Research Article 

Translation

 

Autism Spectrum Disorders - Exogenous Protein Insult (Hev-b)

Michael J. Dochniak

 

                                                                                                                                       

     1.       Introduction                                        
    
2.       Background
    3.       Discussion
    4.       Incidence
                
4.1     Timing
                
4.2     Frequency
                
4.3     Intensity
                4.4     Type of Exposure
    
5.       Gender
    
6.       Endorphins
    7.       Neurotransmitters/Neuromodulators
    
8.       Vaccines
    
9.       Hev-b Protein Elucidation
    
10.     Isoprenoids and Cholesterol
    
11.     Cysteine & Proteins
    
12.     Spina Bifida
    
13.     Hev-b Toxicity
    
14.     Sleep
    
15.     Hearing
    
16.     Touch Allodynia
    
17.     Regressive Autism
    
18.     Other NRL Induced Cross-Reactivity
    
19.     Infection & Allergy
    
20.     Fever
    
21.     Hev-b Proteins and ASD
                
21.1     Hev-b 1
                
21.2     Hev-b 2, 7, 13
                
21.3     Hev-b 5
                
21.4     Hev-b 6
                
21.5     Hev-b 8
                
21.6     Hev-b 9
                
21.7     Hev-b 10
                
21.8     Hev-b 11
    22
.     Food-stuff Proteins and NRL
    
23.     Maternal/Fetal IgE
    24
.     Blood Type
    25
.     Antibody Formation & Decay
    26
.     IgE and Evolution
    27
.     Allergy Testing & Immunotherapy
    28
.     Candidate Gene Loci, Epigenetics, Sporadic
    
29.     Iatrogenic Autism
    30.     Oxytocin and Natural-Latex Allergy
    31.     Medical History (Natural-Latex Allergy & Autism)
    32.     Gut Microflora and Allergy Induced Autism
    33.     Falsifiable Hypothesis
    34.     Hev-b Protein Standards
    35.     Miscellaneous
 
    36.     Natural-Latex Waste Disposal
    37.     Conclusion
    
38.     Father of Autism Spectrum Disorders
    
39.     Acknowledgments
    40.     Admonishment
    41      Apology
    42
.     References

1.     Introduction 

     The immune-response perspective described herein is intended to explore how certain environmental proteins may affect neuro-cognitive development in children.  Specifically, proteins inherent in natural rubber latex (NRL) are known to cause severe and pervasive immune responses.  More specifically, the Hev-b proteins in NRL may trigger IgE [ 1 ] mediated reaction antibodies and influence cross-react immune responses [ 2 ] to other exogenous/endogenous proteins. 

     In adults, repeated exposure to Hev-b proteins has been shown to cause an increased incidence of sensitization, adverse allergic reactions, and even death through anaphylactic shock.  There has not been sufficient research to determine how such non-infectious antigenic proteins affect prenatal/neonatal development. 

     NRL has seen a dramatic increase in usage over the last 30-years (e.g., health care industry, consumer products).  Prenatal/Neonatal exposure to such proteins may affect neuro-cognitive development through cross-react immune-responses to endogenous proteins.  The timing, frequency, intensity, and type of exposure to such proteins may influence the incidence, degree of atypicality, and prevalence of classical/regressive autism spectrum disorders (ASD).

     Therefore, research efforts should be directed at exploring how immune responses to such proteins affect lymphocyte sensitivity, enzyme regulation, and neural formation during prenatal/neonatal development.

2.     Background

     Some on the autism spectrum have severe and pervasive impairment in thinking, feeling, language, and the ability to relate to others.  Autism is usually first diagnosed in early childhood and range from a severe form called Autistic Disorder Not Otherwise Specified to a much milder form called Aspergers Syndrome. [ 3 ]  Alternatively, some on the autism spectrum have exceptional cognitive skills without impairment in feeling, language, and often relate well with others. [ 4 ]

     Most recently, there has been an epidemic of developmental, learning and behavioral disabilities in children.  It is estimated that about seventeen percent of children in the United States currently suffer from such disabilities.  With autism, a study suggests that the apparent rise in numbers is not the result of "Diagnosis Shifting".  ASD is increasing with successively younger children, particularly those born between 1987 and 1992. [ 5 ]  In contradiction, a paper published in the American Psychological Society describes three reasons not to believe in an autism epidemic [ 6 ]

     It is generally recognized that repeated exposure to certain materials may affect neuro-cognitive development in children.  For example, toxic metals including aluminum, antimony, arsenic, cadmium, lead, and mercury may affect chemical synaptic transmissions in the brain and in the peripheral nervous system. [ 7]  Furthermore, antigenic proteins trigger IgE [ 8 ] mediated reaction antibodies that cause mast cells and basophils to release histamine.

     Allergy induced autism is an area of research wherein immune responses to certain foodstuff proteins and/or certain environmental materials (e.g., dust, pollen, molds, animal dander, and tiny microorganisms called mites) may affect some of the symptoms of ASD. [ 9] - A recent study has shown that levels of blood markers for allergies were significantly higher in children compared to parents. [ 10]     

     Although the materials described above may affect neuro-cognitive development, it is reasonable to assume that exposure to such materials, on a global scale, has not substantially increased over the last 30-years.  An immune responsive material that has dramatically presented itself over the last 30-years are the Hev-b proteins inherent in natural rubber latex. 

     NRL is a milky white extract from trees and bushes including the Hevea Brasiliensis [ 11 ] and Sapotaceae. Tapping a rubber tree involves cutting channels into the bark (controlled wounding) and bleeding out the milky white extract.  Natural latex is produced by special cells called laticifiers and is thought to be a defense against insect pathogens and possibly a site for the depositing of metabolic waste of the tree. [ 12 



     It is well known that the Hev-b proteins [ 13 , 14] present in NRL may cause allergic reactions.  Repeated exposure to these allergens through inhalation and/or dermal absorption has been shown to cause an increased incidence of sensitization, adverse allergic reactions, and death through anaphylactic shock.  For example, health care workers have experienced an increased number of sensitization's and deaths from natural-rubber-based gloves in an attempt to reduce the accidental spread of viral infections including Autoimmune Deficiency Syndrome (i.e., AIDS).  Because of such worker exposure data, NRL is currently recognized as a hazardous material by the National Institute for Occupational Safety and Health (NIOSH). [ 15 ]

    A recent study concluded that the frequency of allergic manifestations is increased in autistic children. [ 15.1 ]  

3.     Discussion

     It has been estimated that approximately five percent of the population have an allergic reaction to the Hev-b proteins in NRL.  The adversity of such reactions is often influenced by the timing, frequency, intensity, and type of exposure.  Efforts have been made to deproteinize NRL [ 16 , 16.1 ] but a significant number of highly atopic individuals remain hypersensitive to even minute quantities of the allergens. 

     A guayule rubber producing plant, having inherently reduced protein content, is currently being evaluated as a potential hypoallergenic alternative to Hevea Brasiliensis [ 17 ]  The major protein in guayule rubber (~50% protein total) is cytochrome P-450 which has been shown to have ~25% homology to other cytochrome P-450. [ 1819 ]  

     Children are often exposed to products formed from NRL.  For example, prenatal/neonatal exposure during routine hospital visits
 [ 2021 ] (e.g., iatrogenic allergy associated with the Hev-b proteins in natural-latex gloves), adhesives [ 22 ], food packaging [ 23 ], nipples for baby bottles [ 24 ], pacifiers, diapers, mattresses [ 25], bed pads, balloons, teething articles, toys, rubber bands, pencil erasers, carpet padding, sporting equipment, and septum-capped medicinal vials (e.g., vaccines) are often formed from NRL.

     With medicinal vials, Hopkins Researchers Encourage FDA and Pharmaceutical Companies to End NRL Stopper Use. [ 26 ]  A single exposure may cause an immune response and a study investigating NRL allergy in children concluded that the prevalence is about 1% among atopic children. [ 27 ]

     It is known that proteins in foodstuff that are homologous to Hev-b proteins may cross-react with IgE antibodies induced by NRL. For example, one study showed that almost 50% of patients with NRL allergy showed food allergy. [ 28 Compared to other antibodies free-floating in the blood stream, IgE has low concentration (~ 0.001%) and a short half-life (~ 2-days) [ 29

     IgE antibodies are specific to a select group of antigens, rather than a wide range, and are extremely biologically active despite low concentrations in circulation. This is because IgE antibodies bind to high-affinity receptors on the surface of mast cells and basophils, so that these cells may be highly sensitive to antigens even when the concentration of IgE in the circulation is very low.  Thus, unlike other immunoglobulin (Ig), IgE plays a major role in reactivity to an antigen. The degree of IgE selectivity may play a critical role in the onset of ASD.  For example, an immune response associated with Hev-b proteins may induce IgE-secreting lymphocytes (e.g., plasma B-cells and memory B-cells [ 30 ] ) to form antibodies that target dissimilar exogenous/endogenous proteins through the cross-react mechanism. 

     Immune response during prenatal/neonatal development may affect lymphocyte sensitivity and neural formation.  For example, neuron growth factor (NGF) is a protein critical for the survival and maintenance of sympathetic and sensor neurons.  A study has shown that circulating NGF levels are increased in humans with allergic diseases. [ 31 ]  Furthermore, a study has shown that increased levels of NGF proteins induce growth and differentiation of human B lymphocytes [ 32 ] and NGF expression has been linked to autism. [ 33 ]  An infant may be more susceptible to NGF in that the blood brain barrier is not fully developed compared to adults.

    NGF has been observed in human saliva [ 33.05 ]; in speculation, if the over-expression of NGF plays a role in allergy-induced-autism neonatal saliva testing may be a useful non-invasive medical procedure to determine if a child is susceptible to the development of an autism spectrum disorder.     

