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THE ROLE OF ENDOCRINE DISRUPTORS by Raphael Kellman, M.D.

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According to the CDC 1 in 110 US eight year olds have autism spectrum disorder. US Centers for Disease Control and Prevention (CDC) 2007. Counting Autism According to US centers for disease control and prevention (CDC) approximately 4.5 million children have been diagnosed with ADHD. CDC 2007 Summary Health Statistics for US Children: National Health Interview Survey, 2006 Prevalence of learning disabilities in United States children is approximately 9.7% according to a 2007 pediatrics article. Altakac M. et al 2007 Lifetime Prevalence of Learning Disability among US Children, 119; 77-83 EPIDEMIC ONE AUTISM AND NEURO-DEVELOPMENTAL DISORDERS

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According to a 1994 study 16% of US children have a developmental disability. Boyle CA et al Prevalence of Health Impact of Developmental Disabilities in US Children Pediatrics 93 (3): 399-403 According to an article in JAMA in 2007 developmental disorders and chronic conditions in general is on the rise. Perrin JM The Increase of Childhood Chronic Conditions in the United States JAMA 297 (24): 2755- 9

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EPIDEMIC TWO THYROID DISEASE According to the Colorado Thyroid Disease Prevalence Study in 2000 The prevalence of abnormal thyroid function is 9.5% If the upper level of TSH reference range is reduced to 2.5, as suggested by the National Academy of Clinical Biochemistry, this number will at least double 24% of women older than 60 have hypothyroidism G. Canaris et al The Colorado Thyroid Disease Prevalence Study Arch Intern Med 2000; 160:526-534

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Thyroid cancer is rising in incidence faster than any other cancer in the United States According to the NCI, thyroid cancer is increasing by 6.5% per year since 1997 Papillary carcinoma between 1999 and 2005, and 2003 and 2005 increased nearly 100% Enewald V. et al Rising Thyroid Cancer Incidence in the US by Demographic Tumor Characteristics 1980-2005 Cancer Epidemiology Biomarkers 2009; 18:784-791 Increasing Incidence of elevated TSH levels in newborn screening in Northern England Pearce MS et al J. Thyroid Research, Jan 2010

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Thyroid auto-immune disease is the most common auto-immune disease 7-8% of the population, totaling 24 million Dayan CM et al Chronic Autoimmune Thyroiditis New England Journal of Medicine 1996; 335: 99-107 Because only one-third of those with autoimmune diseases are diagnosed, the statistics are estimated to be 3x higher than that, as high as 72 million NIH Autoimmune Coordinating Committee Autoimmune Research, 2005 US Dept. of Health and Human Services, NHI pub March 25

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IS THE EPIDEMIC OF NEURO- DEVELOPMENTAL DISEASES LARGELY REDUCIBLE TO A MORE PRIMARY DISORDER - HYPOTHYROIDISM?

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Many of the same chemicals that are associated with autism, also cause thyroid disease Toxins thought to contribute to the development of autism and ASD mediate their effects via their adverse effects on the thyroid Thyroid hormone known to play a critical role in orchestrating brain development Thyroid dysfunction in utero, and neonates leads to many of the same symptoms associated with autism and ASD EVIDENCE SUPPORTING THYROID-AUTISM CONNECTION

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Celiac disease/gluten intolerance is associated with hypothyroidism. Gluten-free diets known to help with autism, may mediate via its positive effects on the thyroid Autism and ASD frequently associated with auto-immune diseases. A percentage of thyroid disease is auto-immune in nature Mitochondrial dysfunction found to be associated with autism -hypothyroidism causes mitochondrial dysfunction Hypothyroidism contributes to methylation defects

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THE CRITICAL ROLE OF THYROID HORMONE IN BRAIN DEVELOPMENT Phase I First trimester, before synthesis of fetal TH, fetus dependent on maternal TH Proliferation, migration and differentiation of neurons that develop into the forebrain, orchestrated by TH Phase II Fetal TH production, some role of maternal TH Proliferation, migration and differentiation of neurons that develop into the cerebellum Forebrain maturation and synapse formation Orchestrated by TH

