Children and neurodevelopmental behavioural intellectual disorders (NDBID)

<<NOTE TO USER: Please add details of the date, time, place and sponsorship of the meeting for which you are using this presentation in the space indicated.>> <<NOTE TO USER: This is a large set of slides from which the presenter should select the most relevant ones to use in a specific presentation. These slides cover many facets of the problem. Present only those slides that apply most directly to the local situation in the region.>> <<NOTE TO USER: This module presents several examples of risk factors that affect neurodevelopment, you can find more detailed information in other modules of the training package that deal with specific risk factors, such as lead, mercury, pesticides, persistent organic pollutants, endocrine disruptors; or prenatal exposures and developmental effects.>> October 2011 TRAINING FOR THE HEALTH SECTOR [Date ... Place ... Event ... Sponsor ... Organizer} ILDRENAND PMENTAtBE DISORDERS (NDBID) Children's Health and the Environment WHO Training Package for the Health Sector World Health Organization www. who.intlceh WHOIHSEIPHEIEPE/11.01 .04 <<READ SLIDE>> Children & neurodevelopmental behavioural intellectual disorders OBJECTIVES ❖ To define & describe common Neurodevelopmental Behavioral Intellectual Disorders (NDBID) and their prevalence. ❖ To understand the neurodevelopmental process in the context of basic science and environmental data. ❖ To discuss key epidemiological studies addressing environmental risk factors. ❖ To gain insight into environmental neurotoxic potential exposures and complexities of attributing causality. <<READ SLIDE>> Children & neurodevelopmental behavioural intellectual disorders ❖ ❖ ❖ ❖ ❖ OVERVIEW Descriptions of common Neurodevelopmental Behavioral Intellectual Disorders (NDBID). Brief epidemiology of Neurodevelopmental Behavioral Intellectual Disorders. Summary of neurodevelopmental processes. Discussion of environmental linkages. Impacts of Neurodevelopmental Behavioral Intellectual Disorders and challenges of adequately protecting children. Physiological differences between children and adults are not only manifest in immature metabolic pathways. Because important systems are still differentiating and growing, children have unique susceptibilities not seen in adults — and critical time windows for those susceptibilities. The critical times are as follows: •preconception •gestation (susceptibility to: thalidomide, DES, ionizing radiation, methylmercury, lead) •postnatal (susceptibility to: SHTS (second-hand tobacco smoke), lead. There has been an explosion of knowledge about child development in past decade or so, and it is hard to remember that it was only about 50 years ago that the discovery was made that the fetus is vulnerable to exposures. The phocomelia epidemic resulting from use of thalidomide by pregnant women was an early and dramatic example of the ability of chemicals to traverse the placenta and damage the fetus. Additionally, thalidomide administered during a small, 4-day window between gestational days 20 and 24, may increase the risk of autism (Stromland, 1994). More than one system can be susceptible and different pathology may occur depending upon the dose and timing of exposure. Now we know that other exposures during gestation, some of which are listed here, can harm the systems of the developing child. We also know that preconception exposure of parents, as well as postnatal exposure of both parents, can harm children. <<NOTES TO USER: It is important to point out the different responses to insults shown on the bottom bar of the figure. Significant insult during the embryonic phase will result in pregnancy loss (first 2 weeks) or major organ malformation. During the fetal stage, damage is more subtle and related to system dysfunction.>> Ref: •Stromland. Autism in thalidomide embryopathy: a population study. Developmental Medicine & Child Neurology, 1994, 36:351. Of a population of 100 Swedish thalidomide embryopathy cases, at least four met full criteria for DSM-III-R autistic disorder and ICD-10 childhood autism. Thalidomide embryopathy of the kind encountered in these cases affects fetal development early in pregnancy, probably on days 20 to 24 after conception. It is argued that the possible association of thalidomide embryopathy with autism may shed some light on the issue of which neural circuitries may be involved in autism pathogenesis. Figure: Reprinted from Moore. The developing human. Elsevier Inc., 1973. Used with copyright permission (2004) Children & neurodevelopmental behavioural intellectual disorders WINDOWS OF DEVELOPMENT embryonoe. pe riod (in weeks) Schematic iUusuntion or the SCRsiri\'c or criti'-'1 pcnods rn human dC\.'-C:lopmcnL R,cd dc:OO(es h.ighly !Ctlsiti,-c periods; ydiO'il>' rndiQfcs !elagt.'S th:111-., I~ :ilf!nsili" e to tc 1rstogc1a. Moore KL The Dc\·eJoping. Human: Clinically Oriented Embr)•ology. PbiladclpWa· W. B. Saunders CODlJlGD>'. 1973. Moore, Elsevier Inc, 1973 from Elsevier. Neurodevelopment begins in the early prenatal stage with a complex neurological development that begins with proliferation of radial glia and neurons. These continue to develop in the postnatal years. This process is not complete until almost 3 years of age. Migration of neurons, which occurs from the 2nd to the 6th month of gestation, and again within the cerebellum postnatally, is a very important and complex process. Synapse formation, which occurs essentially in the last trimester as well as in the first 2 years of life, is critical to ongoing functioning and development. Myelination is an important process that begins in the second half of gestation and goes on to adolescence, with different systems myelinating at different times, as shown in the diagram. Ref: •Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environmental Health Perspectives, 2000, 108(S3):511-533. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTALPROCESSES Time Lines of Developmental Processes in Humans •• I Rteo and Barono . EHP 108(S3) 511-533 , 2000 Adoptod from Horschkowrtz ct al . 1997 Rice D. Environ Health Perspectives , 2000; 108(S3) Refs: •Gogtay N et al. From the Cover: Dynamic mapping of human cortical development during childhood through early adulthood. Proceedings of the National Academy of Sciences, 2004, 101: 8174-8179 •National Institute of Mental Health (NIMH) / University of California Los Angeles (UCLA). Time-lapse imaging tracks brain developing from ages 5 to 20. NIMH/UCLA Project visualizes maturing brain - available at www.loni.ucla.edu/~thompson/DEVEL/PR.html - accessed 15 June 2011 The brain's center of reasoning and problem solving is among the last to mature. The decade-long magnetic resonance imaging (MRI) study of normal brain development, from ages 4 to 21, by researchers at NIH's National Institute of Mental Health (NIMH) and University of California Los Angeles (UCLA) shows that such "higher-order" brain centers, such as the prefrontal cortex, don't fully develop until young adulthood. A time-lapse 3-D movie that compresses 15 years of human brain maturation, ages 5 to 20, into seconds shows gray matter - the working tissue of the brain's cortex - diminishing in a back-to-front wave, likely reflecting the pruning of unused neuronal connections during the teen years. Cortex areas can be seen maturing at ages in which relevant cognitive and functional developmental milestones occur. The researchers scanned the same 13 healthy children and teens every two years as they grew up, for 10 years. After co- registering the scans with each other, using an intricate set of brain anatomical landmarks, they visualized the ebb and flow of gray matter - neurons and their branch-like extensions - in maps that, together, form the movie showing brain maturation from ages 5 to 20. It was long believed that a spurt of overproduction of gray matter during the first 18 months of life was followed by a steady decline as unused circuitry is discarded. Then, in the late 1990s, NIMH's Dr. Jay Giedd, a co-author of the current study, and colleagues, discovered a second wave of overproduction of gray matter just prior to puberty, followed by a second bout of "use-it-or-lose-it" pruning during the teen years. The new study found that the first areas to mature (e.g. extreme front and back of the brain) are those with the most basic functions, such as processing the senses and movement. Areas involved in spatial orientation and language (parietal lobes) follow. Areas with more advanced functions -- integrating information from the senses, reasoning and other "executive" functions (prefrontal cortex) - mature last Thompson says that researchers debate whether teens are actually losing tissue when the gray matter disappears, trimming connections, or just coating gray matter with insulation. Imaging doesn’t provide high enough resolution to distinguish among the possibilities, he notes: “Right now we can image chunks of millions of neurons, but we can’t look at individual cells.” Tremendous rate of growth in areas of vision and sensation occur in the early school years. In middle school areas in language development show repid growth. Late teens exhibit rapid growth in areas controlling inhibition, judgment. Healthy development means an increase and loss of neurological tissue. Maturation of the central nervous system is critical in the development of neurodevelopmental disorders. Cell pruning or synapse pruning, which occurs between the ages of 5 – 20 years appears to be a critical process whereby if increased may be linked with childhood onset schizophrenia and if decreased may be linked with autism. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTALPROCESSES Cortex maturation from ages 5 to 20 years: "synaptic pruning" of unused neural connections ❖ Abnormalities in maturation may underlie neurodevelopmental disorders ❖ Increased pruning with childhood-onset schizophrenia; decreased with autism A newborn baby, although fully formed, is born with an immature neurological system which does not allow the baby to be anything more than helpless. There is poor head control, the limbs are flexed and newborn babies have no opportunity to defend themselves from harm other than by crying. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTALPROCESSES CLINICAL MILESTONES WHO Development occurs very quickly as the neurological system matures in the first few years and months of life. By 4 months of age, a baby is able to hold his/her head against gravity when in the prone position, is fixing on and following objects with their eyes, responding to sounds and even beginning to grab at toys. In the sitting position a 4 month baby brightens to sounds, coos and interacts socially. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTALPROCESSES CLINICAL MILESTONES • Good head control, supports self on forearms 4 months By 9 months of age the baby is sitting unsupported, is able to pick up toys, transfers them from hand-to-hand and is able to pick up very small objects between the thumb and first finger. At this time they are babbling consonants and vowels and modulating pitch and volume. They are able to make their needs understood for eating, drinking and the need for diaper change. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTALPROCESSES CLINICAL MILESTONES WHO •Good pincer grasp •Sits, bears weight on legs •Vision and hearing as an adult •Babbles consonant and vowels, modulates pitch and volume By 18 months of age a child is walking and running, can throw a ball and kick a ball, can stack toys, can walk up stairs, help with dressing and undressing and is able to say 10 – 20 words and understand more complex phrases. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTALPROCESSES CLINICAL MILESTONES 18 months 10 By 3 years of age a child has the ability to ride a tricycle, speak sentences using a subject, verb and object which is understandable by strangers, asks questions what, where and who and understands more complex instructions. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTALPROCESSES CLINICAL MILESTONES 13 years I •Rides a tricycle •Speaks in sentences (subject, verb, & object) •Asks: What? Where? and Who? questions •Understands three points By 4 years of age, the neurological system is becoming quite complex in that the child can hop on one foot, can climb a ladder, asks more complex questions when, why and how, understands opposites and is able to follow full instructions in a row. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTALPROCESSES CLINICAL MILESTONES 12 Neurodevelopmental paediatrics is a developing field that addresses complex aspects of central nervous system (CNS) development in children. Some definitions include physical aspects consequent on early damage to the CNS e.g. cerebral palsy. Other definitions restrict themselves to functional impairment. The definition on this slide can be found in the draft baseline report on neurodevelopmental disorders in the framework of the European Environment and Health Strategy. Ref: •European Union. Draft Baseline Report on neurodevelopmental disorders in the framework of the European Environment and Health Strategy. Technical working group on priority diseases, subgroup neurodevelopmental disorders, 2003. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL BEHAVIORAL INTELLECTUAL DISORDERS Inconsistencies in terminology and definitions European Definition: Neurodevelopmenta l disorders are disabil ities in the function ing of the brain that affect a child's behaviour , memory or ability to learn e.g. mental retardation , dyslex ia, attention deficit hyperactivity disorder (ADHD) , learning deficits and autism. Draft Baseline Report on Neurodevelopmental Disorders In the Framework of the European Environment and Health Strategy, 2003 13 In North America, the definition of neurodevelopmental behavioural intellectual disorder has traditionally included physical as well as functional abnormalities. Neurodevelopmental behavioural disorders occur commonly in industrialized countries. Figures as high as 15% of children are described as having learning disabilities, developmental delay, attention deficit hyperactivity disorder, autism, reduced intelligence quotient and cerebral palsy. In Aboriginal children, the prevalence is often much higher. Although some cases are linked to identified exposures, e.g. fetal alcohol, tobacco smoke, low birth weight and obstetric complications, in most cases specific etiology is unknown. Ref: •Dietrich K et al. Principles and practices of neurodevelopmental assessment in children: Lessons learned from the centers for children's environmental health and disease prevention research. Environ Health Perspect, 2005, Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL BEHAVIORAL INTELLECTUAL DISORDERS 1 in 6 children in the industrialized countries: ►cerebral palsy ► J IQ ► attention deficit hyperactivity disorder (ADHD) ► learning disabilities ►autism ►developmental delay Commonest class of birth defects Specific etiology in most cases unknown Dietrich K, 2005 ADHD: Attention Deficit Hyperactiv ity Disorder 14 113(10):1437-1446. Neurodevelopmental behavioural intellectual disorders consist of many conditions. The commonest functional conditions identified are Attention Deficit Hyperactivity Disorder (ADHD) and autism which each now consist of various subgroups depending on an individual child’s predominant symptomatology. For instance, Attention Deficit Disorder without hyperactivity is described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) typically diagnosed in older girls of about 9 years of age. Refs: •American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition. Washington, US. American Psychiatric Association, 2000. •Kaneshiro NK. Autism. Available at www.nlm.nih.gov/medlineplus/ency/article/001526.htm - accessed 15 June 2011 •Mosby. ADHD. In: Mosby's Medical Dictionary, 8th edition, Elsevier, 2009. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL BEHAVIORAL INTELLECTUAL DISORDERS - DEFINITIONS Attention Deficit Hyperactivity Disorder (ADHD) ❖ A childhood mental disorder with onset before 7 years of age and involving impaired or diminished attention, impulsivity, and hyperactivity. Autism ❖ A developmental disorder that appears in the first 3 years of life, and affects the brain's normal development of social and communication skills. Amer ican Psychiatric Assoc iation , 2000 Mosby's Medical Dictionary , 2009 www.nlm.nih.gov/medlineplus/ency/article/001526 .htm 15 Wide variations reported in previous rates due often to diagnostic and reporting variations. However, differences occur between gender (males higher than females), ethnic background (higher in Aboriginal children) and socioeconomic groups (higher in lower socioeconomic groups). A study from Canada reports “findings suggest[ive] of either a high prevalence of attention deficit hyperactivity disorder (ADHD) in [Canadian] Aboriginal children or unique learning and behavioral patterns in Aboriginal children that may erroneously lead to a diagnosis of ADHD if screening questionnaires are used.” (Baydala, 2006) Although increases noticed over the last 2 decades may reflect increased awareness of these disorders and broader diagnostic criteria, there is general concern about the possible implication of environmental factors in the etiology of neurodevelopmental disorders. Refs: •Baydala L et al. ADHD characteristics in Canadian Aboriginal children. Journal of Attention Disorders, 2006, 9(4):642-647. •Brown RT, et al. Prevalence and assessment of Attention-Deficit/Hyperactivity Disorder in primary care settings. Pediatrics, 2001;107(3):E43. •Charman T. The prevalence of autism spectrum disorders. Recent evidence and future challenges. Eur Child Adolesc Psychiatry, 2002, 11:249-256. •Gurney JG et al. Analysis of prevalence trend of autism spectrum disorder in Minnesota. Arch Pediatr Adolesc Med, 2003, 157:622-7. •Weiss B, Landrigan PJ. The developing brain and the environment: an introduction. Environ Health Perspect, 2000, 108(3):373-376. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL BEHAVIORAL INTELLECTUAL DISORDERS - PREVALENCE Prevalence varies between studies and regions and suggest ion that rates may have increased for attention deficit hyperact ivity disorder (ADHD) and aut ism in the last two decades. 1 •2 ❖ Neurodevelopmental Behav ioral Intellectual Disorders - 3 - 8% of the children in USA & Europe .3 ❖ ADHD prevalence rates ranging from 4% to 12% in the general population of 6 to 12 year olds .4 ❖ ADHD is 22.7% in Canadian Abor iginal children .5 1) Gurney JG, 2003 2) Charman T, 2002 3) Weiss B, 2000 4) Brown RT, 2001 ADHD : Attention Deficit Hyperactivity Disorder 5) Bayda la L, 2006 16 It is the perception of many general clinicians that the incidence of autism is rising. Until recently, genetics has been attributed as the major risk factor for development of autism in children which is commoner in certain ethnic backgrounds, e.g. Caribbean. There, however, are few databases to confirm this. This graph from the State of California identifies a significant rise in cases of autism during the last 30 years. Refs: •Byrd RS. The epidemiology of autism in California: a comprehensive pilot study. Report to the legislature on the principal findings. Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California, Davis, 2002. •Keen DV, Reid FD, Arnone D. Autism, ethnicity and maternal immigration. Br J Psychiatry, 2010, 196(4):274-81. Image: California Department of Developmental Services. Changes in the population of persons with autism and pervasive developmental disorders in California’s Developmental Services System: 1987 through 1998. A report to the Legislature. Sacramento CA: California Health and Human Services Agency, 1999. Available at www.dds.ca.gov/Autism/docs/autism_report_1999.pdf - accessed June 2011 Children & neurodevelopmental behavioural intellectual disorders PREVALENCE OF AUTISM IN CALIFORNIA E 600 1/) :,:, :, ~ 500 § 1/) ~ 400 ~ j 300 e C w 0 200 ai .n 5 100 ., - - V i.,,- ,- w l.,.r' r- I ! -.J - v ~ ✓ z 1960 1963 1966 1969 1972 1975 1978 1981 1984 1987 1990 Year of Birth www.dds.ca.gov/Aulism/docs/autism_report_ 1999.pdf 17 It is widely recognized that although some children with Neurodevelopmental Behavioral Intellectual Disorders, especially Attention Deficit Hyperactivity Disorder (ADHD), “grow out” of their condition, many remain affected and frequently develop co-morbidities i.e. oppositional defiant disorder, depression/anxiety, substance abuse, conduct disorder. This may lead to school failure and incarceration. Persistance of ADHD into adulthood is well- recognized although data collection and methodologies for reporting appear inconsistent. Refs: •Hechtman L, Weiss G, Perlman T. Hyperactives as young adults: Past and current substance abuse and antisocial behavior. American Journal of Orthopsychiatry, 1984, 54:415-425. •Pliszka SR, Carlson CL, Swanson JM. ADHD with co-morbid disorders: Clinical assessment and management. New York, The Guilford Press, 1999. •Rabiner D. How often does ADHD persist into adulthood? ADHD library. Available at www.adhdlibrary.com/library/how-often-does-adhd-persist-into-adulthood - accessed 15 June 2011 Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL BEHAVIORAL INTELLECTUAL DISORDERS Co-morbidity and adult outcomes ❖ Anxiety/depression, oppositional defiant disorder, bipolar disorder, Tourette's Syndrome. ❖ Substance abuse, antisocial behavior, and even criminality are among the better-known problems persisting into adulthood. 18 Cell proliferation may be adversely affected by alcohol intake, exposure to chlorpyrifos or methylmercury. Migration of neurons may be affected by exposure to x-ray radiation, alcohol or methylmercury. Cell migration may be adversely affected by x-ray irradiation, ethanol and methylmercury. Ref: •Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspectives, 2000, 108(S3):511-533. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL LINKAGES ❖ Proliferation ■ Alcohol ■ Methylmercury ■ Chlorpyrifos ❖ Migration ■ X-ray irradiation ■ Ethanol ■ Methylmercury Rice 0 , 2000 19 Differentiation of neuroblasts may be adversely affected by ethanol, nicotine, methylmercury and lead. Gliogenesis and myelination may be adversely affected by postnatal malnutrition, thyroid hormone/endocrine disruption, exposures to alcohol, and lead. Ref: •Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. EHP, 2000, 108(S3):511-533. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL LINKAGES ❖ Differentiation of neuroblasts ■ Ethanol ■ Nicotine ■ Methylmercury ■ Lead ❖ Gliogenesis and myelination ■ Postnatal malnutrition ■ Thyroid hormone I endocrine disrupt ion ■ Alcohol ■ Lead Rice 0 , 2000 20 Synaptogenesis may be adversely affected by ethanol, lead, methylmercury, polychlorinated biphenyls (PCBs), triethyltin, parathion, permethrin, and serotonin antagonists. Apoptosis or cell death is a complex process in which appropriate cells are removed to ensure optimal neurodevelopmental behavioural intellectual development. However, this intricate, balanced process may be adversely affected at critical stages of gestation and postnatal development by exposure to ethanol, lead, mercury and chlorpyrifos. Neurotransmission processes may be adversely affected by cholinesterase inhibitors, ethanol, methylmercury, aluminum, as well as pharmaceuticals and pesticides designed to target specific neurotransmitter systems. Ref: •Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspectives, 2000, 108(S3):511-533. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL LINKAGES ❖ Synaptogenesis ■ Ethanol ■ Lead, methylmercury ■ Polychlor inated biphenyls ■ Triethyltin ■ Parathion, permethrin ■ Serotonin antagonists ❖ Apoptosis ■ Ethanol ■ Lead, methylmercury ■ Chlorpyrifos ❖ Neurotransmission processes ■ Cholinesterase inhibitors ■ Ethanol ■ Methylmercury ■ Aluminum ■ Pharmaceuticals and pesticides designed to target specific neurotransmitter systems Rice 0 , 2000 21 Many important factors interact to determine the outcome of the neurodevelopmental process in each individual child. Determinants of Neurodevelopmental Behavioral Intellectual Development (NDBID) can be categorized according to the diagram. Sociocultural factors may include nutrition, prenatal care, education, access to healthcare, maternal IQ, ethnicity, gender, culture, support networks, quality of childrearing. Genetic factors may include chromosomal abnormalities, e.g. trisomy 21 Down’s syndrome. Specific gene location (chromosomes 6, 15) are linked with reading disability. Girls with Turner’s syndrome may exhibit specific visuo- spatial difficulties. Children with Fragile X syndrome may have specific language deficits. Medical factors may include hypoxic ischemic encephalopathy, very low birth weight, severe intrauterine growth retardation, prenatal exposure to alcohol, tobacco and drugs, brain injury from head trauma intraventricular hemorrhage. Conductive hearing loss (from otitis media with effusion) may lead to language problems. Environmental factors may lead to infections in early life e.g. AIDS, meningitis, septicemia may result in Neurodevelopmental Behavioral Intellectual Disorders. Many chemical exposures have been investigated. The community ones studied to date are environmental tobacco smoke, lead and mercury. Prenatal and early childhood offers windows of vulnerability for adverse effects on healthy neurodevelopment. Concern is growing regarding high volume industrial neurotoxic emissions into the environment. Refs: •Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet, 2006, 368(9553):2167- 2178. •Kliegman RM et al. Nelson textbook of pediatrics. 18th edition. Elsevier Health Sciences Division, 2007. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTALPROCESSES Sociocultural factors Genetic factors Determinants of Neurodevelopmental Behavioral Intellectual Development Medical factors Environmental factors Grandjean P, Landrigan PJ, 2006 22 A Canadian National Longitudinal Survey of Children and Youth which has been in effect for over 20 years, identifies various social factors influencing neurodevelopment. Poverty, maternal mental health and education are reported to be key determinants of neurobehavioural intellectual development. The survey showed that single mothers who are new immigrants to Canada are particularly at risk of having children with neurobehavioural intellectual developmental problems. Refs: •To T et al. Risk markers for poor developmental attainment in young children: results from a longitudinal national survey. Archives of Pediatrics & Adolescent Medicine, 2004, 158(7):643-9 •To T et al. What factors are associated with poor developmental attainment in young Canadian children? Canadian Journal of Public Health. Revue Canadienne de Santé Publique, 2004, 95(4):258-63 Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS National Longitudinal Survey of Children and Youth ❖ The strongest and consistent associations with living in a low- income household, having a mother with low educational attainment or a mother who is an immigrant highlight the need for targeting developmental assessments and services to this population. ❖ Having a mother who has symptoms of depression, has low education, or is an immigrant, and living in a household with low income adequacy increase the risk of poor developmental attainment in children aged 1 to 5 years. 23 When lead poisoning begins in the womb, the most critical system is the central nervous system of the fetus. This article, published in 1987, was essential in increasing understanding of the potential for lead to cause damage at levels much lower than those that cause overt symptoms. It showed a high correlation between blood lead level in the umbilical cord and mental development index at 2 years of age. Ref: •Bellinger D et al. Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development. N Engl J Med, 1987, 316:1037. In a prospective cohort study of 249 children from birth to two years of age, we assessed the relation between prenatal and postnatal lead exposure and early cognitive development. On the basis of lead levels in umbilical-cord blood, children were assigned to one of three prenatal-exposure groups: low (less than 3 micrograms per decilitre), medium (6 to 7 micrograms per decilitre), or high (greater than or equal to 10 micrograms per decilitre). Development was assessed semiannually, beginning at the age of six months, with use of the Mental Development Index of the Bayley Scales of Infant Development (mean +/- SD, 100 +/- 16). Capillary-blood samples obtained at the same times provided measures of postnatal lead exposure. At all ages, infants in the high-prenatal-exposure group scored lower than infants in the other two groups. The estimated difference between the overall performance of the low-exposure and high-exposure groups was 4.8 points (95 per cent confidence interval, 2.3 to 7.3). Between the medium- and high-exposure groups, the estimated difference was 3.8 points (95 per cent confidence interval, 1.3 to 6.3). Scores were not related to infants' postnatal blood lead levels. It appears that the fetus may be adversely affected at blood lead concentrations well below 25 micrograms per decilitre, the level currently defined by the Centers for Disease Control as the highest acceptable level for young children. Children & neurodevelopmental behavioural intellectual disorders CORD BLOOD LEAD LEVEL AND MENTAL DEVELOPMENT INDEX Be/lingo,, N Eng J Med . /1987)316 :1037 24 Picture: Copyright (1987) Massachussets Medical Society, All rights reserved. Used with permission. Deficits in psychological and classroom performance of children with elevated lead levels in teeth was among the first evidence that low levels of lead intoxication caused loss of intellectual capacity and changes in behaviour. Ref: •Needleman. Deficits in psychological and classroom performance of children with elevated dentine lead levels. N Engl J Med, 1979, 300:689. To measure the neuropsychological effects of unidentified childhood exposure to lead, the performance of 58 children with high and 100 with low dentine lead levels was compared. Children with high lead levels scored significantly less well on the Wechsler Intelligence Scale for Children (Revised) than those with low lead levels. This difference was also apparent on verbal subtests, on three other measures of auditory or speech processing and on a measure of attention. Analysis of variance showed that none of these differences could be explained by any of the 39 other variables studied. Also evaluated by a teachers' questionnaire was the classroom behaviour of all children (2146 in number) whose teeth were analysed. The frequency of non-adaptive classroom behaviour increased in a dose- related fashion to dentine lead level. Lead exposure, at doses below those producing symptoms severe enough to be diagnosed clinically, appears to be associated with neuropsychological deficits that may interfere with classroom performance. Picture: Copyright (1979) Massachussets Medical Society, All rights reserved. Used with permission. Children & neurodevelopmental behavioural intellectual disorders ASSOCIATION BETWEEN DENTINE LEAD LEVEL AND CLASSROOM BEHAVIOUR flG.2._111_.,.,. bi'- - ,_,._,,..,..,... .. -llrd4 :PS - __ .,,. , .. ISi Needleman . N. Engl J Mod. /1979) :300(13):6il9. 25 Lead is a well studied neurotoxin. This slide shows the association of rising blood lead concentrations and reduction of cognitive functioning in young children. ETS: Environmental tobacco smoke / second-hand tobacco smoke AOR: Adjusted odds ratio Ref: •Braun J et al. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environmental Health Perspectives, 2006, 114(12):1904-1909. <<NOTE TO USER: For more information see module on lead.>> Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS Lead & attention deficit hyperactivity disorder (ADHD) 5 4 a: 3 0 c:i: 2 0 < 0.8 0.8- 1.0 1.1- 1.3 1.4-2.0 > 2.0 Quintiles of blood lead concentratio n (µg/dl) AOR for ADHD among U.S. children , NHANES 1999-2002, by blood lead concentrat ion (µg/dl) . The model was adjusted for child's age, sex, race/ ethnicity, preschool attendance, serum ferritin , prenatal ETS exposure , smoker in the household, and insurance status. p-value for trend = o.o, 2. Braun J . Environ Health Perspect . 2006 ;114(12) :1904-1909 . 26 Lead has been identified as adversely affecting speech in young children. Functional magnetic resonance imaging (MRIs) in adolescents who showed levels of lead toxicity in young childhood affecting speech may show compensation in second language centres. This compensation may depend on type of insult, intensity and timing. However, performance may not be equivalent. Even low-level lead exposure can negatively affect a wide range of cognitive functions: attention, language, memory, cognitive flexibility, and visual-motor integration; underlying mechanism by which lead disrupts brain function in children, especially for low lead concentrations that do not produce noticeable physical signs. It is suggested that as lead exposure impedes development of normal language areas, the brain recruits other regions for compensation but does not necessarily yield equivalent performances. The amount of compensation may not only depend on the type of insult but also on the timing, duration and intensity of insult as the brain develops. However, it should be noted that the compensatory alternative pathway does not necessarily yield equivalent performance to that achieved using the normative cortical circuitry for the same function. The degree to which this compensation mechanism is able to meet the demand for the development of language function is assumed to be associated not only with the type of insults, but also with the timing, duration, and intensity of the insult requiring further investigation. Elevated childhood lead exposure exerts a substantial influence on the cortical organization of semantic language function in young adulthood, demonstrated by a selective, deleterious effect on normal language areas with concomitant recruitment of contralateral regions, resulting in striking, exposure-dependent patterns of recruitment for language function. These imaging data provide further confirmation of the adverse consequences of environmental lead exposure on cognitive abilities. Refs: •Yuan W. et al. Functional magnetic resonance imaging study of language function. The impact of early childhood lead exposure on brain organization. Pediatrics, 2006, 118:971-977 The purpose of this work was to assess the long-term impact of childhood lead exposure on the neurosubstrate of language function and brain organization. METHODS. Young adults from the Cincinnati Lead Study were recruited to undergo functional magnetic resonance image scanning while performing a verb generation task. These subjects have been followed from birth through early childhood with extensive documentation of lead exposure, neuropsychology, and behavior. Forty-two subjects provided useful imaging data. The locale, strength, and the correlation between brain language activation and childhood blood lead concentration were studied. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS ❖Childhood lead exposure impedes development of normal language areas ❖Brain recruits other regions for compensation but does not necessarily yield equivalent performances 27 RESULTS. After adjusting for potential confounders, the activation in left frontal cortex, adjacent to Broca's area, and left middle temporal gyrus, including Wernicke's area, were found to be significantly associated with diminished activation in subjects with higher mean childhood blood lead levels, whereas the compensatory activation in the right hemisphere homolog of Wernicke's area was enhanced in subjects with higher blood lead levels. CONCLUSION. This study indicates that childhood lead exposure has a significant and persistent impact on brain reorganization associated with language function. •WHO. Childhood lead poisoning. WHO, 2010. Available at www.who.int/ceh/publications/childhoodpoisoning/en/index.html - accessed March 2011. Composite fMRI activation map for the verb generation task showing z-score statistics in young adults with childhood lead exposure (n = 42). Most highly activated areas include left inferior frontal gurus, left medial temporal gyrus, and right medial temporal gyrus. The orientation of the images follows radiologic convention. Ref: Yuan W et al. The Impact of Early Childhood Lead Exposure on Brain Organization: A Functional Magnetic Resonance Imaging Study of Language Function. Pediatrics. 2006, 118(3):971-977 OBJECTIVES. The purpose of this work was to assess the long-term impact of childhood lead exposure on the neurosubstrate of language function and brain organization. METHODS. Young adults from the Cincinnati Lead Study were recruited to undergo functional magnetic resonance image scanning while performing a verb generation task. These subjects have been followed from birth through early childhood with extensive documentation of lead exposure, neuropsychology, and behavior. Forty-two subjects provided useful imaging data. The locale, strength, and the correlation between brain language activation and childhood blood lead concentration were studied. RESULTS. After adjusting for potential confounders, the activation in left frontal cortex, adjacent to Broca's area, and left middle temporal gyrus, including Wernicke's area, were found to be significantly associated with diminished activation in subjects with higher mean childhood blood lead levels, whereas the compensatory activation in the right hemisphere homolog of Wernicke's area was enhanced in subjects with higher blood lead levels. CONCLUSION. This study indicates that childhood lead exposure has a significant and persistent impact on brain reorganization associated with language function. Figure from Yuan W et al. The Impact of Early Childhood Lead Exposure on Brain Organization: A Functional Magnetic Resonance Imaging Study of Language Function. Pediatrics. 2006, 118(3):971-977. Reproduced with permission from Pediatrics, Copyright 2010 by the American Academy of Pediatrics. Children & neurodevelopmental behavioural intellectual disorders Composite fMRI activation map for the verb generation task showing z-score statistics in young adults with childhood lead exposure (n = 42). Yuan Wet al . Pediatrics 2006 ;118:971-9TT 28 Ref: •Yuan W et al. The Impact of Early Childhood Lead Exposure on Brain Organization: A Functional Magnetic Resonance Imaging Study of Language Function. Pediatrics. 