ‘Mercury - an element of mystery’,
Clarkson,T.W. 1993. Molecular and ionic mimicry of toxic metals. Annu. Rev. Pharmacol. Toxicol 32:545-571
Cloarec S, Deschenes G, Sagnier M, Rolland JC, Nivet H, ‘Arterial hypertension due to mercury poisoning: diagnostic value of captopril’, Arch Pediatr 1995 Jan;2(1):43-46
Close AH, Guo TL, Shenker BJ, ‘Activated human T lymphocytes exhibit reduced susceptibility to methylmercury chloride-induced apoptosis’, Toxicol Sci 1999 May;49(1):68-77
Coccini T, Randine G, Candura SM, Nappi RE, Prockop LD, Manzo L, ‘Low-Level Exposure to Methylmercury Modifies Muscarinic Cholinergic Receptor Binding Characteristics in Rat Brain and Lymphocytes: Physiologic Implications and New Opportunities in Biologic Monitoring’, Environ Health Perspect, 2000 Jan;108(1):29-33
Coleman M, ‘Nutritional treatments currently under investigation in autism’, Clinical Nutrition, Sept/Oct 1989, Vol. 8, No. 5, pp. 210-212
Comi AM, Zimmerman A et al, 'Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism', Journal of Child Neurology, 1999, Vol. 14, pp. 388-394
Connolly AM, et al, ‘Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders’, Journal of Pediatrics, May 1999, Vol. 134, No. 5, pp. 607-613
Cook EH, ‘Autism: review of neurochemical investigation’, Synapse, 1990, 6:292-308
Courchesne E, et al, ‘More evidence links autism, cerebellar defects’, reviewed in Autism Research Review International, 1994, Vol. 8, No. 2, pp. 1&7
Courchesne E, Press GA, Young-Courchesne R, 'Parietal lobe abnormalities detected with MR in patients with infantile autism', AJR Am J Roentgenol 1993 Feb;160(2):387-93
Courchesne E, 'Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism', Current Opin Neurobiol 1997 Apr;7(2):269-78
Courchesne E, Saitoh O, Townsend J, Yeung-Courchesne R, Lincoln AJ, Schreibman L, Haas RH, Press GA, 'Cerebellar Abnormalities in Autism: New Evidence and A Re-Analysis of Old Evidence', pp. 211-214
Courchesne E, Yeung-Courchesne R, Elmasian R, Grillon C, 'Pathophysiologic findings in non-retarded autism and receptive developmental language disorder', Journal of Autism and Developmental Disorders, 1989; 19:1-17
Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, Jernigan TL, ‘Hypoplasia of cerebellar vermal lobules VI and VII in autism’, New England Journal of Medicine 1988 318:1349-1354
Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, Jernigan TL, ‘Hypoplasia of cerebellar vermal lobules VI and VII in autism’, New England Journal of Medicine, May 26, 1998; pp. 1349-1354
Courchesne E, reported in ,The New York Times, 'Science Times' section, Dec 28, 1999, by Blakeslee S
Cox NH, Forsyth A, ‘Thiomersal allergy and vaccination reactions’, Contact Dermatitis 1988:18:229-233
Creel DJ, Crandall AS, Pingree C, Ritvo ER, 'Abnormal electroretinograms in autism', Clinical Vision Science 1989 4(1):85-88
Cuomo V, Ambrosi L, Annau Z, Cagiano R, Brunello N, Racagni G 1984, ‘Behavioral and neurochemical changes in offspring of rats exposed to methyl mercury during gestation’, Neuobehavior Toxicology Teratol 1984 May-June;6(3):249-254
D’Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M, Cardi E, Giardini O, ‘Abnormal intestinal permeability in children with autism’, Acta Pædiatr 1996:85:1076-1079
D’Eufemia P, Finocchiaro R, Celli M, Viozzi L, Monteleone D, Giardini O, ‘Low serum tryptophan to large neutral amino acids ratio in idiopathic infantile autism’, Biomed. & Pharmacother., 1995, Vol. 49, pp. 288-292
Dales LD, ‘The Neurotoxicity of Alkyl Mercury Compounds’, American Journal of Medicine, August 1972, Vol. 53, 219-232
Dally A, 'The Rise and Fall of Pink Disease', Wellcome Institute for the History of Medicine, 1997, available at www.powerup Dathan JG, 'Pink Disease-Ten Years After (The Epilogue), British Medical Journal, 1965, Vol 1, pp. 1181-1182
Dave V, Mullaney KJ, Goderie S, Kimelberg HK, Aschner M, ‘Astrocytes as mediators of methylmercury neurotoxicity: effects on D-aspartate and serotonin uptake’, Dev Neurosci 1994;16(3-4):222-231
Davis LE, Kornfeld M, Mooney HS, Fiedler KJ, Haaland KY, Orrison WW, Cernichiari E, Clarkson TW, ‘Methylmercury poisoning: long term clinical, radiological, toxicological, and pathological studies of an affected family’, Annals of Neurology 1994 35:6 680-688
Dawson G, ‘Brief Report: Neuropsychology of Autism: A Report on the State of the Sciende’, Journal of Autism and Developmental Disorders, 1996, Vol. 26, No. 2, 179-184
Deb S and Thompson B, ‘Neuroimaging in autism’, British Journal of Psychiatry 1998 Oct 173:299-302
DelGiuidce-Asch G, Hollander E, ‘Altered immune function in autism’, CNS Spectrums: International Journal of Neuropsychiatric Medicine, 1997, 2:61-68
DeLong GR, ‘Autism: new data suggest a new hypothesis’, Neurology, March 1999, Vol. 52, No. 5, pp. 911-916
Deutsch S, Campbell M, Sachar E, Green W, David R, ‘Plasma growth hormone response to oral L-dopa in infantile autism’, Jour. of Aut. and Dev. Disorders, June 1985, Vol. 15, No. 2, pp. 205-212
Deyab P, Gochfeldbc M, Reuhlabca K, 'Developmental Methylmercury Administration Alters Cerebellar PSA-NCAM expression and Golgi sialyltransferase Activity', 1999
Diner Barry, M.D., Brenner Barry, M.D.,Toxicity, Mercury, 1998
Edelson MG, Edelson SM, Jung S, ‘Assessing the Intelligence of Individuals with Autism: A Cross-Cultural Replication of the Usefulness of the TONI’, Focus on Autism and Other Developmental Disabilities, Winter 1998, Vol. 13, No. 4, 221-227
Edelson MG, Schubert DT, Edelson SM, ‘Factors Predicting Intelligence Scores on the TONI in Individuals with Autism’, Focus on Autism and Other Developmental Disabilities, Spring 1998, Vol. 13, No. 1, 17-26
Edelson SB, Cantor DS, ‘Autism: xenobiotic influences’, Toxicol Ind Health, 1998 Jul-Aug;14(4):553-563
Egan, William M. 1999 ‘Thimerosal in Vaccines’, presentation to the FDA, September 14, 1999
Eisenmayer R et al, 'Delayed language onset as a predictor of clinical symptoms in pervasive developmental disorders',Journal of Autism and Developmental Disorders, 1998 Dec 28(6):527-33
El-Fawal HA, Waterman SJ, De Feo A, Shamy MY, ‘Neuroimmunotoxicology: Humoral Assessment of Neurotoxicity and Autoimmune Mechanisms’, Environ Health Perspect 1999 Oct;107(Suppl 5):767-775
Elferink JG Thimerosal: a versatile sulfhydryl reagent,calcium mobilizer, and cell function-modulating agent.Gen Pharmacol 1999 Jul;33(1):1-6
Environmental Protection Agency (EPA), lead authors - Hassett-Sipple B, Swartout J, Schoeny R, 'Vol. V - Health Effects of Mercury and Mercury Compounds', Mercury Study Report to Congress, December 1997
Ernst M, Zametkin AJ, Matochik JA, Pascualvaca D, Cohen RM, 'Low medial prefrontal dopaminergic activity in autistic children', Lancet 1997 Aug 30;350(9078):638
Eto K, Takizawa Y, Akagi H, Haraguchi K, Asano S, Takahata N, Tokunaga H, ‘Differential diagnosis between organic and inorganic mercury poisoning in human cases - the pathologic point of view’, Toxicol Pathol 1999 Nov-Dec;27(6):664-671
Fagala GE,Wigg CL, ‘Psychiatric Manifestions of Mercury Poisoning’, J. Am. Acad. Child. Adolesc. Psychiatry, March 1992, 31(2):306-311.