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Phase III After birth, continuation of proliferation, migration, and differentiation Myelination, gliogenesis Thyroid hormones act as a time clock stimulating and subsequently terminating proliferation, migration and differentiation at the precise time with the precise dose and in the correct sequence Central Nervous System symphony, thyroid hormone the conductor S. Porterfield; Endocrine Reviews; 14 (1) 94-106; 1993 If TH plays such a critical role in neurodevelopment, that is the system where we should be concentrating our efforts to better understand the origins of neuro- developmental disorders

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Low thyroid function in the fetus and newborn associated with similar symptoms associated with ASD and ADHD General developmental delays Cognitive dysfunction Hyperactivity Attention disorders Speech delays Hypotonia/Fine motor dysfunction Repetitive behavior Social and communication dysfunction Zoeller RT et al Timing of Thyroid Hormone Function in the Developing Brain: Clinical Observations and Experimental Findings J. Neuroendocrinol 16:809-818

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HYPOTHYROXINEMIA IN PREGNANCY AND NEURO- DEVELOPMENTAL DYSFUNCTION IN CHILDREN Children of mothers with low normal T4 (T4-0-10 th percentile) due to iodine deficiency from early gestation to birth increases the risk of neuro- developmental delay in their offspring Lower performance in gross and fine motor coordination Lower performance in socialization Delayed Neurobehavioral Development in Children Born to Pregnant Women with Mild Hypothyroxinemia During First Month of Gestation The Importance of Early Iodine Supplementation P.Berbel et al Thyroid Number 6, December 19, 2009

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Thyroid function can be damaged by the same toxins associated with autism and other developmental disorders: PCBs Dioxins Perchlorate Phthalates PBDEs Lead Mercury Cadmium Insecticides Bisphenol-A P. Landrigan Curr Opin Pediatr 2010 What Causes Autism? Exploring the Environmental Contribution

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According to research reported in Digestive Diseases and Sciences: Gluten sensitivity/celiac disease associated with thyroid disease Celiac disease can play a role in the etiology of thyroid disease We believe that undiagnosed celiac disease can cause other disorders by switching on some as yet unknown immunological mechanism. Untreated celiac patients produce organ specific antibodies. Digestive Diseases and Sciences February 2000; 45:403-406 HYPOTHYROIDISM AND GLUTEN INTOLERANCE/CELIAC DISEASE

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T4 regulates the conversion of riboflavin to FAD. Levels of FAD in the liver of hypothyroid rat is similar to rats on a riboflavin-deficient diet Erythrocyte Glutathione Reductase (EGR) an FAD enzyme low in adults with hypothyroidism Hypothyroidism - conversion of riboflavin to FAD and MTHFR J Cimino et al Riboflavin Metabolism in the Hypothyroid Newborn American Journal of Clinical Nutrition 1988; 47: 481-483 HYPOTHYROIDISM AND METHYLATION PATHWAY DEFECTS

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Decreased NADH Increased oxidative stress Mitochondrial DNA over replication or deletion Whether the mitochondrial dysfunction in children with autism is primary or secondary to an as yet unknown event remains the subject of future work; however mitochondrial dysfunction could greatly amplify and propagate brain dysfunction, such as that found in autism. JAMA. 2010; 304 (21):2389-2396. JAMA Dec 1, 2010 MITOCHONDRIAL DYSFUNCTION IN AUTISM

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Hypothyroidism Alters Mitochondrial Morphology and Induces Release of Apoptogenic Proteins R. Singh J Endocrinol 2003; 176: 321-329 TH deficiency leads to extensive apoptosis during cerebellar development TH maintains mitochondrial architecture and inhibits release of apoptogenic molecules to prevent excess apoptosis during cerebellar development

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TH REGULATES MITOCHONDRIAL ACTIVITY Nuclear pathway Direct mitochondrial pathway stimulation of mitochondrial genome transcription Both pathways mitochondriogenesis Mitochondrial pathway involved in regulation of cell differentiation TH regulation of mitochondrial activity - link between metabolism and development Thyroid Hormone Action in Mitochondria C. Wrutniak-Cabello et al Journal Molecular Endocrinology 2001; 26: 67-70

