Current biomonitoring studies for FR; general information ... · Current human biomonitoring studies for FR; general information about setup of human ... hypothesis generation and

27/06/2012

Current human biomonitoring studies for FR; general information about setup of human biomonitoring studies.

Ann Colles, Roel Smolders

(Flemish Institute for Technological Research, Mol, Belgium)

27/06/2012 2 © 2011, VITO NV

What is human biomonitoring?

» Human biomonitoring (HBM)

» Originates from occupational exposure

» Measures “biomarkers”

» Definition:

A method for assessing human exposure to

chemicals by measuring the chemicals, their

metabolites or reaction products in human tissues or

specimens, such as blood or urine

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What is human biomonitoring?

Chemical source

Ingestion

Inhallation

Skin contact

Routes of exposure

environmental

monitoring

Changes

in the body

growth curves

hormone levels

DNA damage

gene expression

cytokines

…

HUMAN BIOMONITORING

Internal dose

serum PCBs

urinary triclosan

serum PBDEs

p,p’-DDE in milk fat

…

biomarkers

of exposure

biomarkers

of effects

Health

effects

growth

IQ

behaviour

puberty

asthma

cancer

…

health

effects

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FLAME RETARDANTS IN HUMAN BIOMONITORING PROGRAMS

Part 1:

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0

5

10

15

20

25

30

35

40

45

50

USA, Texas 2001

(n=47)

Canada 2003

(n=40)

UK 2003

(n=34)

Norway 2003-2005

(n=393)

Sweden Belgium 2006

(n=200)

France 2004-2006

(n=77)

Spain Poland 2004

(n=22)

Russia 2002

(n=23)

South Africa 2004

(n=28)

Australia 2002-2003

(n=157)

China (n=27)

Japan 2004

(n=1000)

Me

dia

n c

on

c. in

hu

man

milk

(n

g/g

lw)

sum 6 PBDEs (BDE28, BDE47, BDE99, BDE100, BDE153, BDE154) in human milk

Schecter et al., 2003

She et al., 2007

Thomsen et al., 2010

Colles et al., 2006

Antignac et al., 2009

Polder et al., 2008

Darnerud et al. 2011

Bi et al., 2006

Eslami et al., 2006

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0

5

10

15

20

25

30

USA 2002-2003

(n=8)

UK 2003 (n=34)

Norway 2003-2005

(n=393)

Sweden Belgium 2006

(n=197)

France 2004-2006

(n=77)

Spain 2006-2007

(n=33)

Russia 2002 (n=23)

South Africa 2004 (n=28)

Ghana 2009 (n=42)

China 2003-2005

(n=21)

Philippines 2004 (n=33)

me

dia

n c

on

c. in

hu

man

milk

(n

g/g

lw)

∑ HBCD in human milk

Ryan et al., 2006

Abdallah & Harrad, 2011

Thomsen et al., 2010

Covaci et al., 2006

Colles et al., 2006

Antignac et al., 2009

Eljarrat et al., 2009

Polder et al., 2008

Darnerud et al. 2011

Asante et al., 2011

Zhao et al., 2007

Malarvannan et al., 2009

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GETTING STARTED WITH HUMAN BIOMONITORING

Part II:

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Types of HBM studies

» Survey projects: screening a respresentative part of the population for

• prevalence of exposure to environmental agents

• prevalence of related public health impact

» Research studies: hypothesis generation and testing

» Source-based case-control study: comparing a population exposed to a known source with a control population which is not or less exposed.

» Health-based case-control study: comparing a population showing symptoms of health effects with a control population not showing those symptoms.

» Dose-effect study: relationship between internal dose and observed health effects.

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HBM survey: trends over time

» Swedish breast milk data

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Temporal trend of BDE47

and 153 and HBCD in

human milk of Sweden

(Fängström et al., 2008)

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» In the United States: no federal regulatory action has been taken to ban or restrict PBDEs

» In Sweden: PBDE phase-out began in 1990 and accelerated at the end of the decade

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» TBBP-A and sum 6 PBDEs in pooled serum samples from 40-50 year old Norwegean men (Thomsen et al., Environ. Sci. Technol. 2002)

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HBM survey: spatial trends

Dioxin-like compounds ! !

PCBs ! ! ! !

p,p'-DDE ! !

HCB ! !

Dioxin-like compounds

PCBs !

p,p'-DDE ! ! ! ! ! !