2006, 118(3):971-977 OBJECTIVES. The purpose of this work was to assess the long-term impact of childhood lead exposure on the neurosubstrate of language function and brain organization. METHODS. Young adults from the Cincinnati Lead Study were recruited to undergo functional magnetic resonance image scanning while performing a verb generation task. These subjects have been followed from birth through early childhood with extensive documentation of lead exposure, neuropsychology, and behavior. Forty-two subjects provided useful imaging data. The locale, strength, and the correlation between brain language activation and childhood blood lead concentration were studied. RESULTS. After adjusting for potential confounders, the activation in left frontal cortex, adjacent to Broca's area, and left middle temporal gyrus, including Wernicke's area, were found to be significantly associated with diminished activation in subjects with higher mean childhood blood lead levels, whereas the compensatory activation in the right hemisphere homolog of Wernicke's area was enhanced in subjects with higher blood lead levels. CONCLUSION. This study indicates that childhood lead exposure has a significant and persistent impact on brain reorganization associated with language function. Figure from Yuan W et al. The Impact of Early Childhood Lead Exposure on Brain Organization: A Functional Magnetic Resonance Imaging Study of Language Function. Pediatrics. 2006, 118(3):971-977. Reproduced with permission from Pediatrics, Copyright 2010 by the American Academy of Pediatrics. Children & neurodevelopmental behavioural intellectual disorders Diminished activity of dominant language areas (left hemisphere) with higher blood lead level AI I ~ 6 0 10 ?O JO teun blood lead le.-. 1, µg/dL 0 0 0 _2.,~o ~tf>o o 0 0 10 ?O JO Mcun blood lead le.-. 1, µg/dL Yuan Wet al. Pediatr ics 2006;118:971-977 A, Mult.lvarlate linear regression of brain activation In left Inferior frontal gyrus (ROI_ 1) versus chlldhood mean blood lead level adjusted for confounders. A, Multivariate linear regression of brain activation in left inferior frontal gyrus (ROI_ 1) versus childhood mean blood lead level adjusted for confounders. Partial R = -0.328 ; P = .039. B, Multivariate linear regression of brain activation in right middle temporal gyrus (ROl_2) versus childhood mean blood lead level adjusted for confounders . Partial R = 0.354; P = .025. Compensatory activity of contralateral regions 29 There is now strong evidence that prenatal tobacco exposure is linked with the development of Attention Deficit Hyperactive Disorder (ADHD) in children whose mother either smoked or were exposed to second-hand cigarette smoke in the home. This study is one example. Ref: •Braun J et al. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environmental Health Perspectives, 2006, 114(12):1904-1909. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS Risk of ADHD by prenatal tobacco exposure in US children , 4 to 15 years, NHANES 1999-2002 3 0 ti 2.5 a:: II) 2 "'0 "'0 0 1.5 "'0 GI 1 1il I I ::, '6' 0.5 <( 0 Unexposed Exposed Braun J . Environ Health Perspect . 2006 ;114(12):1904-1909. ADHD : Attention Deficit Hyperactive Disorder 30 Children exposed to mercury by mother’s consuming a high fish diet contaminated with mercury, may develop reduced IQ, learning and behavioural problems. Mercury with its known neurotoxic properties is identified as a significant risk factor for neurodevelopmental behavioural disorders in children. Refs: •Grandjean P, et.al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotox Teratol. 1997, 19:417-428 •WHO. Children's exposure to mercury compounds. WHO, 2010. Available at www.who.int/ceh/publications - accessed June 2011. <<NOTE TO USER: For more information see module on mercury.>> Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS Mercury ❖ Children exposed to mercury by mother's consuming a high fish diet contam inated with mercury, may develop reduced IQ, learning and behavioural problems. ❖ Mercury is identified as a significant risk factor for neurodevelopmental behav ioural disorders in children . Grandjean P. Neurotox Teratol . 1997;19:417-428 31 Refs: •Grandjean P et al. Cardiac autonomic activity in methylmercury neurotoxicity: 14-year follow-up of a Faroese birth cohort. J Pediatr. 2004, 144(2):169. •Grandjean P et al. Cognitive deficit in 7 year old children with prenatal exposure to methylmercury. Neurotoxicology and teratology. 1997, 19:417 A cohort of 1022 consecutive singleton births was generated during 1986-1987 in the Faroe Islands. Increased methylmercury exposure from maternal consumption of pilot whale meat was indicated by mercury concentrations in cord blood and maternal hair. At approximately 7 years of age, 917 of the children underwent detailed neurobehavioral examination. Neuropsychological tests included Finger Tapping; Hand-Eye Coordination; reaction time on a Continuous Performance Test; Wechsler Intelligence Scale for Children-Revised Digit Spans, Similarities, and Block Designs; Bender Visual Motor Gestalt Test; Boston Naming Test; and California Verbal Learning Test (Children). Clinical examination and neurophysiological testing did not reveal any clear-cut mercury-related abnormalities. However, mercury-related neuropsychological dysfunctions were most pronounced in the domains of language, attention, and memory, and to a lesser extent in visuospatial and motor functions. These associations remained after adjustment for covariates and after exclusion of children with maternal hair mercury concentrations above 10 microgram(s) (50 nmol/g). The effects on brain function associated with prenatal methylmercury exposure therefore appear widespread, and early dysfunction is detectable at exposure levels currently considered safe. •Grandjean P. Neurodevelopmental disorders. In: Children´s health and the environment: A review of evidence. Tamburlini G, von Ehrenstein O, Bertollini R. (eds). WHO, Rome, 2002. •Murata K et al. Delayed brainstem auditory evoked potential latencies in 14-year-old children exposed to methylmercury. J Pediatr, 2004, 144(2):177. To determine possible exposure-associated delays in auditory brainstem evoked potential latencies as an objective measure of neurobehavioral toxicity in 14-year-old children with developmental exposure to methylmercury (MeHg) from seafood. Prospective study of a birth cohort in the Faroe Islands, where 878 of eligible children (87%) were examined at age 14 years. Latencies of brainstem evoked potential peaks I, III, and V at 20 and 40 Hz constituted the outcome variables. Mercury concentrations were determined in cord blood and maternal hair, and in the child's hair at ages 7 and 14. Results: Latencies of peaks III and V increased by about 0.012 ms when the cord blood mercury concentration doubled. As seen at age 7 years, this effect appeared mainly within the I-III interpeak interval. Despite lower postnatal exposures, the child's hair mercury level at age 14 years was associated with prolonged III-V interpeak latencies. All benchmark dose results were similar to those obtained for dose-response relationships at age 7 years. Conclusions: The persistence of prolonged I-III interpeak intervals indicates that some neurotoxic effects from intrauterine MeHg exposure are irreversible. A change in vulnerability to MeHg toxicity is suggested by the apparent sensitivity of the peak III-V component to recent MeHg exposure. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS ❖ Cohort of 1022 children born 1986-1987 ❖ Exposure of mothers to methylmercury: • Pilot whale meat - episodic, and potentially high • Fish consumption - continuous , but low ❖ Neuropsychological dysfunctions (age 7) • Language • Attention • Memory ❖ Neurophysiologic dysfunctions (age 14) Faroe Islands study Mercury • Delayed brainstem auditory evoked potentials • Decreased autonomic heart rate variability ❖ Attributed to prenatal exposure 32 Refs: •Grandjean P. Neurodevelopmental disorders. In: Children´s health and the environment: A review of evidence. Tamburlini G, von Ehrenstein O, Bertollini R. (eds). WHO, Rome, 2002. “A large prospective study in the Seychelles has not revealed any clear adverse effects related to maternal hair mercury concentrations” •Myers GJ et al. Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study. Lancet, 2003, 361:1686 Exposure to methylmercury (MeHg) before birth can adversely affect children's neurodevelopment. The most common form of prenatal exposure is maternal fish consumption, but whether such exposure harms the fetus is unknown. We aimed to identify adverse neurodevelopmental effects in a fish-consuming population. We investigated 779 mother-infant pairs residing in the Republic of Seychelles. Mothers reported consuming fish on average 12 meals per week. Fish in Seychelles contain much the same concentrations of MeHg as commercial ocean fish elsewhere. Prenatal MeHg exposure was determined from maternal hair growing during pregnancy. We assessed neurocognitive, language, memory, motor, perceptual-motor, and behavioural functions in children at age 9 years. The association between prenatal MeHg exposure and the primary endpoints was investigated with multiple linear regression with adjustment for covariates that affect child development. Mean prenatal MeHg exposure was 6.9 parts per million (SD 4.5 ppm). Only two endpoints were associated with prenatal MeHg exposure. Increased exposure was associated with decreased performance in the grooved pegboard using the non-dominant hand in males and improved scores in the hyperactivity index of the Conner's teacher rating scale. Covariates affecting child development were appropriately associated with endpoints. Interpretation: These data do not support the hypothesis that there is a neurodevelopmental risk from prenatal MeHg exposure resulting solely from ocean fish consumption. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS ❖ Cohort of 779 mother-infant pairs Seychelles study Mercury ❖ Exposure from mothers' high fish consumption ❖ At age 9: neuropsychological tests ❖ Neurodevelopmental risks due to prenatal MeHg exposure notseen 33 Women exposed in pregnancy to the pesticide chlorpyrifos have been studied and identified as having increased risk of producing children with autism and with Attention Deficit Hyperactive Disorder. Image based on: Rauh V et al. Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children. Pediatrics, 2006, 118(6):e1845-e1859 <<NOTE TO USER: For more information see module on pesticides.>> Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS Effects of prenatal chlorpyrifos exposure on behavioural problems in 3-year old children 8 O +--~-- PDD I □ Low ■ Hgh I Based on Rauh V. Pediatrics. 2006;118(6):e1845-e1859 POD: Pervasive Developmental Disorder ADHD : Attent ion Deficit Hyperactivity Disorder ADl-0 Chlorpyrifos 34 Polychlorinated biphenyls (PCBs): This cohort study identifies that prenatal exposure to PCBs is detrimental to cognitive functioning in young children. The study showed reduction in verbal scale scores as PCB levels rise in umbilical cord blood. Although PCBs may be present in breast milk, studies have shown that this postnatal exposure is far less harmful than prenatal intrauterine exposure. Breastfeeding should not be discontinued. Ref: •Jacobson JL, Jacobson SW, Humphrey HEB. Effects of in utero exposure to polychlorinated biphenyls and related contaminants on cognitive functioning in young children. J of Paeds, 1990, 116:38-45 Because prenatal exposure to polychlorinated biphenyls (PCBs) and related contaminants has been associated with reduced birth weight, neonatal behavioral anomalies, and poorer recognition memory in infants born to women who have consumed Lake Michigan sports fish, 236 children, previously evaluated for PCB-related deficits in infancy, were assessed at 4 years of age. Prenatal exposure (indicated by umbilical cord serum PCB level) predicted poorer short-term memory function on both verbal and quantitative tests in a dose-dependent fashion. These effects cannot be attributed to a broad range of potential confounding variables, the impact of which was evaluated statistically. Although much larger quantities of PCBs are transferred postnatally via lactation than prenatally across the placenta, exposure from nursing was unrelated to cognitive performance. The data demonstrate the continuation of a toxic impact received in utero and observed initially during infancy on a dimension of cognitive functioning fundamental to learning. •WHO. Persistent organic pollutants: impact on child health. WHO, 2010. Available at www.who.int/ceh/publications - accessed June 2011. <<NOTE TO USER: For more information see module on persistent organic pollutants.>> Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS Cohort study identified prenatal exposu re to PCBs as detrimental to cognitive function ing in young children . Reduction in verbal scale scores as PCB levels rise in umbilical cord blood. Although PCBs may be present in breast milk, breastfeeding should not be discontinued. Jacobs on JL, 1990 Polychlorinated biphenyls (PCBs) 35 This Canadian study identifies exposure to manganese, mainly from manganese air pollution from gasoline containing methylcyclopentadienyl manganese tricarbonyl (MMT), and suggests a link with poor attention in young children. Ref: •Takser L et al. Manganese, monoamine metabolite levels at birth, and child psychomotor development. NeuroToxicology, 2003, 24:667-674. Several studies have demonstrated neurobehavioral impairment related to manganese (Mn) exposure in the workplace. Exposure to high doses of manganese is associated with irreversible neurodegenerative disorders resembling idiopathic Parkinson disease. Although there is a risk of Mn accumulation in the foetus during pregnancy, little information exists about developmental effects of environmental low-level exposure in human. For this reason, we conducted a prospective epidemiological study in 247 healthy pregnant women and their babies to determine the long-term effect of in utero Mn levels on child’s psychomotor development. Concurrently, we examined the relationship between Mn tissue levels at delivery and foetal plasma monoamine metabolites. Of the newborns, 195 were examined at 9 months, 126 at 3 years and 100 at 6 years. At 9 months, the Brunet–Lézine scales were administered. The McCarthy scales of children’s abilities were used at 3 and 6 years. After adjustment for potential confounding co-factors (child’s gender, mother’s educational level), negative relationships were observed between cord blood Mn levels and several psychomotor sub-scales at age of 3 years: “attention” (partial r=−0.33, P<0.001), “non-verbal memory” (partial r=−0.28, P<0.01), and “hand skills” (partial r=−0.22, P<0.05). No significant relationships were observed between Mn measures at birth and the general psychomotor indices, Brunet–Lézine developmental quotient (DQ) at 9 months or McCarthy general cognitive index (GCI) at 3 and 6 years. Maternal blood Mn levels were negatively associated with foetal plasma HVA and 5-HIAA concentrations (adjusted for labour duration, child’s gender, and smoking during pregnancy), but the adjustment for monoamine levels at birth did not change the association between the Mn levels and the psychomotor scores. These results suggest that environmental Mn exposure in utero could affect early psychomotor development. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS Manganese & poor attention A Canadian prospective epidemiological study (n= 247 pregnant women and their babies) identified exposure to manganese, mainly from manganese air pollution from gasoline containing methylcyclopentadienyl manganese tricarbonyl (MMT) and suggested a link with poor attention in young children. Takser , 2003 36 This study from California, US, suggests there may be an association between metals, and possibly solvents in ambient air, around birth residence and development. Further studies are required for confirmation. Ref: •Windham GC et al. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay area. Environ Health Perspect, 2006, 114(9):1438-1444. Objective: To explore possible associations between autism spectrum disorders (ASD) and environmental exposures, we linked the California autism surveillance system to estimated hazardous air pollutant (HAP) concentrations compiled by the U.S. Environmental Protection Agency. Methods: Subjects included 284 children with ASD and 657 controls, born in 1994 in the San Francisco Bay area. We assigned exposure level by census tract of birth residence for 19 chemicals we identified as potential neurotoxicants, developmental toxicants, and/or endocrine disruptors from the 1996 HAPs database. Because concentrations of many of these were highly correlated, we combined the chemicals into mechanistic and structural groups, calculating summary index scores. We calculated ASD risk in the upper quartiles of these group scores or individual chemical concentrations compared with below the median, adjusting for demographic factors. Results: The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs), 1.1–2.1], but not for aromatic solvents. Adjusting for these three groups simultaneously led to decreased risks for the solvents and increased risk for metals (AORs for metals: fourth quartile = 1.7; 95% CI, 1.0–3.0; third quartile = 1.95; 95% CI, 1.2–3.1). The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride. Conclusions: Our results suggest a potential association between autism and estimated metal concentrations, and possibly solvents, in ambient air around the birth residence, requiring confirmation and more refined exposure assessment in future studies. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS A potential association has been noted between autism and estimated metal concentrations, and possibly solvents, in ambient air around the birth residence. This requires confirmation and more refined exposure assessment in future studies Windham GC, 2006 37 Following the events of 11 September in New York, US, polycyclic aromatic hydrocarbons (PAHs), in relation to children’s cognitive development, through prenatal exposure have been studied. Results show that prenatal exposures at the levels recently encountered have implications for school performance. Ref: •Perera FP et al. Effect of prenatal exposure to airborne polycyclic aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner-city children. Environ Health Perspect, 2006, 114(8):1287-1292. Our prospective cohort study of nonsmoking African-American and Dominican mothers and children in New York City is evaluating the role of prenatal exposure to urban pollutants, including polycyclic aromatic hydrocarbons (PAHs), environmental tobacco smoke (ETS), and pesticides, in the pathogenesis of neurobehavioral disorders. We used the Bayley Scales of Infant Development to evaluate the effects on child mental and psychomotor development of prenatal exposure to airborne PAHs monitored during pregnancy by personal air sampling. Behavioral development was assessed by the Child Behavior Checklist. We adjusted for potential confounders including sociodemographic factors and prenatal exposure to ETS and chlorpyrifos. Prenatal exposure to PAHs was not associated with psychomotor development index or behavioral problems. However, high prenatal exposure to PAHs (upper quartile) was associated with lower mental development index at age 3 [β= –5.69; 95% confidence interval (CI), –9.05 to –2.33; p < 0.01]. The odds of cognitive developmental delay were also significantly greater for children with high prenatal exposure (odds ratio = 2.89; 95% CI, 1.33 to 6.25; p = 0.01). General estimated equation analysis showed a significant age × PAH effect on mental development (p = 0.01), confirming the age-specific regression findings. Further adjustment for lead did not alter the relationships. There were no differences in effect sizes by ethnicity. The results require confirmation but suggest that environmental PAHs at levels recently encountered in New York City air may adversely affect children’s cognitive development at 3 years of age, with implications for school performance. <<NOTE TO USER: For more information see modules on air pollution.>> Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS Air pollution Prenatal exposure to environmental polycyclic aromatic hydrocarbons at levels encountered in New York City air may adversely affect children's cognitive development at 3 years of age. This may have implications for school performance. Perera FP. Environ Health Perspect. 2006 ; 114(8):1287-1292 . 38 Evidence is accumulating that dietary factors may play a role in Neurodevelopmental Behavioral Intellectual Disorders in children. Diets with adequate omega-3 fatty acids and low in artificial food colors and preservatives may benefit children’s behaviors and learning. Children with attention deficit hyperactive disorder (ADHD), dyslexia & autism have been studied and found to benefit from omega-3 replacement. Withdrawing fatty food coloring from the diet of children with ADHD symptoms may be beneficial in a small subgroup. When dealing with Neurodevelopmental Behavioral Intellectual Disorders in children, health professionals could advise a diet with sufficient omega-3 fatty acids and low in food coloring. Refs: •Bateman B et al. The effects of a double blind, placebo controlled, artificial food colourings and benzoate preservative challenge on hyperactivity in a general population sample of preschool children. Arch Dis Child, 2004, 89:506-511. •McCann D et al. Food additives and hyperactive behaviour in 3 year old and 8/9 year old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet, 2007, 370:1560-1567. •Richardson AJ. Omega-3 fatty acids in ADHD and related neurodevelopmental disorders. Int Rev Psych, 2006, 18(2):155-172. •Schab DW, Trinh NH. Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blinded placebo-controlled trials. J Developmental & Behavioral Pediatrics, 2004, 25(6):423-434. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS Diet ❖ Replacement of omega-3 fatty acids linked with improvement of symptoms of attention deficit hyperactive disorder, dyslexia , autism. ❖ Artificial colors in food may increase hyperactivity in a subgroup of children. Richardson AJ , 2006 Mccann D, 2007 Schab DW, 2004 Bateman B, 2004 39 A 5-point loss in IQ might not affect the ability of an individual to live a productive life. But if that loss is experienced by an entire population, the implications for that society could be profound. Bernard Weiss, a behavioural toxicologist at the University of Rochester, US, examined the societal impact of seemingly small losses of intelligence. Imagine an unaffected population numbering 260 million people (such as that of the US) with an average IQ of 100 and a standard deviation of 15 (left- hand graph). In that population there would be 6 million people with IQs above 130 and 6 million below 70. A decrease in average IQ of 5 points would shift the distribution to the left (right-hand graph). The number of people scoring above 130 would decline by 3.6 million while the number below 70 would increase by 3.4 million. Picture adapted from Schettler T. In harm' s way. Greater Boston Physicians for Social Responsibility, 2000. Used with permission. Children & neurodevelopmental behavioural intellectual disorders NEURODEVELOPMENTAL PROCESSES & ENVIRONMENTAL RISK FACTORS Significance of 5 point IQ reduction mea 100 mean 95 70 l.Q. 130 Greater Bo.stoo Physicians for Social Responsibi/ny , 2000 40 To focus specifically on the costs of fetal exposure to mercury released by U.S. coal-fired power plants, scientists examined the impact of the 41% of U.S. anthropogenic emissions of mercury attributable to these facilities. They estimate that the attributable cost of methylmercury exposure from U.S: electric generation facilities to the developing fetus is $1.3 billion. Applying a sensitivity analysis in this model, they find that the true cost of methylmercury exposure from electric generation facilities to the U.S. birth cohort ranges from $0.1 to $6.5 billion/year. Again, the major source of these costs is loss of earnings over a lifetime. Ref: •Trasande L, Schechter C, Landrigan PJ. Public health and economic consequences of environmental methyl mercury toxicity to the developing brain. Environ Health Perspect, 2005, 113:590-596. Methyl mercury is a developmental neurotoxicant. Exposure results principally from consumption by pregnant women of seafood contaminated by mercury from anthropogenic (70%) and natural (30%) sources. Throughout the 1990s, the U.S. Environmental Protection Agency (EPA) made steady progress in reducing mercury emissions from anthropogenic sources, especially from power plants, which account for 41% of anthropogenic emissions. However, the U.S. EPA recently proposed to slow this progress, citing high costs of pollution abatement. To put into perspective the costs of controlling emissions from American power plants, we have estimated the economic costs of methyl mercury toxicity attributable to mercury from these plants. We used an environmentally attributable fraction model and limited our analysis to the neurodevelopmental impacts--specifically loss of intelligence. Using national blood mercury prevalence data from the Centers for Disease Control and Prevention, we found that between 316,588 and 637,233 children each year have cord blood mercury levels > 5.8 microg/L, a level associated with loss of IQ. The resulting loss of intelligence causes diminished economic productivity that persists over the entire lifetime of these children. This lost productivity is the major cost of methyl mercury toxicity, and it amounts to $8.7 billion annually Children & neurodevelopmental behavioural intellectual disorders CHALLENGES & IMPACTS OF NEURODEVELOPMENTAL BEHAVIORAL INTELLECTUAL DISORDERS Cost of American anthropogenic emissions : SO. 15.8 billion Portions of cost of methyl mercury expo- sure attributed to sources . Assumpt ions: 18- 36% attributable to American sources; 41 % of American emissions attributable to American power plants. Public health and economic consequences of methylmercury toxicity to the developing brain Trasande L, Landrigan PJ, Schechter C. Environ Health Perspectives, 2005 , 113(5):590-596 . 41 (range, $2.2-43.8 billion; all costs are in 2000 US$). Of this total, $1.3 billion (range, $0.1-6.5 billion) each year is attributable to mercury emissions from American power plants. This significant toll threatens the economic health and security of the United States and should be considered in the debate on mercury pollution controls. Approximately 300 high-volume industrial chemicals with neurotoxic properties are emitted into the environment with known neurotoxic effects on adults as well as known neurotoxic effects on laboratory animals. Researchers raised the question of whether each of these substances should be tested appropriately for neurodevelopmental effects on children or whether protective policies can be instituted in the absence of the detailed science that we currently have for lead, others. Very few environmental neurotoxics have been studied to identify potential harmful effects on Neurodevelopmental Behavioral Intellectual Disorders processes in the fetus and the young child. Risk assessment methods for chemicals being released into the environment are not adequate to protect children from Neurodevelopmental Behavioral Intellectual Disorders. We are identifying increasing numbers of environmental chemicals that contribute to Neurodevelopmental Behavioral Intellectual Disorders damage in the fetus and the young child. Researchers need to ask the question "which chemicals do we need to study?". Many chemicals may have direct neurotoxic effects or indirect effects by contributing to causality of other risk factors of Neurodevelopmental Behavioral Intellectual Disorders, e.g. low birth weight. Refs: •Dietrich K et al. Principles and practices of neurodevelopmental assessment in children: Lessons learned from the centers for children's environmental health and disease prevention research. Environ Health Perspect, 2005, 113(10):1437-1446. •Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. The Lancet, 2006, 368:2167- 2178. Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the Children & neurodevelopmental behavioural intellectual disorders CHALLENGES OF ADDRESSING NEURODEVELOPMENTAL DISORDERS Potential environmental neurotoxic exposures ► Known neurotoxic effects on adults ► 300 high-volume industrial chemicals emitted into environment ► Known neurotoxic effects on laboratory animals Chemical emissions with potential for neurodeveloomental harm ► Toxicants linked with in utero growth retardation ► Toxicants low molecular weight, low protein binding, lipid affinity, no polarity Grandjea n P, 2006 42 great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals. Ref: Bjoling-Poulsen M, Andersen HR, Grandjean P. Potential developmental neurotoxicity of pesticides used in Europe. Environ Health, 2008, 7:50. Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development. Children & neurodevelopmental behavioural intellectual disorders CHALLENGES OF ADDRESSING NEURODEVELOPMENTAL DISORDERS Prevention of exposures to neurotoxic pesticides ► Many pesticides target the nervous system of insect pests . ► Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Bjoling- Poulsen M, 2008 43 Canada, Mexico and the US maintain inventories of industrial toxic emissions. These include a number of neurotoxins. Industries that meet the criteria for reporting are legislated to submit an estimate of releases annually. This is a Google-generated map identifying location (longitude & latitude) of industrial facilities that participate in these inventories. This data is publically available from www.cec.org/ - accessed 15 June 2011. Children & neurodevelopmental behavioural intellectual disorders CHALLENGES OF ADDRESSING NEURODEVELOPMENTAL DISORDERS Facilities reporting emissions National Pollutant Release Inventory Toxic Release Inventory Registry of Emissions and Contaminants Transfers 44 The Commission for Environmental Cooperation which is the environmental side arm of the North American Free Trade Agreement (NAFTA) produced this map from national emissions inventories to demonstrate visibly sources of emissions of mercury in North America. Inventories of this kind demonstrated on maps bring awareness to communities of sources of potentially harmful emissions. This information can be used for education, awareness and protective policies as well as ongoing research by scientists. Image from www.cec.org/ - accessed 15 June 2011. Children & neurodevelopmental behavioural intellectual disorders CHALLENGES OF ADDRESSING NEURODEVELOPMENTAL DISORDERS www.cec .org/ ,,-. '"'·. . _, ~-. . ' ' i - ..> •• . - ·. ! ' . l ·• , ' . . ,. . The United Nations Environment Programme (UNEP) Global Mercury Partnership is a voluntary initiative where government, non-government, public and private entities have agreed to work together in a systematic way to achieve the goal of the Partnership. The overall goal is to protect human health and the global environment from the release of mercury and its compounds by minimizing and, where feasible, ultimately eliminating global anthropogenic mercury releases to air, water and land. Ref: •UNEP Global Mercury Partnership. Available at www.unep.org/hazardoussubstances/Mercury/tabid/434/language/en-US/Default.aspx – accessed 15 June 2011 Children & neurodevelopmental behavioural intellectual disorders UNEP GLOBAL MERCURY PARTNERSHIP The overall goal is to protect human health and the global environment from the release of mercury and its compounds UNEP Global Mercury Partnersh ip www.chem.unep.ch/mercury UNEP: United Nations Environment Programme 46 <<READ SLIDE>> More information on the Global Alliance to Eliminate Lead Paint available at www.unep.org/hazardoussubstances/LeadCadmium/PrioritiesforAction/GAELP/tabid/6176/D efault.aspx – accessed 15 June 2011 Children & neurodevelopmental behavioural intellectual disorders WHO/UNEP GLOBAL ALLIANCE TO ELIMINATE LEAD PAINT Key activities areas for the elimination of lead paints a) Raising awareness of toxicity to human health and the environment and alternatives; (b) Guidance and assistance to identify potential lead exposure; (c) Assistance to industry (manufacturers, wholesalers and retailers); (d) Prevention programmes to reduce exposure; (e) Promotion of national regulatory frameworks. UNEP: United Nations Environment Programme www.unep.org/hazardoussubslances/LeadCadm/um/PrioriliesforAclion/GAELP/labld/6176/Defau/l .aspx 47 <<READ SLIDE>> Refs: •Neira M et al. Environmental threats to children's health – a global problem. Int J Environment and Health, 2008, 2(3/4):276. •Pronczuk J, Bruné MN, Gore F. Children’s environmental health in developing countries. In: Encyclopedia of Environmental Health. Nriagu J, ed. Elsevier, 2011. Children & neurodevelopmental behavioural intellectual disorders CHALLENGES OF ADDRESSING NEURODEVELOPMENTAL DISORDERS Neurodevelopmental disorders are largely preventable. Countries can develop: ❖ Better surveillance ■ Access to environmental data ❖ Appropriate public health interventions ■ Relevant health databases, identification and action on all risk factors ❖ Coordinated research plan ■ Ecological, basic science, epidemiological & qualitative ❖ Adequate risk assessment, management & communication ❖ National, regional, global strategies 48 <<READ SLIDE>> Children & neurodevelopmental behavioural intellectual disorders SUMMARY 1. Neurodevelopmental Behavioral Intellectual Disorders are common in industrialized countries. 2. The neurodevelopment process is a delicate, vulnerable, very complex process. It is affected by many genetic & environmental factors. 3. Neurodevelopmental Behavioral Intellectual Disorders carry an enormous economic and emotional impact on societies. 4. Exposures to environmental chemicals with potential for contributing to Neurodevelopmental Behavioral Intellectual Disorders are poorly understood. 5. Neurodevelopmental Behavioral Intellectual Disorders are largely preventable through a coordinated plan to identify and mitigate relevant risk factors. 49 Children & neurodevelopmental behavioural intellectual disorders ACKNOWLEDGEMENTS WHO is grateful to the US EPA Office of Children 's Health Protection for financial support that made this project possible and for some of the data, graphics and text used in preparing these materials for a broad audience . Further support was kindly provided by the UK Department of Health . First draft prepared by Irena Buka MD (Canada) With the advice of the Working Group Members on the Training Package for the Health Sector: Cristina Alonzo MD (Uruguay); Vona Amitai MD MPH (Israel); Stephan Boese-O'Reilly MD MPH (Germany); Stephania Borgo MD (ISDE, Italy); Irena Buka MD (Canada); Ernesto Buri:1io (ISDE, Italy); Lilian Corra MD (Argentina); Ligia Fruchtengarten MD (BrazilJ; Amalia Laborde MD (Uruguay); Jenny Pronczuk MD (WHO) Christian Schweizer TO (WHO/EURO); Kathy Shea MD (USA). Reviewers: Dr Huw Brunt (UK), Prof Gary Coleman (UK), Dr Raquel Duarte- Davidson (UK), Dr Elaine Lynch Farmery (UK), Alison M Good BSc Dip Med Tox MSc (UK), Dr Mark Griffiths (UK), Dr John Thompson (UK), Dr Laura Yates (UK) WHO Project coordination: Ruth A. Etzel, MD PhD Marie-Noel Brune, MSc Latest u date: October 2011 so Children & neurodevelopmental behavioural intellectual disorders Disclaimer WHO/HSE/PHE/EPE/11 .01 .04 C) World Health Organ i1atlon 2011 . All rfthts reserved . This e•leaming train ing was deve loped by the World Health Organization {WHO). It is intended to be used as a self.learn ing course on Children's Health and the EnvironmenL All reasonab le precautions have been taken by WHO to verify the information conta ined in this e•learning tra ining. However, thee-learning tra inin,: is be ing distributed without war ranty of any kind, either expressed or implied . The re sponsi bility for the interpre tatio n and use of the e--learnlng tra ining lies with the reader . In no event shall WHO be liable for damages a rising from its use . The mention of spec ific companies or of c.ertain manufacturers' products does not imply that they are endoBed or recommended by the World Health Organization in preference to others of a similar nat ure that are not mentioned . Eno rs and omissions exce pted , the names of propr ietary products are distinguished by initial capita l lette rs. 51

<<NOTA AO USUÁRIO: Por favor, adicione detalhes da data, hora, local e patrocínio da reunião para a qual você está usando esta apresentação no espaço indicado. >> <<NOTA AO USUÁRIO: Este é um grande conjunto de slides a partir do qual o apresentador deve selecionar os mais relevantes para usar em uma apresentação específica. Esses slides cobrem muitas facetas do problema. Apresente apenas os slides que se aplicam mais diretamente com a situação local na região. >> <<NOT AO USUÁRIO: Este módulo apresenta vários exemplos de fatores de risco que afetam o neurodesenvolvimento, você pode encontrar informações mais detalhadas em outros módulos do pacote de treinamento que lidam com fatores de risco específicos, tais como chumbo, mercúrio, pesticidas, poluentes orgânicos persistentes, disruptores endócrinos; ou exposição pré-natal e efeitos sobre o desenvolvimento. >> TREINAMENTO PARA O SETOR DE SAÚDE [Data ... Local ... Evento ... Patrocinador ... Organizador] CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS, INTELECTUAIS E DO NEURODESENVOLVIME~TO (ACIN) Saúde Infantil e o Meio Ambiente Pacote de Treinamento da OMS para o Setor de Saúde Organização Mundial da Saúde www.who.int/ceh Traduzido pela Pootiflcia Universidade Cató lica do Rio Grande do Sul com permissão da Organização Mundial da Saúde Publicado pela Organização Mundial da Saúde sob o titulo Children's hsal th and lhe environms nt. Pacote de treinamento da OMS para o setor de saúde Criança s e Alterações Comportamenta is, Intelectuais e do Neurodasenvolvimenro (ACtN) @ Wo~d Health Organ izatioo A Organiza ção Mundial da Saúde cedeu os direitos de tradução e publicação para uma edição em português para a Pontilícia Universidade Católica do Rio Grande do Sul (PUCRS) , que é a única responsável pela qualidade e fidelidade da tradução em português . No caso de qualquer inconsistência entre as edições em inglês e português, a edição original em inglês será a autêntica e mandatória . Outubro 2011 << LER SLIDE>> CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO OBJETIVOS ❖ Definir e descrever alterações comportamentais, intelectuais e do neurodesenvolvimento (ACIN) comuns e sua prevalência. ❖ Entender o processo de neurodesenvolvimento no contexto das ciências básicas e de dados ambientais. ❖ Discutir estudos epidemiológicos importantes que analisam fatores de risco ambientais. ❖ Conhecer exposições ambientais potencialmente neurotóxicas e a complexidade da determinação de causalidade. <<LER SLIDE>> CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO RESUMO ❖ Descrição de alterações comportamentais, intelectuais e do neurodesenvolvimento (ACIN) comuns. ❖ Breve epidemiologia das alterações comportamentais, intelectuais e do neurodesenvolvimento. ❖ Sumário dos processos de neurodesenvolvimento. ❖ Discussão das relações com o meio ambiente. ❖ Impactos das alterações comportamentais, intelectuais e do neurodesenvolvimento e desafios de proteger adequadamente as crianças. Diferenças fisiológicas se manifestam de formas mais variadas do que as vias metabólicas imaturas. Como importantes sistemas ainda estão se diferenciando e crescendo, as crianças têm suscetibilidades únicas em relação aos adultos - e janelas críticas de tempo para essas suscetibilidades. •Preconcepção •Gestação - Talidomida, DES - Radiação ionizante - Metilmercúrio, chumbo •Pós-natal - Fumaça do tabaco - Chumbo. Houve uma explosão de conhecimento sobre o desenvolvimento na última década, e é duro lembrar que foi apenas há cerca de 50 anos que descobriu-se que o feto é vulnerável a exposições. A epidemia de focomelia, resultante do uso de talidomida na gravidez, foi um dos primeiros e dramáticos exemplos da capacidade de um produto químico de atravessar a placenta e danificar o feto. A talidomida tipicamente causa defeitos congênitos quando tomada entre 34 e 51 dias após o primeiro dia do último período menstrual da mulher. Os defeitos de nascimento mais comuns observados em bebês expostos durante esse período foram defeitos dos membros, olhos e ouvidos. Um estudo realizado em 1994 sugeriu que a talidomida administrada durante uma pequena janela de 4 dias entre os dias 20 e 24 da gestação pode aumentar o risco de autismo (Stromland, 1994). Mais de um sistema pode ser susceptível e diferentes patologias podem ocorrer dependendo da dose e do tempo de exposição. Agora sabemos que outras exposições durante a gestação podem prejudicar os sistemas, e alguns estão listados aqui. Sabemos também que a exposição preconcepção de um dos pais pode causar danos às crianças, bem como exposições pós-natais. << NOTAS AO USUÁRIO: É importante ressaltar as diferentes respostas às agressões mostradas na barra inferior da figura. Agressões ambientais significativas durante a fase embrionária irão resultar em perda da gravidez (nas 2 primeiras semanas) ou malformação dos órgãos. Durante a fase fetal, o dano é mais sutil e relacionado à disfunção do sistema. >> Refs: •Koren G et al. Drugs in pregnancy. N Engl J Med 1998, 338: 1128-1137. •Stromland K et al. Autism in thalidomide embryopathy: a population study. Developmental Medicine & Child Neurology, 1994, 36:351. De uma população de 100 casos suecos de embriopatia por talidomida, pelo menos quatro reuniram critérios para o transtorno autista DSM-III-R e autismo infantil CID-10. Embriopatia por Talidomida do tipo encontrado nesses casos afeta o desenvolvimento fetal no início da gravidez, provavelmente nos dias 20 e 24 após a concepção. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO JA vwolly no/ susceptibl~ lo terot090"'1 ELAS DE DESENVOLVIMENTO 5 6 7 8 -~---- Sditmll(1<:: ill11s1nulOt1 oft hé sais, 11,t <>r c:ritte3J pen~ 1n hum~n devcloprnen1 Red d(ll()fts ti1sh.ly seos1tn·e pt:riodi. ycll-Ow mdica1ies st.,ie s 11\.1 are kss scnsitivc lo lcmto(tms , too~ KL. Tbc De\·doping llumoo; lmi;;ullyOrientcd EmbryolO@.}', Pluladelphiu \V, O Saunders ompi..y. 1973, Moore. El.vevier lnc. /9 73 Argumenta-se que a possível associação de embriopatia por talidomida com o autismo pode fazer alguma revelação sobre quais circuitos neurais podem estar envolvidos na patogênese do autismo. Figure: Reprinted from: Moore KL. The developing human. Elsevier Inc., 1973. Used with copyright permission (2004) from Elsevier. Neurodesenvolvimento começa na fase pré-natal precoce com um desenvolvimento neurológico complexo que começa com a proliferação de células gliais radiais e neurônios. Estes continuam a se desenvolver nos anos pós-natais. Este processo não está completo até quase 3 anos de idade. A migração de neurônios, que ocorre do segundo ao sexto mês de gestação, e outra vez dentro do cerebelo após o nascimento, é um processo muito importante e complexo. A formação de sinapses, que ocorre essencialmente no último trimestre de gravidez, bem como nos primeiros 2 anos de vida, é essencial para o funcionamento e desenvolvimento em curso. Mielinização é um processo importante que começa na segunda metade da gestação e continua na adolescência, com diferentes sistemas mielinizantes em diferentes momentos, conforme mostrado no diagrama. Ref: •Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environmental Health Perspectives, 2000, CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO NEURODESENVOLVIMENTO Time Lines of Developmental Proce sses in Humans •• 1 Rteo and Barono . EHP 108(S3) 511 -533 , 2000 Adoptod from Horschkowrtz ct ai . 1997 Rice D. Environ Heallh Perspectives , 2000; 108(S3) 108(S3):511-533. Refs: •Gogtay N et al. From the Cover: Dynamic mapping of human cortical development during childhood through early adulthood. Proceedings of the National Academy of Sciences, 2004, 101: 8174-8179 •National Institute of Mental Health (NIMH) / University of California Los Angeles (UCLA). Time-lapse imaging tracks brain developing from ages 5 to 20. NIMH/UCLA Project visualizes maturing brain - available at www.loni.ucla.edu/~thompson/DEVEL/PR.html - accessed 15 June 2011 The brain's center of reasoning and problem solving is among the last to mature. The decade-long magnetic resonance imaging (MRI) study of normal brain development, from ages 4 to 21, by researchers at NIH's National Institute of Mental Health (NIMH) and University of California Los Angeles (UCLA) shows that such "higher-order" brain centers, such as the prefrontal cortex, don't fully develop until young adulthood. A time-lapse 3-D movie that compresses 15 years of human brain maturation, ages 5 to 20, into seconds shows gray matter - the working tissue of the brain's cortex - diminishing in a back-to-front wave, likely reflecting the pruning of unused neuronal connections during the teen years. Cortex areas can be seen maturing at ages in which relevant cognitive and functional developmental milestones occur. The researchers scanned the same 13 healthy children and teens every two years as they grew up, for 10 years. After co- registering the scans with each other, using an intricate set of brain anatomical landmarks, they visualized the ebb and flow of gray matter - neurons and their branch-like extensions - in maps that, together, form the movie showing brain maturation from ages 5 to 20. It was long believed that a spurt of overproduction of gray matter during the first 18 months of life was followed by a steady decline as unused circuitry is discarded. Then, in the late 1990s, NIMH's Dr. Jay Giedd, a co-author of the current study, and colleagues, discovered a second wave of overproduction of gray matter just prior to puberty, followed by a second bout of "use-it-or-lose-it" pruning during the teen years. The new study found that the first areas to mature (e.g. extreme front and back of the brain) are those with the most basic functions, such as processing the senses and movement. Areas involved in spatial orientation and language (parietal lobes) follow. Areas with more advanced functions -- integrating information from the senses, reasoning and other "executive" functions (prefrontal cortex) - mature last Thompson says that researchers debate whether teens are actually losing tissue when the gray matter disappears, trimming connections, or just coating gray matter with insulation. Imaging doesn’t provide high enough resolution to distinguish among the possibilities, he notes: “Right now we can image chunks of millions of neurons, but we can’t look at individual cells.” Tremendous rate of growth in areas of vision and sensation occur in the early school years. In middle school areas in language development show repid growth. Late teens exhibit rapid growth in areas controlling inhibition, judgment. Healthy development means an increase and loss of neurological tissue. Maturation of the central nervous system is critical in the development of neurodevelopmental disorders. Cell pruning or synapse pruning, which occurs between the ages of 5 – 20 years appears to be a critical process whereby if increased may be linked with childhood onset schizophrenia and if decreased may be linked with autism. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DE NEURODESENVOLVIMENTO Maturação do córtex dos 5 aos 20 anos: "Poda sináptica" de conexões neurais não utilizadas ❖ Anormalidades na maturação podem ser a base de desordens do desenvolvimento neurológico ❖Aumento da "poda" com o início de esquizofrenia na infância; redução com autismo Um recém-nascido, ainda que completamente formado, nasce com um sistema neurológico imaturo que não permite que o bebê seja nada mais do que indefeso. Há pouco controle da cabeça, os membros são flexionados e a única possibilidade que os recém-nascidos têm para se defender de perigos é através do choro. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO NEURODESENVOLVIMENTO MARCOS CLÍNICOS OMS O desenvolvimento ocorre muito rapidamente a medida em que o sistema neurológico amadurece nos primeiros meses e anos de vida. Por volta dos 4 meses de idade, um bebê é capaz de manter sua cabeça contra a gravidade quando na posição prona, fixar e seguir objetos com seus olhos, responder a sons e até mesmo começar a pegar os brinquedos. Na posição sentada um bebê quatro meses reage a sons, assobios e interage socialmente. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO NEURODESENVOLVIMENTO MARCOS CLÍNICOS • Bom controle da cabeça, sustenta-se no antebraço • Fixa, acompanha e tem interesse no entorno com os olhos 4 meses Com 9 meses de idade o bebê se senta sem apoio, é capaz de pegar brinquedos, transferi- los de mão-a-mão e é capaz de pegar objetos muito pequenos entre o polegar e o indicador. Neste momento, balbuciam consoantes e vogais e modulam tom e volume. Eles são capazes de se fazer entender em relação às suas necessidades de comer, beber e a necessidade de trocar a fralda. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO NEURODESENVOLVIMENTO MARCOS CLÍNICOS . -. •Boa preensão em pinça •Senta-se, suporta o peso nas pernas •Vê e ouve como um adulto •Balbucia consoantes e vogais, modula o timbre e o volume Aos 18 meses de idade, uma criança anda e corre, pode jogar uma bola e chutar, pode empilhar brinquedos, pode subir escadas, ajuda a se vestir e despir e é capaz de dizer 10- 20 palavras e compreender frases mais complexas. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO NEURODESENVOLVIMENTO MARCOS CLÍNICOS 18 meses 10 Aos 3 anos de idade a criança tem a capacidade de andar de triciclo, falar frases usando um sujeito, verbo e objeto que é compreensível por estranhos, faz perguntas que, onde e quem e entende instruções mais complexas. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO NEURODESENVOLVIMENTO MARCOS CLÍNICOS Por volta dos 4 anos de idade, o sistema neurológico está se tornando bastante complexo de forma que a criança consegue pular em um pé só, pode subir uma escada, faz perguntas mais complexas, de quando, como e por que, entende opostos e é capaz de seguir as instruções completas em sequência. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO NEURODESENVOLVIMENTO MARCOS CLÍNICOS 12 Pediatria do neurodesenvolvimento é um campo em desenvolvimento que aborda aspectos complexos do desenvolvimento do sistema nervoso central (SNC) em crianças. Algumas definições incluem aspectos físicos consequentes a danos precoces ao SNC p.ex. paralisia cerebral. Outras definições limitam-se à incapacidade funcional. A definição neste slide pode ser encontrada no relatório provisório sobre desordens do neurodesenvolvimento no painel da European Environment and Health Strategy. Ref: •European Union. Draft Baseline Report on neurodevelopmental disorders in the framework of the European Environment and Health Strategy. Technical working group on priority diseases, subgroup neurodevelopmental disorders, 2003. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO ALTERAÇÕES COMPORTAMENTAIS, INTELECTUAIS E DO NEURODESENVOLVIMENTO Inconsistências na terminologia e definições Definição Europeia: Desordens do neurodesenvolvimento são as deficiências no funcionamento do cérebro que afetam o comportamento , a memória ou capacidade de aprender de uma criança , p.ex. retardo mental, dislexia , transtorno de déficit de atenção e hiperatividade (TDAH) , autismo e déficit de aprendizagem . Draft Baseline Repari on Neurodevelopmenlal Disorders in lhe Frameworl< of lhe European Environmenl and Hea/lh Stralegy, 2003 13 Na America do Norte, a definição de Transtornos Neurodesenvolvimentais, Comportamentais e Intelectuais inclui tradicionalmente anormalidades físicas, bem como funcionais. Transtornos no neurodesenvolvimento comportamental ocorrem geralmente em países industrializados. Números tão elevados como 15% das crianças são descritas como tendo dificuldades de aprendizagem, atraso no desenvolvimento, déficit de atenção e hiperatividade, autismo, redução do quociente de inteligência e paralisia cerebral. Em crianças indígenas, a prevalência é muitas vezes muito maior. Embora alguns casos estejam ligados a exposições identificadas, por exemplo, álcool fetal, o fumo do tabaco, baixo peso ao nascer e complicações obstétricas, em muitos casos a etiologia específica é desconhecida. Ref: •Dietrich K et al. Principles and practices of neurodevelopmental assessment in children: Lessons learned from the centers for children's environmental CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO ALTERAÇÕES COMPORTAMENTAIS, INTELECTUAIS E DO NEURODESENVOLVIMENTO 1 em 6 crianças nos países industrializados: ► paralisia cerebral ► J QI ►dificuldades de aprendizagem ► transtorno de déficit de atenção e hiperatividade(TDAH) ►autismo Etiologia específica desconhecida na maioria dos casos Dietrich K, 2005 TDAH : Transtorno do Déficit de Atenção e Hiperat ividade 14 health and disease prevention research. Environ Health Perspect, 2005, 113(10):1437-1446. Alterações comportamentais, intelectuais e do neurodesenvolvimento consistem em muitas condições. As doenças funcionais mais comuns identificadas são Transtorno de Déficit de Atenção e Hiperatividade (TDAH) e autismo, e cada uma consiste hoje em vários subgrupos, dependendo da sintomatologia predominante de cada criança. Por exemplo, o Transtorno de Déficit de Atenção sem hiperatividade é descrito no Manual Diagnóstico e Estatístico de Transtornos Mentais, quarta edição (DSM-IV), diagnosticada normalmente em meninas mais velhas de cerca de 9 anos de idade. Refs: •American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition. Washington, US. American Psychiatric Association, 2000. •Kaneshiro NK. Autism. Available at www.nlm.nih.gov/medlineplus/ency/article/001526.htm - accessed 15 June 2011 •Mosby. ADHD. In: Mosby's Medical Dictionary, 8th edition, Elsevier, 2009. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO ALTERAÇÕES COMPORTAMENTAIS, INTELECTUAIS E DO NEURODESENVOLVIMENTO - DEFINIÇÕES Transtorno do Déficit de Atenção e Hiperatividade (TDAH) ❖ Um transtorno mental na infância com início antes dos 7 anos de idade e envolvendo prejuízo ou diminuição da atenção, impulsividade e hiperatividade. Autismo ❖ Transtorno do desenvolvimento que aparece nos primeiros 3 anos de vida, e afeta o desenvolvimento cerebral de habilidades sociais e de comunicação. Amer ican Psychiatric Association , 2000 Mosby's Medical Dictionary , 2009 www.nlm.n ih.gov/medlineplus/ency/article/00 1526.htm 15 Grandes variações relatadas nas taxas anteriores são decorrentes muitas vezes a variações de diagnóstico e notificação. No entanto, as diferenças ocorrem entre os sexos (maior no sexo masculino do que feminino), etnia (maior em crianças aborígenes) e grupos socioeconômicos (maior nos grupos socioeconômicos mais baixos). Um estudo do Canadá relata “achados sugestivos ou de uma alta prevalência de Transtorno de Déficit de Atenção e Hiperatividade (TDAH) em crianças aborígenes [canadenses] ou então a ocorrência de padrões de aprendizagem e comportamento em crianças aborígenes que podem levar erroneamente a um diagnóstico de TDAH quando questionários de rastreamento são utilizados. "(Baydala, 2006) Embora o aumento notado ao longo das últimas 2 décadas possa refletir uma maior consciência desses transtornos e critérios diagnósticos mais amplos, há uma preocupação geral sobre a possível implicação de fatores ambientais na etiologia das desordens do desenvolvimento neurológico. Refs: •Baydala L et al. ADHD characteristics in Canadian Aboriginal children. Journal of Attention Disorders, 2006, 9(4):642-647. •Brown RT, et al. Prevalence and assessment of Attention-Deficit/Hyperactivity Disorder in primary care settings. Pediatrics, 2001;107(3):E43. •Charman T. The prevalence of autism spectrum disorders. Recent evidence and future challenges. Eur Child Adolesc Psychiatry, 2002, 11:249-256. •Gurney JG et al. Analysis of prevalence trend of autism spectrum disorder in Minnesota. Arch Pediatr Adolesc Med, 2003, 157:622-7. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO ALTERAÇÕES COMPORTAMENTAIS, INTELECTUAIS E DO NEURODESENVOLVIMENTO A prevalência varia entre os estudos e regiões, e sugerem que as taxas de transtorno de déficit de atenção e hiperatividade (TDAH) e autismo podem ter aumentado nas últimas duas décadas. 1,2 ❖ Alterações comportamentais , intelectua is e do neurodesenvolvimento - 3-8% das crianças nos EUA e Europa.3 ❖ As taxas de prevalência de TDAH variam de 4% a 12% na população em geral, de 6 a 12 anos.4 ❖ TDAH é de 22,7% em crianças aborígenes canadenses .. 5 1) Gumey JG, 2003 2) Charman T, 2002 3) Weiss B, 2000 4) Brown RT, 2001 TDAH: Transtorno de Déficit de Atenção e Hiperatividade 5) Bayda la L, 2006 1s •Weiss B, Landrigan PJ. The developing brain and the environment: an introduction. Environ Health Perspect, 2000, 108(3):373-376. É a percepção de muitos clínicos que a incidência de autismo está aumentando. Até recentemente a genética tem sido atribuída como o principal fator de risco para o desenvolvimento de autismo em crianças, o que é mais comum em certos grupos étnicos, p.ex. caribenhos. Há, no entanto, poucos bancos de dados para confirmar isso. Este gráfico do Estado da Califórnia identifica um aumento significativo nos casos de autismo nos últimos 30 anos. Refs: •Byrd RS. The epidemiology of autism in California: a comprehensive pilot study. Report to the legislature on the principal findings. Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California, Davis, 2002. •Keen DV, Reid FD, Arnone D. Autism, ethnicity and maternal immigration. Br J Psychiatry, 2010, 196(4):274-81. Imagem: California Department of Developmental Services. Changes in the population of persons with autism and pervasive developmental disorders in California’s Developmental Services System: 1987 through 1998. A report to the Legislature. Sacramento CA: California Health and Human Services Agency, 1999. Available at www.dds.ca.gov/Autism/docs/autism_report_1999.pdf - accessed June 2011 CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PREVALÊNCIA DE AUTISMO NA CALIFÓRNIA E 600 1/) :,:, :, ~ 500 § 1/) ~ 400 ~ j 300 e e w Õ 200 ai .n 5 100 ., - - V i.,,- ,- w l.,.r' r- ! ! -.J - lí ~ ✓ z 1960 1963 1966 1969 1972 1975 1978 1981 1984 1987 1990 Year of Birth www.dds.ca.gov/Aulismldocs/aulism_report_ 1999.pdf 17 É mundialmente reconhecido que, embora algumas crianças com desordens do desenvolvimento neurológico comportamental e intelectual, especialmente Transtorno do Déficit de Atenção e Hiperatividade (TDAH), não apresentem mais esta condição na idade adulta, muitas permanecem com o distúrbio e frequentemente apresentam outras comorbidades, como o Transtorno desafiador opositor, depressão/ansiedade, abuso de substâncias, desordens de conduta. Isto poderá levar ao abandono escolar e encarceramento. A persistência de TDAH na idade adulta é bem reconhecida, embora a coleta de dados e metodologias para comunicação sejam inconsistentes. Refs: •Hechtman L, Weiss G, Perlman T. Hyperactives as young adults: Past and current substance abuse and antisocial behavior. American Journal of Orthopsychiatry, 1984, 54:415-425. •Pliszka SR, Carlson CL, Swanson JM. ADHD with co-morbid disorders: Clinical assessment and management. New York, The Guilford Press, 1999. •Rabiner D. How often does ADHD persist into adulthood? ADHD library. Available at www.adhdlibrary.com/library/how-often-does-adhd-persist-into-adulthood - accessed 15 June 2011 CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO ALTERAÇÕES COMPORTAMENTAIS, INTELECTUAIS E DO NEURODESENVOLVIMENTO Comorbidades e desfechos em adultos ❖ Ansiedade/depressão , transtorno desafiador opositor , transtorno bipolar , Síndrome de Tourette. ❖ Abuso de substâncias, comportamento antissocial , e até mesmo criminalidade estão entre os problemas mais conhecidos que persistem na idade adulta . 