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Increased prevalence of familial autoimmune diseases in families of a child with autism Comi Am et al J. Child Neurol, June 14, 1999 (6) 388-94 Frequency of autoimmune disorders is significantly higher in families of children with PDD compared with families of both autoimmune and healthy control bands Hypothyroidism significantly increased in PDD families compared to autoimmune families Sweeten TL et al Pediatrics, Nov 2003, 112 (5) 420-426 AUTISM, ASD, PDD AND AUTOIMMUNE DISORDERS

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Endocrine disrupting chemicals, EDCs are synthetic substances in environment, food and consumer products. According to the EPA, EDC is an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action or elimination of natural blood borne hormones that are present in the body and responsible for homeostasis reproduction and developmental processes.

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Growing list of chemicals now known to disrupt bodys communication network Blocks or impersonate hormone messages Scrambles messages Sows misinformation- fools the endocrine system to accept new instructions Toxicology I Focus on cancer, dose makes the poison Toxicology II Endocrine disrupting chemicals Plays by different rules: Even low doses can have devastating effects Hormones, mostly TH, orchestrate neurological development, even low doses of EDCs that have little effect on adults, can have devastating effects on the unborn, neonate and child ENDOCRINE DISRUPTOR THEORY GENERAL CONCEPTS

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Toxicology II continued Normal development depends on the right hormone message at the right time and the right amount chemical ballet Windows of vulnerability Timing makes the poison ENDOCRINE DISRUPTOR THEORY GENERAL CONCEPTS

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Thyroid system is one of the most frequent targets of synthetic chemicals Linda Birnbaum; Director of Environmental Toxicology Division at the US Environmental Protection Agency

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ENDOCRINE DISRUPTORS AND ITS EFFECTS ON THE THYROID AND NEURO-DEVELOPMENT IN UTERO TO FIRST TWO YEARS OF LIFE Effects include: Learning disabilities Behavioral problems Fine motor dysfunction Poor response to stress Attention problems and hyperactivity Language speech deficits Social development deficits S. Porterfield Vulnerability of Developing Brain to Thyroid Abnormalities Environmental Insults to the Thyroid Systems Environmental Health Perspectives 1994, 102 (2): 125-130 S. Porterfield Thyroidal Dysfunction and Environmental Chemicals-Potential Impact on Brain Development Environmental Health Perspectives, Vol 108 Supplement 3 June 2000

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Other effects of thyroid disruption on neuro- development in infants and children: Visuospatial deficits Motor and visual motor delays Decreased social and perceptual abilities Decreased auditory discriminating abilities JF Robet Neurodevelopment in Infants and Preschool Children with Congenital Hypothyroidism Etiological and Treatment Factors Affecting Outcome Journal of Pediatric Psychology 1990, vol 17: 187-213

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Wingspread Consensus Statement 1991 We are certain of the following: a large number of man made chemicals have the potential to disrupt the endocrine system of animals including humans. Endocrine disruptors cause: Thyroid dysfunction in birds and fish Decreased fertility in birds, fish and mammals Gross birth deformities in birds, fish and turtles Behavioral abnormalities in animals CHRONOLOGY OF KEY EVENTS IN THE DEVELOPMENT OF THE ENDOCRINE DISRUPTOR THEORY

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May 1996 scientific conference in Erice, Sicily concluded: Endocrine disrupting chemicals at levels found in the environment and in humans threaten brain development We are certain of the following: endocrine disrupting chemicals can undermine neurological and behavioral development and subsequent loss of potential of individuals exposed in the womb This loss of potential in humans and wildlife is expressed as behavioral and physical abnormalities. It may be expressed as reduced intellectual capacity and social adaptability, as impaired responsiveness to environmental demands.

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The extreme sensitivity of the developing brain to chemical disruption of the endocrine system[can cause] reduced intelligence, learning disabilities, attention deficit problems and intolerance to stress. Many of the endocrine disrupting chemicals can affect the thyroid which plays a key role in brain development.