    The 1986 Nobel Prize in Medicine was awarded to Stanley Cohen and Rita Levi-Montalcini for work showing that NGF is an extremely potent biological substance for the growth of sensory and sympathetic nerves. [ 33.1 ]

    It is known that NGF plays a critical role in the development of the sympathetic nervous system. [ 33.2 ]  We therefore can ask the question:

Q.    Does an over expression of NGF, induced by hyper adaptive-immunity, affect sympathetic nervous system development and the incidence of allergy induced autism. 

    Adding clarity to the mechanisms of neurological development it has been proposed that the elimination of synapses (i.e., pruning) may be universal to all neural systems and that the patterned connections within the brain are based solely on large-scale regressive events. [ 33.3 ]  Pruning, or loss of synapses in the absence of cell death, is thought to be influenced by the expression of neurotrophic factors including NGF.  Specifically, an over-expression of NGF may affect the pruning mechanism resulting in over-connectivity.  Recent studies indicate overconnectivity in ASD. [ 33.4

     Finally, the best means to eliminate the incidence and prevalence of natural-latex allergy is avoidance.  All products that come into contact with individuals having a developing nervous system should be reviewed for NRL in that the critical period for the development of the brain is from about three weeks to about sixteen weeks, although major structures of the brain continue to develop throughout childhood.  Specifically, non-infectious antigenic proteins such as the Hev-b proteins can induce atypical immune responses and should be avoided especially during prenatal/neonatal development.

4.     Incidence

     Approximately 85% of the world's NRL comes from the Far East.  The three largest producers in 2004 were Thailand, Indonesia, and Malaysia.  All three countries have reported that the incidence of ASD is increasing at an alarming rate.  For example, in Thailand it is estimated that about 10% of the student population has developmental, learning and behavioral disabilities.

     The world's three largest importers of NRL are China, U.S.A., and Japan.  These countries have also reported that the incidence of ASD is increasing at an alarming rate.  For example, in the United States the largest user of NRL is the state of Ohio.  Researcher's have reported a 6,822% increase in ASD in Ohio from 1992-1999. [ 34 ]  Other states that have seen a dramatic increase in ASD include Oregon, Minnesota, and Maine all of which have industries that are significant users of NRL.  Although products formed from NRL are used extensively around the world, the primary producers and users described above may be experiencing an increased incidence of allergy induced autism due to acquired Hev-b protein immunity.

     On the other extreme, communities that are less likely to use products formed from NRL have shown an astonishingly low autism rate.  For example, the ASD rate for Amish around Middlefield, Ohio, is 1 in 15,000.  Researchers have also found scant evidence of ASD among sizable Amish settlements in Indiana and Kentucky. [ 35

     Atopy in a U.S. Amish population has been studied.  Sib-pair analysis of 170 individuals from 11 Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum IgE.  The study suggests that IgE or a nearby gene in 5q31.1 regulates IgE production in a nonantigen-specific (noncognate) fashion [ 36 ] indicating that the Amish population is not resistant to atopy. 

     It is speculated that the factors that may influence the incidence, degree of atypicality, and prevalence of ASD may be related to timing, frequency, intensity, and type of exposure to the Hev-b proteins in NRL:

     4.1     Timing

     The central nervous system (CNS) is known to be susceptible to environmental insult (e.g., toxins and allergens) especially during prenatal/neonatal development. [ 37]  The CNS is particularly vulnerable at this stage in that there is a proliferation of nerve cell reproduction, growth, and migration.  A study indicates that allergen exposure and sensitization during pregnancy favor the development of atopy in the neonate [ 38 ]  In humans, repeated exposure to the antigenic proteins during pregnancy may affect the genetic code of immune cells making the fetus more susceptible to ASD. [ 39 

    A study has indicated that 75% of people with a natural-latex allergy are female [ 40 ] and this is possibly due to a higher proportion of women in the exposed population.  For example, additional exposure risks may arise from: a) obstetric procedures; b) gynecological examinations; c) contact with contraceptives; and d) certain female professions (e.g., doctors, nurses, scientists) which carry an increased risk of occupational exposure to the Hev-b proteins.  Thus, prenatal exposure to the Hev-b allergens may affect the incidence of allergy induced autism. 

     In contradiction, a study that evaluated house dust mite (HDM)-specific IgE and IgG4 concluded that the priming of TH2 responses associated with persistent HDM-IgE production occurs entirely postnatally, as HDM reactivity in cord blood seems nonspecific and is unrelated to subsequent development of allergen-specific TH2 memory or IgE.  The researcher's suggested that these findings question the scientific basis for existing recommendations for allergen avoidance by high-risk women during pregnancy [ 41 

     4.2     Frequency

     The frequency of exposure to the Hev-b proteins from NRL continues to rise.  For example, approximately 25% of the rubber used today comes from rubber trees while 75% are petroleum based (i.e., synthetic rubbers).  Global conflicts, politics, and petroleum supplies continue to affect the price and availability of synthetic rubbers making the use of natural rubber more desirable.

     Over the past 43 years, the world NRL consumption has grown at an average of 4.2% per year, increasing to an estimated 925,000 tonnes in 2003.  However, the growth was not smooth; NRL consumption had a slower growth period from 1960 to 1983, with an average growth rate of 2.1% per year and a faster growing period from 1984 to 2003, averaging 5.6% per year.  In terms of actual tonnage the increase was 159,000 tonnes and 597,000 tonnes for the respective periods.

     The main driving force of the faster growth rate of the latter period was and still is the AIDS-HIV threat and the consequent growing awareness of the need for protection, reflected in the rapid rise of demand for medical gloves, in particular, since the mid-1980s.  Gloves were the main reason for the rising NRL uptake over the past 20 years; it was and still is playing the leading role in the natural-latex world. The product range of NRL is wide and varied, ranging from industrial, household, and medical applications.

     Currently, it is estimated that more than 40,000 products contain NRL.  Another example of a pervasive source of exposure to NRL for children and adults is automobile tires.  Disposal of spent tires continues to be an environmental concern in that such materials are not easily recycled and disposal through incineration is often not cost effective due to the proper handling of pyrolytic byproducts including airborne particulate and toxic gases.  Efforts have been made to find new uses for spent automobile tires wherein they are ground into crumb rubber and used as filler in gardens or as playground surfaces.  Although such efforts are well intended, these practices continue to increase Hev-b protein exposure to the general population.

    Unfortunately, the U.S. Environmental Protection Agency (EPA) is also involved in the promotion of recycled natural rubber latex.  [41.5 ]  The use of crumb rubber from recycled tires has been touted by the EPA and a number of state environmental agencies as having beneficial impact on the environment.  [ 41.6

    A specific example wherein the United States Government is involved in the recycling of natural rubber latex, without regard for the antigenic proteins therein, is in U.S. Pat. 6,407,144.  In the Government Interests section of the patent it states, "The United States Government has rights to this invention pursuant to contract number DE-AC09-96-SR18500 between the U.S. Department of Energy and Westinghouse Savannah".  

    We should question if the recycling of Hevea-Brasiliensis natural rubber latex, without regard to the antigenic proteins therein, is good government policy when considering the health and safety of all Americans. 

    In other studies, tire dust from tread wear has been shown to be another route of exposure to NRL allergens. [ 42 ]   

     Futhermore, a study indicates that allergies are increasing [ 43 ] and one may reasonably suggest that NRL exposure has contributed.  In industrial societies, the Hev-b proteins may indeed be the most pervasive non-infectious antigens of the late twentieth century.

    
In the book Silent Spring wildlife biologist Rachel Carson taught that man-made chemicals (e.g., pesticides, insecticides) that become universally common or repetitive can assume "the harmless aspect of the familiar".  In parallel the Hev-b proteins, some of which are suspected to be natural insecticides, have attained the harmless aspect of the familiar.  Even though many of the health and safety hazards of natural rubber latex (Hev-b) are well understood, industrial societies magnificent exploitation and comfortable dependence on such a material continues to stress human health based on an inertia sustained by the harmless aspect of the familiar.
  
     4.3     Intensity

     The intensity of immune responses during prenatal/neonatal development may be related to the severity of ASD. Inadvertently subjecting children to antigenic proteins can stimulate the immune system to form increased levels of IgE primed mast-cells and basophils that may bind to proteins essential for proper growth and development.  For example, the first time a child is exposed to an antigenic protein large amounts of IgE antibody are made.  These IgE molecules attach themselves to mast cells and basophils to form IgE primed cells. Thereafter, exposure to the antigenic proteins (Ag) cause the IgE primed cells to release granules and powerful chemical mediators including histamine, proteases, chemotactic factors, cytokines, and metabolites of arachidonic acid.

Click on Mast Cell to Animate.                 
                                                                                                                   
 


       

   A = Human Mast Cell                             B = Human Basophil

  Unfortunately, the IgE primed cells can also bind to other proteins having similar or homologous characteristic to the antigenic protein (i.e., cross-reaction).  Examples of homologous proteins that have been shown to cross-react with the IgE primed cells include foodstuff proteins and lipocalins. 
  

