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Training Program for Health Professionals

Training Program for Health Professionals. Greater Boston Physicians for Social Responsibility www.igc.org/psr/ September 2002. PROGRAM OUTLINE. Section I. Neurodevelopmental Disabilities Section II. Links Between Chemicals and Disabilities

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Training Program for Health Professionals

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  1. Training Program for Health Professionals Greater Boston Physicians for Social Responsibility www.igc.org/psr/ September 2002

  2. PROGRAM OUTLINE Section I. Neurodevelopmental Disabilities Section II. Links Between Chemicals and Disabilities Section III. Magnitude of the Chemical Threat

  3. Section I. Outline: Neurodevelopmental Disabilities • Clinical/Public Health Dimensions • The Research/Evidence Problem • Conceptual Framework • Clinical Traits Syndromes • Underlying Cellular Biology

  4. Public Health Dimensions Prevalence of Learning and Behavioral Disabilities • Total: 17%, 12 million children • Learning disabilities: 5-10% • ADHD: 3-5% • Autism: 0.05%

  5. Public Health Dimensions Reported Trends: Real? Better reporting? Changing criteria? • Learning disabilities • 191%Children in special education: • 1977-1994 • ADHD • 1 20%Reported prevalence • >800% Ritalin use • since 1971

  6. Public Health Dimensions Trends, Prevalence, and Clusters Autism • 100% Autism over 30 years • 210% Autism in California DSS System: 1987-1998 • 400% Above nation: Prevalence in Brick Township, NJ

  7. Public Health Dimensions Problem of Staggering Proportions Whether new, newly recognized, or a combination of both, developmental disabilities are a problem of staggering proportions.

  8. Public Health Dimensions • Financial stress • Emotional stress • Suicide • Substance abuse • Employment problems • Academic difficulties Associated Effects on Individuals, Families, and Communities

  9. Economic Dimensions Economic Implications • $81.5 – 167 billion/yr • $9.2 billion/yr • Over $8,000/yr $80-100,000/yr • Estimated U.S. costs of neuro-developmental deficits, hypo-thyroidism, related childhood disorders • Est. costs of neurobehavioral disorders attributable to environmental pollutants • Special education costs for a child with autism; • costs of residential treatment ADHD doubles health care costs for children – comparable to costs for children with asthma.

  10. The Research/Evidence Problem Difficulties in Epidemiological Research • What makes evidence convincing? • The current state of evidence – what do we know/not know?

  11. The Research/Evidence Problem Difficulties in DNT Epidemiological Research • Latency: Long periods between when exposures occur and effects surface • Windows of vulnerability • Gene-environment interactions • Susceptible sub-populations • Multiple exposures • Epidemiological shortcomings

  12. The Research/Evidence Problem Epidemiology Shortcomings • Confounders • Exposure misclassification • Recall bias • Difficult outcome classification

  13. POTENTIAL ERROR IN PROSPECTIVE DNT Under-Recognition of Toxic Threats Confounding Statistical analysis Exposure measures Outcome measures Confounding Statistical power Statistical analysis Alpha error (type I) FALSE POSITIVES Beta error (type II) False Alarm FALSE NEGATIVES False Assurance

  14. WhatMakes Evidence Convincing? MORE CONVINCING • Controlled Clinical Trials • Case-Control and Cohort Epidemiologic Studies • Cross-Sectional Epidemiologic Studies LESS CONVINCING Consistent animal toxicity

  15. The Research/Evidence Problem WhatMakes Evidence Convincing? Building Blocks for a Strong Epidemiology Study • Short latency • Specific outcomes • Adequate sample size • Control of confounding • Precise exposure measures • Well-defined outcome measures

  16. WHAT WE DON’T KNOW WHAT WE KNOW Under-recognition of Toxic Threats:Epistemological Bias Known Effects Thousands of chemicals THE “UNKNOWN UNKNOWN” Long latency effects Billions of mixtures Gene-environment interactions Windows of vulnerability

  17. LEARNING, BEHAVIOR, AND DEVELOPMENT:A SPECTRUM OF ACADEMIC DISCIPLINES C L I N I C A L family practice developmental pediatrics adolescent medicine behavioral psychology educational psychology developmental psychology ob- gyn psychiatry pediatrics cognitive psychology behavioral genetics developmental neuro- psychology neurotoxicology R E S E A R C H

  18. NUTRITION GENETICS SOCIAL ENVIRONMENT Framework for Understanding TOXICANTS Traits/ Abilities NUTRITION Asperger’s syndrome Learning ?? disability ADHD Autism Developmental Syndromes

  19. Clinical Traits Traits/Abilities vs. Clinical Syndromes • Trait/Ability • Attention ability • Impulsivity • Executive function • Memory • Social adjustment • Reading and verbal skills • Clinical Syndrome • ADHD • Learning disabilities • Asperger’s syndrome • Autism