Fagan DG, Pritchard JS, Clarkson TW, Greenwood MR, ‘Organ mercury levels in infants with omphaloceles treated with organic mercurial antiseptic’, Archives of Disease in Childhood, 1977 52:962-964
Farnsworth D, ‘Pink Disease Survey Results’, Pink Disease Support Group Site, 1997 www.users.bigpond.com/difarnsworth
Faro LR, Duran R, do Nascimento JL, Alfonso M, Picanco-Diniz CW, ‘Effects of methyl mercury on the in vivo release of dopamine and its acidic metabolites DOPAC and HVA from Striatum of rats’, Ecotoxicol Environ Saf 1997 Nov;38(2):95-98
Faro LRF, Nascimento JLM do, Alfonso M, Duran R, ‘Acute Administration of
Methylmercury Changes In Vivo Dopamine Release from Rat Striatum’,
FDA, HHS, ‘Mercury Containing Drug Products for Topical Antimicrobial Over-the-Counter Human Use; Establishment of a Monograph’, Federal Register, January 5 1982, Vol. 47, No. 2, 436-442
FDA, 'Mercury Compounds in Drugs and Food', 98N-1109, November 16, 1999
Feldman R, 'Neurological Manifestations of Mercury Intoxication', Journal of Occupational Neurology, 1982, Vol. 66, pp. 201-209
Filipek P, Accardo P, Baranek G, Cook E, Dawson G, Gordon B, Gravel J, Johnson C, Kallen R, Levy S, Minshew N, Prizant B, Rapin I, Rogers S, Stone W, Teplin S, Tuchman R, Volkmar F, 'The Screening and Diagnosis of Autistic Spectrum Disorders', Journal of Autism and Developmental Disorders, 1999, Vol. 29, No. 6, pp. 439-484
Finegan J, Quarrington B, 'Pre-, peri-, and neonatal factors and infantile autism', J Child Psychol Psychi, 1979; 20.119-128
Florentine MJ and Sanfilippo II DJ, ‘Grand Rounds: Elemental mercury poisoning’, Clinical Pharmacy 1991 Mar 10:213-221
Fombonne E, Rogé B, Claverie J, Courty S, Frémolle J, ‘Microcephaly and Macrocephaly in Autism’ Journal of Autism and Developmental Disorders, 1999, Vol. 29, No. 2, 113-119
Food and Drug Administration, 1997 ‘Status of Certain Additional Over-the-Counter Drug Category II and III Active Ingredients’, Docket Nos. 75N-183F, 75N-183D, and 80N-0280, October 19,1998
Fournier L, Thomas, G, Garnier, R, Buisine, A, Houze, P, Pradier, F, and Dally, S 1988, ‘2,3-Dimercaptosuccinic Acid Treatment of Heavy Metal Poisoninig in Humans’, Medical Toxicology 3: 499-505 (1988)
Frackelton JP, Christensen RL, ‘Mercury Poisoning and Its Potential Impact on Hormone Regulation and Aging: Preliminary Clinical Observations Using a New Therapeutic Approach’, Journal of Advancement in Medicine 1998 Spring 11(1):9-25
Fredriksson A, Dencker L, Archer T, Danielsson BGR, ''Prenatal coexposure to metallic mercury vapour and methylmercury produce interactive behavioural changes in adult rats', Neurotoxicol Teratol 1996 19(2):129-134
Fuchs J, Packer L, Zimmer G, Lipoic Acid in Health and Disease, Marcel Dekker, Inc., 1997
Fuchs J, Schöfer H, ‘Redox Modulation of Signal Transduction and Gene Expression in HIV Infection: The Role of the Antioxidant Lipoate’, Lipoic Acid in Health and Disease, Marcel Dekker, Inc., 1997, 435-454
Fudenberg HH, ‘Dialysable Lymphocyte Extract (DLyE) in Infantile Onset Autism: A Pilot Study’, Biotherapy (1996) 9:143-147
Fukino H, Hirai M, Hsueh YM, Yamane Y, ‘Effect of zinc pretreatment on mercuric chloride-induced lipid peroxidation in the rat kidney’, Toxicol Appl Pharmacol 1984 May;73(3):395-401
Gaffney GR, Kuperman S, Tsai LY, Minchin S, ‘Morphological evidence for brainstem involvement in infantile autism’, Biological Psychiatry, September 1988, 24:578-586
Gedye A, ‘Anatomy of self-injurious, stereotypic, and aggressive movements: evidence for involuntary explanation’, Journal of Clinical Psychology, November 1992, Vol. 48, No. 6, pp. 766-778
Gilbert SG, Grant-Webster KS, ‘Neurobehavioral effects of developmental methymercury exposure’, Environmental Health Perspectives, 1995 Sept; 103 Suppl 6:135-142
Gillberg C, Coleman M, The Biology of the Autistic Syndromes - 2nd Edition,Mac Keith Press, 1992
Gillberg C, Dev Med Child Neurol 37, 23-45 (1995)
Gillberg C, Gillberg IC, 'Infantile Autism: a total population study of reduced optimality in the pre-, peri- and neonatal period', Journal of Autism and Developmental Disorders, 1983, Vol 13, No. 2, pp. 153-166
Gillberg C, Svennerholm L, ‘CSF monoamines in autistic syndromes and other pervasive dev. disorders of early childhood’, British Jour. of Psychiatry, 1987, No. 151, pp. 89-94
Gillberg C, Wing L, ‘Autism: not an extremely rare disorder’, Acta Psychiatr Scand 1999 Jun;99(6)399-406
Goldberg M, Mena I, Miller B, ‘Frontal and temporal lobe dysfunction in autism and other related disorders: ADHD and OCD’, Latin American Journal of Nuclear Medicine, July 1999, available online: http://www.alabimnjournal.cl
Golse B, Debray-Ritzen P, Durosay P, Puget K, Michelson AM, ‘Alterations in two enzymes: superoxide dismutase and glutathion peroxidase in developmental infantile psychosis’, Revue Neurologic (Paris) 1978 Nov;134(11):699-705
Gosselin RE, Smith RP, Hodge HC. Clinical toxicology of commercial products, section III, Therapeutic index (ed 5). Baltimore, Williams & Wilkins, 1984: pp262-271.
