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Philippe Grandjean, MD, DMSc (University of Southern Denmark and Harvard School of Public Health)
toxicants
Silent pandemic of developmental neurotoxicity:
New evidence
Neurotoxic effects are determined by:
1. the neurotoxicant2. the dose3. the timing in regard
to windows of vulnerabilityThe Faroes statement:www.pptox.dk
Learning from Minamata:
…in every case the mother was healthy, and it was not until more than three months after birth that the symptoms were recognized
Shoji Kitamura (1959)
Focal
Widespread
Diffuse
Early science warnings 20-60 years ago
1943 Byers & Lord reported mental sequelae in subjects surviving childhood lead poisoning
1963 Methylmercury causation of Minamata disease recognized
1968 Fetal alcohol syndrome first described
1979 Needleman reported dose-related CNS deficits in children with “background” lead exposure
1985 The Jacobsons reported cognitive deficits in children exposed to PCBs from Great Lakes
1986 New Zealand study reported negative cognitive effects of methylmercury from seafood
Declining threshold with time
From: In Harm’s Way, 2002
2000199019801970
0.01
0.1
1
10
100
YEAR
level associated with harmful effect
regulatory standard (maximum safe exposure or high
end exposure from allowed fish contamination)
severe retardation (newborns, Iraq,NOEL) [1&2]
delayed walking - (2 yr olds,Iraq) [3]
delayed development (2 yr olds,Iraq) [4]
FDA
abnormal reflexes (2 yr old boys,Quebec) [6]
decreased IQ (7 yr olds, New Zealand) [9]
ATSDR
EPA
delayed walking (2 yr olds, Iraq) [8]
developmental delays (4 yr olds, New Zealand)
[7] decreased activity (2 yr old males, Seychelles I.)[10]
ATSDR
delayed walking (2 yr olds,Iraq) [5]
DA
ILY
IN
TA
KE
(mic
rogr
ams/
kg/
day
Hg)
decreased attention,
memory, learning (7 yr olds, Faroe I.) [11]
IncreasedbloodPresure(Faroe I.)
DelayedBAEPPeak V (14yr oldsFaroe I.)
Lanphear et al., 2005
Developmentalneurotoxicantwith the mostsubstantialdocumentation:
Inorganic lead
How many human neurotoxicants?
(Grandjean & Landrigan, The Lancet, 2006)
• Net search at NLM Hazardous Substances Data Bank• Industrial chemicals only (no biological toxins or drugs)• Evidence from human poisoning cases or
epidemiological studies• Published in peer-reviewed literature
201 documented human neurotoxicants
• Pesticides (N = 90)
• Metals and inorganics (N = 25)
• Solvents (N = 43)
• Other industrial chemicals (N = 43)
~50% are HPV chemicals
Types of neurotoxic chemicals(N = 201)
Documented developmental neurotoxicants
• Lead• Methylmercury• PCBs• Arsenic • Toluene• Manganese (?)• OP pesticides (?)• Fluoride (?)
Grandjean & Landrigan, The Lancet, 2006
Challenges in assessing clinical manifestations of developmental toxicity
• Non-specific effects are sensitive to confounders
• Effects may depend on the exact time of exposure
• Effects may not be immediately apparent, because the organ system must mature to express relevant functions
• Influence of compensation / reversibility, reserve capacity, and unmasking
Child with fetal alcohol syndrome
Alcohol, Lead, Mercury, PCBs, PBDEs, Manganese, Arsenic, Solvents, PAHs, Pesticides, Nicotine and environmental tobacco smoke,Endocrine disruptors (?), Fluoride (?), Food additives (?)
http://www.iceh.org
OP pesticides can inhibit cholinesteraseor affect thyroid function (EBDTCs) with possible neurotoxic outcomes:- Acetylcholin is an important neurotransmitter, but also functions as ‘guidance substance’ for cell migration- Thyroid hormone is essential for normal brain development
Recent pesticide neurotoxicity studies
• Children exposed to methylparathion illegally used in Mississippi/Ohio had problems on tests for memory and attention, and the parents more often indicated that the child had behavioral problems (Ruckart PZ et al., EHP 2004; 112: 46-51)
• City children prenatally exposed to chlorpyrifos at home had a poorer Bayley score and a greater risk of delayed development at 36 months (Rauh VA et al., Pediatrics 2006; 118: 1845-59)
• Two-year-old Latino children from Californian farms showed delayed development and more frequent deficits at higher concentrations of dialkyl phosphates in maternal pregnancy urine (Eskenazi B et al., EHP 2007; 115: 792-8)
Guillette et al. EHP 1998; 106: 347-53.
