Ryozo Tsuji, DVM', PhD'

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DNT in Japan Past, Present and Future
Ryozo Tsuji, DVM., PhD.
Sumitomo Chemical Co., Ltd Environmental Health
Science Laboratory
Osaka, JAPAN
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Neurotoxicity incidents in Japan
DNT related incidents
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DNT in Hiroshima/ Nagasaki
(1945)
Radiation from atomic bomb induced DNT
Hiroshima
In-utero survivors, close to the epicenter, were
exposed to radiation and born with
microencephaly.
Nagasaki
A woman with microcephaly and her mother
Microencephaly is often accompanied by mental
retardation
Threshold of deterministic effects of
irradiation in utero
by International Commission on Radiological
Protection in 1990
The Spirit of Hiroshima (1999)
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Minamata disease
(1956 - )
Methyl mercury induced Minamata Disease
Clinical symptoms
Patients
Minamata
Sensory disturbance Constriction of the visual
field Coordination disturbance Dysarthria Hearing
disturbance Tremor
12,615
Minamata Disease Archives
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Fetal Minamata disease
Children, born of women who ate polluted fish,
developed Fetal Minamata disease.
They suffered with more serious symptoms than
their mothers.
DNT patients 16 (gt64)
Clinical symptoms
Mental Retardation Primitive reflex Coordination
disturbance Dysarthria Limb deformation Growth
disorder Choreoathetosis Hyper salivation
S. Kuwahara, 1998
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Second Minamata disease
(1965 - )
Second Minamata disease occurred in Niigata.
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.
DNT patient 1
7
(1955)
DNT by Morinaga dry milk
A large number of babies were poisoned with
arsenic accidentally mixed into dry milk
products.
Proportion of disorder/symptoms in relief fund
recipients
by Hikari Foundation(2003)
Poisoned 12,131 (Dead 130)
DNT patients 798
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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
Bottled rice bran oil and its label
Babies, born of patients, had dark brown
pigmented skin.
They were also seen to be apathetic and had low
IQs
Cola Colored baby
("?????????"??)
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DNT patients now
With aging of the patients, nursing care problems
have become serious due to the deaths of parents,
who previously cared for them.
Nursing care by their family Demand for Social
support system
In 2005, the Government decided to establish new
support measures for Fetal Minamata disease
patients (about 80 patients)
Patient with fetal Minamata disease (Asahi News
Paper on Jan 25, 2006)
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(2003)
DNT from arsenic compound in well water
18 of 33 residents drinking water from a well
showed acute arsenic poisoning
A child exhibited mental retardation
High concentration of diphenylarsine was detected
- in the well water - in a concrete mass
found in the ground nearby
Decomposed chemical weapon made during World War
II ?
However, drink cans made in 1990 were discovered
from the mass.
Who did it? and why?
Cans from Concrete mass
Truth lies at the bottom of the well
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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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Potential causes of abnormal behavior in children
Researchers have proposed various hypotheses
Changes in society Education / Discipline Electron
ic games / TV Shortened sleeping time Foods/
Nutrition Chemical substances
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Endocrine disrupters
Endocrine disrupters have been big social
problems.
The target is shifting to the brain from
genitalia, because hormones are essential to
brain development
Research subjects
Genitalia Brain, CNS
Our stolen future (Japanese edition)
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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
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.
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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)
Japan follows after EPA and OECD
GLGuideline, 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
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Acceptable limit of methylmercury intake
3.4
3.4
3.4
3.3
3.3
TWI (µg/kg/week)
2.0
1.6
1.6
0.7
0.7
FAO/WHO
Japan -2005 2005.6-
EPA 2001
UK AUS/NZ
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In terms of tuna sushi
Acceptable intake per day
For an adult,
2.6
2.7
0.6
For a pregnant woman (including potentially
pregnant)
1.6
1.3
0.6
FAO/WHO UK, AUS/NZ
Japan
USA
Modified from KUMAMOTO UNIVERSITY LIBRARY(2005)
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Recent DNT study in Japan
By Masuo Ishido
In vivo screening system for DNT
For chemicals which induce hyperkinetic disorder
Motor activity in dark and light phase
PND 5
Intracisternal administration
4-5 week Motor Activity
(8 week DNA chip array)
Regulatory Peptides 123, 225-234, 2004
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In vitro screening system for DNT
By Kurodas group
Spontaneous calcium oscillations and synapse
Effect of thyroid hormones on synapse formation
Folia Pharmacol.Jpn. 124, 11-17 2004
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DNT guideline validation study
By Sumitomo Chemical
We conducted a small-scale DNT study Extra
testing
Correlations between behavioral changes and genes
expression
Group PTU(Propylthiouracil) at 0.4, 1, 2.5 mg/kg
and control (0.5MC), N11 Administration Oral
administration to dams from GD 18 to postpartum
day 21, 5mL/kg
Study schedule
Postpartum
Parturition
Weaning
Gestation
0 18 21/0
21 28day
Dams
Administration
0 4 14 16 21 22 28
63
70day
Pups
Motor activity(M) Acoustic startle
response(S) E-maze learning (W) Gene expression
(G)
M
M S
W G
M S
W G
G
G
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Results DNT study with PTU
ASR acoustic startle response
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mRNA levels (PND22)
Genes Related to Development or Learning
Dendrite
Cell body
Synaptophisin
NCAM
Cerebral cortex
Hippocampus
Synapse
PSD95
L1
BDNF
Axon
GAP-43
M1 NR2B
Cerebral cortex
Hippocampus
Meaning of gene changes ?
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Evaluation of mRNA levels in developing brain
GAP-43
GAP-43
Cerebral Cortex
Postnatal Day
M1
Hippocampus
To obtain data on developmental changes is
important.
More information about gene changes DNA
chip study
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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
Development of effective therapy (Hamamatsu
University School of Medical)
Elucidation of mental mechanism of developmental
disorder (Autism, LD etc ) from gene changes
(Osaka University)
Japan Childrens Study
Cohort Study in Japan like the National Children
study in USA
Following new born babies and 5-year-old infants
for 5 years
To examine what factors affect childrens mental
development in their daily lives (e.g.
parent-child relationship, electronic game,
internet etc., )
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DNT in Japan Past, Present and Future
Summary
Many DNT incidents happened. e.g. Minamata
disease, Arsenic in Milk, PCBs inRice Oil etc.
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.