Grandin T, ‘Brief Report: Response to National Institutes of health Report’, Journal of Autism and Developmental Disorders, 1996, Vol. 26, No. 2, 185-187
Grandin T, ‘The Learning Style of People With Autism: An Autobiography’, Teaching Children with Autism, Kathleen Ann Quill, 33-52
Grandjean P, Budtz-Jorgensen E, White RF, Jorgensen PJ, Weihe P, Debes F,
Keiding N, ‘Methylmercury exposure biomarkers as indicators of neurotoxicity in
children aged 7 years’,
Grandjean P, Guldager B, Larsen IB, Jergensen PJ, Holmstrup P, ‘Placebo Response in Environmental Disease’, JOEM 1997 August, Vol. 38, No. 8,707-714
Grandjean P, Weihe P, White RF, Debes F, ‘Cognitive performance of children prenatally exposed to “safe” levels of methylmercury’, Environmental Research 1998 May; 77(2): 165-172
Grandjean P, White RF, Nielsen A, Cleary D, de Oliveira Santos EC, ‘Methylmercury neurotoxicity in Amazonian children downstream from gold mining’, Environ Health Perspect 1999 Jul;107(7):587-591
Grundt IK, Stensland E, Syverson TL, ‘Changes in fatty acid composition of myelin cerebrosides after treatment of the developing rat with methylmercury chloride and diethylmercury’. J Lipid Res,1980 Feb;21(2):162-168
Gunderson, VM, Grant KS, Burbacher TM, Fagan 3rd JF, Mottet, NK, ‘The effect of low-level prenatal methyl mercury exposure on visual recognition memory in infant crab-eating macaques’, Child Dev., 1986, 57(4):1076-1083
Gunderson, VM, Grant KS, Burbacher TM, et al, ‘Visual recognition memory deficits in methyl mercury exposed Macaca fascicularis infants’, Neurotoxicol Teratol., 1988, 10(4):373-379
Gupta S, Aggarwal S, Heads C, ‘Brief Report: Dysregulated Immune System in Children with Autism: Beneficial Effects of Intravenous Immun Globulin on Autistic Characteristics’, Journal of Autism and Developmental Disorders, 1996, Vol. 26, No. 4, 439-452
Gupta S, Aggarwal S, Rashanravan B, Lee T, ‘Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism’, J Neuroimmunol 1998 May 1;85(1):106-109
Haeney MR, Carter GF, Yeoman WB, Thompson RA, ‘Long-term parental exposure to mercury in patients with hypogammaglobulinaemia’, British Medical Journal 1979 2:12-14
Hagerman RJ, 'Possible similarities between the fragile X and Asperger syndrome', American Journal of Diseases of Children, 1987;141:601-602
Halsey NA, 'Perspective on the use of thimerosal-containing vaccines', presentation at the National Vaccine Advisory Committee Workshop on Thimerosal and Vaccines, August 11-12, 1999, available on Institute of Vaccine Safety website, www.vaccinesafety.edu
Halsey NA, ‘Limiting Infant Exposure to Thimerosal in Vaccines and Other Sources of Mercury’, JAMA, November 10, 1999, Vol. 282, No. 18
Hartman DE, 'Missed diagnoses and misdiagnoses of environmental toxicant exposure', Diagnostic Dilemmas, Part I, 1998 Sep;21(3):659-671
Hashimoto T, Tayama M, Miyazaki M, Sakurama N, Yoshimoto T, Murakawa K, Kuroda Y, ‘Reduced brainstem size in children with autism’, Brain & Development, 1992, Vol. 14, No. 2, pp. 94-97
Hashimoto T, Tayama M, Murakawa K, Yoshimoto T, Miyazaki M, Harada M, Kuroda Y, ‘Development of the brainstem and cerebellum in autistic patients’, Journal of Autism and Developmental Disorders, 1995, Vol. 25, No. 1, pp. 1-18
Haznedar MM, Buchsbaum MS, Metzger M, Solimando A, Spiegel-Cohen J, Hollander E, ‘Anterior Cingulate Gyrus Volume and Glucose Metabolism in Autistic Disorder’, Amercian Journal of Psychiatry 1997 Aug 154(8):1047-1050
Hepatitis Control Report, ‘Uproar over a little-known preservative, thimerosal, jostles U.S. hepatitis B vaccination policy’, Summer 1999, Vol. 4, No. 2
Hollander E, Kaplan A, Cartwright C, Reichman D, ‘Venlafaxine in children, adolescents, and young adults with autism spectrum disorders: an open retrospective clinical report’, J Child Neurol, 2000, Feb;15(2):132-135
Hoon AH and Riess AL, ‘The mesial-temporal lobe and autism: case report and review’, Developmental Medicine and Child Neurology 1992 34:252-265
Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT, ‘Gastrointestinal abnormalities in children with autistic disorder’, Journal of Pediatrics 1999 Nov 135(5):559-563
Hoshino Y, Watanabe M, Kumashiro H, ‘The hypothalamo-pituitary function in autistic children: the change of serum 5HT, plasma human growth hormone, prolactin level after L-5HTP loading’, Neurosciences, 1984, Vol. 10, pp. 285-291
Hoshino Y, Watanabe M, Kumashiro H, ‘The TRH and LH-RH loading test in autistic children’, Journal of Medical Science, 1985, Vol. 31, No. 1
Howlin P, 'Outcome in adult life for more able individuals with autism or Asperger syndrome', Autism 2000 Mar;4(1):63-84
Hrdina PD, Peters DA, Singhal RL 1976, ‘Effects of chronic exposure to cadmium, lead and mercury of brain biogenic amines in the rat’, Research Communications in Chemistry, Pathology and Pharacology 1976 Nov;15(3):483-493
Hu H, Abedi-Valugerdi M, Moller G, ‘Pretreatmet of lymphocytes with mercury in vitro induces a response in T cells from genetically determine low-responders and a shift of the interleukin profile’, Immunology, 1997 90:198-204
Hu H, Möller G, Abedi-Valugerdi M, ‘Major histocompatibility complex class II antigens are required for both cytokine production and proliferation induced by mercuric chloride in vitro’, J Autoimmun, Oct 1997, 10(5):441-446
Hu H, Moller G, Abedi-Valugerdi M, ‘Mechanism of mercury-induced autoimmunity: both T helper 1- and T helper 2-type responses are involved’,Immunology, March 1999, 96(3):348-357
Hua MS, Huang CC, Yang YJ, 'Chronic elemental mercury intoxication: neuropsychological follow up case study', Brain Inj 1996 May;10(5):377-84
Hultman P, Hansson-Georgiadis H, ‘Methyl mercury-induced autoimmunity in mice’, Toxicol Appl Pharmacol, Feb 1, 1999, 154(3):203-211
Hultman P, Nielsen JB, ‘The effect of toxicokinetics on murine mercury-induced automimunity’, Environ Res, May 1998, 77(2):141-148
Hultman P, Turley SJ, Eneström S, Lindh U, Pollard KM, ‘Murine genotype influences the specificity, magnitude and persistence of murine mercury-induced autoimmunity’, J Autoimmun, April 1996, 9(2): 139-149
Hussain S, Atkinson A, Thompson SJ, Khan AT, ‘Accumulation of mercury and its effect on antioxidant enzymes in brain, liver, and kidneys of mice’, J Environ Sci Health B 1999 Jul;34(4):645-660
Ikeda M, Komachi H, Sato I, Himi T, Yuasa T, Murota S, ‘Induction of neuronal nitric oxide synthase by methylmercury in the cerebellum’, Journal of Neuroscience Research 1999 Feb 1;55(3):352-356.