     The antigenic proteins in NRL that have been shown to significantly affect the level of IgE primed cells are the water soluble Hev-b proteins (e.g., Hev-b 1-3).  An example of prenatal/neonatal exposure to such proteins includes medical gloves used in health care facilities.  A study has shown that the antigenic protein content of such gloves can vary greatly and is due in part to processing techniques (i.e., protein leaching step). [  44 45 ] 

     4.4     Type of Exposure

     NRL is used in many products including medical gloves, nipples for baby bottles, pacifiers, clothing, and toys.  Additionally, medicinal vials are often sealed with NRL-based septums.  Routes of exposure may play a role in determining the NRL sensitization.  For example, differences in natural-latex specific IgE profiles and pulmonary function following sensitization of mice by four different routes suggest that exposure routes leading to NRL sensitization may play a role in determining the primary allergens and the clinical manifestation of the immune response. [ 46 

     Additionally, NRL is used in many adult products including condoms.  The prevalence of sexually transmitted diseases and birth control measures have dramatically increased the use of natural-latex based condoms.  Such products are another route of exposure to the Hev-b proteins which may be increasing atopy globally.  Efforts are being made to deproteinize natural-latex based condoms to help reduce acquired immune responses therefrom. [ 47 ]  

5.     Gender

     The ratio of ASD by gender is about 4:1 (male/female).  Immunological differences based on gender may affect the frequency and intensity of an adverse immune response.  For example, it is generally known that the ratio of food allergies is 2:1 (male/female).  In addition, childhood asthma has shown a 3:1 (male/female) ratio, especially amongst young children. [ 48 ]  A study on the effects of gender on allergen-induced histamine release in ongoing allergic cutaneous reactions concluded gender influences the degree of in vivo antigen-induced histamine release from mast cells. [ 49]

    In animal studies, research on the differences in concentration of endogenous proteins in sex organs of BALB/c mice has shown that levels of NGF and IgE were consistently higher in organs of male mice in comparison to their female siblings. [ 49.1 ]

     Another theory on the incidence of ASD and gender has been directed at testosterone which is the principle male sex hormone.  For example, recent research suggests that there may be a link between ASD and testosterone levels in the womb as the fetus develops.  For example, according to researchers from Cambridge University, babies who produce high levels of testosterone while they are still in the womb have a higher chance of showing traits of ASD later on. [ 50 ]

     In other studies, testosterone deprivation has been shown to proliferate T-cell populations.  In general, testosterone blunts immunity when present and enhances immunity when absent. [ 5152 ]

    In animal studies, researchers have shown that testosterone reduces macrophage expression in the mouse of toll-like receptors 4, a trigger for inflammation and innate immunity. [ 53 ]

    Finally, the testosterone induced suppression of innate immunity may shift the bodies defense mechanism towards adaptive immunity (e.g., IgE), affecting the incidence of allergy-induced-autism. 

6.     Endorphins

    Endorphins are endogenous opioid neuropeptides that are considered "natural pain killers". [ 55 ]  Increased levels of endorphins may affect some of the symptoms associated with ASD. [ 56 ]  In parallel, a study has shown that circulating leukocytes can synthesize, store, and release neuropeptides including endorphins. [ 57 ] 

     Additionally, the recent finding of nerve growth factor in mast cells widens the spectrum of potential responses that back-fed peripheral neurons can produce during neuroimmune interactions. [ 58 ]  

    In animal studies, nerve growth factor has been shown to govern the enhanced ability of opioids to suppress inflammatory pain.
[ 58.1 ]

    Therefore, the frequency and intensity of an acquired immune response can affect opioid and NGF levels which may influence some of the symptoms associated with ASD.

7.     Neurotransmitters/Neuromodulators

     A cross-react immune response, induced by NRL, may affect the body's protein-cycle resulting in a temporary neurotransmitter imbalance.  Within cells, exogenous proteins (e.g., foodstuff proteins) are often broken down into amino acids.  These amino acids can then be assimilated into other compounds (e.g., neurotransmitters/neuromodulators).  There are certain amino acids that are classified as "essential" meaning they must be attained from foodstuff proteins.  For example, tryptophan is an essential amino acid that serves as a precursor for the neurotransmitter serotonin. 

     A cross-react immune response induced by NRL-allergy may induce IgE antibodies to bind certain foodstuff proteins potentially limiting the bodies source of essential amino acids such as methionine and tryptophan [ 59 ].  At the same time, an atypical immune response induces mast cells to release histamine resulting in a temporary excess of this neurotransmitter/neuromodulator.  Throughout this immune response, the protein cycle is further stressed to accommodate antibody and mast cell proliferation and/or replacement.  Such an imbalance may adversely affect neuro-cognitive development during critical stages of brain development.

8.  Vaccines

     Much attention has been given to the theory that vaccinations may have increased the incidence of ASD. For example, it has been proposed that the mercurial-based preservative (i.e., Thimerosal) in vaccines cause adverse neurological development, and other biochemical disruptions, that may increase the incidence of ASD. [ 60 ]  Although mercury-based organics are well known to be harmful to the central nervous system in all individuals, its role in the development of ASD continues to be debated.  Furthermore, MMR vaccines have also been suspected of affecting ASD.  Several studies have shown that thimerosal and MMR exclusion failed to decrease the incidence of ASD. [ 61 , 62 , 63]

     Vaccines are a preparation of killed microorganisms, or living attenuated organisms, or living fully virulent organisms that are administered to produce or artificially increase immunity to a particular disease.  The microorganisms in the vaccines are composed of exogenous proteins that inherently trigger an immune response. [ 64 ]  Furthermore, other protein additives in the vaccines have been shown to cause allergic reactions.  For example, the presence of gelatin [ 65 ] in MMR vaccines may intensify the immune response in atopic individuals. [ 66 

     Finally, it is speculated that a combination of vaccine and non-infectious antigenic protein insult may be comorbid factors in the etiology of allergy induced autism.  For example, temporary vaccine-induced hyper immunity may affect immune sensitivity to non-infectious antigenic protein insult. [ 67 ]  Therefore, research efforts should explore if a combination of infectious-based protein insult (e.g., MMR) and non-infectious antigenic protein insult  (e.g., Hev-b proteins, food allergens) affects the incidence and prevalence of allergies.    

9.     Hev-b Protein Elucidation

     NRL contains hundreds of proteins and the International Union of Immunological Societies currently recognizes 16 to be allergens (i.e., Hev b-1 to Hev b-16).  For example, recently the Rubber Research Institute of Malaysia has discovered the Hev b-13 (43kDA in size) to be most allergenic.  Protein analysis on Hev b-13 at Yale University has revealed a similarity to the Early Nodule Specific Protein of leguminous plants (e.g., peanuts, soybeans). [ 68 ]

     The prevalence of cystine in Hev-b proteins, or proteins homologous to Hev-b proteins, reinforces its tertiary structure through intramolecular disulfide crosslinks. [ 6970 ]  A Study has shown that cross-link density often decreases the exogenous protein's digestive characteristic (i.e., denaturation), possibly increasing the probability of an immune response. [ 71 

     Amino acid analysis of Hev-b 5 has shown a complete absence of cysteine (i.e., cystine). [ 72 ]  Hev-b 5 has been shown to have an unusually high glutamic acid content (i.e., 39% based on total amino acid residues).  Many of the proteins associated with food allergy are also rich in glutamic acid (e.g., fruits, meat, poultry, fish, eggs, dairy products).  Furthermore, Hev-b 5 has high proline content (14%) [ 73 ] to provide a tertiary structure having random coil arrangement .  Such an arrangement may inhibit enzymatic degradation, due to steric factors, inducing antibody recognition.   

     In speculation, an acquired immune response to the Hev-b 5 protein may affect the development of ASD through glutamic acid disruption.  For example, glutamic acid is the most abundant excitatory neurotransmitter and is involved in cognitive functions like learning and memory in the brain. [ 74 ]  Organisms synthesize GABA [ 75 ] from glutamic acid, GABA disruption may affect prenatal purkinje cell activity and formation. [ 76, 77 ]

    
If immune responses to Hev-b and proteins homologous to Hev-b proteins affect the protein cycle and compromise the levels of cysteine and glutamic acid, endogenous polypeptides formed from these amino acids may also be affected.  An example may be glutathione which is a tripeptide of cysteine, glutamic acid, and glycine. [ 78 ]  A study has shown that children with autism often have reduced levels of glutathione compared to non-autistic children. [ 79 ]  Glutathione functions to denature cytoplasmic proteins wherein disulfide bonds (i.e., cystine) are reduced to cysteine.  A deficiency of glutathione may be affecting protein denaturation increasing the probability of an immune response to exogenous cystine-based proteins.  

10.     Isoprenoids and Cholesterol

     Plants and animals have protein kinase that affects the expression of isoprenoids which are essential to growth and development. [ 80 ]  Protein kinase (e.g., small rubber particle protein, rubber transferase) in NRL play a major role in isoprenoid synthesis to provide polyisoprene having high molecular weight. [ 81 ]   In humans, protein kinases play a major role in isoprenoid synthesis (e.g., farnesyl pyrophosphate and geranylgeranyl pyrophosphate) which are synthetic precursors for numerous molecules essential for cellular function as well as substrates in isoprenylation reactions. [ 82 ]  

     An acquired immune response to NRL-based protein kinase may affect allergy-induced-autism through disregulated kinase activity. For example, the isoprenoid pathway and its metabolites -- digoxin, dolichol, and ubiquinon -- has been assessed in autism.  There was reported an upregulation of the isoprenoid pathway as evidenced by elevated HMG-CoA reductase activity [ 83 ] in autism.  It has been proposed that autism may be considered a syndrome of hypothalamic digoxin hyper secretion consequent to an up regulated isoprenoid pathway. [ 84 ]  

     Additionally, a study has indicated that children with autism can have unusually low levels of cholesterol. [ 85 ]  It is known that mutations at chromosome 11q12-13 can affect the expression of cholesterol and ASD. [ 86 ]  For example, autism has been documented in a number of individuals with Smith-Lemli-Opitz syndrome (SLOS). A recent study of 26 individuals with SLOS found that 17 of them (53%) met criteria for autism (Tierney et al 2001). Clinical features of SLOS include microcephaly, 2-3 syndactyly of the toes, mental retardation, cleft palate, hypospadias in males and growth retardation. SLOS is an autosomal recessive condition, with carriers being unaffected. SLOS is caused by mutations in the DHCR7 gene on chromosome 11 (11q12-q13). DHCR7 produces 7-dehydrocholesterol reductase, which typically converts 7-dehydrocholesterol to cholesterol. Diagnosis is established by detection of elevated serum concentration of 7-dehydrocholesterol. [ 87 ]  In parallel, IgE responsiveness (i.e., atopy) has been associated with mutations at chromosome 11q12-13. [ 88 ]

11.     Cysteine & Proteins

     The cysteine residues in Hev-b proteins have been shown to play a major role in allergenicity.  For example, research has shown that recombinant NRL allergens wherein the cysteine residues are replaced with alanine form peptide variants that have markedly decreased IgE binding.  Furthermore, basophil activation testing has shown decreased activation with successive cysteine exclusion. [ 89 

     In parallel, studies have indicated that children with ASD have significantly lower baseline plasma concentrations of cysteine. An acquired immune response to Hev-b proteins may affect the methionine pathway [ 90 ] and P450 detoxification [ 91 ] system through an NRL cross-react immune response to proteins having similar epitopes based on primary and/or tertiary structure. [ 92 ]

     The expression of other cysteine-rich endogenous proteins have been implicated in ASD including metallothionein proteins [ 93 ], IgA antibodies [ 94, 95 ], dipeptidyl peptidase [ 9697 ], and lipocalins (e.g., human retinol-binding protein).