  20. Clinical Traits Traits/Abilities vs. Clinical Syndromes Trait/Ability Quantitative, dimensional Objective tests Animal models Apply to “normal” populations Definable criteria Useful research tools Clinical Syndrome Qualitative, categorical Clinical judgment (subjective) No animal models Different from “normal” Variable diagnostic criteria Provide management strategies

  21. Underlying Cellular Biology Neuronal Migration Neuronal Migration

  22. Underlying Cellular Biology Cellular Events in Neurodevelopment • Events: • Division • Migration • Differentiation • Formation of synapses • Pruning of synapses • Apoptosis • Myelination Active throughout childhood & adolescence

  23. Time Lines of Developmental Processes in Humans Prenatal Period (Months) Postnatal Period (Years) 0 1 2 3 4 5 6 7 8 9 Birth 1 2 3 4 5 6 7 8 9 10 Cell radial glia,neurons glia Proliferation Migration brain, spinal cord ext. granular layer cerebellum of Neurons Subplate Neurons Synapse mz sp hp rf visual cortex association cortex Formation Myelination (see text) Key: mz – marginal zone; sp – subplate; hp – hippocampus; rf – reticular formation

  24. Human Brain Growth Rate Herschkowitz et al., 1997; Neuropediatrics, 28:296-306.

  25. Neural Proliferation (rodent) P Rodier EHP 102(Suppl 2) 1994

  26. Cellular Events in Neurodevelopment Underlying Cellular Biology • Summary: • Critical sequence • Vulnerable to disruption • Size, timing, duration • influence impact • Downstream effects • Susceptible throughout • adolescence

  27. Basic Toxicology: Exposure-related Concepts • Persistence • Bioconcentration • Transient exposures

  28. Section II Outline Links: Chemicals and Disabilities • Basic Toxicology • Lead • Mercury • PCBs • Pesticides

  29. Basic Toxicology Toxicity-related Concepts: specific processes disrupted by neurodevelopmental toxicants proliferation radiation, ethanol, mercury, cholinesterase inhibitors migration radiation, mercury, ethanol differentiation ethanol, nicotine, mercury, lead synaptogenesis radiation, ethanol, lead, triethyl tin, parathion, PCBs gliogenesis & dec. thyroid, ethanol, lead myelinization apoptosis ethanol, lead, mercury signaling ethanol, cholinesterase inhibitors, mercury, lead, PCBs

  30. Basic Toxicology Neurodevelopmental Toxicants:The State of Knowledge • Only 12 chemicals tested for neurodevelopmental toxicity according to current EPA guidelines. • Extensive data on effects of lead, mercury, polychlorinated biphenyls (PCBs), alcohol, nicotine. • Less extensive but substantial data on neurotoxic pesticides, solvents other than alcohol. • Still fewer data on other compounds including manganese, fluoride. Problem: Most data obtained for a few chemicals. No data available for majority.

  31. 1960 1970 1980 1990 2000 DECLINING THRESHOLD OF HARM - LEAD lead 100 REPORTED HARM 10 EXPOSURE – blood lead, ug/dl 1 0.1 YEAR REPORTED Note: Exposures expressed in micrograms/deciliter (blood lead)

  32. 80 40 60 100 120 140 160 70 130 The Significance of Small Effects: EFFECTS OF A SMALL SHIFT IN IQ DISTRIBUTION IN A POPULATION OF 260 MILLION mean 100 6.0 million 6.0 million "mentally retarded" "gifted" I.Q.

  33. 40 80 100 120 140 160 60 70 130 5 Point Decrease in Mean IQ mean 95 57% INCREASE IN "Mentally Retarded” Population 2.4 million 9.4 million "gifted" "mentally retarded" I.Q.

  34. Lead Effects of Lead on Cognitive and Behavioral Traits • ADHD LD OTHER • hyperactivity reading, math fine motor • impulsivity spelling visual motor • distractibility pattern recognition aggressive • dif. w. instructs word recognition antisocial • conduct problems off-task • executive function • attention/vigilance • social skills

  35. Lead Association of Teacher Ratings With Student Lead Burden Class Dentine Lead (ppm) 1 <5.1 2 5.1-8.1 3 8.2-11.8 4 11.9-17.1 5 17.2-27.0 6 >27 Percent Class Distractible Nonpersistent Dependent Not Hyperactive Impulsive Organized Class Blood Lead, (micrograms/dl) 1 7-10 2 11-12 3 13-16 4 17-32 Percent Class Distracted Persist Work Disorganized Hyperactive Impulsive Independent Organized

  36. Blood lead levels in the U.S. population 1976 -1999 NHANES II, III, 99+ 18 16 14 12 10 Blood lead levels (mg/dL) 8 6 4 2 0 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 Year