Ilback NG, ‘Effects of methyl mercury exposure on spleen and blood natural-killer (NK) cell-activity in the mouse’, Toxicology, 1991, 67(1):117-124
Islam MS, Berggren PO, Larsson O, ‘Sulfhydryl oxidation induces rapid and reversible closure of the ATP-regulated K+ channel in the pancreatic beta cell’, FEBS Lett 1993 Mar 15;319(1-2):128-132
Jaffe JS, et al, ‘Functional abnormalities of CD8+ t cells define a unique subset of patients with common variable immunodeficiency’, Blood, 1993, 82.1.192-2001
Jaselskis C, Cook E, Fletcher K, and Bennett L, ‘Clonidine treatment of hyperactive and impulsive children with autistic disorder’, Journal of Clinical Psychopharmacology 1992
Johansson U, Hansson-Georgiadis H, Hultman P, ‘The genotype determines the B cell response in mercury-treated mice’, Int Arch Allergy Immunol, Aug 1998, 116(4):295-305
Joselow MM, Louria DB, Browder AA, ‘Mercurialism: Environmental and Occupational Aspects’, Annals of Internal Medicine 1972 76:119-130
Joseph SK, Ryan SV, Pierson S, Renard-Rooney D, Thomas AP, ‘The effect of mersalyl on inositol trisphosphate receptor binding and ion channel function’, J Biol Chem 1995 Feb 24;270(8):3588-3593
Journal of Autism and Developmental Disorders, 1995, Vol. 25, No. 2
Kabuto M, ‘Chronic effects of methylmercury on the urinary excretion of catecholamines and their responses to hypoglycemic stress’, Arch Toxical 1991;65(2):164-167
Kanner L, ‘Autistic Disturbances of Affective Contact’, The Nervous Child 1942-1943, Vol. 2, No. 3, 217-250
Karhapaa l, Titievsky A, Kaila K, Tornquist K, ‘Redox modulation of calcium entry and release of intracellular calcium by thimerosal in GH4C1 pituitary cells’, Cell Calcium 1996 Dec;20(6):447-457
Kark RA, Poskanzer DC, Bullock JD, Boylen G. ‘Mercury poisoning and its treatment with N-acetyl-D, L-penicillamine’, New England Journal of Medicine 1971;285:10-16
Kates WR, Mostofsky SH, Zimmerman AW, Mazzocco MM, Landa R, Warsofsky IS, Kaufmann WE, Reiss AL, ‘Neuroanatomical and neurocognitive differences in a pair of monozygous twins discordant for strictly defined autism’, Ann Neurol 1998 Jun; 43(6):782-791
Kinoshita Y, Ohnishi A, Kohshi K, Yokota A, ‘Apparent diffusion coefficien ton rat brains and nerves intoxicated with methylmercury’, Environ Res 1999 May;80(4):348-354.
Klin A, Sparrow SS, de Bildt A, Cicchetti DV, Cohen DJ, Volkmar FR, 'A Normed Study of Face Recognition in Autism and Related Disorders', Journal of Autism and Developmental Disorders December 1999 29:6 499-508
Koegel LK, Koegel RL, Smith A, ‘Variables Related to Differences in Standardized Test Outcomes For Children with Autism’, Journal of Autism and Developmental Disorders, 1997, Vol. 27, No. 3, 233-243
Koos BJ and Longo LD, ‘Mercury toxicity in the pregnant woman, fetus, and newborn infant’, American Journal of Obstetrics and Gynecology 1976 Oct 126(3):390-406
Kugler B, 'The differentiation between autism and Asperger syndrome', Autism, 1998 Mar;2(1):11-32
Kurita H, ‘Infantile autism with speech loss before the age of thirty months’, Journal of the American Academy of Child Psychiatry, 1985, Vol. 24, Issue 2, pp. 191-196
LaCamera RG, LaCamera AC, 'Routine Health Care', Handbook of Autism and Pervasive Developmental Disorders, Cohen D, Donnellan AM, Paul R, eds, 1987 by John Wiley & Sons, Inc., p584-595
Larkfors L, Oskarsson A, Sundberg J, Ebendal T, ‘Methylmercury induced alterrations in the nerve growth factor level in the developing brain’, Brain Res Dev Brain Res 1991 Oct 21; 62(2) 287-291
Leboyer M, Philippe A, Bouvard M, Guilloud-Bataille M, Bondoux D, Tabuteau F, Feingold J, Mouren-Simeoni MC, Launay JM, 'Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives', Biol Psychiatry 1999 Jan 15;45(2):158-63
Lewine 'Magnetoenchalography in Children with an Autistic Epileptiform Regression', J Pediatrics, 1999 405-418
Lewis MH, ‘Brief Report: Psychopharmacology of Autism Spectrum Disorders’, Journal of Autism and Developmental Disorders, 1996, Vol. 26, No. 2, 231-235
Li S, Thompson SA, Woods JS, ‘Localizatin of gamma-glutamylcysteine synthetase mRNA expression in mouse brain following methylmercury treatment using reverse transcription in situ PCR amplification’, Toxicol Appl Pharmacol, Sept 1996, 140(1):180-187
Lombard J, ‘Autism: a mitochondrial disorder?’, Medical Hypotheses 1998 Jun;50(6):497-500
Lorscheider FL, Vimy MJ, Summers AO, ‘Mercury exposure from “silver” tooth fillings: emerging evidence questions a traditional dental paradigm’, The FASEB Journal, April 1995, Vol. 9, 504-508
Lowell JA, Burgess S, Shenoy S, Curci JA, Peters M, Howard TK, ‘Mercury Poisoning Associated with High-Dose Hepatitis-B Immune Globulin Administration After Liver Transplantation for Chronic Hepatitis B’, Liver Transplantation and Surgery, Nov 1996, Vol. 2, No. 6, 475-478
Magos L, Brown AW, Sparrow S, Bailey E, Snowden RT, Skipp WR, ‘The comparative toxicology of ethyl- and methylmercury’, Archives of Toxicology, 1985 Sep;57(4):260-267
Malhotra S, Gupta N, 'Childhood Disintegrative Disorder', Journal of Autism and Developmental Disorders Dec 1999 29;6 491-498
Markovich D, Knight D, 'Renal Na-Si Cotransporter NaSi-1 is inhibited by heavy metals', American Journal of Renal Physiology, February 1998, Vol. 274, No. 2, pp283-289
Marty MS, Atchison WD, ‘Elevations of intracellular Ca2+ as a probable contributor to decreased viability in cerebellar granule cells following acute exposre to methyl mercury’, Toxicol Appl Pharmacol 1998 May’ 150(1):98-105
Matheson DS, Clarkson TW, Gelfand EW, ‘Mercury toxicity (acrodynia) induced by long-term injection of gammaglobulin’, Journal of Pediatrics 1980;97(1):153-155.
Mathiesen T, Ellingsen DG, Kjuus H, ‘Neuropsychological effects associated with esposure to mercury vapor among former chloralkali workers’, Scand J Work Environ Health, 1999, Aug:25(4):342-350
Mattsson JR, Miller E, Alligood JP, Koering JE, Levin SG, ‘Early effects of methylmercury on the visual evoked response of the dog’, Neurotoxicology 1981 Nov;2(3):499-514
McClelland RJ, Eyre D, Watson D, Calvert J, ‘A neurophysiological study of autistic children’, Electroencephalography and Clinical Neurophysiology, Sept. 1985, Vol. 61, p. 16
McClelland RJ, Eyre DG, Watson D, Calvert GJ, Sherrard E, British Journal of Psychiatry, 1992, 160: 659-663
McDougle CD, Psycholopharmacology, Handbook of Autism and Pervasive Developmental Delay, 2nd ed. New York: John Wiley and Sons, 1997;707:729
McDougle CJ, Brodkin ES, Yeung PP, Naylor ST, Cohen DJ, Price LH, ‘Risperidone in adults with autism or pervasive developmental disorder’, Journal of Child and Adolescent Psychopharmacology, 1995, Vol. 5, No. 4, pp. 273-282
McDougle CJ, Homes JP, Bronson MR, Anderson GM, Volkmar FR, Price LH, Cohen DJ, ‘Risperidone treatment of children and adolescents with pervasive developmental disorders: A prospective open-label study’, Journal of the American Academy of Child and Adolescent Psychiatry, 36, 685-693
McKay SJ, Reynolds JN, Racz WJ, ‘Effects of mercury compounds on the spontaneous and potassium-evoked release of [3H]dopamine from mouse striatal slices’, Canadian Journal of Physiology and Pharmacology 1986 Dec 64(12):1507-1514
McKeown-Eyssen GE, Ruedy J, Neims A, ‘Methyl mercury exposure in northern Quebec: II. Neurologic findings in children’, Am. J. Epidemiol., 1983, 118:470-479
Merck & Co., Inc., ‘Merck Launches Preservative-Free Hepatitis-B Vaccine’, press release, Sept 9, 1999 Messahel S, Pheasant AE, Pall H, Ahmed-Choudhury J, Sungum-Paliwal RS, Vostanis P, ‘Urinary levels of neopterin and biopterin in autism’, Neurosci Lett 1998 Jan 23;241(1):17-20
Minamata Disease, 1973
Minnema DJ, Cooper GP, Greenland RD, ‘Effects of methylmercury on neurotransmitter release from rat brain synaptosomes’, Toxicology and Applied Pharmacology 1989 Jul 99(3):510-521
Minshew NJ, ‘Brief Report: Brain Mechanisms in Autism: Functional and Structural Abnormalities’, Journal of Autism and Developmental Disorders,1996, Vol. 26, No. 2, 205-209
Moreno H, Borjas L, Arrieta A, Saez L, Prassas A, Estevez J, Bonilla E, ‘Clinical heterogeneity of the autistic syndrome: a study of 60 families’ (Spanish), Invest Clin 1992;33(1):13-31
Moreno-Fuenmayor H, Borjas L, Arrieta A, Valera V, Socorro-Candanoza L, ‘Plasma excitory amino acids in autism’, Invest Clin 1996 Jun;37(2):113-128
Muris P, Steerneman P, Merckelbach H, Holdrinet I, Meesters C, ‘Comorbid anxiety symptoms in children with pervasive developmental disorders’, Journal of Anxiety Disorders, 1998, Vol. 12, No. 4, pp. 387-393
Musiek FE, Hanlon DP, ‘Neuroaudiological effects in a case of fatal dimethylmercury poisoning’, Ear Hear 1999 Jun;20(3):271-275
Myers GJ, Davidson PW, ‘Prenatal methylmercury exposure and children: neurologic, developmental, and behavior research’, Environmental Health Perspectives, 1998 Jun;106 Suppl 3:841-847.