HCB

City of Antwerp City of Ghent Fruit region Rural area

Harbour Non ferro industry

(Olen)

Chemical industry

(Albert canal)

Waste incinerators

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Case-control: occupational exposure

» Computer clerks (n=30) vs. no computer use (n=31) (Kalantzi et al., Environment international 2011)

» PBDEs in 3 occupational groups in Sweden (Sjödin et al., Environment International 2003)

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Case-control: health based

» PBDEs in breast milk samples and occurence of cryptorchidism (= undescended testis)

(Main et al., Environ. Health Persp. 2007)

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Step 1: research question

» Research question

» Aim of the study: what do I want to study?

» Determining for:

» Study area

» Study population – age groups

» Sampling matrix

» biomarkers

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Step 2: study area

» Representative area

» Urban vs. rural

» Case vs. control

» Information:

» Geography

» Environmental data (air, soil, water, vegetables, eggs, …)

» Sources of pollution

» Meteorological data

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Step 3: selecting biomarkers

» Biomarker of exposure: The chemical or its metabolite that is measured in a compartment in an organism.

» Examples: PBDEs, TBBPA, HBCD in blood or human milk

» Biomaker of effect: A measurable biochemical, physiological, behavioral, or other alteration in an organism that is associated with an established or possible health impairment or disease.

» Examples: DNA damage, hormone imbalance, IQ, asthma, …

» Biomarkers of susceptibility: An indicator of an inherent or acquired ability of an organism to respond to the challenge of exposure to a specific chemical substance.

» Examples: Gene polymorphism, metabolic enzymes, iron status

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Step 4: sampling matrix

» Depends on selected biomarkers

» Organs (eg. Liver)

» Adipose tissue

» Blood

» Cord blood

» Placenta

» Urine

» Breast milk

» Exhaled breath

» Hair

Invasive

Non-invasive

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0

10

20

30

40

50

60

70

80

90

100

adipose tissue (n=86) breast milk (n=77) maternal serum (n=91) cord serum (n=90)

% < LOQ

BDE28

BDE47

BDE99

BDE100

BDE153

BDE154

BDE183

France: number of samples < LOQ

Antignac et al. Environmental

Pollution 2009

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Total PBDE

concentration in

paired samples

from China.

(Bi et al.

Environmental

Pollution 2006)

Congener profiles

of PBDEs (Bi et al.

Environmental

Pollution 2006)

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Step 5: study population

» Representative

» Study area

» Target population

» Sufficient population size: statistically significant results

» Comparing groups

» Dose-response relations

» Gradients

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» Age class

» Newborns

» Exposure early in life

» Non-invasive (cord blood, placenta, human milk)

» Recruiting in maternities

» Children – adolescents

» Recruiting in schools

» Adults

» Invasive and non-invasive

» Occupational exposure

» Elderly

» Invasive and non-invasive

» Life-time exposure

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» Who can participate? Inclusion criteria

» Study area

» Age

» Time

» Life style (smoking, diet, …)

» Personal factors (gender, …)

» Health

» How many can participate? Statistical analysis

» Critical number of participants

» Stratified sampling strategy

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Step 6: questionnaire

» Description of the study population

» Information about:

» Personal characteristics: age, BMI, gender, …

» Lifestyle factors: diet, smoking, alcohol consumption, …

» Medication

» Health: asthma and allergies

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US National Health and Nutrition Examination Survey (NHANES)

Sjödin et al. Environ. Sci. Technol. 2008

Factors of influence

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» TBBP-A and PBDEs in pooled serum from different age groups of Norwegian participants (Thomsen et al. Environ. Sci. Technol. 2002)

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» PBDEs in serum from 20 pairs of children and their mothers (Lunder et al., Environ. Sci. Technol. 2010)

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» Influence of age and diet on plasma levels of BDE47 (Sjödin et al., Environment International 2003)

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EXAMPLES OF HBM STUDIES Part III:

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Flemish Environment and Health Survey (FLEHS), Second survey, 2007-2011

» Flemish Center of Expertise on Environment and Health

» Consortium of researcher: • All Flemish universities:

o University of Antwerp (UA) o Free University of Brussels (VUB) o University of Ghent (UGent) o Catholic University of Leuven (KULeuven) o University of Hasselt (UHasselt)

• Research Institutes: o Provincial Institute of Hygiene (PIH) o Flemish Institute for Technology Research (Vito)

