Human biomonitoring: prenatal environmental

exposure to chemicals and effects on the

newborn
30/06/2011

Greet Schoeters
Unit Environment and Health Risk- VITO
University of Antwerp
Outline

» Are current levels of environmental pollution associated with adverse

health effects on the newborns?
» Some examples
» Biomonitoring contributes to the weight of evidence
» Prospective birth cohorts

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Between 1953 and 1965 there were Methyl mercury
over a hundred adult men and
women developing symptoms of poisoning in Japan
central nervous system disorders such Congenital Minamata Syndrome
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.

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Reproductive Effects Of Lead
• lead crosses the placenta
• miscarriages
• premature birth
• Stillbirth
• low infant birth weight
• retarded mental development

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 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

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 Organic Pollutants with hormone disrupting
properties
Endocrine disrupting Class Model compound
activity

Thyroid hormone Brominated flame retardants PBDE-47, 99

PXR/CAR induction HBCD
Anti-androgenic
AhR binding Dioxin-like compounds TCDD
CYP1A induction
Anti-estrogenic
PXR/CAR induction, Non dioxinlike PCBs PCB 153
Thyroid hormone
Estrogenic Organochlorine pesticides HCB, DDT
anti-androgenic p,p’DDE
Peroxisome proliferator- Perfluorinated compounds PFOA, PFOS
activated receptor (PPAR)
induction
PPAR induction Phthalates metabolites

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Comparison of potency of environmental
chemicals versus endogene hormones

Witters H. et al., Reproductive Toxicology 30 (2010), 60-72

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 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

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 Human biomonitoring:
direct measurement in human tissues
Environmental biomarkers
monitoring of exposure

Preconception Mothers / fathers

Blood
air Urine
air
Hair

dust Pregnancy Mothers

Blood
Consumer Urine
products Hair
Neonate
Birth
water Cord blood
Placenta
soil meconium
soil Urine
Post natal Neonate
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exposure Breast milk9
Swedish mothers milk data

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 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 milk
which concentrates lipophylic compounds such as dioxins,
PCBs,…

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 Fetuses, infants and children are especially
vulnerable to toxic chemical exposure
» Reduced ability to break down and excrete many chemicals
compared to adults
» Great vulnerability during windows of susceptibility in early
development

» More years of future life –i.e., many decades in which

consequences of early exposures can become manifest

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 Human biomonitoring:
direct measurement in human tissues

Environmental biomarkers biomarkers adverse

monitoring of exposure of effects health effects

air
air
Birth weight
dust Blood lead Hormone levels
Growth

Cotinine in urine DNA damage

Consumer IQ
products behaviour
MeHg in hair Gene expression
… puberty
water Epigenetic changes
soil Asthma
soil
Cancer
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Flemish human biomonitoring campaign
Environmental health
Monitoring for action…
2002-2006-2011
Commissioned, financed , steered by the Ministry of the Flemish Community (Dept of
Science, Public Health and Environment )

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 1600 youngsters
Oct 2003- July 2004

42 schools
18 mL blood, 50 mL
urine

1200 newborns
1600 adults
Sept 2002- Dec 2003
Sept 2004- June 2005
25 maternities + 2
stem cell banks 43 municipalities
30 mL cord blood 35 mL blood, 50 mL
urine

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Birth cohorts in Flanders

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Asthma/allergy follow-up (N=150)
Neurodevelopment follow-up (N=200)
Exhaled breath:
•condensate proteins
•Gas phase VOC
Questionnaire: growth, diet, pets, 8-oxodG urine
Cord blood diseases, allergy symptoms, hygiene, indoor
Pb, Cd, PCBs, Gut flora (faeces: 3wk, 6m, 12m) eNO
Questionnaire:
dioxin-like compounds SPT growth,diet, pets,
TSH, fT3, fT4 diseases, allergy
symptoms, hygiene,
swimming, indoor

0 1 2 3 4 5 6……12m……..2y……………………3y….……4y…5y…6y…7y…8y

Interpolated outdoor air conc.

NO2, PM10 weight
circumfe-
rence,
Cognitive and fat/fat free
Questionnaire: behavioural tests
behaviour child, mass
child, IQ-test mother, (impedance),
emotional status mother, Observation Home
life-events arm/back
Environment (HOME), fold…
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 ENvironmental health RIsks in European birth COhorts:

Birth weight declined by 150g per 1µg/L

increase in PCB 153 cord serum concentration

OBesogenic Endocrine disrupting chemicals: LInking prenatal

eXposure to the development of obesity later in life

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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).

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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)

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 Negative relation between POPs and thyroid
hormones measured in cord blood
Multiple linear regression model /contaminant , 200 participants
adjusted 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

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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)

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Neurological behaviour follow-up

Info on pregnancy
Postnatal depression

0 1 12 24 36 months

Cord blood
(Pb, Cd, PCB’s, dioxins, Cognitive and
TSH,FT3, FT4),nutrition, Behaviour child, Behavioural tests
covariates emotional status mother, child, IQ-test mother,
life-events Observation Home
Environment,
Cortisol
monthly quesionnaire on food & development
3-monthly “ “ “
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Prenatal exposures and health outcomes:
methylmercury in maternal hair
Fish intake : Faroe island cohort

Grandjean , Weihe
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 Prenatal exposures: a wide range of effects
with 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?

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Mechanisms of late effects?
» hormone levels,
» oxidative stress
» epigenetic changes?

 mechanistic
early warning

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Control of Persistent Pollutants: Global POPs
Convention (Stockholm Convention on
Persistent Organic Pollutants)
Covers the “dirty dozen” POPs chemicals and pesticides + 9 chemicals
recently 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; beta
hexachlorocyclohexane; chlordecone; hexabromobiphenyl;
hexabromodiphenyl ether and heptabromodiphenyl ether (commercial
octabromodiphenyl ether); lindane; pentachlorobenzene; perfluorooctane
sulfonic acid, its salts and perfluorooactane sulfonyl fluoride;
tetrabromodiphenyl ether and pentabromodiphenyl ether (commercial
pentabromodiphenyl ether).

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The tip of the iceberg?

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