Nass R, Gross A, Devinsky O, 'Autism and autistic epileptiform regression with occipital spikes', Dev Med Child Neurol 1998 Jul;40(7):453-8
‘Neville’s (a Pinkie) Recollection of Pink Disease’, Pink Disease Support Group, www.users.bigpond.com/difarnsworth Nielsen JB and Hultman P, ‘Experimental Studies on genetically determined susceptibility to mercury-induced autoimmune response’, Renal Failure 1999 21(3&4):343-348
Nishio H, Nezasa K, Hirano J, Nakata Y, ‘Effects of thimerosal, an organic sulfhydryl modifying agent, on serotonin transport activity into rabbit blood platelets’, Neurochemistry International 1996 29(4):391-396
Nordin V, Gillberg C, ‘Autism Spectrum disorders in children with physical or mental disability or both. I: Clinical and epidemiological aspects’, Dev Med Child Neurol 1996 Apr; 38(4):297-313
Nowell MA, Hackney DB, Muraki AS, Coleman M, 'Varied MR appearance of autism: fifty-three pediatric patients having the full autistic syndrome', Magn Reson Imaging 1990;8(6):811-6
O’Carroll RE, Masterton G. Dougnall N. Ebmeier KP, 1995, ‘The neuropsychiatric sequelae of mercury poisoning: The Mad Hatter’s disease revisited’, British Journal of Psychiatry 167(1):95-98 (1995)
O’Kusky JR, Boyes BE, McGeer EG, ‘Methylmercury-induced movement and postural disorders in developing rat: regional analysis of brain catecholamines and indoleamines’, Brain Research1988 Jan 26;439(1-2):138-146
O’Neill JL, Through the Eyes of Aliens, Jessica Kingsley Publishers Ltd., 1999
O’Neill M, Jones RSP, ‘Sensory-Perceptual Abnormalities in Autism: A Case For More Research?’, Journal of Autism and Developmental Disorders, 1997, Vol. 27, No. 3, 283-293
O’Reilly BA and Waring, R, ‘Enzyme and sulfur oxidation deficiencies in autistic children with known food/chemical intolerances’, Journal of Orthomolecular Medicine 1993 4:198-200
Ono B, Sakamoto E, ‘Saccharomyces cerevisiae strains sensitive to inorganic mercury. I. Effect of tyrosene’, Curr Genet 1985;10(3):179-185
Ono B, Sakamoto E, Yamaguchi K, ‘Saccharomyces cerevisiae strains sensitive to inorganic mercury. III. Tyrosine uptake’, Curr Genet 1987;11(5):399-406
O'Reilly B, Waring R, 'Enzyme and Sulphur Oxidation Deficiencies in Autistic Children with Known Food/Chemical Intolerences', pp. 249-252
Ornitz EM, ‘Neurophysiologic Studies of Infantile Autism’, Handbook of Autism and Pervasive Developmental Disorders, John Wiley & Sons, Inc., 1987, 148-165
Otsuka H, 'Brain Metabolites in the Hippocampus-amygdala Region and Cerebellum in Autism: an 1H-MR Spectroscopy Study', Neuroradiology1999 Jul
Page T, Coleman M, ‘Purine metabolism abnormalities in a hyperuricosuric subclass of autism’, Biochim Biophys Acta, 2000 Mar 17;1500(3):291-296
Page T, Yu A, Fontanesi J, Nyhan WL, ‘Developmental disorder associated with increased cellular nucleotidase activity’, Proc. Natl. Acad. Sci. USA, Vol. 94, October 1997, 11601-11606
Paul R, ‘Natural History’, Handbook of Autism and Pervasive Developmental Disorders, John Wiley & Sons, Inc., 1987, 121-132
Pedersen MB, Hansen JC, Mulvad G, Pedersen HS, Gregersen M, Danscher G, ‘Mercury accumulations in brains from populations exposed to high and low dietary levels of methyl mercury. Concentration, chemical form and distribution of mercury in brain samples from autopsies’, Int J Circumpolar Health 1999 Apr;58(2): 96-107
Pediatrics 1999; 104:570-574, 'Thimerosal in vaccines: an interim report to clinicians', Committee on Infectious Disease and Committee on Environmental Health Pendergrass JC, Haley BE, Vimy MJ, Winfield SA, Lorscheider FL, ‘Mercury vapor inhalation inhibits binding of GTP to tubulin in rat brain: similarity to a molecular lesion in Alzheimer diseased brain’, Neurotoxicology 1997;18(2):315-324
Perry E, Lee M, Court J, Perry R, 'Cholinergic Activities in Autism: Nicotinic and Muscarinic Receptor Abnormalities in the Cerebral Cortex' , presentation to Cure Autism Now, 2000
Pfab R, Muckter H, Roider G, Zilker T, ‘Clinical course of severe poisoning with thiomersal’, Clinical Toxicology 1996;34(4):453-460
Pierce PE, Jon F. Thompson, MPH William H. Likosky, MD; Laurance N. Nickey, MD; William F. Barhtel; and Alan R. Hinman, MD, MPH, ‘Alkyl Mercury Poisoning in Humans’, JAMA 1972 Vol 220, No11 1439-1442
Piikivi L, Hanninen H, Martelin T, et al, ‘Psychological performance and long-term exposure to mercury vapors’, Scand. J. Work Environ. Health, 1984, 10:35-41
Piikivi L, Tolonen U, ‘EEG findings in chlor-alkali workers subject to low long term exposure to mercury vapor’, Br. J. Ind. Med., 1989, 46(6):370-375
Pink Disease Support Group, www.users.bigpond.com/difarnsworth Pirker C, Möslinger T, Wantke F, Götz, Jarisch R, ‘Ethylmercuric chloride: the responsible agent in thimerosal hypersensitivity’, Contact Dermatitis 1993:29:152-154
Piven J, Berthier M, Starkstein S, Nehme E, Pearlson G, Folstein S, ‘Magnetic resonance imaging evidence for a defect of cerebral cortical development in autism’, American Journal of Psychiatry, June 1990, 147:6, pp. 734-739
Piven J, Palmer P, ‘Psychiatric disorder and the broad autism phenotype: evidence from a family study of multiple-incidence autism families’, American Journal of Psychiatry, April 1999, Vol. 156, No. 4, pp. 557-563
Pless R, 'Summary of the Workshop on Thimerosal in Vaccines', Report from the National Immunization Program, CDC, 1999 Plioplys A, 'Autism: Biomedical Perspectives', Presentation for the Autism Society of America meeting, July 1989
Plioplys AV, Greaves A, Kazemi K, Silverman E, ‘Immunoglobin reactivity in autism and Rett’s syndrome’, Developmental Brain Dysfunction, 1994, 7:12-16
Plioplys AV, Greaves A, Kazemi K, Silverman E, ‘Lymphocyte function in autism and Rett Syndrome’, Neuropsychobiology 1994;29(1) :12-6
Plioplys AV, Hemmens SE, Regan CM, 'Expression of a neural cell adhesion molecule serum fragment is depressed in autism', J Neuropsychiatry Clin Neurosci, 1990 Fall;2(4):413-7
Plotkin S, Orenstein W, Vaccines 1999
Prechtl HFR, 'Neurological Findings in Newborn Infants after Pre- and Paranatal complications', Jonxis et al editors: Aspects of Prematurity and Dysmaturity: a Nutrica symposium, Leiden:Stenfert Kroesse, 1968
Prizant BM, ‘Brief Report: Communication, Language, Social, and Emotiuonal Development’, Journal of Autism and Developmental Disorders, 1996, Vol. 26, No. 2, 173-178
Purine Research Society, 'What We Learn About Metabolic Disease Will Benefit Each and Every One of Us', Purine Research Society Website Puschel G, Mentlein R, Heymann E, 'Isolation and characterization of dipeptidyl peptidase IV from human placenta', Eur J Biochem 1982 Aug;126(2):359-65