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August 1996 Food Quality Protection Act passed Requires the EPA to obtain data about the potential hormone disrupting effects of pesticides in food. October 1996 EPA forms Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) The EDSTAC establishes a comprehensive screening and testing program for pesticides and other chemicals The EDSTAC decides program should focus on estrogen, testosterone and thyroid hormone disruptors The EDSTAC charged to coordinate research in the field of endocrine disruptors to more accurately characterize the risks of endocrine disruptors March 1996 publication of Our Stolen Future

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THYROID DISRUPTING CHEMICALS MUTIPLE MECHANISMS CHEMICALMECHANISM OF ACTION SOURCE Perchlorates Bromates Thyocinate Phthalates Blocks Iodide UptakeBlount BC 2007 Crofton KM 2008 PCBs Pentachlorophenol Flame Retardants Phthalates Competitive Binding to Thyroid Transport Protein eg. TTR Cheek D. 1999 Whitefield GR 1999 Purkey HR 2004 Pluim J 1993 Mancozeb Amitrole Benzophenone Blocks Production of Thyroid Hormone Crofton KM 2008

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THYROID DISRUPTING CHEMICALS MUTIPLE MECHANISMS CHEMICALMECHANISM OF ACTION SOURCE PCBs Bisphenol A Flame Retardants Dioxin Phthalates Binds to Thyroid Receptor Boas M. 2006 Shen O. 2009 Moriyama 2002 Lead Cadmium FD&C Red Dye #3 PCBs PBDE Octylmethoxycinnamate Mercury HCB Inhibition of Deoidinases Santini 2003 Mori K. 2008 Boas M. 2006 Takser L 2005

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THYROID DISRUPTING CHEMICALS MUTIPLE MECHANISMS CHEMICALMECHANISM OF ACTION SOURCE DDT PCBs Binds to TSH ReceptorSantini F. 2003 Acetochlor PCBs PBDE Enhanced Hepatic Metabolism Hosokawa S. 1992 Zhou T. 2001 PCBs TCDD Chlorinated Pesticides Mercury PBDE Direct Toxic Effect on Thyroid Gland Ness DK 1993 Porterfield S. 1994 Takser L. 2005 Zhou T. 2001

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Endocrine disruptors may have similar or different effects on the thyroid. This can create a cumulative and/or synergistic effect. Crofton K.M. et al Thyroid Hormone Disrupting Chemicals: Evidence for Dose Dependent Additivity or Synergism. Environmental Health Perspectives 2005, 113; 1549-1554

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There is substantial evidence that polychlorinated biphenyls dioxins and furans cause hypothyroidism in exposed animals, and that environmentally occurring doses affect human thyroid homeostasis. Thyroid disruption may be caused by a variety of mechanisms as different chemicals interfere with the hypothalamic-pituitary thyroid axis at different levels. PCBs

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Growth and development in fetal life and childhood is highly dependent on normal levels of TH (thyroid hormone). Normal levels of THs are crucial for the development of the Central Nervous System. This critical phase may be vulnerable to even subtle effects of synthetic chemicals. Such developmental deficiencies may not be identifiable until late in life. European Journal of Endocrinology. Environmental Chemicals and Thyroid Function. Malene Boas et al 2006, vol. 154 Issue 5: 599-611

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PCBs in maternal blood during pregnancy. Negative correlation between maternal TT3 and PCBs, three pesticides (p- -DDE, cis-nonachlor, hexachlorobenzene) and inorganic mercury at low levels of exposure. Positive correlation to fetal TSH L. Takser et al Thyroid Hormones in Pregnancy in Relation to Environmental Exposure to Organochlorine Compounds and Mercury Environmental Health Perspective 113: 1039-1045 (2005)

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PCBs interfere with HPT axis by producing a subnormal response of the pituitary to TRH stimulation. Khan & Hansen 2003. Orthosubstituted, PCB Congeners (95 or 101) Decrease Pituitary Response to Thyrotropen Releasing Hormone. Toxicol Lett. 144; 173-182 In human adults, adolescents and children from highly exposed areas: PCB levels correlated negatively to TH levels. Hagmar C. et al PCB toxicity in children: Positive correlation between PCB exposure and TSH levels. Osius N et al Exposure to PCBs and Levels of Thyroid Hormones in Children. Environmental Health Perspectives 1999. 107 843-849

