30/06/2011
Human biomonitoring: prenatal environmentalexposure to chemicals and effects on the newborn
Greet Schoeters
Unit Environment and Health Risk- VITO
University of Antwerp
30/06/2011 2© 2011, VITO NV
Outline
» Are current levels of environmental pollution associated with adversehealth effects on the newborns?
» Some examples
» Biomonitoring contributes to the weight of evidence
» Prospective birth cohorts
30/06/2011 3© 2011, VITO NV
Between 1953 and 1965 there were over a hundred adult men and women developing symptoms of central nervous system disorders such as ataxia, alterations in gait, tremors, altered sight and sensation. In 1955 in the Minamata Bay area of Kyushu, Japan, there was a large influx of cases of severe neurological disorders in newborn children. There were cases of cerebral palsy, some children were diplegic and others were tetraplegic. They were all mentally handicapped. Some villages had 6-12% of their newborns affected. Together, these disorders are now known as Congenital Minamata Syndrome. In 1959, it was found that methylmercury was being dumped into the bay by a plant of the Chisso Corporation.
Methyl mercurypoisoning in JapanCongenital Minamata Syndrome
30/06/2011 4© 2011, VITO NV
• lead crosses the placenta • miscarriages• premature birth• Stillbirth• low infant birth weight• retarded mental development
Reproductive Effects Of Lead
30/06/2011 5© 2011, VITO NV
Health outcomes in prenatally – exposed children to dioxins and PCBs
Dioxins: Seweso accident (1976)
PCBs: Yusho (Japan 1968) and Yucheng (Taiwan1978)
US (Michigan, North Carolina, Lake Oswego)- fish eaters
Sweden, Finland, The Netherlands,
Fetal PCB syndrome : altered dentition, altered skull calcification
Intrauterine growth retardation
Cognitive and Behavioral Impairment
Increased incidence of middle ear infections
Developmental Alterations Occurring at “High End” of Background population
30/06/2011 6© 2011, VITO NV
Organic Pollutants with hormone disruptingproperties
Endocrine disrupting
activity
Class Model compound
Thyroid hormone
PXR/CAR induction
Anti-androgenic
Brominated flame retardants PBDE-47, 99
HBCD
AhR binding
CYP1A induction
Anti-estrogenic
Dioxin-like compounds TCDD
PXR/CAR induction,
Thyroid hormone
Non dioxinlike PCBs PCB 153
Estrogenic
anti-androgenic
Organochlorine pesticides HCB, DDT
p,p’DDE
Peroxisome proliferator-
activated receptor (PPAR)
induction
Perfluorinated compounds PFOA, PFOS
PPAR induction Phthalates metabolites
30/06/2011 7© 2011, VITO NV
Comparison of potency of environmentalchemicals versus endogene hormones
Witters H. et al., Reproductive Toxicology 30 (2010), 60-72
30/06/2011 8© 2011, VITO NV
Exposure to environmental chemicals
» Transported, through air, water and migratory species, across international boundaries and deposited far from their place of release
» Resist degradation
» Bioaccumulate in terrestrial and aquatic ecosystems,
» Transfer through the food chain
» Inhalation of polluted air
» Ingestion of soil
» Ingestion of drinking water
» Consumer products – electronics, flame retardants, solvents, pesticides
» Personal care products
30/06/2011 9© 2011, VITO NV
Human biomonitoring: direct measurement in human tissues
air
soil
Consumer
products
biomarkers
of exposure
Environmental
monitoring
soil
water
dust
air
Preconception
Pregnancy
Birth
Post natal
exposure
Mothers / fathers
Blood
Urine
Hair
Mothers
Blood
Urine
Hair
Neonate
Cord blood
Placenta
meconium
Urine
Neonate
Breast milk
30/06/2011 10© 2011, VITO NV
Swedish mothers milk data
30/06/2011 11© 2011, VITO NV
A toxic environment early in life?