    An example of an immune response to exogenous proteins includes proteases.  Specifically, it is well known that botanically-based proteases (e.g., papain [ 98 ], bromelain [ 99 ], etc.), which are homologous proteins to the Hev-b proteins, may cause allergic responses in atopic individuals.  Such proteases are often used as food additives and function as digestive enzymes. 

    Finally, it is speculated herein that the activity of some endogenous cysteine proteases (e.g., caspase [ 99.1 ] ) may be affected through non-competitive inhibition (i.e., allosteric inhibitor) wherein Hev-b protein sensitive primed-mast-cells hydrogen-bond to epitopes on said protease.    

12.     Spina Bifida

     Studies have shown that about 73% of individuals with spina bifida/hydrocephalus have NRL allergy.  It’s theorized that the increased sensitization in this population is related to early, frequent exposure to rubber products such as catheters used in bladder programs. These children also tend to have frequent surgeries and diagnostic tests, which increases their exposure to natural-latex gloves. Unfortunately, frequent surgical intervention is a risk factor even in children who do not have spina bifida; sensitivity to natural latex has been found in 34.1% of children with a history of three or more surgical procedures.

     There is a broad range of scores on intelligence tests among children with spina bifida/hydrocephalus ranging from the gifted to the retarded.  It is generally recognized that learning problems are routinely a part of children with spina bifida/hydrocephalus including attention, perceptual motor processes, reasoning and problem solving, organization and sequencing skills, and memory. [ 100 ]  It is speculated that immune responses to the Hev-b proteins, and cross-reactivity therefrom, may be affecting neuro-cognitive development in individuals with spina bifida/hydrocephalus.

13.     Hev-b Toxicity

     LD50 is a measure of how much constitutes a lethal dose.  In animal testing studies, the dose administered that kills half the test population is referred to as the LD50.  The LD50 of several chemicals that have been implicated in the etiology of ASD are described below:

     Thimerosal (ORL-RAT)                         =  75 mg./Kg. [ 101 ]

     Aspartame (ORL-RAT)                          =  >10,000 mg./Kg. [ 102 ]

     Natural Rubber Latex (Hev-b proteins)     =   unknown*

    * The Hev-b proteins are considered chronic non-infectious agents (i.e., allergens).  Their toxicity may be influenced by the intensity of an induced immune response based on genetic susceptibility and exposure (i.e., incidence, prevalence, and intensity of Hev-b protein insult).  Therefore, LD50 data on such proteins are extremely difficult to quantify even though individual's have died from anaphylactic shock. [ 103 ]

    In a study that evaluated NRL allergy in sudden infant death syndrome (SIDS), NRL-specific IgE concentrations were detected in 1 of 112 unselected cases.  The researchers concluded that NRL allergy is not a cause of SIDS. [ 103.1 ]  As a suggestion, based on the brief half-life of IgE, the inactivation of IgE-primed mast cells after an immune response, and IgE cross-reactivity it may be prudent to evaluate the expression of by-products (e.g., histamine and NGF) of the adaptive immune response to determine if anaphylactic shock is involved in the etiology of SIDS.  Researcher's continue to study the effects that mast cells and histamine release has on heart failure [ 103.2 ]

     It is generally accepted that allergies are increasing worldwide.  As previously discussed, Malaysia is one of the world's largest producers of Hevea Brasiliensis and it has been reported that allergies are increasing at an alarming rate. [ 104 ]  If  repeated Hev-b protein exposure is increasing the prevalence of allergies it's reasonable to ask the questions:

     Q.     Are the Hev-b proteins, or the unclassified proteins within Hevea Brasiliensis and its hybrids, becoming more antigenic based

              on structure change (i.e. molecular evolution); [ 105 ]

     Q.     Are future generations becoming more sensitive to the Hev-b proteins, or the unclassified proteins within Hevea Brasiliensis

              and its hybrids, based on inherited immunity (i.e., adaptive immune response); and

     Q.     Does the prevalence of diseases within Hevea affect the dynamics of the antigenic proteins therein.  [ 106 ]    

14.     Sleep

     It is generally accepted that individuals with ASD often have sleep difficulties. [ 107 ]  In the Ontogenetic Hypothesis of rapid eye movement (REM) [ 108 ] sleep, active sleep in neonates is particularly important to the developing brain, possibly because it provides the neural stimulation that newborns need to form mature neural connections and for proper nervous system development (Marks et al. 1995).

     Studies investigating the effects of Active Sleep deprivation have shown that deprivation early in life can result in behavioral problems, permanent sleep disruption, decreased brain mass (Mirmiran et al. 1983), and result in an abnormal amount of neuronal cell death (Morrissey, Duntley & Anch, 2004). REM sleep is necessary for proper central nervous system development (Marks et al. 1995). Furthermore, the release of certain neurotransmitters, the monoamines (norepinephrine, serotonin and histamine), are completely shut down during REM.   

     In other sleep studies, histamine has been implicated as a significant endogenous compound involved with wakefulness. [ 109110 ]  In contradiction, a study has indicated that the use of an antihistamine doesn't help babies sleep. [ 111 ] 

     The frequency and intensity of IgE immune responses may induce irregular patterns of active sleep during neonatal development, affecting allergy induced autism.  For example atopic individuals, especially those having hevea brasiliensis sensitivity, may be continuously exposed to the Hev-b protein allergens (e.g., baby bottle nipples, pacifiers) increasing the frequency and intensity of mast cell degranulation and histamine release.  Additionally, cross-react immune responses (e.g., food allergies) induced by the Hev-b proteins may further intensify the immune response. 

     Therefore, irregular patterns of active sleep during neonatal development may be directly related to the frequency and intensity of IgE immune responses to the Hev-b proteins and cross-react immune responses therefrom.

15.     Hearing

     Hearing sensitivity has been observed in ASD.  Autoimmune inner ear disease (AIED) is a syndrome of progressive hearing loss and/or dizziness. [ 112 ]  AIED can cause reduction of hearing accompanied by tinnitus (ringing, hissing, roaring). [ 113 ]  The favored theory of AIED is cross reactions wherein antibodies or rogue T-cells cause accidental inner ear damage because the ear shares common antigens with a potentially harmful substance that the body is fighting off.

16.     Touch Allodynia

     Tactile sensitivity has also been observed to be an intermittent symptom of ASD.  Touch allodynia is an exaggerated response to a non-noxious stimulus and can be either static or mechanical.  For example, a person with touch allodynia may perceive light pressure or the movement of clothes over the skin as painful, whereas a "normal" individual will not feel pain.  An animal study has indicated that the balance of prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2) may play a role in innocuous tactile stimuli evoked pain. [ 114 

     Immune responses to allergens which can cause mast cells and basophils to release neurotrophins and inflammatory agents [ 115 , 115.5] may affect the neurochemical mechanism of touch allodynia.

     During prenatal development, maternal immune responses to allergens are known to increase the expression of (PGE2) [ 116 ] effecting the levels of cytokine IL-6.  IL-6 overexpression has been implicated in recurrent misscarriages. [ 117]    

17.     Regressive Autism

     Regressive autism refers to a segment of children that initially develop normally for a period of time then lose skills and acquire the symptoms of autism, commonly at 18-24 months of age. [ 118 ]   A study indicates that the "normal" development phase prior to the onset of regressive autism may be misleading in that early delays are evident. [ 119 ]

     With respect to the allergy-induced autism theory, children with autism have been shown to have distinctly different immune system reactions compared to typical children. [ 120 ]  For example, cytokine levels, monocyte count, and neopterin levels in some Autistic children have shown significant variability. [ 121 , 122 ]   The differential onset (e.g., early infantile vs. regressive) of ASD indicates an etiology influenced by immunology and environmental insult.

     If the etiology of regressive autism is influenced by IgE immune responses during prenatal/neonatal development, then later onset of such an acquired immune response may affect neuro-cognitive development in older children.  Attention-deficit hyperactivity disorder (ADHD) [ 123 ] often occurs in children between the ages of 3-7.  An acquired Hev-b immune response, and cross-react immune responses therefrom, at this period of brain development may influence the development of ADHD.