  37. An Overview of Mercury Wet Deposition Particulates & Vapor Combustion Dry Deposition Volcanoes Industry & Incinerators Landfills Farming WasteWater Releases Volatilization Ground-water Flow Runoff Pesticides Fertilizers Methylation Hg to HgCH3 Rain & Streams to Groundwater Sedimentation to Streams, lakes, vegetation, soil Bioaccumulation in Fish

  38. Mercury Mercury Effects of Higher Dose Prenatal Exposure • Mental retardation • Seizures • Cerebral palsy • Disturbances of vision, hearing, sensation • Abnormal gait • Abnormal speech • Disturbances of swallowing and sucking • Abnormal reflexes

  39. 100 10 1 0.1 0.01 1970 1980 1990 2000 Mercury:Declining Threshold of Harm Level associated with harmful effect Regulatory standard (maximum safe exposure or high end exposure from allowed fish contamination) (micrograms/kg/day Hg) DAILY INTAKE FDA WHO ATSDR EPA YEAR

  40. MercuryEffects of Low Dose Prenatal Exposure Per cent of children with low test scores at age 7 years Children with high prenatal mercury exposure Children with low prenatal mercury exposure < 15 15-30 30-50 >50 µg/l % Children with lowest scores at age 7 years Figure shows prenatal mercury exposure levels of Faroese children with scores in the lowest quartile after adjustment for cofounders. For each of the five major cognitive functions, one neuropsychological test with a high psychometric validity was selected. Source: Grandjean, et. al., "Cognitive Deficit in 7-year-Old Children with Prenatal Exposure to Methylmercury", Neurotoxicology and Teratology, Vol. 19, No. 6, 1997

  41. Mercury Mercury Exposures Advised Exposure Limit • EPA Reference Dose (“safe” upper limit) – 0.1 microgram/kilogram/day • Equivalent consumption limit • Women: 1.5 oz. swordfish or 7 oz. tuna/week • Child: 1 oz. tuna per 20 lb. body weight/week

  42. Mercury Mercury Exposures Current exposures • >10% of women of reproductive age exceed Reference Dose (RfD) • 50% of women who eat fish exceed RfD on any given day • Higher risk: Subsistence fishers,immigrants, Native Americans

  43. PCBs From Factory to the Fetus Dioxins and PCBs: Pathways of Exposure and Neurodevelopmental Effects AIR Dioxins PCBs: Transformers Landfills Hazardous Waste Sites Dioxins: PVC Manufacturing Medical/Municipal Incinerators PCBs SOIL WATER FOOD

  44. PCBs Full-Scale IQ Prenatal Exposure to Polychlorinated Biphenyls (PCBs) ug/g of fat

  45. PCBs Reading Mastery -Word Comprehension Prenatal Exposure to Polychlorinated Biphenyls (PCBs) ug/g of fat

  46. PCBs PCBs: PERVASIVE DEVELOPMENTAL EFFECTS Infant • Birth weight • Head circumference • Gestational age • Performance on Brazelton Neonatal Behavioral Assessment (BNBA) - motor immaturity, poor lability, startle

  47. PCBs: PERVASIVE DEVELOPMENTAL EFFECTS Early Childhood • Memory, attention, verbal ability, information processing • Psychomotor development • Sustained activity, high level play • Withdrawn, depressed behavior • Hyperactivity Preteen • Word and reading comprehension • Full scale and verbal IQ • Memory and attention

  48. 20 15 10 5 0 PCBs: Inadequate Margin of Safety PCB BLOOD LEVELS (ppb) REPORTED REPORTED HUMAN HEALTH EFFECTS IN OFFSPRING EXPOSURES Great Lakes fish eaters Great Lakes non-fish eaters Decreased reflexes, memory, IQ, attention, & visual discrimination Midwest and Northeast US women Michigan mothers North Carolina mothers Decreased attention, cognitive ability, high level play, & psychomotor development; Increased withdrawn/depressed, increased hyperactivity. Wisconsin women Dutch mothers

  49. PCBs PCB Effects on Thyroid Hormone • Altered thyroid hormone Mothers: Thyroid Hormone, Thyroid Stimulating Hormone (TSH) Infants: Thyroid Hormone, TSH Seals and Rats: Thyroid Hormone • Developmental Implications Elevated maternal TSH during pregnancy, with or without reductions of thyroid hormone, associated with reduced IQ at age 7-9 yrs.

  50. PCBs PCBNeurodevelopmental Effects: Possible Mechanisms • Altered neurotransmitter levels • Ah receptor mediated effects(dioxin-like PCBs) Disruption of production of growth factors and hormones including enzyme induction, modulation of growth factors, hormones • Interference with thyroid hormone • ­metabolism through enzyme induction • interference with thyroid-hormone-mediated gene transcription • displacement of thyroxin from carrier protein

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