Association between prenatal urine-DAPs and Brazelton abnormal reflexes in two US cohorts
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
All DAPs Dimethyls Diethyls
Poi
sson
Rat
io
Berkeley
Mt. Sinai
N=381
N=381
N=381
N=249
N=238
N=238
Tabacundo
There are 120 flower plantations In the Tapacundoarea.About 30belong to the local employers’organization.The workersare notunionized.
Most exposure is likely due to skin contact
Study design
• Cross-sectional examination of children attending 1st / 2nd grade of primary school
• Major public school in Tabacundo in the heart of the floriculture district
• Physical examination, neurobehavioral tests, and questionnaires
• Maternal exposure retrospectively assessed by questionnaire
100% of the school children participated in the study
Pediatrics 2006;117;546-56
Study 2 collaborators:
Raul Harari and IFA team
(Quito, Ecuador)
Katsuyuki Murata
(University of Akita, Japan)
Jordi Julvez and David
Bellinger (Harvard University)
Dana Barr (Centers for
Disease Control)
Frodi Debes (University of
Southern Denmark)
Multivariate analysis showed effect of prenatal pesticide exposure also on blood pressure
(Grandjean, Harari et al., 2006)
Study 2 results
Stanford-Binet Copying Test
ControlsPrenatalexposure
p
Copying score (Designs 13-20), β (SD)
1.0 (0.7) 0.47 (0.24) <0.05
Low number of Correct Recalls, OR (CI)
1.006.97
(1.08-45.10)<0.05
Also clear deficit on finger tapping (Harari et al., in prep.)
Uncertainties in studies of developmental neurotoxicity
• Exposure assessment - also prenatally
• Profile of exposure vs. development
• Maternal metabolism (e.g., paraoxonase)
• Age at outcome assessment
• Impact of compensation
• Long-term significance
• Covariates
Water-fluoride exposure on IQ deficits of Chinese children
Xiang et. al.2003,2005
Hu et al. 1989;Chen et al. 1991;Zhao et al. 1996;Wang et al. 2007
Lu et. al. 2000;Liu et al. 2000
Qin et. al. 1990
Li et. al.2004
Wang et. al. 2005
Li et al. 2003
Wang et al. 1996
Li et. al. 1994Guo et. al. 1991
Chen et al.1991
Hong et. al. 2001;Ren et al. 1989;Yang et al. 1994
Electromagnetic fields• Non-ionizing radiation causes thermal effects (other mechanisms are not documented)• Maternal hyperthermia can cause adverse effects on brain development • One recent study suggested increased risk of behavioral abnormalities in children whose mothers had used cell phones during pregnancy (Divan et al., 2008)
In an RCT, artificial colors or a sodium benzoate preservative (or both) in the diet resulted in behavioralchanges / hyperactivity in healthy non-selected3-year-old and 8/9-year-old children.
McCann et al., Lancet2007; 370:1560-1567
Food additives – RCT Sweets and soft drinks often contain artificial colorants, sodium benzoate is also often present in soft drinks. Hyperactive children may be hypersensitive to these substances.
Time of recognition
Neurotoxicant dose (inverted scale)
Num
ber
of s
ubje
cts
affe
cted
Silent pandemic
NeurotoxicityIn adults
Poisoning incidents
Subclinical effectsin child populations
Pb
MeHg
PCB Mn FluorideOP pesticides
Emerging paradigm: Time course of recognition
Other toxicants
Grandjean & Landrigan, The Lancet, 2006
Chemical universe N ~ 100,000
Current status of the documentation
Neurotoxic in lab tests N > 1,000
Neurotoxic to humans N > 200
Known neurotoxic to humans during development, N > 5
Dealing with the next wave of developmental neurotoxicants
• Screen chemicals for developmental neurotoxicity
• Identify and track human neurotoxicants • Document extent of human exposures• Record long-term consequences of
developmental neurotoxicity • Apply precautionary action to protect
against chemical brain drain
Only one chance to develop a brain