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Positive Association Between PCB levels in breast milk and TSH levels in infants Koopman-Esseboom et al Effects of Dioxins and Polychlorinated Biphenyls on Thyroid Hormone Status of Pregnant Women and Their Infants Pediatric Research 36: 468-473, 1994 1971 Women in Taiwan consumed cooking oil contaminated with PCBs and furans 128 Children studied who were in womb: Impairment in mental and motor abilities Behavioral problems Hyperactivity Attention deficits W Rogan et al Congenital Poisoning by PCBs and Their Contaminants in Taiwan Science 241: 334-336; 1998

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Widespread and persistent and highly toxic environmental pollutants from: Industrial burning processes Production of herbicides TCDD prototype and most toxic DIOXINS PCDs AND PCDF

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Single dose of TCDD in rats: dose-dependently decreased T4 and free T4 and increased TSH Viluksela M. et al Tissue Specifics Effects of TCDD on the Activity of 5-Deiodinases I and II in Rats. Toxicology letters 2004:147: 133-145 In offspring a single dose of TCDD to the dam during gestation was: Correlated to decreased T4 A two-fold increase in TSH Hyperplasia of the thyroid gland Nishimura N. Rat Thyroid Hyperplasia Induced by Gestational and Lactational Exposure to TCDD. Endocrinology 2003; 144: 2075-2083

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Large study of Vietnam veterans Group with highest TCDD levels showed a significant increase in TSH Pavuk M. et al Serum TCDD Levels and Thyroid Function in Air Force Veterans of the Vietnam War. Annals of Epidemiology 2003 13:335-343

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PCBs and dioxins measured in human milk. Higher levels in human milk correlated significantly with: Lower plasma levels of maternal TT3 and TT4 Higher TSH levels in the infants in the second week and third month after birth. Similar study of breast-fed infants: Chlorinated dioxins and furans (dioxins) positively correlated with TSH levels in infants. Dioxins may interfere with transport of T4 into the cell and the conversion of T4 to T3 or binding of T3 to nuclear receptor.

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Inhibition of enzyme 5-deiodinase and decreased conversion of T4 to T3. Decreased nuclear T-3 receptor occupancy. In pituitary gland decreased nuclear T-3 occupancy stimulates TSH secretion. Pluim J et al Effects of dioxins on the thyroid function in newborn babies Environmental Health Perspectives, vol 101 number 6 1993: 504-508

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PBDEs used as flame retardants in plastics, paints, electrical equipment and synthetic textiles TBPH used in electrical equipment such as televisions, computers, copying machines and video displays Commercial PBDE mixture DE-7: Decreases levels of TH Induces activity of hepatic enzymes UDPGT High doses DE-7 causes histopathological changes Zhou T. et al Effects of Short-term in Vivo Exposure to Polybrominated Diphenyl Ethers (PBDE) Mixture on Thyroid Hormones and Hepatic Enzymes Activities in Weaning Rats Toxicological Sciences 2001: 61; 26-82 FLAME RETARDANTS TBBPA AND PBDEs

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Maternal residence near agricultural pesticide applications during key periods of gestation could be associated with the development of autism spectrum disorder (ASD) in children ASD risk increased with the poundage of organochlorine pesticides applied and decreased with distance from field sites. Roberts EM Maternal Residence Near Agricultural Pesticide Applications and ASD among Children in California of Central Valley Environmental Health Perspectives 115 (10): 1482-1489 INSECTICIDES AND DEVELOPMENTAL DISORDERS