18 A proliferação celular pode ser afetada negativamente pelo consumo de álcool, exposição a clorpirifós e metilmercúrio. A migração dos neurônios pode ser afetada pela exposição ao raio-x, álcool ou metilmercúrio. A migração celular também pode ser afetada negativamente pela irradiação, etanol e metilmercúrio. Ref: •Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspectives, 2000, 108(S3):511-533. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO E LIGAÇÕES AMBIENTAIS ❖ Proliferação ■ Álcool ■ Metilmercúrio ■ Clorpirifós ❖ Migração ■ Irradiação com Raio-x ■ Etanol ■ Metilmercúrio Rice O, 2000 19 A diferenciação de neuroblastos pode ser afetada negativamente por etanol, nicotina, metilmercúrio e chumbo. A gliogênese e mielinização podem ser afetadas adversamente por desnutrição pós-natal, hormônio da tireoide/disrupção endócrina, exposição a álcool, e chumbo. Ref: •Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. EHP, 2000, 108(S3):511-533. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO E LIGAÇÕES AMBIENTAIS ❖ Diferenciação de neuroblastos ■ Etanol ■ Nicotina ■ Metilmercúrio ■ Chumbo ❖ Gliogênese e mielinização ■ Desnutrição pós-natal ■ Hormônio da tireoide / disrupção endócrina ■ Álcool ■ Chumbo Rice O, 2000 20 A sinaptogênese pode ser afetada negativamente pelo etanol, chumbo, metilmercúrio, bifenilpoliclorados (PCBs), trietilamina, paration, permetrina e antagonistas da serotonina. A apoptose ou morte celular programada é um processo complexo no qual as células são removidas de forma apropriada para assegurar o adequado desenvolvimento neurológico comportamental e intelectual. Entretanto, este processo complexo e equilibrado pode ser adversamente afetado nos estágios críticos da gestação e no desenvolvimento pós-natal devido à exposição a etanol, chumbo, mercúrio e clorpirifós. O processo de neurotransmissão pode ser negativamente afetado por inibidores da colinesterase, etanol, metilmercúrio, alumínio, assim como por produtos farmacêuticos e pesticidas desenvolvidos para atingir sistemas específicos de neurotransmissores. Ref: •Rice D, Barone Jr S. Critical periods of vulnerability for the developing CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO E LIGAÇÕES AMBIENTAIS ❖ Sinaptogênese ❖ Processos de ■ Etanol neurotransmissão ■ Chumbo , metilmercúrio ■ Inibidores da colinesterase ■ Bifenilpoliclorado ■ Etanol ■ Trietilamina ■ Metilmercúrio ■ Paration , permetrina ■ Alumínio ■ Antagonista da serotonina ■ Produtos farmacêuticos e ❖ Apoptose pesticidas desenvolvidos para atingir sistemas específicos de ■ Etanol neurotransmissores ■ Chumbo , metilmercúrio 1 ■ Clorpirifós - Rice O, 2000 21 nervous system: evidence from humans and animal models. Environ Health Perspectives, 2000, 108(S3):511-533. Muitos fatores importantes interagem para determinar o resultado do processo do desenvolvimento neurológico em cada criança. Determinantes do desenvolvimento neurológico comportamental e intelectual podem ser classificados de acordo com o diagrama. Nos fatores socioculturais podem fazer parte nutrição, assistência pré-natal, educação, acesso à saúde, QI materno, etnia, gênero, cultura, redes de apoio, qualidade de educação dos filhos. Nos fatores genéticos podem fazer parte as anomalias cromossômicas como Trissomia do 21 (Síndrome de Down). A localização específica de genes (cromossomos 6, 15) está associada a dificuldades de leitura. As meninas com síndrome de Turner podem apresentar dificuldades de visão e espaciais específicas. Crianças com Síndrome do X Frágil podem ter déficits específicos de linguagem. Nos fatores médicos podem fazer parte a encefalopatia hipóxica isquêmica, CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO Fatores socioculturais Fatores genéticos Determinantes do Desenvolvimento Neurológico Comportamental e Intelectual Fatores médicos Fatores ambientais Grandjean P, Landrigan PJ, 2006 22 muito baixo peso ao nascer, retardo do crescimento intrauterino grave, exposição pré-natal ao álcool, tabaco e drogas; dano cerebral causado por hemorragia intraventricular por traumatismo craniano. A perda auditiva condutiva (por otite média com efusão) pode levar a problemas de linguagem. Nos fatores ambientais estão relacionadas as infecções no início da vida, como AIDS, meningite, septicemia, que podem resultar em perturbações do desenvolvimento neurológico comportamental e intelectual. Muitas exposições a agentes químicos têm sido investigadas. O período pré-natal e a primeira infância oferecem janelas de vulnerabilidade para efeitos adversos sobre o desenvolvimento neurológico saudável. A preocupação é crescente em relação ao grande volume de emissões industriais neurotóxicas no meio ambiente. Refs: •Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet, 2006, 368(9553):2167-2178. •Kliegman RM et al. Nelson textbook of pediatrics. 18th edition. Elsevier Health Sciences Division, 2007. Uma Pesquisa Canadense Nacional Longitudinal da Criança e da Juventude, que está em curso há mais de 20 anos, identifica vários fatores sociais que influenciam o desenvolvimento neurológico. A pobreza, a saúde mental materna e educação são relatadas como os fatores determinantes no desenvolvimento neurológico comportamental e intelectual. A pesquisa mostra que mães solteiras que são imigrantes no Canadá estão particularmente sob risco de terem crianças com problemas no desenvolvimento neurológico comportamental e intelectual Refs: •To T et al. Risk markers for poor developmental attainment in young children: results from a longitudinal national survey. Archives of Pediatrics & Adolescent Medicine, 2004, 158(7):643-9 •To T et al. What factors are associated with poor developmental attainment in young Canadian children? Canadian Journal of Public Health. Revue Canadienne de Santé Publique, 2004, 95(4):258-63 CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO E FATORES DE RISCO AMBIENTAIS Pesquisa Nacional Longitudinal de Crianças e Adolescentes ❖ As associações mais fortes e consistentes com baixa renda familiar, mãe com baixa escolaridade ou mãe imigrante, destacam a necessidade de direcionar as avaliações do desenvolvimento e os serviços de suporte para esta população. ❖ Ter uma mãe que apresenta sintomas de depressão , baixa escolaridade ou é imigrante, e mora em uma casa de baixa renda, aumenta o risco de atraso no desenvolvimento de crianças de 1 a 5 anos. 23 Quando a intoxicação por chumbo inicia no útero, o sistema mais crítico é o sistema nervoso central do feto. Este artigo, publicado em 1987, foi essencial para aumentar a compreensão sobre o dano potencial causado pelo chumbo em níveis muito inferiores do que aquelas que causariam sintomas. Ele demonstrou uma significativa correlação entre os níveis de chumbo no sangue do cordão umbilical e o índice de desenvolvimento mental até os dois anos de idade. Ref: •Bellinger D et al. Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development. N Engl J Med, 1987, 316:1037. In a prospective cohort study of 249 children from birth to two years of age, we assessed the relation between prenatal and postnatal lead exposure and early cognitive development. On the basis of lead levels in umbilical-cord blood, children were assigned to one of three prenatal-exposure groups: low (less than 3 micrograms per decilitre), medium (6 to 7 micrograms per decilitre), or high (greater than or equal to 10 micrograms per decilitre). Development was assessed semiannually, beginning at the age of six months, with use of the Mental Development Index of the Bayley Scales of Infant Development (mean +/- SD, 100 +/- 16). Capillary-blood samples obtained at the same times provided measures of postnatal lead exposure. At all ages, infants in the high-prenatal-exposure group scored lower than infants in the other two groups. The estimated difference between the overall performance of the low-exposure and high-exposure groups was 4.8 points (95 per cent confidence interval, 2.3 to 7.3). Between the medium- and high-exposure groups, the estimated difference was 3.8 points (95 per cent confidence interval, 1.3 to 6.3). Scores were not related to infants' postnatal blood lead levels. It appears that the fetus may be adversely affected at blood lead concentrations well below 25 micrograms per decilitre, the level CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO NÍVEL DE CHUMBO EM SANGUE DE CORDÃO E ÍNDICE DE DESENVOLVIMENTO MENTAL. Bel/ingor . N Eng J Mod . /1987)316 : 1037 24 currently defined by the Centers for Disease Control as the highest acceptable level for young children. Picture: Copyright (1987) Massachussets Medical Society, All rights reserved. Used with permission. Os déficits no desempenho psicológico e em sala de aula de crianças com elevados níveis de chumbo nos dentes foram os primeiros indícios de que baixos níveis de intoxicação por chumbo causam perda da capacidade intelectual e mudanças de comportamento. Ref: •Needleman. Deficits in psychological and classroom performance of children with elevated dentine lead levels. N Engl J Med, 1979, 300:689. To measure the neuropsychological effects of unidentified childhood exposure to lead, the performance of 58 children with high and 100 with low dentine lead levels was compared. Children with high lead levels scored significantly less well on the Wechsler Intelligence Scale for Children (Revised) than those with low lead levels. This difference was also apparent on verbal subtests, on three other measures of auditory or speech processing and on a measure of attention. Analysis of variance showed that none of these differences could be explained by any of the 39 other variables studied. Also evaluated by a teachers' questionnaire was the classroom behaviour of all children (2146 in number) whose teeth were analysed. The frequency of non-adaptive classroom behaviour increased in a dose- related fashion to dentine lead level. Lead exposure, at doses below those producing symptoms severe enough to be diagnosed clinically, appears to be associated with neuropsychological deficits that may interfere with classroom performance. Picture: Copyright (1979) Massachussets Medical Society, All rights reserved. Used with permission. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO ASSOCIAÇÃO ....----- -- - - ---- ENTRE NÍVEL DE -01- CHUMBO ~ PRESENTE NA ! >0r DENTINA E ~ COMPORTAMENTO ~ »- EM SALA DE AULA ~ '1G.J.-01-•111ng11>r_,an11 oom - '°'"" _31,,0, ~ -•• ,_, lil Noedfsman, N. Eng/ J Mod. ( 1979):300( 13):689. 25 O chumbo é uma neurotoxina bem estudada. Este slide demonstra a associação entre o aumento da concentração dos níveis de chumbo no sangue e a redução da função cognitiva em crianças pequenas. ETS: Fumaça do tabaco presente no ambiente/ tabagismo passivo AOR:Odds ratio ajustado Ref: •Braun J et al. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environmental Health Perspectives, 2006, 114(12):1904-1909. <<NOTA AO USUÁRIO: Para maiores informações, vide o módulo sobre chumbo.>> CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO E FATORES DE RISCO AMBIENTAIS um oe Transtorno do Déficit de Atenção e Hiperatividade TDAH 5 4 a: 3 o c:i: 2 o < 0.8 0.8- 1.0 1.1- 1.3 1.4-2.0 > 2.0 Quintil es of blood lead concentratio n (µg/ dl ) Odds Ratio ajustado para TDAH em crianças americanas , NHANES 1999-2001 , por concentração sanguínea de chumbo (µg/dl). O modelo foi ajustado para idade, sexo , raça/etnia , frequência à pré-escola , nível de ferritina , exposição pré-natal à fumaça do tabaco , fumantes dentro de casa , e cobertura de plano de saúde . Braun J . Envíron Health Perspect . 2006 ;114(12) :1904-1909. 26 Foi identificado que o chumbo afeta negativamente a fala em crianças pequenas. A ressonância magnética (RM) em adolescentes que apresentaram níveis de intoxicação por chumbo na primeira infância afetando a fala pode mostrar compensação em centros de linguagem secundários. Esta compensação pode depender do tipo de insulto, intensidade e duração. No entanto, o desempenho pode não ser equivalente. Mesmo a exposição a baixos níveis de chumbo pode afetar negativamente uma ampla gama de funções cognitivas: atenção, linguagem, memória, flexibilidade cognitiva e integração visual-motora; mecanismo subjacente pelo qual chumbo altera o funcionamento do cérebro em crianças, especialmente em baixas concentrações de chumbo que não produzem sinais físicos visíveis. Sugere-se que a exposição ao chumbo impede o desenvolvimento normal de áreas de linguagem; o cérebro recruta outras regiões para compensação, mas não necessariamente produz resultados equivalentes. O montante da compensação não depende apenas do tipo de insulto, mas também do tempo, duração e intensidade enquanto o cérebro se desenvolve. No CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO E FATORES DE RISCO AMBIENTAIS ❖Exposição ao chumbo durante a infância impede o desenvolvimento normal das áreas de linguagem. ❖ O cérebro recruta outras regiões para compensar, porém não produz, necessariamente, resultados equivalentes. 27 entanto, deve-se notar que a via alternativa de compensação não produzirá necessariamente um desempenho equivalente ao obtido utilizando o circuito cortical normal para a mesma função. O grau em que este mecanismo de compensação é capaz de atender a demanda para o desenvolvimento da função da linguagem está associado não apenas aos tipos de insulto, mas também com o tempo, duração e intensidade do insulto, o que exige uma investigação mais aprofundada. A exposição elevada ao chumbo na infância exerce uma influência substancial sobre a organização cortical na função da linguagem semântica na idade adulta jovem, demonstrada por um efeito deletério seletivo em áreas de linguagem normais com recrutamento concomitante de regiões contralaterais, resultando em padrões dependentes da exposição para o recrutamento para a função da linguagem. Estes dados continuam a confirmar as consequências negativas nas habilidades cognitivas devido à exposição ao chumbo ambiental. Refs: •Yuan W. et al. Functional magnetic resonance imaging study of language function. The impact of early childhood lead exposure on brain organization. Pediatrics, 2006, 118:971-977 The purpose of this work was to assess the long-term impact of childhood lead exposure on the neurosubstrate of language function and brain organization. METHODS. Young adults from the Cincinnati Lead Study were recruited to undergo functional magnetic resonance image scanning while performing a verb generation task. These subjects have been followed from birth through early childhood with extensive documentation of lead exposure, neuropsychology, and behavior. Forty-two subjects provided useful imaging data. The locale, strength, and the correlation between brain language activation and childhood blood lead concentration were studied. RESULTS. After adjusting for potential confounders, the activation in left frontal cortex, adjacent to Broca's area, and left middle temporal gyrus, including Wernicke's area, were found to be significantly associated with diminished activation in subjects with higher mean childhood blood lead levels, whereas the compensatory activation in the right hemisphere homolog of Wernicke's area was enhanced in subjects with higher blood lead levels. CONCLUSION. This study indicates that childhood lead exposure has a significant and persistent impact on brain reorganization associated with language function. •WHO. Childhood lead poisoning. WHO, 2010. Available at www.who.int/ceh/publications/childhoodpoisoning/en/index.html - accessed March 2011. Mapa composto de uma RM ativa para a tarefa de geração de verbos, mostrando estatísticas de escore z em adultos jovens expostos ao chumbo na infância (n=42). A maioria das áreas altamente ativadas incluem o lobo frontal esquerdo inferior, o giro temporal médio esquerdo, e o giro temporal médio direito. A orientação das imagens segue a convenção radiológica. Ref: Yuan W et al. The Impact of Early Childhood Lead Exposure on Brain Organization: A Functional Magnetic Resonance Imaging Study of Language Function. Pediatrics. 2006, 118(3):971-977 OBJECTIVES. The purpose of this work was to assess the long-term impact of childhood lead exposure on the neurosubstrate of language function and brain organization. METHODS. Young adults from the Cincinnati Lead Study were recruited to undergo functional magnetic resonance image scanning while performing a verb generation task. These subjects have been followed from birth through early childhood with extensive documentation of lead exposure, neuropsychology, and behavior. Forty-two subjects provided useful imaging data. The locale, strength, and the correlation between brain language activation and childhood blood lead concentration were studied. RESULTS. After adjusting for potential confounders, the activation in left frontal cortex, adjacent to Broca's area, and left middle temporal gyrus, including Wernicke's area, were found to be significantly associated with diminished activation in subjects with higher mean childhood blood lead levels, whereas the compensatory activation in the right hemisphere homolog of Wernicke's area was enhanced in subjects with higher blood lead levels. CONCLUSION. This study indicates that childhood lead exposure has a significant and persistent impact on brain reorganization associated with language function. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO Mapa composto de uma RM ativa para a tarefa de geração de verbos , mostrando estatísticas do escore z em adultos jovens expostos ao chumbo na infância (n=42) Yuan W et ai. Pediatrics 2006 ;118:971-9TT 28 Figure from Yuan W et al. The Impact of Early Childhood Lead Exposure on Brain Organization: A Functional Magnetic Resonance Imaging Study of Language Function. Pediatrics. 2006, 118(3):971-977. Reproduced with permission from Pediatrics, Copyright 2010 by the American Academy of Pediatrics. Ref: •Yuan W et al. The Impact of Early Childhood Lead Exposure on Brain Organization: A Functional Magnetic Resonance Imaging Study of Language Function. Pediatrics. 2006, 118(3):971-977 OBJECTIVES. The purpose of this work was to assess the long-term impact of childhood lead exposure on the neurosubstrate of language function and brain organization. METHODS. Young adults from the Cincinnati Lead Study were recruited to undergo functional magnetic resonance image scanning while performing a verb generation task. These subjects have been followed from birth through early childhood with extensive documentation of lead exposure, neuropsychology, and behavior. Forty-two subjects provided useful imaging data. The locale, strength, and the correlation between brain language activation and childhood blood lead concentration were studied. RESULTS. After adjusting for potential confounders, the activation in left frontal cortex, adjacent to Broca's area, and left middle temporal gyrus, including Wernicke's area, were found to be significantly associated with diminished activation in subjects with higher mean childhood blood lead levels, whereas the compensatory activation in the right hemisphere homolog of Wernicke's area was enhanced in subjects with higher blood lead levels. CONCLUSION. This study indicates that childhood lead exposure has a significant and persistent impact on brain reorganization associated with language function. Figure from Yuan W et al. The Impact of Early Childhood Lead Exposure on Brain Organization: A Functional Magnetic Resonance Imaging Study of Language Function. Pediatrics. 