     In other neuro-cognitive research, a study indicates that the prevalence of allergy in adults may affect the incidence of Parkinson's disease. [ 124 ]

18.     Other NRL Induced Cross-Reactivity

    Wheat              [ 124.1 ]     

    Pine Wood/      [ 125 ] [ 125.1 ]
    Pine Chemicals

     Poinsettia         [ 126 ]

     Mold               [ 127 ]

     Vegetables       [ 128 ]

      Insect Venoms [ 129 ]

      Grass & Weed Pollen [ 130 ]

     Sugar Beets      [ 131]

      Fruits               [ 132 ]

     Tobacco           [ 133 ]

19.     Infection & Allergy

     A study published in Pediatrics investigated the association between infections in the first 2 years and subsequent diagnosis of autism spectrum disorders.  The researchers concluded that children with subsequent diagnosis of autism do not have more overall infections in the first 2 years of life than children without autism. [ 134 ]

     It is well known that allergies are often prevalent in children with autism spectrum disorders. [ 135A combination of infection and environmental insult may affect the development of allergies.  For example, Johns Hopkins scientists have found the first hard evidence that viral infections can help cause asthma and allergies, a connection long suspected but never directly confirmed in the lab. They showed that weak viral infections can cause immune system B cells to produce immunoglobulin E or IgE, a protein that orchestrates the reactions that cause allergies. [ 136 

     Infection and environmental insult during prenatal/neonatal development may also affect the development of allergies.  For example, it has been shown that prenatal and early postnatal environments are significant predictors of total immunoglobulin concentration in adolescents.  The researchers concluded that infectious disease in infancy, as well as interactions between prenatal and postnatal environments, appear to have long-term effects on adolescent total IgE production. [ 137 ]

     An example wherein a stealth chronic-infection may be a comorbid factor in the etiology of allergy induced autism is Lyme disease.  An epidemiologic study is evaluating if there is a connection to the prevalence of Lyme disease and autism in children. [ 138 ]  

    If comorbid factors such as infectious insult affects adaptive-immunity sensitivity, then everyone is potentially a "natural-latex sensitive individual".  As previously discussed, the timing, frequency, intensity, and type of exposure to the Hev-b proteins must be considered, not just genetic susceptibility. 

     Furthermore, infection may also induce autoimmunity when atopy is present.  Specifically,
infectious agents may cause mammalian cells to release endogenous protein-fragments that can induce an immune response.  Briefly, in the formation of endogenous-proteins deoxyribonucleic acid (DNA) is transcribed in the cells nucleus into messenger ribonucleic acid (mRNA).  The mRNA is then exported to the cytoplasm for translation into protein.  Translation occurs in ribosomes wherein transfer RNA (tRNA) deliver amino acids which are then bonded together to form a protein chain.  During an infection (e.g., viral), propagation within the cell can rupture the cell wall. Once cell containment is breached, tRNA-based protein-fragments within the cytoplasm can then leach into circulation through diffusion.  When atopy is present, the increased prevalence of b-cells (i.e., plasma & memory) and the fragments incomplete structure (e.g., nucleoprotein fragments) may induce an immune response.  An immune response to the protein fragment may increase the probability of a cross-react immune response to endogenous proteins having a homologous protein-fragment therein.  Because different cells produce different proteins, the type of cell infected may induce autoimmunity based on the cells genetic information. 

     Finally, as previously discussed chronic infection and/or dampened immunity may affect the gender incidence of allergy induced autism.  Studies have shown that increased testosterone levels tend to blunt immunity affecting the prevalence of infection. If enabling, the interaction of infection/allergy/testosterone-levels may explain the 4:1 (male/female) gender incidence of allergy induced autism.

20.     Fever

     Collision theory of reaction rates associated with an IgE immune response are important in guiding our understanding of allergy induced autism.  Several factors that may affect the frequency and intensity of the immune response include:

     i)     the number of antigens (e.g., Hev-b or proteins homologous to Hev-b proteins) in a unit volume of blood;

     ii)    prevalence of somatic hypermutation [ 139 ] or affinity maturation [ 140 ] of lymphocytes (e.g.,memory B
            cells) specific to the
antigen in a unit volume of blood; and

     iii)   increased body temperature and blood flow.

     Increased body temperature and blood flow has been been shown to affect the binding rates of antibodies and antigens.  For example, leukocytes are known to display a "shear threshold effect"; this effect is due to an increase in collisions between receptor and ligand with increasing shear. 141 ]  Infection induced fever may be a co-morbid factor which increases the intensity of a Hev-b induced immune response.

     As an example, reducing Hev-b protein exposure (e.g., latex-based gloves and bottle nipples), especially during postoperative fever after birth, may help reduce the incidence of allergy induced autism in atopic individuals. [ 142 ]

     In contrast, the hygiene hypothesis states that an excessively hygienic environment early in childhood may predispose some people towards asthma, allergies, and other autoimmune diseases. [ 143]  Furthermore, the use of fever suppressants (e.g., acetaminophen) has been speculated in the etiology of autism.  [ 144 ]   

21.     Hev-b Proteins and ASD

     NRL from Hevea Brasiliensis contains about 2-5% protein by weight.  Analysis indicates about 200 dissimilar proteins [ 145] therein and about 50-60 are suspected allergens.  The World Health Organization - International Union of Immunological Societies (WHO - IUIS) has assigned names to about 13 of these allergens.  Several Hev-b proteins and their potential relationship to ASD are described below:  

     21.1     Hev-b 1 (rubber elongation factor)

    The Hev-b 1 protein has been shown to have HLA-DR4Dw4 (DRB1*040)-binding motif. [ 146 ]  An Hev-b 1 immune response may induce HLA antibodies [ 147 ] based on epitope homology.  A study indicates that abnormal HLA-DR expression may affect the developing CNS during the second and third trimester. [ 148 ]

     21.2     Hev-b 2 (beta-1,3-glucanases), Hev-b 7 (Patatin-like protein), and Hev-b 13 (Lipolytic esterase)

     The Hev-b 2,7, and 13 proteins have been shown to have carbohydrate epitopes that may induce an IgE response.  [ 149 , 150 ]   A Hev-b induced immune response to homologous glycoproteins may affect some of the symptoms of ASD. [ 151 ]  For example, the glycoprotein maltase [ 152 ] is an endogenous digestive enzyme that breaks down disaccharides (i.e.,.maltose to glucose) in the small intestine.  Lower maltase activity has been associated with gastrointestinal dysfunction in some autistic children. [ 153 ]  Other glycoproteins that may have homology to Hev-b 2,7, and 13 include antibodies, major histocompatability complexes, and hormones;

     21.3     Hev-b 5 (acidic latex protein)

      A study has indicated that about 75% of the ASD population is classified as mentally retarded. [ 154 ]  An endogenous protein that is known to greatly affect neuro-cognition is Fragile X Mental Retardation (FMRP). [ 155 ]  FMRP inhibition through a Hev-b cross-react immune response may play a direct role in the neural maturation process during prenatal/neonatal development.  For example, as previously discussed an immune response to Hev-b 5 may cause glutamate disruption.  In parallel, FMRP inhibition by glutamate disruption has been shown to affect the body's ability to translate mRNA. [ 156

     In continuation, it is suspected that glutamate receptors and Shank3 proteins play a synergistic role in the density and maturation of elongated spines.  [ 157 ]  For example, a secondary cooperative effect may exist between glutamate receptor activity and Shank3 during maturation of a nascent spine in a feedforward mechanism.  Therefore, disruption of the glutamate/Shank3 mechanism may induce the formation of low-density and immature elongated spines often associated with mental retardation. 

     21.4     Hev-6 (Hevein)

     CD23 (or Fc epsilon RII) is a C-type lectin that functions as a receptor for IgE and are found on mature B cells.  In parallel, Hev-6 protein is a lectin-like protein that is a dominant allergen in NRL. [ 158 ]  A Hev-b 6 induced immune response may affect the expression of CD23 on mature B cells and regulation of IgE.   

     21.5     Hev-b 8 (Latex profilin)

     An immune-response to proteins homologous to Hev-b 8 proteins may affect dendritic spine morphology during prenatal/neonatal allergy syndrome.  For example, profilin from mammalian cells are known homologous proteins to Hev-b 8 [ 159 , 160 ]  A Hev-b 8 induced cross-react IgE immune response to human profilin I, and to a lesser extent profilin II, may affect actin [ 161 ] dynamics in synaptic plasticity. [ 162 ]  Atypical dendrite spine morphology associated with profilin disruption may be associated with some of the symptoms of ASD;  

     21.6     Hev-b 9 (Latex enolase)

     Enolases are enzymes that participate in glycolysis by assisting in the conversion of glucose to pyruvate. [ 163 ]  Hev-b 9 displays an overall identity of 72% to human beta enolase. [ 164 ]  A Hev-b 9 induced cross-react immune response to human enolase may affect pyruvate levels through enzyme inhibition.  Pyruvate deficiency has been associated with seizure and epilepsy.  A study indicates that epilepsy in ASD is a comorbid complication at rates of up to 33%.  [ 165]  

     Furthermore, homologous enolases from yeasts, molds, and fungi are known to cross-react with Hev-b 9.  [  166167 ]  A study indicates that elevated levels of Candida Albicans in some autistic individuals may exacerbate many behavior and health problems, especially those with late-onset autism. [ 168 ]  A Hev-b 9 induced cross-react immune response to exogenous enolases (e.g., yeast infection) may further affect allergy induced autism;

     21.7     Hev-b 10 (Mn-superoxide dismutase)

    Superoxide dismutase is a potential cross-react protein associated with an Hev-b 10 immune response. [ 169 ]  Superoxide dismutase enzymes such as magnesium superoxide dismutase (MnSOD) are important antioxidant-defense proteins in nearly all cells exposed to oxygen. [ 170 ]  Furthermore, a study has indicated that superoxide dismutase imbalance may play a role in the pathophysiological mechanisms involved in autism; [ 171 ] and

     21.8     Hev-b 11 (Class I endochitinase)

     The latex from Hevea Brasiliensis contains high levels of both chitinases and chitinases/lysozymes. [ 172 ]  Human chitotriosidase is a potential cross-react protein associated with a Hev-b 11 immune response based on its homology to the chitinase family of proteins. [ 173 , 174 ]  A Hev-b 11 induced cross-react immune response to human chitotriosidase and plant-based chitinase may affect fungal immunity and food allergies in ASD.  For example, chitotriosidase deficiency may play a role in digestion of chitin-containing food as well as defense against chitin-coated microorganisms and parasites (e.g., fungal and bacterial pathogens).  [ 175 ] 

    Finally, t
he incidence and prevalence of multiple chemical sensitivity may be triggered by immune recognition of the known and suspected Hev-b proteins described above.  Therefore, it may be speculated that a immune-response to the Hev-b proteins during prenatal/neonatal development may influence the frequency and intensity of autoimmune responses [ 176 ] affecting the degree of atypicality within the autism spectrum.  