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Neuro-developmental effects include: Decreased psychomotor function Decreased mental function: depressed memory, attention and verbal skills Mechanism of action: thyroid disruption Jurewicz J 2008: Prenatal and Childhood Exposure to Pesticides and Neurobehavioral Development: Review of Epidemiological Studies. International Journal of Occupational Medicine. Environmental Health 21 (2): 121-132 Korrick S. et al 2008: PCBs Organochlorine Pesticides and Neuro-development Current Open Pediatric 20 (two): 178-204 Ribas-Fito N et al 2006 In utero Exposure to Background Concentrations of DDT and Cognitive Functioning among Preschoolers AM J P. Epidemiol 164:955-962 ORGANOCHLORINE PESTICIDES

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BPA levels correlated with increased weight of thyroid Positive finding between increasing BPA and activity of hepatic enzyme UDPGT. Tan BL et al Assessment of Pubertal Development in Juvenile Male Rats after Sub-acute Exposure to Bisphenol and Nonylphenol Toxicology letters 2003, 143; 261-270 BPA

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BPA acts as a TH antagonist on specific TR in the pituitary, which mediates the negative feedback of TH on the pituitary, causing: T4, TSH normal to borderline high BPA does not antagonize peripheral TR receptors Result: Hyperthyroidism in certain neurons in the developing brain leading to a mosaic effect Endocrinology. 2005 Feb;146(2):607-12. Epub 2004 Oct 21. Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brain Zoeller RT, Bansal R, Parris C.

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Miodouinik A. et al Neurotoxicology 2010 Dec 20 Mt. Sinai Children's Environmental Health Study between 1998-2002 evaluated relationship between phthalates and bisphenol-A (BPA) exposure in mothers collected during third trimester of pregnancy and neuro-developmental disorders in their children when they reach ages 7-9. Increasing phthalates associated with: Greater social deficits: Poorer social cognition, social communication and social awareness Mechanism of action thyroid disruption ENDOCRINE DISRUPTORS AND CHILDHOOD SOCIAL IMPAIRMENT

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Prenatal Phthalate exposure is associated with childhood behavior and executive function S.M. Engel Environmental Health Perspectives April 2010 Urine of mothers collected on third trimester from Mt. Sinai Environmental Health Study Their children evaluated at ages 4-9 for behavioral issues and executive function Phthalate levels correlate with poor executive function and decreased ability to: Control impulses

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continued Transition between situations Modulate emotional responses Initiate a task Retain information for task completion Set goals

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ASSOCIATION BETWEEN ORGANOCHLORINES AND ASD ASD risk increase with poundage of organochlorine applied and decreased with distance from field sites Mechanism of action thyroid disruption Binding of Gaba receptors Estrogenic effects Eric Roberts Maternal Residence near Agricultural Pesticide Application and ASD among Children in the California Central Valley Environmental Health Perspectives 2007 October: 115 (10):1482-1489

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IODINE DEFICIENCY AS A CAUSE OF AUTISM Increase incidence associated with increased iodine deficiency Iodine necessary for TH production BMJ 2004; 328:226

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If autism is an environmental disease, then based on the overwhelming evidence, hypothyroidism is likely to be a underlying metabolic state significantly contributing to its pathophysiology Hypothyroxinemia may have began in a percentage of children with autism as early as the first trimester in utero; this may be caused by sub- biochemical maternal hypothyroidism that either preceded pregnancy or developed subsequently due to the excessive need of TH and/or to a decrease in available iodine PUTTING THE PIECES TOGETHER

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continued Reported in the Journal of the Neurological Sciences 2007 Autism: Transient in utero Hypothyroxinemia Related to Maternal Flavonoid Ingestion During Pregnancy and to Other Environmental Anti-thyroid Agents - The current surge of autism could be related to transient maternal hypothryoxinemia resulting from dietary and/or environmental exposure to anti- thyroid agents. - Decrease TH in utero causes alterations of cerebral cortical architecture by affecting neuronal migration reminiscent of those observed in brains of patients with autism G Roman Journal of the Neurological Sciences 262 (2007) 15-26

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continued Although the etiology of autism is multi-factorial, hypothyroidism at any point during neurodevelopment can be a central cause of autism Therefore treating hypothyroidism place a vital role in the treatment of autism

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IF THERE IS SUCH A PROFOUND THYROID-AUTISM CONNECTION, WHY IS IT NOT BEING DETECTED BY ROUTINE BLOOD TESTS?