Rajanna B and Hobson M, ‘Influence of mercury on uptake of [3H]dopamine and [3H]norepinephrine by rat brain synaptosomes’, Toxicology Letters 1985 Sep 27(1-3):7-14
Rajanna B, Hobson M, Harris l, Ware L, Chetty CS, ‘Effects of cadmium and mercury on Na(+)-K+, ATPase and uptake of 3H-dopamine in rat brain synaptosomes’, Arch Int Physiol Biochim 1990 Oct;98(5):291-296
Rice D, 'Lack of Effect of Methylmercury Exposure from Birth to Adulthood on Information Processing Speed in the Monkey', September 1997
Rice DC, ‘Sensory and cognitive effects of developmental methylmercury exposure in monkeys, and a comparison to effects in rodents’, NeuroToxicol.,1996, 17:139-154
Rice DC, Gilbert SG, ‘Early chronic low-level methylmercury poisoning in monkeys impairs spatial vision’ Science 1982 May 14;216(4547):759-761
Richdale AL, 'Sleep problems in autism: prevalence, cause, and intervention', Developmental Medicine and Child Neurology, 1999 Jan 41(1):60-6
Rimland B, ‘Recovery from autism is possible’, cited in Autism Research Review International, 1994, Vol. 8, No. 2, p. 3
Rimland B, Baker SM, ‘Brief Report: Alternative Approaches to the Development of Effective Treatments for Autism’, Journal of Autism and Developmental Disorders, 1996, Vol. 26, No. 2, 237-241
Ritvo ER, Freeman BJ, Scheibel AB, Duong T, Robinson H, Guthrie D, Ritvo A, 'Lower Purkinje cell counts in the cerebella of four autistic subjects: intitial findings of the UCLA-NSAC Autopsy Research Report', American Journal of Psychiatry, 1986;143:862-866
Ritvo ER, Freeman BJ, Creel D, Crandall AS, Pingree C, Barr R, Realmuto G, ‘Retinal Pathology in Autistic Children - A Possible Biological Marker for Subtype?’ (letter), Journal of the American Academy of Child Psychiatry, January 1986, 25:137
Rodier PM, Ingram JL, Tisdale B, Croog VJ, ‘Linking etiologies in humans and animal models: studies of autism’, Reproductive Toxicology, 1997, Vol. 11, Nos. 2/3, pp. 417-422
Rogers SJ, ‘Brief Report: Early Intervention in Autism’,Journal of Autism and Developmental Disorders, 1996, Vol. 26, No. 2, 243-246
Rogers T, Kalaydjieva, Hallmayer et al, 'Exclusion of Linkage to the HLA Region in Ninety Multiplex Sibships with Autism', Journal of Autism and Developmental Disorders, 1999 Jun;29(3):195-202
Rohyans J, Walson PD, Wood GA, MacDonald WA, ‘Mercury toxicity following merthiolate ear irrigations’, The Journal of Pediatrics, 1984 Feb:311-313
Romani L, ‘Immunity to Candida albicans: Th1, TH2 cells and beyond’, Curr Opin Microbiol 1999 Aug;2(4): 363-367
Rosenhall U, Johansson E, Gillberg C, ‘Oculomotor findings in autistic children’, Journal of Laryngology and Otology, May 1988, Vol. 102, pp. 435-439
Rosenhall U, Nordin V, Sandstrom M, Ahlsen G, Gillberg C, 'Autism and Hearing Loss', Journal of Autism and Developmental Disorders, Oct 1999 29(5) 349-358
Ross W. Donald, Gechman A, Sholiton M, Paul H, 'Alertness to Neuropsychiatric Manifestations', Comprehensive Psychiatry, Vol. 18, No. 6, pp. 595-598
Rossi AD, Ahlbom E, Ogren So, Nicotera P, Ceccatelli S, ‘Prenatal exposure to methylmercury alters locomotor activity of male but not female rats’, Exp Brain Res 1997 Dec;117(3):428-436
Roux S, Adrien J-L, Bruneau N, Malvy J, Barthelemy C, 'Behavior Profiles within a population of 145 children with autism using the Behaviour Summarized Evaluation scale: influence of Developmental age', Autism, 1998 (Dec) 2(4) 235-266
Rumsey J, ‘Conceptual problem-solving in highly verbal, nonretarded autistic men’, Journal of Autism and Dev. Disorders, 1985, Vol. 15, No. 1, pp. 23-36
Rumsey JM, Hamburger SD, ‘Neuropsychological findings in high-functioning men with infantile autism, residual state’, Journal of Clinical and Experimental Neuropsychology, 1988, Vol. 10, No. 2, pp. 201-221
Russell J, Jarrold C, Hood B, ‘Two Intact Executive Capacities in Children with Autism: Implications for the Core Executive Dysfunctions in the Disorder’, Journal of Autism and Developmental Disorders, 1999, Vol. 29, No. 2, 103-112
Rutter M, 'Autism research: prospects and priorities', Journal of Autism and Developmental Disorders 1996 Apr;26(2):257-75
Rutter M, ‘The development of infantile autism’, Psychological Medicine 1974 4:147-163
Ryu YH, Lee JD, Yoon PH, Kim DI, Lee HB, Shin YJ, ‘Perfusion impairments in infantile autism on technetium-99m ethyl cysteinate dimer brain single-photon emission tomography: comparison with findings on magnetic resonance imaging’, Eur J Nucl Med 1999 Mar;26(3):253-259
Sager. P.R., Aschner, M., and Rodier, P.M. Persistent differential alteration in developing cerebellar cortex of male and female mice after methylmercury exposure. Dev. Brain Res. 12: 1-11 (1984)
Sakamoto E, Urata H, Ono B, ‘Saccharomyces cerevisiae strains sensitive to inorganic mercury. II. Effect of glucose’, Curr Genet 1985;10(3):187-195
Sarafian TA, Bredesen DE, Verity MA, ‘Cellular resistance to methylmercury’, Neurotoxicology, 1996 Spring Abstract, 17(1):27-36
Sayers LG, Brown GR, Michell RH, Michelangeli F, ‘The effects of thimerosal on calcium uptake and inositol 1,4,5-triosphate-induced calcium release in cerebellar microsomes’, Biochem J 1993 Feb 1;289 (Pt 3):883-887
Scheyer RD, 'Involvement of Glutamate in Human Epileptic Activities', Prog Brain Res, 1998, Vol. 116, pp. 359-369
Schuler AL, ‘Thinking in Autism: Differences in Learning and Development’, Teaching Children with Autism, Kathleen Ann Quill, ed., 1995, 11-32
Sears LL, 'An MRI Study of the Basal Ganglia in Autism', Prog Neuropsychopharmacol Biol Psychiatry, 1999 May
Shafer TJ, Atchison WD, ‘Transmitter, ion channel and receptor properties of pheochromocytoma (PC12) cells: a model for neurotoxicological studies’, Neurotoxicology 1991 Fall;12(3):473-492
Shattock P, Savery D, Autism as a Metabolic Disorder, Autism Research Unit, University of Sunderland, Sunderland, UK, 1997
Shenker BJ, Datar S, Mansfield K, Shapiro IM, ‘Induction of apoptosis in human T-cells by organomercuric compounds: a flow dytometric analysis’, Toxicol Appl Pharmacol, April 1997, 143(2): 397-406
Shenker BJ, Guo TL, Shapiro IM, ‘Low-level methylmercury exposure causes human T-cells to undergo apoptosis: evidence of mitochondrial dysfunction’, Environmental Research, 1998 May; Section A 77(2):149-159
Shenker, B.J., Berthold, P., DeBolt, K., Rooney, C., Vitale, L.A., and Shapiro, I.M. (1992). Immunotoxic effects of mercuric compounds on human lymphocytes and monocytes. II. Alterations in cell viability. Immunopharm. Immunotox. 14, 555-577.
