tel aviv pg neuro

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