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Studies are revealing the complexity of the ways in which endocrine disruptors may interfere with TH signaling Some endocrine disruptors can cause decreased T4 and yet normal TSH Other endocrine disruptors due to its effects on receptors can cause increased T4 and TSH normal or slightly increased Endocrine disruptors can also affect diodinase, for example organochlorines can cause over-expression of D3 causing high reverse T3 and low T3

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continued The complex effect of EDCs have on the HPT access can elude routine thyroid blood tests A reason of why hypothyroidism is frequently overlooked is because routine thyroid blood tests are often conflicting and not very revealing The current clinical strategy of evaluating thyroid disease (measurement of blood levels of hormones) is not sufficient to identify EDC action or thyroid hormone signaling that may well be associated with disease in the human population Thomas Zoeller Environmental Chemicals Targeting Thyroid Hormones 2010, 9 (1): 28-40

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TSH VALUES ARE OFTEN UNRELIABLE AND MISLEADING AND MAY NOT ADEQUATELY REPRESENT THYROID STATUS Biologic variation is important for interpretation of thyroid function tests S.Anderson et al Thyroid, Vol 13 number 11 2007 Individual set point for normal thyroid function- unique for each individual Some individuals with TSH within reference range have a TSH outside the individual reference range Laboratory reference ranges are relatively insensitive to aberrations from normality in the individual

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Subclinical thyroid disease may be defined in purely biochemical termsunder certain conditions such as pregnancy where normal thyroid function is of importance for fetal brain development subclinical thyroid disease should be treated. Even TSH within reference range may be associated with slightly abnormal thyroid function in the individual.

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Many studies shed doubt on validity of reference range of TSH Subclinical and sub-biochemical hypothyroidism can adversely affect target organs and systems: Developing brain Adult brain (depression studies) Cardio-vascular system: angina patients who underwent cardiac cath: those with TSH levels above 2.1 were more likely to have multiple vessel disease. Yun KH et al Int. J Cardiol 2007

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Treatment of patients with subclinical hypothyroidism and hyperlipidemia with thyroid hormone resulted in significant reduction in LDL cholesterol and improved endothelial function. Razvi S et al Endocrinol Metab 2007; 92:1715-1723

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Depressed patients with normal TSH could have an exaggerated response to TRH Kraus RP et al Exaggerated TSH Response to TRH in Depressed Patients with Normal Baseline TSH J Clin Psychiatry 1997; 58: 266-270 Concept of Sub-biochemical Hypothyroidism coined by Sheth J 1999. TH and TSH within normal range yet TRH test is abnormal. Sheth J et al Sub-biochemical Hypothyroidism: An Exaggerated TSH response to TRH J Assoc Physicians India 1999; 47:275-279

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Landmark study 2007 demonstrates routine thyroid test frequently fails to detect hypothyroidism. Patients with normal TSH and TH with suggestive clinical symptoms of hypothyroidism evaluated with TRH test. Conclusion of researchers: We document that an exaggerated TRH response indeed occurs in many subjects with normal biochemistry Even though the TRH test is

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continued seldom used in clinical practice at present, a larger prospective study is in order. Until then physicians may once again need access to TRH for diagnostic use. TRH Stimulation When Basal TSH is within normal reference range: Is there Sub-Biochemical Hypothyroidism? Suhail A.R Doi et al Clinical Medicine and Research Volume 8 Number 3 145-148

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Dr. Rosa and colleagues compared TRH stimulation testing with sensitive 2 nd generation TSH testing Basal TSH frequently failed to exclude hypothyroidism 35.3% sensitivity In conclusion, after the introduction of the current 2 nd generation TSH assay the diagnostic role of the TRH test can provide additional information to that obtained with simple basal TSH measurement in the diagnosis of subclinical hypothyroidism DeRosa et al Comparison between TRH Stimulation Test and Basal TSH Measurement by a Commercial Immunoradiometric Assay in the Management of Thyroid Disease J. Nucl Med 1996; 40:182-187