Shenker, B.J., Berthold, P., Decker, S., Mayro, J.S., Rooney, C., Vitale, L.A., and Shapiro, I.M. (1993). Immunotoxic effects of mercuric compounds on human lymphocytes and monocytes. III. Alterations in B-cell function and viability. Immunopharm. Immunotox. 15, 87-112.
Siegel BV, Nuechterlein KH, Abel L, Wu JC, Buchsbaum MS, ‘Glucose metabolic correlates of continuous performance test performance in adults with a history of infantile autism, schizophrenics, and controls’, Schizophrenia Research 1995 Sep 17(1):85-94
Sigman M, Ungerer JA, Mundy P, Sherman T, ‘Cognition in Autistic Children’, Handbook of Autism and Pervasive Developmental Disorders, John Wiley & Sons, Inc., 1987, 103-130
Singh VK, 'Plasma increase of Interleuken-12 and Interferon-gamma. Pathological significance in autism', J Neuroimmunology, 1996 May;66(1-2):143-5
Singh VK, Warren RP, Odell D, 'Immune response to brain myelin in autistic children', July 1992
Singh V, Warren R, Odell J, Warren W, Cole P, 'Antibodies to myelin basic protein in children with autistic behavior', Brain, Behavior and Immunity, 1993 Mar;7(1):97-103
Singh VK et al, Biological Psychiatry 1997 41: 753-755
Singh VK, Fudenberg HH, Emerson D, Coleman M, ‘Immunodiagnosis and immunotheraphy in autistic children’, Annals of the New York Academy of Science, 540, 1988, 602-604
Singh VK, Journal of Neuroimmunology 1996 66: 143-145
Singh,VK et al, Brain, Behavior and Immunity 1993 7: 97-103
Smalley SL, Collins F, ‘Brief Report: Genetic, Prenatal, and Immunologic Factors’, Journal of Autism and Developmental Disorders, 1996, Vol. 26, No. 2, 195-198
Smith D., 'Mental Effects of Mercury Poisoning', Presentation before the Section on Family Practice, Southern Medical Association, 71st Annual Scientific Assembly, November 6-9, 1977
Snyder RD. ‘The involuntary movements of chronic mercury poisoning’, Archives of Neurology 1972;26:379-3381.
Sperry VW, 'Family and personal section: From the inside out - a view of the world as seen by one with Asperger syndrome', Autism, 1998 Marc;2(1):81-86
Sternberg RJ, 'A Unified Theoretical Perspective on Autism', Handbook of Autism and Pervasive Developmental Disorders, Cohen DJ, Donnellan AM, Paul R, eds, 1987 by John Wiley & Sons, p.690-696
Stevenson RE, Schroer RJ, Skinner C, Fender D, Simensen RJ, 'Autism and macrocephaly', Lancet, 1997, 349:1744-1745
Stores G, Wiggs L, 'Abnormal sleeping patterns associated with autism: a brief review of research findings, assessment methods and treatment strategies', Autism, 1998 Jun;2(2):157-170
Stubbs EG, ‘Autistic children exhibit undetectable hemagglutination-inhibition antibody titers despite previous rubella vaccination’, Journal of Autism and Childhood Schizophrenia, 6, 269-274, 1976
Sutton KG, McRory JE, Guthrie H, Murphy TH, Snutch TP, 'P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-1A', Nature 1999 Oct 21;401(6755):800-4
Szasz A, Barna B, Szupera Z, De Visscher G, Galbacs Z, Kirsch-Volders M, Szente M, ‘Chronic low-dose maternal exposure to methylmercury enhances epileptogenicity in developing rats’, Int J. Devl Neurosci, 1999, 17.7.733-742
Szatmari P, Bartolucci G, Bremner R, Bond S, Rich S, ‘A follow-up study of high-functioning autistic children’, Journal of Autism and Developmental Disorders, June 1989, Vol. 19, No. 2, pp. 213-225
Tan XX, Tang C, Castoldi AF, Manzo L, Costa LG, ‘Effects of inorganic and organic mercury on intracellular calcium levels in rat T lymphocytes’, Journal of Toxicology & Evironmental Health, 1993 Feb;38(2):159-170
Teitelbaum P, Teitelbaum O, Nye J, Fryman J, Maurer RG, ‘Movement analysis in infancy may be useful for early diagnosis of autism’, Proc. Natl. Acad. Sci. USA, Vol. 95, November 1998, 13982-13987
The MAAP, Volume IV, 1996; Volume VI, 1996; Volume III, 1999; Volume IV, 1997; Volume II, 1997; Volume I, 1997; Volume II, 1998; Volume IV, 1998, MAAP Services, Inc., PO Box 524, Crown Point, IN 46308
Thrower EC, Duclohier H, Lea EJ, Molle G, Dawson AP, ‘The inositol 1,4,5-trisphosphate-gated Ca2+ channel: effect of the protein thiol reagent thimerosal in channel activity’, Biochem J 1996 Aug 15;318 (Pt 1): 61-66
Tokuomi H. Uchino M. Imamura S. Yamanaga H. Nakanishi R. Ideta T, ‘Minamata disease (organic mercury poisoning): Neuroradiologic and electrophysiologic studies’, Neurology 1982;32:1369-1375
Tonge BJ, Brereton AV, Gray KM, Einfeld SL, 'Behavioural and emotional disturbance in high-functioning autism and Asperger's syndrome', Autism, 1999 Jun;3(2):117-130
Trottier G, Srivastava L, Walker CD, ‘Etiology of Infantile Autism: a review of recent advances in genetic & neurobiological research’, Journal of Psychiatry & Neuroscience, 1999 March 24(2):103-115
Tsai LY, 'Brief Report: Comorbid Psychiatric Dosorders of Autistic Disorder', Journal of Autism and Developmental Disorders, April 1996 26(2)159-164
Tuunanen J, Halonen T, Pitkanen A, ‘Decrease in somatostatin-immunoreactive neurons in the rat amygdaloid complex in a kindling model of temporal lobe epilepsy’, Eiplepsy Res, 1997, 26.315-327
Tuunanen J, Halonen T, Pitkanen A, ‘Status epilepticus causes selective regional damage and loss of GABAergic neurons in the rat amygdaloid complex,’ Eur J Neurosci, 1996, 8:2711-2725
Tuunanen J, Lukasiak K, Halonen T, Pitkanen A, ‘Status epilepticus-induced neuronal damage in the rat amygdaloid complex: distribtuion, time-course and mechanisms’, Neurosci, 1999, 94.2.473-495
Uchida T, Naito S, Kato H, Hatano I, Harashima A, Terada Y, Ohkawa T, Chino F, & Eto K, ‘Thimerosal induces toxic reaction in non-sensitized animals’, International Archives of Allergy & Immunology, 1994 104(3):296-301
