46 DNT Japan Tsuji

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Ryozo Tsuji, DVM., PhD. Sumitomo Chemical Co., Ltd Environmental Health Science Laboratory DNT in Japan: Past, Present and Future Osaka, JAPAN

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Neurotoxicity incidents in Japan : DNT related incidents

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DNT in Hiroshima/ Nagasaki A woman with microcephaly and her mother In-utero survivors, close to the epicenter, were exposed to radiation and born with microencephaly. The Spirit of Hiroshima (1999) (1945) Radiation from atomic bomb induced DNT Nagasaki Hiroshima Microencephaly is often accompanied by mental retardation Threshold of deterministic effects of irradiation in utero by International Commission on Radiological Protection in 1990

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Minamata disease Methyl mercury induced Minamata Disease (1956 - ) Sensory disturbance Constriction of the visual field Coordination disturbance Dysarthria Hearing disturbance Tremor Clinical symptoms: Patients: 12,615 Minamata Minamata Disease Archives

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Fetal Minamata disease DNT patients: 16 (>64) Children, born of women who ate polluted fish, developed Fetal Minamata disease. They suffered with more serious symptoms than their mothers. S. Kuwahara, 1998 Mental Retardation Primitive reflex Coordination disturbance Dysarthria Limb deformation Growth disorder Choreoathetosis Hyper salivation Clinical symptoms:

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Second Minamata disease (1965 - ) Second Minamata disease occurred in Niigata. DNT patient: 1 Niigata Patients: 690 Nursing babies were given baby formula, instead of breast milk. Pregnant women with hair methylmercury levels of 50 ppm or more were advised to abort their babies.

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DNT by Morinaga dry milk (1955) A large number of babies were poisoned with arsenic accidentally mixed into dry milk products. DNT patients: 798 Proportion of disorder/symptoms in relief fund recipients Poisoned: 12,131 (Dead: 130) by Hikari Foundation(2003)

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DNT from cooking with rice bran oil (1968) Yusho oil disease was caused by ingestion of rice oil contaminated with PCBs and PCDFs. Patients: 1,871 (14,000) - acne-like eruptions - pigmentation of skin - eye discharge Babies, born of patients, had dark brown pigmented skin. They were also seen to be apathetic and had low IQs Cola Colored baby Bottled rice bran oil and its label

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DNT patients now Patient with fetal Minamata disease (Asahi News Paper on Jan 25, 2006) With aging of the patients, nursing care problems have become serious due to the deaths of parents, who previously cared for them. In 2005, the Government decided to establish new support measures for Fetal Minamata disease patients (about 80 patients) Nursing care by their family Demand for Social support system

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18 of 33 residents drinking water from a well showed acute arsenic poisoning DNT from arsenic compound in well water Who did it? and why? However, drink cans made in 1990 were discovered from the mass. A child exhibited mental retardation Cans from Concrete mass (2003) Decomposed chemical weapon made during World War II ? Truth lies at the bottom of the well High concentration of diphenylarsine was detected - in the well water - in a concrete mass found in the ground nearby

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Survey of teachers Difficulties in learning or behavior without mental retardation (6.3%) Difficulty in both learning and behavior (1.2%) by MEXT 2003 (Ministry of Education, Culture, Sports, Science and Technology)

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Increasing concern for physical and mental health of children - LD (learning disorder) - ADHD (attention-deficit hyperactivity disorder) - Autism - Bullying - Refusal to go to school - Social withdrawal - Suicide - Assault/murder cases by children - Chemical sensitivity

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Changes in society Education / Discipline Electronic games / TV Shortened sleeping time Foods/ Nutrition Chemical substances Potential causes of abnormal behavior in children Researchers have proposed various hypotheses

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Endocrine disrupters Endocrine disrupters have been big social problems. Genitalia Brain, CNS Our stolen future (Japanese edition) The target is shifting to the brain from genitalia, because hormones are essential to brain development Research subjects

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Smoking during pregnancy can be a cause of developmental disorders of fetus and premature delivery. In pregnant smokers, risks of low birth weights and premature delivery are epidemiologically estimated to be about two and three times higher than in pregnant non-smokers. Warning to smokers Since 2005, cautions have to be shown on 2 major sides of cigarette packages, using at least 30% of the area of each side. Adverse effects of Cigarettes

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Warning to drinkers Since 2005, cautions have been shown on beer bottles and cans. Adverse effects of Ethanol Drinking during pregnancy can be a cause of developmental disorders of fetus and premature delivery.