» Dozens of chemicals are detectable at measurable levels in humans and in many cases at higher levels in children –CDC surveys.
» exposure of the parents before conception
» Chemicals are transfered in the womb to the fetus via the placenta, the fetus is surrounded by a large number of chemicals.
» Chemicals are transferred to the neonate via breast milkwhich concentrates lipophylic compounds such as dioxins, PCBs,…
30/06/2011 12© 2011, VITO NV
Fetuses, infants and children are especiallyvulnerable to toxic chemical exposure
» Reduced ability to break down and excrete many chemicalscompared to adults
» Great vulnerability during windows of susceptibility in earlydevelopment
» More years of future life –i.e., many decades in whichconsequences of early exposures can become manifest
30/06/2011 13© 2011, VITO NV
Human biomonitoring: direct measurement in human tissues
air
soil
Consumer
products
biomarkers
of exposure
Environmental
monitoring
biomarkers
of effects
adverse
health effects
Birth weight
Growth
IQ
behaviour
puberty
Asthma
Cancer
soil
water
dust
air
Blood lead
Cotinine in urine
MeHg in hair
…
Hormone levels
DNA damage
Gene expression
Epigenetic changes
30/06/2011 14© 2011, VITO NV
Flemish human biomonitoring campaignEnvironmental healthMonitoring for action…2002-2006-2011Commissioned, financed , steered by the Ministry of the Flemish Community (Dept of Science, Public Health and Environment )
30/06/2011 15© 2011, VITO NV
1200 newborns
Sept 2002- Dec 2003
25 maternities + 2
stem cell banks
30 mL cord blood
1600 youngsters
Oct 2003- July 2004
42 schools
18 mL blood, 50 mL
urine
1600 adults
Sept 2004- June 2005
43 municipalities
35 mL blood, 50 mL
urine
30/06/2011 16© 2011, VITO NV
Birth cohorts in Flanders
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Asthma/allergy follow-up (N=150)Neurodevelopment follow-up (N=200)
0 1 2 3 4 5 6……12m……..2y……………………3y….……4y…5y…6y…7y…8y
Questionnaire: growth, diet, pets,
diseases, allergy symptoms, hygiene, indoor
Gut flora (faeces: 3wk, 6m, 12m)
Exhaled breath:
•condensate proteins
•Gas phase VOC
8-oxodG urine
eNO
SPT
Interpolated outdoor air conc.
NO2, PM10
Questionnaire:growth,diet, pets,
diseases, allergy
symptoms, hygiene,
swimming, indoor
Cord bloodPb, Cd, PCBs,
dioxin-like compounds
TSH, fT3, fT4
Questionnaire:
behaviour child,
emotional status mother,
life-events
Cognitive and
behavioural tests
child, IQ-test mother,
Observation Home
Environment (HOME),
cortisol
weight
circumfe-
rence,
fat/fat free
mass
(impedance),
arm/back
fold…
30/06/2011 18© 2011, VITO NV
Birth weight declined by 150g per 1µg/L increase in PCB 153 cord serum concentration
ENvironmental health RIsks in European birth COhorts:
OBesogenic Endocrine disrupting chemicals: LInking prenatal
eXposure to the development of obesity later in life
30/06/2011 19© 2011, VITO NV
Conclusion
» Birth weight declined by 150g per 1µg/L increase in PCB 153 cord serum concentration
» No statistically significant effect for p,p’-DDE
» The magnitude of effect is equivalent to that reported for cigarette smoking (~ 55–189 g reduction) (Dejmek et al. 2002).