Vahter M, Mottet NK, Friberg L, Lind B, Shen DD, Burbacher T, ‘Speciation of mercury in the primate blood and brain following long-term exposure to methyl mercury’, Toxicol Appl Pharmacol, 1994 Feb;124(2):221-229
Volterra A, Trotti D, Cassutti P, Tromba C, Salvaggio A, Melcangi RC, Racagni G, ‘High sensitivity of glutamate uptake to extracellular free arachidonic acid levels in rat cortical synaptosomes and astrocytes’, Journal of Neurochemistry 1992 Aug 59(2):600-606
Von Burg R, Rustam H, ‘Conduction Velocities in Methylmercury Poisoned Patients’, Bulletin of Environmental Contamination & Toxicology, 1974, 12(1):81-85
Von Burg R, Rustam H, ‘Electrophysiological Investigations of Methylmercury Intoxication in Humans. Evaluation of Peripheral Nerve by Conduction Velocity and Electromyography’, Electroencephalography and Clinical Neurophysiology, 1974, 37:381-392
Vostanis P, Smith B, Corbett J, Sungum-Paliwal R, Edwards A, Gingell K, Golding R, Moore A, Williams J, ‘Parental concerns of early development in children with autism and related disorders’, Autism, September 1998, Vol. 2, No. 3, 229-242
Vroom FQ, Greer M, 'Mercury Vapour Intoxication', Brain (1972) 95, 305-318
Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Chillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA, ‘Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children’, The LANCET, February 28, 1998, Vol. 351, 637-641
Warfvinge K, Hua J, Logdberg B, 'Mercury distribution in cortical areas and fiber systems of the neonatal and maternal cerebrum after exposure of pregnant squirrel monkeys to mercury vapor', Environ Res 1994 Nov;67(2):196-208
Warkany J, Hubbard DH, 'Acrodynia and Mercury', J Pediatrics 1953 42;365-386
Warren RP, Margaretten NC, Foster A, ‘Reduced Natural Killer Cell Activity in Autism’, Journal of the American Academy of Child and Adolescent Psychiatry, 1987, Vol. 26, No. 3, pp. 333-335
Warren RP, Margaretten NC, Pace NC, Foster A, ‘Immune Abnormalities in Patients with Autism’, Journal of Autism and Developmental Disorders, 1986, Vol. 16, No. 2, pp. 189-197
Warren RP, Odell JD, Warren WL, Burger RA, Maciulis A, Daniels WW, Torres AR, ‘Strong association of the third hypervariable region of HLA-DRß1 with autism’, Journal of Neuroimmunology 67 (1996) 97-102
Warren RP, Yonk LJ, Burger RA, Cole P, Odell JD, Warren WL, White E, Singh VK, 'Deficiency of Suppressor-inducer (CD4+CD45RA+) T Cells in Autism', Immunological Investigations, 1990 Jun 19(3):245-251
Watanabe C, Kasanuma Y, Dejima Y, Satoh H, ‘The effect of prenatal nethylmercury exposure on the GSH level and lipid peroxidation in the fetal brain and placenta of mice’, Tohoku J Exp Med 1999 Feb;187(2):121-126
Watzl B, Abrahamse SL, Treptow-van Lishaut S, Neudecker C, Hansch GM, Rechkemmer G, Pool-Zobel BL, 'Enhancement of ovalbumin-induced antibody production and mucosal mast cell response by mercury', Food Chem Toxicol 1999 Jun;37(6):627-37
Wecker L, Miller SB, Cochran SR, Dugger DL, Johnson WD, ‘Trace Element Concentrations in Hair From Autistic Children’, J. Ment Defic. Res. (1985) 29, 15-22
Weitzman A, Weisman R, Szekely GA, Wijsenbeek H, Livni E, 'Abnormal immune response to brain tissue antigen in the syndrome of autism', Am J Psychiatry 1982 Nov;139(11):1462-5
Whiteley P, Rogers J, Shattock P, ‘Clinical features associated with autism: observations of symptoms outside the diagnostic boundaries of autistic spectrum disorders’, Autism, December 1998, Vol. 2, No. 4, 415-422
Wild GC, Benzel EC, Essentials of Neurochemistry, Jones and Bartlett Publishers, Inc., 1994
Williams D, Autism - An Inside-Out Approach, 1996, Jessica Kingsley Publishers Ltd, London
Wing L, Attwood A, ‘Syndromes of Autism and Atypical Development’, Handbook of Autism and Pervasive Developmental Disorders, John Wiley & Sons, Inc., 1987, 3-19
Wing, Lorna (1996) ‘Autism Spectrum Disorder’, British Medical Journal 312: 327-328
Wu J, Takeo T, Kamimura N, Wada J, Suga S, Hoshina Y, Wakui M, ‘Thimerosal modulates te agonist-specific cytosolic Ca2+ oscillatory patterns in single pancreatic acinar cells of mouse’, FEBS Lett 1996 Jul 22;390(2):149-152
Yamagata T, 'FRAXE mental retardation', Nippon Rinsho 1990 Apr;57(4):955-9
Yard BA, Lorentz CP, Herr D, and Van Der Woude F, ‘Sulfation-dependent down-regulation of interferon-gamma-induced Major Histocompatibility Complex I and II Intercellular Adhesion Molecule-1 expression on tubular and endothelial cells by glycosaminoglycans’, Transplantation Vol.66(9), November 15, 1998, pp. 1244-1250
Yazbak FE, ‘Autism ‘99, a national emergency’, http://www.garynull.com/documents/autism_99.htm (Internet publication) 1999
Yeates KO & Mortensen ME, ‘Acute and chronic neuropsychological consequences of mercury vapor poisoning in two early adolescents’, Journal of Clinical Exp Neuropsychology, 1994 16(2):209-222
Yip RK, Riley DA, ‘Effects of methylmercury on the motor and sensory and innervation of the rat extensor digitorum longus muscle’, Environ Res 1987 Jun;43(1):85-96.
Yuan Y, and Atchison WD, ‘Comparative effects of methylmercury on parallel-fiber and climbing fiber responses of rat cerebellar slices’, Journal of Pharmacology and Experimental Therapy 1999 Mar;288(3):1015-1025.
Zimmerman A, Brashear R, Frye V, Potter N, 'Anticerebellar Antibodies in Autism', pp. 275-276 Zimmerman A, Frye VH, Potter NT, ‘Immunological aspects of autism’, International Journal of Pediatrics, 8, 1993, 199-204
Zimmerman AW, Gonfardin B, Myers SM, Neuropharmacological therapy in autism, Autism: Clinical and Research Issues, ed. Pasquale Accardo, et al., Timonium, MD: York Press, 1996