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Neurotoxicity study guidelines (for chemicals and pesticides) GL:Guideline, EPA: Environmental Protection Agency, TOSCA: Toxic Substances Control Act, FIFRA: Federal Insecticide, Fungicide and Rodenticide Act, NRC: National Research Council, FQPA: Food Quality Protection Act, OECD: Organization for Economic Co-operation and Development, MAFF: Ministry of Health, Labor and Welfare Japan follows after EPA and OECD

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Acceptable limit of methylmercury intake TWI (μg/kg/week) FAO/WHO UK AUS/NZ Japan -2005 2005.6- EPA 2001 3.3 3.3 3.4 3.4 1.6 1.6 2.0 0.7 3.4 0.7

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In terms of tuna sushi… FAO/WHO UK, AUS/NZ Japan USA For an adult, For a pregnant woman (including potentially pregnant) 2.6 2.7 0.6 1.6 1.3 0.6 Acceptable intake per day Modified from : KUMAMOTO UNIVERSITY LIBRARY(2005)

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Recent DNT study in Japan By Masuo & Ishido Intracisternal administration PND 5: 4-5 week: Motor Activity (8 week: DNA chip array) For chemicals which induce hyperkinetic disorder In vivo screening system for DNT Motor activity in dark and light phase Regulatory Peptides 123, 225-234, 2004

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In vitro screening system for DNT Spontaneous calcium oscillations and synapse Effect of thyroid hormones on synapse formation Folia Pharmacol.Jpn. 124, 11-17 2004 By Kuroda’s group

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Group: PTU(Propylthiouracil) at 0.4, 1, 2.5 mg/kg and control （0.5%MC), N=11 Administration: Oral administration to dams from GD 18 to postpartum day 21, 5mL/kg Dams Motor activity（M） Acoustic startle response（S） E-maze learning （W） Gene expression (G) Study schedule: 0 18 21/0 21 28day Administration M M S W G M S 0 4 14 16 21 22 28 63 70day Pups W G Gestation Parturition Weaning Postpartum G G DNT guideline validation study By Sumitomo Chemical We conducted a small-scale DNT study + Extra testing Correlations between behavioral changes and genes expression

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Results: DNT study with PTU ASR: acoustic startle response

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mRNA levels (PND22) Meaning of gene changes ? BDNF GAP-43 Cell body Dendrite Axon Synaptophisin PSD95 Synapse NCAM M1 NR2B L1 Genes Related to Development or Learning 　Cerebral cortex Hippocampus　 　Cerebral cortex Hippocampus　

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M1 GAP-43 Evaluation of mRNA levels in developing brain To obtain data on developmental changes is important. More information about gene changes DNA chip study Postnatal Day GAP-43 Cerebral Cortex Hippocampus

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Projects have been started More than 15 studies For example,

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Elucidation of disorder of mental development in children Scheduled to be established in 2006 Elucidation of mental mechanism of developmental disorder (Autism, LD etc ) from gene changes (Osaka University) Development of effective therapy (Hamamatsu University School of Medical) Japan Children’s Study Cohort Study in Japan like the “National Children study” in USA To examine what factors affect children’s mental development in their daily lives (e.g. parent-child relationship, electronic game, internet etc., ) Following new born babies and 5-year-old infants for 5 years

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Summary Many DNT incidents happened. e.g. Minamata disease, Arsenic in Milk, PCBs inRice Oil etc. DNT in Japan: Past, Present and Future DNT patients are in old age. Concern for physical and mental health of children is increasing. (ADHD, LD, Autism, Bullying, Injury cases, etc. ) Registration: Japan follows EPA and OECD guideline DNT research and related projects are greatly anticipated.

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Thank you for your attention.