2006, 118(3):971-977. Reproduced with permission from Pediatrics, Copyright 2010 by the American Academy of Pediatrics. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO Atividade reduzida nas áreas dominantes de linguagem (hemisfério esquerdo) com maiores níveis de chumbo no sangue . A'? = ili • N :§." ,., -~ l .i • .§-z õí ·=-4 < o o o rn w JO Mean blood lead le,•el, µi:/dL o o ~~ ~tJ>o o o o o 10 20 30 Mean blood lead levei, µg/dL Yuan W et ai. Ped iatrics 2006;118:971-977 A, Regressão linear multivariada de ativação cerebral no giro frontal inferior esquerdo (ROi_ 1) versus níveis de chumbo no sangue na infância ajustados para fatores de confusão. A, Regressão linear multivariada de ativação cerebral no giro frontal inferior esquerdo (ROi_ 1) versus níveis de chumbo no sangue na infância ajustados para fatores de confusão . R = -0 .328 parcial ; P = .039. B, Regressão linear multivariada da ativação cerebral no giro temporal médio direito (ROl_2) versus níveis sanguíneos de chumbo na infância ajustado para fatores de confusão . Atividade compensatória de regiões contralaterais 29 Existem hoje fortes evidências de que a exposição pré-natal ao tabaco está associada ao desenvolvimento de TDAH em crianças cujas mães fumaram ou foram expostas ao tabaco por tabagismo passivo dentro de casa. Este estudo é um exemplo disto. Ref: •Braun J et al. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environmental Health Perspectives, 2006, 114(12):1904-1909. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO E FATORES DE RISCO AMBIENTAIS Risco de TDAH em crianças americanas de 4 a 15 anos expostas ao tabaco durante a fase pré-natal. NHANES 1999- 2002 3 o 2.5 "Cl ro 2 iií :, ·ro 1.5 o ~ 1 a:: 1 1 "' 0.5 "Cl "Cl o o Não expostos Expostos Braun J . Envíron Health Perspe ct. 2006;114(12):1904-1909. ADHD : Attention Deficit Hyperactive Disorder 30 Crianças expostas ao mercúrio devido à dieta materna rica em peixe contaminado com mercúrio podem apresentar baixo QI, problemas de aprendizado e comportamento. O mercúrio com suas propriedades neurotóxicas é identificado como um significativo fator de risco para desordens do desenvolvimento neurológico e do comportamento em crianças. Refs: •Grandjean P, et.al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotox Teratol. 1997, 19:417-428 •WHO. Children's exposure to mercury compounds. WHO, 2010. Available at www.who.int/ceh/publications - accessed June 2011. <<NOTA AO USUÁRIO: Para maiores informações, vide módulo sobre Mercúrio..>> CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO E FATORES DE RISCO AMBIENTAIS Mercúrio ❖ Crianças expostas ao mercúrio devido a grande consumo de peixe contaminado com mercúrio pelas mães podem apresentar baixo QI, problemas de aprendizado e de comportamento . ❖ O mercúrio é identificado como um importante fator de risco para desordens do desenvolvimento neurológico comportamental em crianças. Grandjean P. Neurotox Teratol . 1997;19:417-428 31 Refs: •Grandjean P et al. Cardiac autonomic activity in methylmercury neurotoxicity: 14-year follow-up of a Faroese birth cohort. J Pediatr. 2004, 144(2):169. •Grandjean P et al. Cognitive deficit in 7 year old children with prenatal exposure to methylmercury. Neurotoxicology and teratology. 1997, 19:417 A cohort of 1022 consecutive singleton births was generated during 1986-1987 in the Faroe Islands. Increased methylmercury exposure from maternal consumption of pilot whale meat was indicated by mercury concentrations in cord blood and maternal hair. At approximately 7 years of age, 917 of the children underwent detailed neurobehavioral examination. Neuropsychological tests included Finger Tapping; Hand-Eye Coordination; reaction time on a Continuous Performance Test; Wechsler Intelligence Scale for Children-Revised Digit Spans, Similarities, and Block Designs; Bender Visual Motor Gestalt Test; Boston Naming Test; and California Verbal Learning Test (Children). Clinical examination and neurophysiological testing did not reveal any clear-cut mercury-related abnormalities. However, mercury-related neuropsychological dysfunctions were most pronounced in the domains of language, attention, and memory, and to a lesser extent in visuospatial and motor functions. These associations remained after adjustment for covariates and after exclusion of children with maternal hair mercury concentrations above 10 microgram(s) (50 nmol/g). The effects on brain function associated with prenatal methylmercury exposure therefore appear widespread, and early dysfunction is detectable at exposure levels currently considered safe. •Grandjean P. Neurodevelopmental disorders. In: Children´s health and the environment: A review of evidence. Tamburlini G, von Ehrenstein O, Bertollini R. (eds). WHO, Rome, 2002. •Murata K et al. Delayed brainstem auditory evoked potential latencies in 14-year-old children exposed to methylmercury. J Pediatr, 2004, 144(2):177. To determine possible exposure-associated delays in auditory brainstem evoked potential latencies as an objective measure of neurobehavioral toxicity in 14-year-old children with developmental exposure to methylmercury (MeHg) from seafood. Prospective study of a birth cohort in the Faroe Islands, where 878 of eligible children (87%) were examined at age 14 years. Latencies of brainstem evoked potential peaks I, III, and V at 20 and 40 Hz constituted the outcome variables. Mercury concentrations were determined in cord blood and maternal hair, and in the child's hair at ages 7 and 14. Results: Latencies of peaks III and V increased by about 0.012 ms when the cord blood mercury concentration doubled. As seen at age 7 years, this effect appeared mainly within the I-III interpeak interval. Despite lower postnatal exposures, the child's hair mercury level at age 14 years was associated with prolonged III-V interpeak latencies. All benchmark dose results were similar to those obtained for dose-response relationships at age 7 years. Conclusions: The persistence of prolonged I-III interpeak intervals indicates that some neurotoxic effects from intrauterine MeHg exposure are irreversible. A change in vulnerability to MeHg toxicity is suggested by the apparent sensitivity of the peak III-V component to recent MeHg exposure. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO E FATORES DE RISCO AMBIENTAIS ❖ Coorte de 1022 crianças nascidas entre 1986-1987 ❖ Exposição das mães ao metilmercúrio: • Carne de Baleia-piloto - episódica, e potencialmente alta. ■ Consumo de peixe - contínuo , porém baixo. ❖ Disfunções neuropsicológicas (7 anos) • Linguagem • Atenção • Memória ❖ Disfunções neurofisiológicas (14 anos) • Atraso auditivo em potenciais evocados. Estudo das Ilhas Faroe Mercúrio • Diminuição na variabilidade autonômica da frequência cardíaca. ❖ Atribuído à exposição pré-natal 32 Refs: •Grandjean P. Neurodevelopmental disorders. In: Children´s health and the environment: A review of evidence. Tamburlini G, von Ehrenstein O, Bertollini R. (eds). WHO, Rome, 2002. “A large prospective study in the Seychelles has not revealed any clear adverse effects related to maternal hair mercury concentrations” •Myers GJ et al. Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study. Lancet, 2003, 361:1686 Exposure to methylmercury (MeHg) before birth can adversely affect children's neurodevelopment. The most common form of prenatal exposure is maternal fish consumption, but whether such exposure harms the fetus is unknown. We aimed to identify adverse neurodevelopmental effects in a fish-consuming population. We investigated 779 mother-infant pairs residing in the Republic of Seychelles. Mothers reported consuming fish on average 12 meals per week. Fish in Seychelles contain much the same concentrations of MeHg as commercial ocean fish elsewhere. Prenatal MeHg exposure was determined from maternal hair growing during pregnancy. We assessed neurocognitive, language, memory, motor, perceptual-motor, and behavioural functions in children at age 9 years. The association between prenatal MeHg exposure and the primary endpoints was investigated with multiple linear regression with adjustment for covariates that affect child development. Mean prenatal MeHg exposure was 6.9 parts per million (SD 4.5 ppm). Only two endpoints were associated with prenatal MeHg exposure. Increased exposure was associated with decreased performance in the grooved pegboard using the non-dominant hand in males and improved scores in the hyperactivity index of the Conner's teacher rating scale. Covariates affecting child development were appropriately associated with endpoints. Interpretation: These data do not support the hypothesis that there is a neurodevelopmental risk from prenatal MeHg exposure resulting solely from ocean fish consumption. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO E FATORES DE RISCO AMBIENTAIS ❖ Coorte de 779 pares mãe-filho Estudo Seychelles Mercúrio ❖ Exposição por grande ingesta materna de peixe . ❖ Aos 9 anos: teste neuropsicológico ❖ Riscos no desenvolvimento neurológico devido à exposição pré-natal de MeHg não foi encontrada . 33 Mulheres expostas durante a gravidez a pesticidas clorpirifós foram estudadas e identificadas como apresentando maior risco para gerar crianças com autismo e com Transtorno do Déficit de Atenção e Hiperatividade. Image based on: Rauh V et al. Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children. Pediatrics, 2006, 118(6):e1845-e1859 <<NOTA AO USUIÁRIO: Para maiores informações, vide módulo sobre pesticidas.>> CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSOS DO DESENVOLVIMENTO NEUROLÓGICO E FATORES DE RISCO AMBIENTAIS Efeitos da exposição pré-natal ao clorpirifós nos problemas comportamenta is em crianças de 3 anos de idade 8 o 6 "O m uí .2, 4 m .Q 1ií 2 e::: (/) "O é'3 o +--~-- TIO □ Baixo ■ Alto Based on Rauh V. Pediatrics. 2006 ;118(6) :e 1845-e1859 TIO: Transtorno invasivo do desenvolvimento TDAH : Transtorno do déficit de atenção e hiperatividade TDAH Clorpirifós 34 Bifenilpoliclorados (PCBs): Este estudo de coorte identifica que a exposição pré-natal aos PCBs é prejudicial para o funcionamento cognitivo em crianças pequenas. O estudo mostrou redução nos escores de escala verbal com altos níveis de PCB no sangue do cordão umbilical. Apesar da possibilidade dos PCBs estarem presentes no leite materno, estudos tem mostrado que essa exposição pós-natal é muito menos prejudicial do que a exposição intra-uterina pré-natal. A amamentação não deve ser interrompida. Ref: •Jacobson JL, Jacobson SW, Humphrey HEB. Effects of in utero exposure to polychlorinated biphenyls and related contaminants on cognitive functioning in young children. J of Paeds, 1990, 116:38-45 Because prenatal exposure to polychlorinated biphenyls (PCBs) and related contaminants has been associated with reduced birth weight, neonatal behavioral anomalies, and poorer recognition memory in infants born to women who have consumed Lake Michigan sports fish, 236 children, previously evaluated for PCB-related deficits in infancy, were assessed at 4 years of age. Prenatal exposure (indicated by umbilical cord serum PCB level) predicted poorer short-term memory function on both verbal and quantitative tests in a dose-dependent fashion. These effects cannot be attributed to a broad range of potential confounding variables, the impact of which was evaluated statistically. Although much larger quantities of PCBs are transferred postnatally via lactation than prenatally across the placenta, exposure from nursing was unrelated to cognitive performance. The data demonstrate the continuation of a toxic impact received in utero and observed initially during infancy on a dimension of cognitive functioning fundamental to learning. •WHO. Persistent organic pollutants: impact on child health. WHO, 2010. Available at www.who.int/ceh/publications - accessed June 2011. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSO DE NEURODESENVOLVIMENTO E FATORES DE RISCO AMBIENTAL Estudo de coorte identificando exposição pré-natal aos PCBs como prejudic iais para o funcionamento cognitivo em crianças pequenas. Redução nos escores de escala verbal com altos níveis de PCB no sangue do cordão umbilical. Apesar da possibil idade dos PCBs estarem presentes no leite materno , a amamentação não deve ser interrompida. Jacobson JL, 1990 Bifenilpoliclorados (PCBs) 35 <<NOTE TO USER: For more information see module on persistent organic pollutants.>> Este estudo canadense identificou a exposição ao manganês, principalmente da poluição do ar por manganês proveniente da gasolina contendo tricarbonil metilciclopentadienil manganês (MMT) e sugeriu uma ligação com déficit de atenção em crianças pequenas. Ref: •Takser L et al. Manganese, monoamine metabolite levels at birth, and child psychomotor development. NeuroToxicology, 2003, 24:667-674. Several studies have demonstrated neurobehavioral impairment related to manganese (Mn) exposure in the workplace. Exposure to high doses of manganese is associated with irreversible neurodegenerative disorders resembling idiopathic Parkinson disease. Although there is a risk of Mn accumulation in the foetus during pregnancy, little information exists about developmental effects of environmental low-level exposure in human. For this reason, we conducted a prospective epidemiological study in 247 healthy pregnant women and their babies to determine the long-term effect of in utero Mn levels on child’s psychomotor development. Concurrently, we examined the relationship between Mn tissue levels at delivery and foetal plasma monoamine metabolites. Of the newborns, 195 were examined at 9 months, 126 at 3 years and 100 at 6 years. At 9 months, the Brunet–Lézine scales were administered. The McCarthy scales of children’s abilities were used at 3 and 6 years. After adjustment for potential confounding co-factors (child’s gender, mother’s educational level), negative relationships were observed between cord blood Mn levels and several psychomotor sub-scales at age of 3 years: “attention” (partial r=−0.33, P<0.001), “non-verbal memory” (partial r=−0.28, P<0.01), and “hand skills” (partial r=−0.22, P<0.05). No significant relationships were observed between Mn measures at birth and the general psychomotor indices, Brunet–Lézine developmental quotient (DQ) at 9 months or McCarthy general cognitive index (GCI) at 3 and 6 years. Maternal blood Mn levels were negatively associated with foetal plasma HVA and 5-HIAA concentrations (adjusted for labour duration, child’s gender, and smoking during pregnancy), but the adjustment for monoamine levels at birth did not change the association between the Mn levels and the psychomotor scores. These results suggest that environmental Mn exposure in utero could affect early psychomotor development. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSO DE NEURODESENVOLVIMENTO E FATORES DE RISCO AMBIENTAL Manganês & déficit de atenção Estudo epidemiológico prospectivo canadense (n=247 gestantes e seus bebês) identificou exposição ao manganês, principalmente oriundo da poluição do ar contendo tricarbonil metilciclopentadienil de manganês (MMT) da gasolina, sugerindo uma ligação com déficit de atenção em crianças pequenas. Takser , 2003 36 Este estudo da Califórnia, EUA, sugere que pode haver uma associação entre metais, solventes e, possivelmente, do ar ambiente, em torno da residência de nascimento e desenvolvimento. Mais estudos são necessários para confirmação. Ref: •Windham GC et al. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay area. Environ Health Perspect, 2006, 114(9):1438-1444. Objective: To explore possible associations between autism spectrum disorders (ASD) and environmental exposures, we linked the California autism surveillance system to estimated hazardous air pollutant (HAP) concentrations compiled by the U.S. Environmental Protection Agency. Methods: Subjects included 284 children with ASD and 657 controls, born in 1994 in the San Francisco Bay area. We assigned exposure level by census tract of birth residence for 19 chemicals we identified as potential neurotoxicants, developmental toxicants, and/or endocrine disruptors from the 1996 HAPs database. Because concentrations of many of these were highly correlated, we combined the chemicals into mechanistic and structural groups, calculating summary index scores. We calculated ASD risk in the upper quartiles of these group scores or individual chemical concentrations compared with below the median, adjusting for demographic factors. Results: The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs), 1.1–2.1], but not for aromatic solvents. Adjusting for these three groups simultaneously led to decreased risks for the solvents and increased risk for metals (AORs for metals: fourth quartile = 1.7; 95% CI, 1.0–3.0; third quartile = 1.95; 95% CI, 1.2–3.1). The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride. Conclusions: Our results suggest a potential association between autism and estimated metal concentrations, and possibly solvents, in ambient air around the birth residence, requiring confirmation and more refined exposure assessment in future studies. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSO DE NEURODESENVOLVIMENTO E FATORES DE RISCO AMBIENTAL Uma potencial associação foi observada entre autismo e concentrações estimadas de metais, e, possivelmente, solventes , no ar ambiente em torno da residência de nascimento. Isso requer confirmação e avaliação mais refinada da exposição em estudos futuros. Windham GC, 2006 37 Na sequência dos acontecimentos do 11 de Setembro em Nova Iorque, EUA, tem-se estudado a relação entre a exposição pré-natal a hidrocarbonatos aromáticos policíclicos (HAPs) e o desenvolvimento cognitivo das crianças. Resultados mostram que exposição pré-natal a níveis recentemente encontrados tem implicações no desempenho escolar. Ref: •Perera FP et al. Effect of prenatal exposure to airborne polycyclic aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner-city children. Environ Health Perspect, 2006, 114(8):1287-1292. Our prospective cohort study of nonsmoking African-American and Dominican mothers and children in New York City is evaluating the role of prenatal exposure to urban pollutants, including polycyclic aromatic hydrocarbons (PAHs), environmental tobacco smoke (ETS), and pesticides, in the pathogenesis of neurobehavioral disorders. We used the Bayley Scales of Infant Development to evaluate the effects on child mental and psychomotor development of prenatal exposure to airborne PAHs monitored during pregnancy by personal air sampling. Behavioral development was assessed by the Child Behavior Checklist. We adjusted for potential confounders including sociodemographic factors and prenatal exposure to ETS and chlorpyrifos. Prenatal exposure to PAHs was not associated with psychomotor development index or behavioral problems. However, high prenatal exposure to PAHs (upper quartile) was associated with lower mental development index at age 3 [β= –5.69; 95% confidence interval (CI), –9.05 to –2.33; p < 0.01]. The odds of cognitive developmental delay were also significantly greater for children with high prenatal exposure (odds ratio = 2.89; 95% CI, 1.33 to 6.25; p = 0.01). General estimated equation analysis showed a significant age × PAH effect on mental development (p = 0.01), confirming the age-specific regression findings. Further adjustment for lead did not alter the relationships. There were no differences in effect sizes by ethnicity. The results require confirmation but suggest that environmental PAHs at levels recently encountered in New York CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSO DE NEURODESENVOLVIMENTO E FATORES DE RISCO AMBIENTAL Poluição do Ar A exposição pré-natal a hidrocarbonetos aromáticos policíclicos do ambiente em níveis encontrados no ar da cidade de Nova Iorque pode afetar o desenvolvimento cognitivo das crianças aos 3 anos de idade. Isto pode ter implicações para o desempenho escolar. Pe rera FP. Environ Heallh Perspect. 