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Subclinical Hypothyroidism in Infertile Women the Importance of Continuous Monitoring and the Role of Thyrotropin Releasing Hormone Stimulation Test T. Ldar-Geva et al Journal of Clinical Endocrinology June 2007; 23 (6):332-337 87 patients with infertility no other symptoms of hypothyroidism TH Normal, TSH 1.72 1.87 Group one: 39 women ovulation disorders, PCOS Group two: 48 women normal ovulation Abnormal TRH test 13.8% Abnormal TRH significantly more prevalent among women in group one 20%

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Baseline-Individual set point normal TSH and TH, TRH test normal Stage 1: Normal T4, TSH slightly above patients individuals set point yet within normal range (such as from 1.7 to 2.1) Abnormality only detected by TRH test Stage 2: gradual elevations of TSH Researchers conclude: we recommend performing TRH stimulation testing in women suffering from ovulations disorders, who have normal basal TSH levels

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My Findings Based on the Use of the TRH Stimulation Test: Approximately 70% of children with autism, ASD and other neuro-developmental disorders have hypothyroidism Most missed by routine test Profound improvement with thyroid hormone treatment, some complete recovery Many mothers of such children show bio- chemical evidence of hypothyroidism If hypothyroidism is confirmed TH is the most effective known treatment for autism

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MY APPROACH TO THE TREATMENT OF AUTISM, ASD AND NEURO-DEVELOPMENTAL DISORDERS TRH stimulation test thyroid hormone treatment Provide enriched brain environment and a second chance for brain organization and development. a. Nutraceuticals, herbs that improve brain function: - EPA, DHA - Phosphatidyl Serine, Choline - CDP Choline - GPC - Galantamine - Carnosine

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continued - Aniracetam - Melatonin - Gaba - Huperizine - Vinpocitene - Inositol - Amyloban - etc

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b. Hyperbaric Oxygen Therapy Immune Modulation Anti-inflammatory compounds: - Curcumin - Boswellia - Luteolin - Transfer-factors - Glutathione - LDN - Liposomal Vitamin C - Lipoic Acid - etc

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Methylation Pathway Improvement - Vitamin B6- P5P - Folinic Acid - MB12 / Glutathione - Taurine - Creatine - etc Mitochondrial Repair - NADH - Ubiquinol - A.L. Carnitine - PQQ

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Detoxification - Clay baths - Chelation - Infrared sauna - Liver detoxification Infectious Disease - GI bacterial infections - Lyme disease - Strep - Viral infections

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Dietary Changes - GF/Diet - Remove allergens

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Implications for the Treatment and Prevention of Neuro-Developmental Disorders All children with neurodevelopment disorders should be tested with the TRH stimulation test Mothers of such children should be tested with the TRH stimulation test Women should be tested with the TRH stimulation test before pregnancy All pregnant mothers should take Iodine 250mcg p/day

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continued We must move beyond the cancer paradigm in order to properly understand the effects of the hormone disrupting chemicals and the threats they pose to human health. We need to bring new concepts to our understanding of toxic chemicals. Our past assumptions about toxicity act as obstacles to understanding a different kind of damage We must change our understanding of testing and treatment of thyroid disease. Routine thyroid testing can be misleading and frequently prevents us from uncovering the root cause of so much suffering

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Summary Thyroid-Autism connection and the role of endocrine disruptors: Reduces a variety of medical disorders and epidemics to a more primary problem Provides a deeper explanation for the known likely causes of autism Proves clinically what researchers are theorizing and finding in animal studies and some human studies in neonates First to connect endocrine disruptors to autism and ASD

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continued TRH stimulation test detects hypothyroidism in children with autism missed by routine test. When diagnosed with hypothyroidism, thyroid hormone is the most effective treatment for autism TH together with other brain-enhancing compounds can provide the necessary enriched environment for brain re-organization and development. With the understanding of the effects of endocrine disruptors on thyroid function and neuro- development we can also significantly reduce the incidence of neuro-developmental disorders in the future.

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Message of Hope We can change the course of autism and neuro- developmental disorders by understanding and treating a deeper cause so often missed.