30/06/2011 20© 2011, VITO NV
pollutants in the perinatal period of life
child’s health
A. Biometry ( lenghth , weight): at birth, 1-3y
B. Thyroid hormone levels at birth
C. Neurobehavioral & cognitive development 0-3y (led by Dr Viaene- OPZ)
D. Respiratory health 0-3y ( led by Dr. Desager-UA)
↕
30/06/2011 21© 2011, VITO NV
Negative relation between POPs and thyroid hormones measured in cord blood
Multiple linear regression model /contaminant , 200 participantsadjusted for plasma total lipids, gestational age, gender, alcohol consumption during pregnancy, and age of the
mother. MAERVOET et al, , Environmental Health Perspectives (2007)
ln fT3 (pmol/L) ln fT4 (pmol/L) ln TSH (mIU/L)β p n β p n β p n
Polychlorinated biphenyls
∑ 5 PCBs (ng/ml) -0.198 0.01 195 -0.345 < 0.001 196 -0.055 0.50 196
Organochlorinated pesticides
HCB (ng/ml) -0.154 0.03 195 -0.287 < 0.001 196 -0.061 0.42 196
p,p´-DDE (ng/ml) -0.074 0.29 195 -0.146 0.04 196 -0.048 0.51 196
Dioxin-like compounds
Calux-TEQ (pg/ml) -0.154 0.04 138 -0.165 0.04 138 -0.018 0.83 138
Heavy Metals
Cadmium (ng/ml) -0.084 0.23 186 -0.041 0.58 187 -0.035 0.63 187
Lead (ng/ml) -0.100 0.15 186 0.064 0.37 187 0.041 0.57 187
30/06/2011 22© 2011, VITO NV
Free thyroxin vs concentration of sum marker PCB’s in cord blood
Clinically irrelevant? (Kimbrough and Krouskas, 2001)
Very subtible changes in T4/TSH homeostasis may affect development of human fetus
(Boas et al., 2006; Zöller, 2001)
30/06/2011 23© 2011, VITO NV
Neurological behaviour follow-up
Cord blood(Pb, Cd, PCB’s, dioxins,TSH,FT3, FT4),nutrition,
covariates
12 24
monthly quesionnaire on food & development
3-monthly “ “ “
Info on pregnancyPostnatal depression
Behaviour child,emotional status mother,
life-events
Cognitive andBehavioural tests
child, IQ-test mother,Observation Home
Environment,Cortisol
36 months 0 1
30/06/2011 24© 2011, VITO NV
Prenatal exposures and health outcomes: methylmercury in maternal hairFish intake : Faroe island cohort
Grandjean , Weihe
30/06/2011 25© 2011, VITO NV
Prenatal exposures: a wide range of effectswith life long consequences
» Wide range of health effects
» Body energy levels
» Growth and development
» Immune effects
» Internal balance of body systems, or homeostasis
» Persistence of biological effects
» Response to low dose matters chemical analytical challenges?
large populations needed
» Combination of doses effective biomarkers of combined internal dose?
30/06/2011 26© 2011, VITO NV
Mechanisms of late effects?
» hormone levels,
» oxidative stress
» epigenetic changes?
mechanistic
early warning
30/06/2011 27© 2011, VITO NV
Control of Persistent Pollutants: Global POPsConvention (Stockholm Convention on Persistent Organic Pollutants)
Covers the “dirty dozen” POPs chemicals and pesticides + 9 chemicalsrecently added
» Such pollutants move around the globe; once they have entered the environment; you can’t just turn off the tap.
» Chemicals included are: the pesticides aldrin, chlordane, DDT, dieldrin, endrin, heptachlor, mirex, toxaphene, and hexachlorobenzene; the industrial chemicals PCB’s; dioxins and furans,
» Recently added: alpha hexachlorocyclohexane; betahexachlorocyclohexane; chlordecone; hexabromobiphenyl; hexabromodiphenyl ether and heptabromodiphenyl ether (commercial octabromodiphenyl ether); lindane; pentachlorobenzene; perfluorooctanesulfonic acid, its salts and perfluorooactane sulfonyl fluoride; tetrabromodiphenyl ether and pentabromodiphenyl ether (commercial pentabromodiphenyl ether).
30/06/2011 28© 2011, VITO NV
The tip of the iceberg?
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