22.     Food-Stuff Proteins & NRL

     Allergic responses to food-stuff proteins have been associated with allergy induced autism. [ 177]  Hev-b proteins may induce immune responses to food-stuff proteins based on antigenic protein/food-stuff protein complexes.  For example, casein is a hydrophobic phosphoprotein that has been used as a stabilizing additive in the manufacture of NRL-based gloves. [ 178]  A protein-protein interaction of Hev-b/casein may induce antigen-presenting cells such as dendritic cells [ 179 ] to inadvertently present fragments from both proteins onto the surface of other immune system cells, subsequently triggering an allergic response to the dissimilar proteins.

    In continuation, we must ask the question why do some neonates get milk-protein allergies. It can be speculated that sucking milk from natural rubber latex nipples may cause dendritic cells to induce an allergic response to the comingled milk food-proteins and latex nipple antigenic-proteins.     

    Corn starch is an example of a non-homologous polymer that has been associated with Hev-b proteins.  For example, corn-starch powder has been used as a slip aid in the manufacture of NRL-based gloves.  It is known that Hev-b proteins migrate from the glove and onto the corn-starch.  The contaminated powder readily becomes air-borne and often increases Hev-b exposure through inhalation. [ 180181 ]  The corn-starch/Hev-b protein commingling may induce memory-b cell recognition of carbohydrate epitopes and affect cross-react immune responses.  For example, amylose [ 182 ] in corn-starch has similar ring-size glucose units and glycosidic linkage configuration to maltose [ 183 ]. 

     Another example where casein is deliberately commingled with the Hev-b proteins is in water-based adhesives.  Specifically, casein thickeners (i.e. rheology modifier) are often added to natural rubber latex adhesives to enhance machining characteristics.  Furthermore, gluten is also commonly used in adhesives.  Thus, the deliberate commingling of food-stuff proteins with NRL should be prohibited in an effort to reduce the global incidence and prevalence of food allergies.  Research efforts should be initiated, using protein-protein docking techniques to predict Hev-b protein and food protein interactions, to explore if such proteins bind in vivo affecting the IgE cross-reactivity mechanism.

    There is growing evidence that dissimilar proteins can complex and be recognized as an antigen.  For example, researchers have found that hormones may combine with dissimilar proteins resulting in a protein-protein complex that may be recognized as foreign.  Thereafter, the hormone part of the molecule complex may be recognized as an antigen. [ 183.1 ]

    Elsewhere, there is an environmental standard initiative in the adhesive industry to supply "Green" adhesives having reduced hazardous ingredients.  The term "Green" is often associated with natural rubber latex in that they are natural and substantially-free of volatile organic chemicals when extracted from the rubber tree.  Unfortunately, the adhesive industry has failed to adequately recognize the health issues associated with the antigenic proteins inherent in natural rubber latex.  Therefore, further guidance is needed.      

    A citizen petition has been sent to the U.S. Environmental Protection Agency which states:

    Pursuant to Section 21 of the Toxic Substances Control Act (TSCA), 15 U.S.C. § 2620, we hereby petition the Environmental Protection Agency (EPA) to establish regulations prohibiting the use and distribution in commerce of Hevea- Brasiliensis natural rubber latex adhesives having a total Hev-b protein content greater than 200 micrograms per dry weight of latex based on The American Society for Testing and Materials method ASTM D1076-06 (Category 4). (Doc E8-9041)

    Unfortunately, the petition was denied 6/3/08.  The reasons for denial by the EPA are described in the following link: (Denial) .  The petitioner response to the denial is disclosed on (page 3) in this website. 

    Recently, Adhesives and Sealants Industry (ASI) published an article entitled, "Natural Rubber Latex Adhesive Issues" which presents some of the health and safety issues associated with such products [ 183.5

    Finally, kudos to Bostik, Inc. (Wauwatosa, WI) for non-natural rubber containing self-seal adhesive development. Specifically, United States Patent Application (20080102232) teaches the production of self-seal packaging adhesives that are free of natural-latex proteins which can cause allergic reactions in people.   


23.     Maternal/Fetal IgE

    The maternal immunoglobulin (Ig) isotype that passes through the placenta to provide passive immunity is IgG. [ 184 ]  Cytokine overexpression may affect total IgE during pregnancy through Ig switching. [ 185 , 186 ]  An immune response to Hev-b 6.01 (Hevein) has been shown to affect IL-4 and IFN-gamma overexpression. [ 187]   Mast cells in the placenta [ 188] are susceptible to degranulation during an Hev-b induced IgE immune response.  Thus, NRL exposure during pregnancy may affect cytokine expression [ 189 ], IgE expression, and mast cell death [ 190 ] which may affect the development of ASD. [ 191 ]   Alternatively, other study suggests that fetal exposure to intact IgE occurs via gastrointestinal tract. [ 192 ]

     The prevalence of an IgE induced immune response during pregnancy may affect the intra uterine environment.  A study indicates that children with allergic mothers had significantly higher sCD14 [ 193] levels compared to children with non-allergic mothers. [ 194195 ]  CD14 expression has been associated with innate immune responses to endogenous proteins and ASD. [ 196]

    A recent study indicates that parental IgE levels may be a indicator of atopy in young children and the study showed that boys have higher Ige levels compared to girls.  [ 196.5 ]

     Trophoblast inclusions have been suggested as a  key to early diagnosis of autism.  [ 
197]  An immunohistological study of the human placenta has revealed the presence of immunoglobulins on the trophoblast basement membrane. [ 198199].  Atypical immune responses may affect the expression of FAS and FasL on CD4+ and CD8+ receptors on the trophoblastic surface. [ 200201

     During neonatal development, the kinetics and courses of allergen-specific antibody responses suggest that, once established, allergen-specific IgE responses are driven by antigen contact rather than cytokines controlling class switch to IgE. [ 202

     Cytokines released during an IgE induced immune response may affect endogenous enzymes.  For example, mast cells are an important source of histamine and the cytokine tumour-necrosis-factor (TNF-gamma). [ 203, 204]  Additionally, B-cells and T-cells secrete the cytokine interferon-alpha (IFN-alpha). [ 205 ] A study has shown that the overexpression of TFN-gamma and IFN-alpha can induce the activity of indoleamine 2,3-dioxygenase (IDO) [ 206 ] which is an enzyme involved with tryptophan degradation. [ 207 ]  Therefore, the frequency and intensity of IgE immune responses during prenatal/neonatal development may affect the expression of TFN-gamma and IFN-alpha resulting in increased activity of IDO and decreased tryptophan.  A study has shown that children with infantile autism often have reduced levels of tryptophan which may affect serotonergic activity in infantile autism. [ 208 ]

24.     Blood Type

     Although there is not a published study, an informal accounting shows a marked prevalence of blood type-A among autistic children.  The other blood types generally appear to have low incidence, risk or severity of  ASD. [ 209210 ]



     Blood type and Hev-b 6 (Hevein) insult may play a role in the etiology of ASD.  For example, Hev-6 is a lectin-type protein that is the major protein of vacuolar structures called lutoids in the latex of rubber trees.  Lectins are known to play important roles in the immune system by recognizing carbohydrates [ 211 ]  Specifically, lectins are a type of receptor protein that recognizes and bind to monosaccharides including N-acetyglucosamine and N-acetygalactosamine.  Unlike other blood types (e.g., B, O), type-A contains extra N-acetylgalactosamine.  An Hev-b 6 induced immune response to homologous lectins/glycoproteins  may affect memory-b cell proliferation and the frequency and intensity of IgE cross-react immune responses.

     Historically, the para rubber tree initially grew in South America where it was the main source of NRL consumed during the 19th century.  Also, the Mayan's of Central America have a long history of rubber usage. [ 212 ]  Hundreds of years of Hev-b protein exposure have not appeared to have dramatically affected ASD in these cultures.  Blood type may have protected them in that Native South American's have 100% blood type-O and 98% of the Mayan population has blood type-O. [ 213 ]    

    In contradiction, allergenic rubber-proteins may have stressed adaptive immune systems (i.e., immunoglobulin E) throughout history independent of blood type.  Modern evidence has shown that the Mesoamericans including the Maya and Aztec, who had some of the most complex and advanced cultures, exploited stabilized natural rubber from the lacticiferous plant Castilla elastica [ 213.5 ] as early as 1600 B.C.

    We can ask several questions:

Q.    Did stressed adaptive-immunity from rubber-protein insult affect the incidence of cognitive atypicality; wherein some cases may have been 
        perceived as "psychological disorders"; and

Q.    Did a misunderstanding and fear of such cognitive atypicality lead to a path of great violence and destruction.



    Finally, the increased incidence of allergy induced autism in industrialized societies presents the ulimate challenge .........

25.     Antibody Formation & Decay

     The frequency of exposure to antigenic proteins may influence the prevalence of an allergy.  For example, a primary challenge to the Hev-b proteins may induce the activation of virgin T & B cells, and long lived memory T & B cells.  Thereafter, repeated exposure to the Hev-b proteins activate existing memory T & B cells and stimulate further production of T & B cells (i.e., virgin cells and memory cells).

     It is understood that repeated exposure to the Hev-b proteins often increases the specific-antibody population ( i.e., IgE primed mast-cells) affecting the intensity and duration of the immune response. [ 214 ]   Alternatively, exclusion of the Hev-b proteins inhibit re-activation of associated T & B cells allowing such cells to substantially decay, dampening the immune response.

     For example, in a follow-up study on natural-latex allergy in children researchers concluded that strict compliance with natural-latex avoidance instructions is essential both inside and outside the hospital and greater emphasis should be placed on reducing natural-latex exposure in the home and school environments, as such contact could maintain positive IgE-antibody levels. [ 215

    What can be exasperating is natural rubber latex allergy can go into remission from reduced exposure, while natural latex induced cross-react allergies to homologous food proteins may remain persistent based on repeated exposure to such foods.  Thus, the after effects of natural-latex allergy may continue to stress immunity long after the natural-latex allergy has gone into remission.  

