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

30/06/2011 17© 2011, VITO NV

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?