2006 ; 114(8):1287-1292 . 38 City air may adversely affect children’s cognitive development at 3 years of age, with implications for school performance. <<NOTE TO USER: For more information see modules on air pollution.>> Há evidências de que fatores dietéticos podem desempenhar um papel nas alterações comportamentais, intelectuais e do neurodesenvolvimento de crianças. Dietas com adequada quantidade de ácidos graxos ômega-3 e pouco corante artificial comestível e conservantes podem beneficiar o comportamento e o aprendizado das crianças. Crianças com Transtorno do Déficit de Atenção e Hiperatividade (TDAH), dislexia e autismo tem sido estudados e considerados benéficos a partir da reposição com ômega-3. A retirada de alimentos gordurosos e coloridos da dieta das crianças com TDAH pode beneficiar um pequeno grupo. Quando se lida com Alterações Comportamentais, Intelectuais e do neurodesenvolvimento das crianças, profissionais de saúde podem aconselhar uma dieta com ômega-3 suficiente e pobre em alimentos coloridos. Refs: •Bateman B et al. The effects of a double blind, placebo controlled, artificial food colourings and benzoate preservative challenge on hyperactivity in a general population sample of preschool children. Arch Dis Child, 2004, 89:506-511. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSO DE NEURODESENVOLVIMENTO E FATORES DE RISCO AMBIENTAL Dieta ❖ A reposição de ácidos graxos ômega-3 está ligada a melhora dos sintomas de déficit de atenção e hiperatividade, dislexia, autismo. ❖ Corantes artificiais em alimentos podem aumentar a hiperatividade em um subgrupo de crianças. Richardson AJ, 2006 McCann D, 2007 Schab DW, 2004 Bateman B, 2004 39 •McCann D et al. Food additives and hyperactive behaviour in 3 year old and 8/9 year old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet, 2007, 370:1560-1567. •Richardson AJ. Omega-3 fatty acids in ADHD and related neurodevelopmental disorders. Int Rev Psych, 2006, 18(2):155-172. •Schab DW, Trinh NH. Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blinded placebo-controlled trials. J Developmental & Behavioral Pediatrics, 2004, 25(6):423-434. A perda de 5 pontos no quociente de inteligência (QI) pode não afetar a capacidade de um indivíduo de viver uma vida produtiva. Mas, se essa perda é vivida por uma população inteira, as implicações para a sociedade podem ser profundas. Professor Bernard Weiss, um toxicologista comportamental da Universidade de Rochester, examinou o impacto social da aparentemente pequena diminuição na inteligência. Imagine uma população afetada de 260 milhões de pessoas (como nos EUA), com uma média de QI de 100 e um desvio padrão de 15 (gráfico da esquerda). Nessa população, haveria 6 milhões de pessoas com QI acima de 130 e 6 milhões abaixo de 70. Uma diminuição na média de QI de 5 pontos mudaria a distribuição para a esquerda (gráfico da direita). O número de pessoas de pontuação acima de 130 cairia 3,6 milhões, enquanto o número pontuação abaixo de 70 aumentaria em 3,4 milhões. IQ: quociente de inteligência Gráfico adaptado de Schettler T. In Harm' s Way. Greater Boston Physicians for Social Responsibility, 2000. Usado com permissão. Ref: CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO PROCESSO DE NEURODESENVOLVIMENTO E FATORES DE RISCO AMBIENTAL meao9S Greater Bo.slon Physicians for Social Respon.sibility, 2000 40 •Schettler T et al. In Harm' s Way. Greater Boston Physicians for Social Responsibility (GBPSR), 2000. Para focar especificamente sobre os custos da exposição do feto ao mercúrio liberado por usinas de energia movidas a carvão nos EUA, os cientistas examinaram o impacto de 41% de emissões antropogênicas norte-americanas de mercúrio atribuíveis a esses recursos. Eles estimam que o custo atribuído à exposição ao metilmercúrio nos EUA, a partir das instalações de geração elétrica para o desenvolvimento do feto, é de $ 1,3 bilhão. Aplicando uma análise de sensibilidade neste modelo, encontra-se que o verdadeiro custo da exposição ao metilmercúrio de instalações de geração elétrica dos EUA para a coorte de nascimento varia de $ 0.1 a 6.5 bilhões dólares americanos / ano. Mais uma vez, a principal fonte destes custos é a perda de rendimentos ao longo da vida. Ref: •Trasande L, Schechter C, Landrigan PJ. Public health and economic consequences of environmental methyl mercury toxicity to the developing brain. Environ Health Perspect, 2005, 113:590-596. Methyl mercury is a developmental neurotoxicant. Exposure results principally from consumption by pregnant women of seafood contaminated by mercury from anthropogenic (70%) and natural (30%) sources. Throughout the 1990s, the U.S. Environmental Protection Agency (EPA) made steady progress in reducing mercury emissions from anthropogenic sources, especially from power plants, which account for 41% of anthropogenic emissions. However, the U.S. EPA recently proposed to slow this progress, citing high costs of pollution abatement. To put into perspective the costs of controlling emissions from American power plants, we have estimated the economic costs of methyl mercury toxicity attributable to mercury from these plants. We used an environmentally attributable fraction model and limited our analysis to the neurodevelopmental impacts--specifically loss of CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO DESAFIOS E IMPACTOS DAS ALTERAÇÕES COMPORTAMENTAIS, INTELECTUAIS E DO NEURODESENVOLVIMENTO Cost of American anthropoge nic emissions : SO. 15.8 blllion Portions of cost of methyl mercury expo- sure attributed to sources . Assumpt ions: 18- 36% attributable to American sources; 41 % of American emissions attributable to American power plants. Saúde pública e consequências econôm icas da toxicidade do metilmercúrio para o cérebro em desenvolvimento Trasande L, Landrigan PJ, Schechte r C . Envíron Health Perspectives , 2005, 113(5) :590 -596 . 41 intelligence. Using national blood mercury prevalence data from the Centers for Disease Control and Prevention, we found that between 316,588 and 637,233 children each year have cord blood mercury levels > 5.8 microg/L, a level associated with loss of IQ. The resulting loss of intelligence causes diminished economic productivity that persists over the entire lifetime of these children. This lost productivity is the major cost of methyl mercury toxicity, and it amounts to $8.7 billion annually (range, $2.2-43.8 billion; all costs are in 2000 US$). Of this total, $1.3 billion (range, $0.1-6.5 billion) each year is attributable to mercury emissions from American power plants. This significant toll threatens the economic health and security of the United States and should be considered in the debate on mercury pollution controls. Aproximadamente 300 grandes volumes de produtos químicos industriais com propriedades neurotóxicas são emitidos para o ambiente com efeitos neurotóxicos conhecidos em adultos, bem como efeitos neurotóxicos conhecidos em animais de laboratório. Os pesquisadores levantaram a questão de saber se cada uma destas substâncias deve ser testada de forma adequada para efeitos no desenvolvimento neurológico em crianças ou se as políticas de proteção podem ser instituídas na ausência de uma ciência detalhada como a que temos atualmente para o chumbo, entre outros. Muito poucos neurotoxicos ambientais tem sido estudados para identificar potenciais efeitos nocivos sobre transtornos de neurodesenvolvimento comportamental Intelectual em fetos e crianças pequenas. Métodos de avaliação de riscos de produtos químicos liberados no meio ambiente não são suficientes para proteger as crianças de transtornos de neurodesenvolvimento comportamental intelectual. Estamos identificando um número crescente de produtos químicos ambientais que contribuem para transtornos de neurodesenvolvimento comportamental intelectual que são CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO DESAFIOS À ABORDAGEM DAS DESORDENS DO NEURODESENVOLVIMENTO Exposições ambientais potencialmente neurotóxicas ► Efeitos neurotóxicos conhecidos em adultos ► 300 produtos químicos industriais são emitidos em grandes volumes no ambiente ► Efeitos neurotóxicos conhecidos em animais de laboratório Emissões químicas com potencial de dano ao neurodesenvolvimento ► Produtos tóxicos ligados a retardo no crescimento intrauterino ► Produtos tóxicos de baixo peso molecular , baixa ligação proteica , afinidade lipídica , nenhuma polaridade Grandjean P, 2006 42 danosos ao feto e à criança pequena. Os pesquisadores precisam fazer a pergunta "quais os produtos químicos que precisamos estudar?". Muitos produtos químicos podem ter efeitos neurotóxicos diretos ou efeitos indiretos, contribuindo para a causalidade de outros fatores de risco de transtornos de neurodesenvolvimento comportamental intelectual, como por exemplo, baixo peso ao nascer. Refs: •Dietrich K et al. Principles and practices of neurodevelopmental assessment in children: Lessons learned from the centers for children's environmental health and disease prevention research. Environ Health Perspect, 2005, 113(10):1437-1446. •Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. The Lancet, 2006, 368:2167-2178. Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals. Ref: Bjoling-Poulsen M, Andersen HR, Grandjean P. Potential developmental neurotoxicity of pesticides used in Europe. Environ Health, 2008, 7:50. Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO DESAFIOS À ABORDAGEM DAS DESORDENS DO NEURODESENVOLVIMENTO Prevenção da exposição a pesticidas neurotóxicos ► Muitos pesticidas atingem o sistema nervoso dos insetos. ► Tem-se levantado preocupações de que o cérebro em desenvolvimento possa ser particularmente vulnerável aos efeitos adversos dos pesticidas neurotóxicos. Bjoling-Poulsen M, 2008 43 Canadá, México e os EUA mantem registro de emissões tóxicas industriais. Estas incluem uma série de neurotoxinas. Indústrias que atendam a exigências de notificação são obrigadas a apresentar uma estimativa de lançamentos anuais. Este é um mapa que identifica a localização gerada pelo Google (longitude e latitude) de instalações industriais que participam desses registros. Esses dados são disponibilizados ao público a partir de www.cec.org/ - acessado em 15 de Junho de 2011. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO DESAFIOS À ABORDAGEM DAS DESORDENS DO NEURODESENVOLVIMENTO Instalações que notificam emissões Registro Nacional de Emissão de Poluente Registro de Emissão de Produtos Tóxicos Registro de Emissão e Transferência de Contaminantes 44 A Comissão para a Cooperação Ambiental, que é um ramo ambiental do Acordo de Livre Comércio da América do Norte (NAFTA) produziu este mapa a partir de registros de emissões nacionais demonstrando visivelmente fontes de emissão de mercúrio na América do Norte. Registros dessa natureza demonstrados em mapas conscientizam as comunidades sobre as fontes de emissões potencialmente prejudiciais. Esta informação pode ser usada para a educação, conscientização e políticas de proteção, bem como para pesquisas em andamento por cientistas. Imagem de www.cec.org/ - acessado em 15 de Junho de 2011. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO DESAFIOS À ABORDAGEM DAS DESORDENS DO NEURODESENVOLVIMENTO www.cec.org/ ,,-. '"'·. . _, ~-. . ' 'i - ..> •• . - ·. ! ' . l ·• , ' . . ,. . 45 O Programa Ambiental das Nações Unidas (UNEP) Parceria Global do Mercúrio é uma iniciativa voluntária onde entidades governamentais, não- governamentais, públicas e privadas concordam em trabalhar juntas e de forma sistemática para atingir a meta da Parceria. O objetivo geral é proteger a saúde humana e o meio ambiente global da liberação de mercúrio e seus compostos para minimizar e, se possível, em última análise eliminar a emissão antropogênica Global de mercúrio no ar, água e terra. Ref: •UNEP Global Mercury Partnership. Available at www.unep.org/hazardoussubstances/Mercury/tabid/434/language/en-US/Default.aspx – accessed 15 June 2011 CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO UNEP PARCERIA GLOBAL DO MERCÚRIO O objetivo geral é proteger a saúde humana e o meio ambiente global da liberação de mercúrio e seus compostos UNEP Parceria Global do mercúrio - www.chem .unep.ch/mercury UNEP: Programa Ambienta l das Nações Unidas 46 <<LER O SLIDE>> Mais informações sobre Aliança Global para a Eliminação da Tinta com Chumbo disponível em www.unep.org/hazardoussubstances/LeadCadmium/PrioritiesforAction/GAELP/tabid/6176/D efault.aspx – accessed 15 June 2011 CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO OMS/UNEP ALIANÇA GLOBAL PARA ELIMINAÇÃO DA TINTA COM CHUMBO Atividades chave para eliminação de tinta com chumbo a) Sensibilização sobre a toxicidade para a saúde humana e meio ambiente e dar alternativas ; (b) Orientação e assistência para identificar potencial exposição ao chumbo ; (c) Assistência à indústria (fabricantes, atacadistas e varejistas); (d) Programas de prevenção para reduzir a exposição ; (e) Promoção de marcos regulatórios nacionais. UNEP: Programa Ambienta l das Nações Unidas www. unep. orglhazardoussubslances/LeadCadmium/ PrioritíesforAction/GAE LP/ tabíd/6176/Defaufl .aspx •1 <<LER O SLIDE>> Refs: •Neira M et al. Environmental threats to children's health – a global problem. Int J Environment and Health, 2008, 2(3/4):276. •Pronczuk J, Bruné MN, Gore F. Children’s environmental health in developing countries. In: Encyclopedia of Environmental Health. Nriagu J, ed. Elsevier, 2011. CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO DESAFIOS À ABORDAGEM DAS DESORDENS DO NEURODESENVOLVIMENTO Desordens no neurodesenvolvimento são amplamente evitáveis. Os países podem desenvolver: ❖ Maior vig ilância ■ Acesso aos dados ambientais ❖ Adequadas intervenções em saúde pública ■ Base de dados de saúde relevantes , identificação e ação sobre todos os fatores de risco ❖ Plano de pesquisa coordenado ■ Ecologia , ciência básica , epidem iológica e qualitat iva ❖ Avaliação de risco adequado, gerenciamento e comunicação ❖ Estratégias nacionais , regionais e globais. <<LER O SLIDE>> CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO SUMÁRIO 1. Alterações comportamentais, intelectuais e do neurodesenvolvimento são comuns em países industrializados . 2. O processo de neurodesenvolvimento é um processo vulnerável , muito complexo e delicado. E é afetado por muitos fatores genéticos e ambientais. 3. Desordens do desenvolvimento neurológico comportamental intelectual carregam um enorme impacto econômico e emocional nas sociedades . 4. Exposição a substâncias químicas ambientais com potencial para contribuir para perturbações do desenvolvimento neurológico comportamental intelectual são pouco compreendidos. 5. Desordens do desenvolvimento neurológico comportamental intelectual são em grande parte evitáveis por meio de um plano coordenado para identificar e atenuar os fatores de risco relevantes 49 CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO AGRADECIMENTOS OMS é grata ao Departamento de Proteção da Saúde da Criança da APA - NU pelo suporte financeiro que tomou esse projeto possível e por alguns dados , gráficos e textos usados na preparação desse material para um público amplo . Um apoio adicional foi gentilmente cedido pelo Departamento de Saúde do Reino Unido. Primeiro esboço preparado por Dr. lrena Buka (Canadá) Com as recomendações dos Membros do Grupo de Trabalho no Pacote de Treinamento do Setor de Saúde : Dra. Cristina Alonzo MD (Uruguai); Dr. Vona Amitai MD MPH (Israel); Dr. Stephan Boese-O'Reilly MD MPH (Alemanha); Dra. Stephania Borgo MD (ISDE, Itália); Dra. lrena Buka MD (Canadá); Dr. Ernesto Burgio (ISDE, Itália); Ora. Lilian Corra MD (Argentina); Dra. Ligia Fruchtengarten MD (Brasil); Dra. Amalia Laborde MD (Uruguai); Dr. Jenny Pronczuk MD (OMS) Dr. Christian Schweizer TO (OMS/EURO); Dra. Kathy Shea MD (EUA). Revisores: Dr Huw Brunt (RU), Prof Gary Coleman (RU), Dr Raquel Duarte- Davidson (RU), Dr Elaine Lynch Farmery (RU), Ahson M Good BSc Dip Med Tox MSc (RU), Dr Mark Griffiths (RU), Dr John Thompson (RU), Dr Laura Yates (RU) OMS Coordenação do Projeto: Última atualização: Outubro de 2011 Ruth A. Etzel, MD PhD Marie-Noel Bruné, MSc 50 CRIANÇAS E Al TERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO AVISO LEGAL □ As designações empregadas e a apresentação do material nesta publicação não implicam a expressão de qualquer opin ião por parte da Organização Mundial da Saúde sobre a situação legal de qualquer pais, território , cidade ou área ou de suas autoridades , nem sobre a delim itação de suas fronteiras ou limites . As linhas pontilhadas nos mapas representam fronte iras aproximadas sobre as quais pode ainda não existir acordo completo . □ A menção de empresas específicas ou de certos produtos não implica que eles sejam endossados ou recomendados pela Organização Mundial da Saúde em detrimento de outros de natureza similar que não sejam mencionados . Salvo erro ou omissões , os nomes de produtos patenteados são distingu idos por iniciais maiúsculas . □ As opiniões e conclusões expressas não representam necessariamente a posição oficial da Organização Mundial da saúde. □ Esta publicação está sendo distribuída sem qualquer tipo de garantia expressa ou implíc ita. Em nenhum caso a Organização Mundial da Saúde será responsável por quaisquer danos , incluindo danos gerais , espec iais, acidentais ou consequentes , decorrentes do uso desta publicação . □ O conteúdo deste módulo de formação é baseado em referênc ias disponíveis na literatura publicada a partir da última atualização . Os usuários são incentivados a pesquisar bancos de dados médicos padrão para atualização na ciência para questões de especial interesse ou sensibilidade em suas regiões e áreas de interesse específicos . □ Se os usuários deste módulo de treinamento acharem necessário fazer qualquer modificação (simplificação , adição ou supressão) para a apresentação , o adaptador deve ser responsável por todas as modificações feitas . A Organização Mundial da Saúde se isenta de qualquer responsabilidade pelas adaptações feitas por outros . Todas as modificações devem ser claramente distinguidas do material original da OMS . 51 CRIANÇAS E ALTERAÇÕES COMPORTAMENTAIS , INTELECTUAIS E DO NEURODESENVOLVIMENTO A tradução em português dos módulos foi realizada por: Ana Carolina Jordão Cuimbra , Ana Paula Jacobs, Andressa Baseggio , Bianca Boff Sandi, Cecília Buratti , Fernanda Chiaradia, Guilherme Foletto, Jéssica Betti , Marieli Grassi , Mayara Brito, Roberta Florian e Stephanie Schafer. (Universidade de Caxias do Sul / Brasil) Revisão e supervisão: Emerson Rodrigues da Silva, M.D., Ph.D. Coordenação do Center for Envíronmental Hazards to Children 's Health (CEHCH) , da Pontifícia Universidade Católica do Rio Grande do Sul/ Brasil: Renato Stein, M.D., Ph.D. 52