   In an effort to decrease IgE immune-responses during prenatal/neonatal development, products containing the Hev-b proteins should be avoided.
  In Germany, studies on the hazards of certain natural-latex based medical products has initiated Government regulations restricting their usage (i.e., Regulation TRGS 540 enacted in 1998 banned the use of all powdered gloves in German health care facilities). [ 216 ]  In the United States, Johns Hopkins Hospital has banned nearly all natural-latex products. [ 216.5 ]

     Although multiple factors play a role in the etiology of ASD, antibody formation and decay based on frequency of exposure to the Hev-b proteins may be a catalyst for the onset of hyper adaptive-immunity and allergy induced autism.               

26.     IgE and Evolution   

     The expression of antibodies and cognition, is there a relationship?  Mammals are the only organisms that produce the antibody IgE.  In humans, IgE plays a primary role in allergic responses resulting in a cascade of chemical reactions including neurotransmitter release and cross-react immune responses that may affect extremes in cognitive skills.  Using allergy-induced-autism as an example on how immune responses may affect cognition, many on the autism spectrum have severe and pervasive impairment in thinking, feeling, language, and the ability to relate to others while many on the autism spectrum have exceptional cognitive skills enabling them to envision and present new thoughts and expressions (i.e., paradigms).  

     Two pioneering models of evolutionary theory, Darwinian/Wallace selection and Mendelian genetics, have failed to shed light on the etiology of autism.  Charles Darwin [ 217 ] conceded that natural selection isn't the sole mechanism of evolutionary change and Alfred Wallace [ 218 ] asserted that natural selection couldn't account for the human brain.  Furthermore, Gregory Mendel's [ 219 ] genetic model of evolution and modern genetic-research techniques thereafter have failed to decipher the genetic code(s) of autism spectrum disorders.

    Science has shown us that our closest genetic relative is the chimpanzee. [ 219.5 ]  A study indicates that humans and chimpanzees may have remarkably dissimilar immunity.  For example, researchers at the University of California - San Diego have disclosed that human T-cells, which are important orchestrators of the immune system, respond much more robustly than chimpanzee cells do. [ 219.6 ]

     The recent proliferation of autism has presented clues to the evolution of the human brain and immunity may play a critical role.  Allergy induced autism is a materialistic evolutionary viewpoint wherein the expression of IgE immune responses during prenatal/neonatal development affects cognitive development. 

     It may be understood that the antithesis of survival of the fittest is mankind.  Cognitive atypicality, ranging from severe mental retardation to fragile genius, based on stressed adaptive-immunity may be one of the most significant evolutionary processes of our species.   

     In other human cognition studies, it has been speculated that natural-latex allergy may affect the incidence of Schizophrenia. [ 220 ]  In parallel, one of the five pervasive developmental disorders officially recognized by the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) is childhood disintegrative disorder, initially termed childhood schizophrenia. 

    Within other theories, the biochemist David Horrobin who was medical advisor to the Schizophrenia Association of Great Britain hypothesized that gene mutation is key to genius and despair and that Schizophrenia 'helped the ascent of man'. [ 220.1 ]     

    If the etiology of autism is affected by exogenous protein insult and cross-react immune responses to endogenous proteins, this may give insight into the evolution of intellectual development as a species.  The ability to exploit exogenous proteins from plants and animals continues to affect the frequency and intensity of human allergies.
 
    .....the potential of mankind rests on the shoulders of immunity.

27.     Allergy Testing & Immunotherapy

     Direct exposure allergy tests (e.g., the skin prick test, patch test, challenge test) when used on neonates is a conundrum in that insult to the Hev-b proteins, to determine if an allergy exists, may induce sensitivity to the antigenic protein(s) - the threshold of sensitivity to such protein(s) is unknown even though some of these tests use minute quantities.  Thus, such neonatal testing for allergies is absolutely contraindicated because of the danger that the antigenic proteins therein may induce allergies.

     When allergy is present, allergy immunotherapy [ 221 ] has been shown to be somewhat effective wherein a predetermined injection/dosage schedule of the antigenic protein is used to gradually shifted the immune response from IgE to IgG.

     If the Hev-b proteins affect the etiology of allergy induced autism, it would be beneficial to have an allergy immunotherapy which effectively triggers a IgG1 response instead of an IgE response, especially during neonatal development.

     In speculation, an alternative allergy-immunotherapy treatment that may be useful would be to alter the secondary structure of the Hev-b proteins, maintaining the primary structure, in an attempt to effectively inhibit an IgE response.  For example, most naturally occurring proteins are formed from L-amino acids which provide a specific steriochemistry essential for epitope/receptor binding.  Engineering the synthesis of Hev-b proteins inclusive with D-amino acids may inhibit the antigenic protein/ IgE binding characteristic shifting the immune response to IgG.  Thus, steriochemical modification of antigenic proteins may be a useful allergy immunotherapy during neonatal development in that the IgE mechanism may be substantially inhibited.  

28.     Candidate Gene Loci, Epigenetics, Sporadic 

     Many researchers suspect that a combination of environmental insult and genetic susceptibility are involved in the etiology of ASD.  With respect to environmental insult, allergy research has provided much information on the adverse immune responses associated with the Hev-b proteins that are inherent in natural rubber.  The Hev-b proteins prevalence in industrial societies and an increased incidence of atopy therefrom continues to be a public health issue. 

     In genetic research, studies continue to find mutations associated with immunity that may affect the incidence of allergy induced autism.  Several candidate gene loci are described below:     

        Chromosome 1   (1q23, Fc fragment of IgE) [  222  ];         

        Chromosome 11 (11q12-q13, IgE responsivesness) [ 223 ];

        Chromosome 19 (19p13.3, CD23) [ 224 ]; and

          Chromosome X  (Xp11.23, FOXP3) [ 225 ].

     Furthermore, allergy induced autism may involve environmentally induced epigenetic mechanisms.  It's generally recognized that epigenetic mechanisms may influence cytokine gene expression in a naive CD4+ T cell as it develops into a Th1 or Th2 cell. [ 226 ]

     Alternatively, it's conceivable that allergy induced autism is based on sporadic environmental insult.  For example, it's well known that individuals can be exposed to the Hev-b proteins for many years and not experience sensitivity and then, without any known risk factor, become severely disabled with allergies.  In the other extreme, individuals can experience severe allergies immediately after the first exposure.

     The concept of Occam's Razor is often paraphrased as "All things being equal, the simplest solution tends to be the best one".  Using this concept, you decide which statements below encompass the spirit of Occam's Razor and autism.

     1.  The increased incidence of ASD is influenced by a global increase of genetic mutations resulting in atypical protein

          transcription/expression;

     2.  The increased incidence of ASD is influenced by a global increase of epigenetic mechanisms resulting in atypical protein

          transcription/expression;

     3.  The increased incidence of ASD is influenced by a global increase of allergies resulting in atypical protein

          transcription/expression.

29.     Iatrogenic Autism

     The term "Iatrogenic Autism" is described herein as physician-induced wherein allergy induced autism is initiated by the use of medical products comprising NRL from Hevea Brasiliensis.  For example, it is well known that Hev-b protein insult often occurs during hospital visits/physician examinations through dermal contact and/or inhalation wherein the use of powdered gloves contaminate the health care environment with aeroallergens inclusive with the Hev-b proteins. [ 226.5227 ]

     Research studies over the past several decades have shown that increased exposure to the Hev-b proteins can affect the incidence of adverse IgE immune responses in health-care workers and patients - There is much litigation related to natural-latex allergies and the evidence of harm is well documented. [ 228

     In a study on a retrospective analysis of risk factors in development of natural-latex allergy in children up to 5 years of age; the researchers concluded that besides the number of operations and an atopic predisposition -- no other definite risk factor for developing sensitization or allergy to natural latex (such as everyday household objects) can be identified in children up to 5 years of age. [ 229 ]

     The Hungarian physician Ignace Semmelweis [ 230] discovered by 1847 that the incidence of puerperal fever could be drastically cut by use of hand washing standards in obstetrical clinics.  Thereafter, the germ theory of disease developed and displaced dyscrasia (i.e., four humours) as the cause of many diseases.  Ironically, medical hygiene products (e.g., Hevea-brasiliensis latex gloves) intended to protect the practitioner and patient from infectious insult (e.g., germs and viruses) has increased non-infectious protein insult (e.g., Hev-b proteins) inducing allergies.

    For most, allergies are a nuisance;
    for many, allergies are debilitating; and
    for some, allergies are deadly. 

    Finally, William Stewart Halsted who was Johns Hopkins Hospital’s first surgeon in chief is widely credited as the first to develop and introduce rubber surgical gloves in the United States: that was in 1894 which was five years after the institution opened.  [ 230.1 ]  Thereafter, in 1930 Leo Kanner [ 230.2 ] developed the first child psychiatry service in a pediatric center at Johns Hopkins hospital, Baltimore.

30.     Oxytocin and Natural-Latex Allergy

     Oxytocin is a mammalian hormone that also acts as a neurotransmitter in the brain. [ 231]  A study on the role of oxytocin in natural-latex allergy during Cesarean-Section showed the vaso-and utero constrictor effects of administered oxytocin worsened the expression of natural-latex allergy. [ 232 ]

     The structure of oxytocin shows similar epitopes to some of the Hev-b proteins based on the presence of cysteine residues that form a sulfur bridge (i.e., cystine). 

     Furthermore, there is speculation that reduced expression of endogenous oxytocin may cause some cases of autism since so many mothers of autistic children had to have exogenous oxytocin (Pitocin®, Syntocinon®) to induce labor.

     Therefore, we can postulate the following questions:

     Q.     Is there a comorbid interaction of administered oxytocin and Hev-b protein insult which may have increased the incidence of 

             prenatal/neonatal natural-latex
allergy during the birthing process.

