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.

ABSTRACT & SYNOPSIS
TABLE OF CONTENTS
AUTISM-MERCURIALISM COMPARISONS

INTRODUCTION
Autism
Mercury
Diagnosing Mercury Poisoning in Autism

I. SYMPTOM COMPARISON
a. Affect/Psychological Presentation
b. Language & Hearing
c. Sensory Perception
d. Movement/Motor Function
e. Cognition/Mental Function
f. Behaviors
g. Vision
h. Physical Presentations
j. Gastrointestinal Function

II. COMPARISON OF BIOLOGICAL ABNORMALITIES
a. Biochemistry
b. Immune System
c. CNS Structure
d. Neurons & Neurochemicals
e. EEG Activity/Epilepsy

III. MECHANISMS, SOURCES & EPIDEMIOLOGY OF EXPOSURE
a. 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
Case Studies
Discussion

DISCUSSION
Diagnostic Criteria Are Met
Unique Form Would be Expected, Implicates Vaccinal Thimerosal
Historical Precedent Exists
Barriers Preventing Earlier Discovery Are Removed

MEDICAL & SOCIETAL IMPLICATIONS
Affected Population
Other Disorders
Vaccination Programs

REFERENCES

Mercury
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).

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).

1. 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).

2. 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).

3. 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).

4. 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).

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).

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.

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)

.

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).

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.

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).

f. Behaviors
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).

g. Vision
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).

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).

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).

II. COMPARISON OF BIOLOGICAL ABNORMALITIES

a. Biochemistry
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.

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).