     Q.     Is there a cross-react immune response to endogenous oxytocin or the oxytocin-neurophysin 1 precursor (~10KDa), based

              on similar epitopes and structure homology with some of the Hev-b proteins, when natural-latex allergy occurs during

              prenatal/neonatal development.

31.     Medical History (Natural-Latex Allergy & Autism)

     Is there a historical connection of natural-latex allergy and autism?

     The first mention of natural-latex allergy in a medical journal was in 1933.  Dr. John G. Downing described two surgeons who came to him complaining of hand dermatitis after wearing rubber gloves during surgery. [ 233

     In parallel, the classification of autism occurred in 1943 when psychiatrist Dr. Leo Kanner [ 234 ] of the Johns Hopkins Hospital in Baltimore reported 11 children with striking behavioral similarities and introduced the label "early infantile autism".  At the same time, an Austrian scientist named Dr. Hans Asperger made similar observations. [ 235 ]

    Thus, it appears that the timing of the discovery for natural-latex allergy and autism coincide in medical history.

32.     Gut Microflora & Allergy Induced Autism

     A study that explored allergy development and the intestinal microflora during the first year of life concluded that differences in the composition of the gut flora between infants who will and infants who will not develop allergy are demonstrable before the development of any clinical manifestations of atopy. [ 235.1

     It is speculated that a Hev-b protein induced immune-response, during prenatal/neonatal development, may affect some of the symptoms of allergy-induced-autism through atypical microflora expression.  For example, the cell wall of gram positive bacteria is primarily composed of peptidoglycans (~90%).  Peptidoglycans are polymers that consist of sugars and amino acids.  Specifically, a Hev-b (i.e., glycoprotein) immune response may induce cross reactivity to some gram positive bacteria including enterococci and bifidobacteria based on carbohydrate epitopes (e.g., n-acetyglucosamine).  In continuation, it is recognized that one of the symptoms that may be associated with a Hev-b protein immune response (i.e., natural-latex allergy) is diarrhea.

     The study also showed that the expression of certain gram positive bacteria (e.g., staphylococcus aureus) increased at 6 months of age.  During an allergic reaction, the production of serum IgE is increased.  Elevated levels of serum IgE have been known to affect staphylococcal infections.  For example, high levels of serum IgE associated with hyper-IgE syndrome are characterized by recurrent staphylococcal infection. [ 235.2

     Other studies indicate that high levels of serum IgE is a major factor driving Fc epsilon R1 expression on dendritic cells.  These findings may have important implications on the development of atopy in that dendritic cells play an important role in antigen presentation to T lymphocytes. [ 235.3 ]

     Thus, IgE cross reactivity and serum IgE levels may both play a role in the expression of gut microflora and atopy.  

33.     Falsifiable Hypothesis

     In 1964 the World Medical Association developed a code of research ethics that came to be known as the Declaration of Helsinki.  It was a reinterpretation of the Nuremberg Code, with an eye to medical research with therapeutic intent.

     Thus, human experimental research directed at prenatal/neonatal induced immune responses to the allergens in natural rubber latex is unethical and prohibited based on non-therapeutic intent.

            Q.  Can animal studies be used to falsify the hypothesis.

            A.  The pursuit of animal studies (i.e., mammals and IgE) currently lacks justification in that autism spectrum disorders are

                  exclusively a human disorder based on the American Psychiatric Association's Diagnostic and Statistical Manual of

                  Mental Disorders (DSM-IV).

            Q.  Can In-vitro experiments falsify the hypothesis.

            A.  Genetic studies (i.e., incremental science) may show utility in deciphering clues to the immune system, but, the 

                  current unpredictability of Hev-b
protein insult, IgE cross-reactivity, and other comorbid factors (e.g., viral induced hyper 
        
                  immunity associated with non-infectious antigenic protein insult) adds complexity to the etiology of
allergy-induced-

                  autism.    

            Q.  Can Hev-b protein exclusionary practices be used to falsify the hypothesis.

            A.  Yes, limit Hev-b protein exposure during neurological development and monitor the global incidence and/or the degree of 

                  atypicality of autism spectrum
disorders thereafter.

34.     Hev-b Protein Standards

     Infant products formed from natural rubber latex (Hevea Brasiliensis) are not required by law to meet the minimum standard of protein content based on The American Society for Testing and Materials method ASTM D1076-06 (Catergory 4) that defines latex containing less than 200 micrograms total protein per gram dry weight of latex.  For example, manufacturer's of baby bottle nipples and pacifiers do not display antigenic protein warnings (i.e., protein content information) on their packaging [ 235.35 ].  Unfortunately, health and safety is often compromised in that rubber manufacturers are not required to disclose such information.

 A citizen petition has been sent to the U.S. Food and Drug Administration (Docket # 2007P-0486) which states:

     "The petition requests that the Commissioner issues a regulation for Hevea Brasiliensis natural-rubber-latex, used in the manufacture of infant products, wherein said latex meets the minimum standard of protein content based on The American Society for Testing and Materials method ASTM D1076-06 (Category 4) that defines latex containing less than 200 micrograms total protein per gram dry weight of latex."

    In a letter from the FDA dated July, 18, 2008, Laura Tarantino (Director - Office of Food Additive Safety) wrote, "The purpose of this letter is to advise you, in accordance with 21 CFR 10.30(e), that we have not reached a decision within 180 days of the filing of the petition because of the limited availability of resources and other agency priorities."

    The FDA is aware of some of the hazards associated with natural rubber latex (Hevea Brasiliensis), based on medical latex
 glove issues. [ 235.4 ]    

    Finally, it has often been said that latex allergy usually affects people who are routinely exposed to natural rubber latex.  Unfortunately, neonates are routinely exposed to bottle nipples and pacifiers that are formed from Hevea Brasiliensis natural rubber latex.  Currently, we are at the mercy of rubber manufacturers; many of which are located in third world countries.

35.     Miscellaneous

 

 

     The hypothesis presented in this research article has been submitted to medical journals for publication with the following results:

                             Accepted                                          Rejected

                    Medical Hypothesis                                The Lancet 

                    (YMEHY-D-07-00035)                          (The Lancet D-07-01788)

                                                                                The New England Journal of Medicine

                                                                                (NEJM Manuscript # 07-1725) 

     Also, research proposals were submitted to Defeat Autism Now (DAN!)and the Bill and Melinda Gates Foundation (BMGF)and subsequently rejected.   The DAN! think-tank committee disclosed that the hypothesis was "not sufficiently convincing" and the BMGF said they are currently funding other projects.  

    The American intellectual Thomas Samuel Kuhn [ 235.5 ] wrote, "A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it". 

     It has been written that white-collar professionals in high technology industries may have an increased incidence of offspring with ASD. [ 236 ]  In high-tech facilities it is often standard practice to use natural-rubber latex gloves in an effort to reduce contamination (e.g., skin cells, hand moisture, dirt, and oils).  Some employees in high-tech industries may be contaminated with the non-infectious antigenic proteins inherent in natural-rubber latex products and thereafter affect others through contact.  For example, after being exposed to the Hev-b proteins contaminated hands and clothing may be a means of protein transfer to other family members (e.g., fetus, neonate) through physical contact.

     A study that evaluated percutaneous penetration of natural rubber latex proteins concluded that the skin is not only a plausible route for latex sensitization but can be a major exposure route when the integument has been compromised. [ 237 ]  Even though the FDA now requires latex warning labels, natural rubber latex adhesives continue to be used in the packaging of Band-Aids [ 238 ]

    The Rubber Manufacturers Association has communicated, "Latex rubber may even reduce the symptoms of autism, according to one member of the Autistic Society who has successfully used 'trance suits' i.e., inflatable natural latex rubber suits".  [ 238.01 ]

    Finally, it has been suggested that there are no folk medicine references to the use of Hevea Brasiliensis.  In contrast, most lacticiferous plants have large folk medicinal roles. [ 238.05 ]

36.    Natural-Latex Waste Management

    The Industrial Latex Corporation (Wallington, N.J.) poor operational procedures and on-site waste disposal practices, resulting in widespread areas of surface and sub-surface soil contamination, triggered EPA Superfund clean-up efforts in 1986. [ 238.055 ]  

    Another abandoned latex property investigated by the EPA was located in Bethel, Connecticut. [ 238.056

    The following question can be asked:

Q. Does the improper disposal of waste natural rubber latex, and increased antigenic protein exposure therefrom, affect the incidence of allergy induced autism.  
 
    It has been suggested that communities located near chemical land fill sites in the state of New Jersey have reported an unusual incidence of ASD (i.e., Brick Township, N.J.). 

37.     Conclusion    

     Increased Hev-b protein exposure may have affected the incidence and/or the degree of atypicality of autism spectrum disorders globally.  The timing, frequency, intensity, and type of exposure to such proteins may have increased atopy and allergy induced autism.  In the autism spectrum, an etiology must be able too explain the extreme range of cognitive atypicality therein including severe mental retardation to brilliance.  Adaptive immunity may be the etiology that provides such an explanation.

38.     Father of Autism Spectrum Disorders   

     Q. Who is the Father of Autism Spectrum Disorders.
 
   
  
                                                                             

                  Eugen Bleuler [ 238.06                        Hans Asperger [ 238.1 ]     Leo Kanner [ 238.2 ]
   

                                                                     

                                                                     Charles Goodyear [ 239 ]

39.     Acknowledgments

    Dain & Basil for conceptualization assistance through the ASD experience.
    Teachers are silently inclusive in the questions we ask and the answers we seek.
 

 40.    Admonishment

     Minnesota Governor Tim Pawlenty for taking resources from disabled children on the autism spectrum in an effort to balance the state budget.

41.    Apology

    
My deepest apologies to those on the autism spectrum who are offended, in any way, with the ideas or information communicated within this research article.


                                          

 

Autismdoc.org 

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Author: Michael J. Dochniak
Origination Date: 08/2005
Last Revision: 9/2008

                                                               

 

 

 
 
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