» Financing and steering: Flemish government • Department of Environment • Department of Health • Department of Science

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Time frame

» 2007-’09: reference values for Flanders

» Large number op pollutants

» Aim:

» Status of the general population (dose distribution)

» International comparison

» Control group for hotspots

» 2009-’11: hot spots in Flanders

» Biomonitoring (of a specific biomarker) in a selected area or a selected population

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Reference values: recruitement strategy

» 3 age groups:

» 250 newborn-mother cohorts - maternities

» 200 adolescents (14-15 yrs.) - schools

» 200 adults (20-40 yrs.) - personnel of provincial institutes

» Multistage sampling plan

» Step 1: stratification by region: 10 clusters in 5 provinces

» Step 2: primary sampling units (PSU) – sampling in all seasons; equal distribution between rural & urban

» Step 3: secundary sampling units (SSU) – no selection

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Biomarkers of exposure: selection (1)

» Pre-selection of pollutants / biomarkers

» Scientists (research proposal)

» Stakeholders

» Fact sheets

» E.g. health effects, sensitive subgroups

» E.g. guidelines external/internal exposures, MOS

» E.g. technical aspects, prices, volumes

» E.g. expected levels in Flanders, international data

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Biomarkers of exposure: selection (2)

» Defining priorities for biomarkers

based on health effects & experience within the research group

» Defining most relevant age group

based on health effects & feasibility

health effects experience priority measurement

known effects experience 1 individual samples

known effects no experience 2 1) prevalidation in 20 samples

2) all individuals

uncertain effects no experience 3 pooled samples

unsufficient data no experience 4 further study

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Selected biomarkers of exposure

Newborns & mothers

N = 250

Adolescents (14-15 yrs.)

N = 200

Adults (20-40 yrs.)

N = 200

BLOOD

priority 1: individual samples

heavy metals

polychlorinated compounds

polybrominated compounds


heavy metals

polychlorinated compounds

polybrominated compounds

priority 2: individual samples after

prevalidation

bisphenol A, TBBPA,

nitro- en polycyclic musks


prevalidation

bisphenol A, TBBPA,

nitro- en polycyclic musks


prevalidation

perfluoro compounds

priority 3: pooled samples

parabens

UVscreens


parabens

UVscreens

URINE


heavy metals

metabolites of phthalates

metabolites of PAHs

metabolites of benzene

metabolites of organophosphate pesticides,

paradichlorobenzene

metabolite of nicotine


heavy metals

metabolites of phthalates

metabolites of PAHs

metabolites of benzene

metabolites of organophosphate pesticides,

paradichlorobenzene

metabolite of nicotine

priority 2: prevalidation

metabolite of parabens

priority 2: prevalidation

metabolite of parabens


new metabolites of PAHs

metabolites of pyrethroid pesticides,

chlorophenoxy pesticides, carbamate pesticides, fungicides


new metabolites of PAHs

metabolites of pyrethroid pesticides,

chlorophenoxy pesticides, carbamate pesticides, fungicides

HAIR

priority 1: individual samples Hg, MeHg

priority 1: individual samples Hg, MeHg

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Biomarkers of effect: strategy

» Aim: » Integrated exposure of multiple pollutants » Dose-effect relationships » Control values for hotspots

» Related to selected biomarkers of exposure 4 groups of health effects:

» Immune effects » Endocrine disruption: growth & development » Genotoxic effects » Neurologic development

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Selected biomarkers of effect

Newborns & mothers

N = 250

Adolescents (14-15 yrs.)

N = 200

Adults (20-40 yrs.)

N = 200

IMMUNE effects

questionnaire:

asthma and allergy of the mother

questionnaire:

asthma and allergy

questionnaire:

asthma and allergy

ENDOCRINE effects

measurements in cord blood

thyroid hormones, sex hormones,

insulin, leptin

data from files (hospital):

birth weight, length, head circumference,…

questionnaire:

miscarriage and fertility of the mother

measurements in blood:

thyroid hormones, sex hormones (boys)

data from files (school doctor):

pubertal stages, growth curves

questionnaire:

pubertal development


sex hormones (men)

questionnaire:

fertility; miscarriage in women

GENTOXIC effects


comet assay, gene expression

NEUROLOGIC effects

Follow-up study:

questionnaires & home visits

fieldwork:

NES test

questionnaire:

score ADHD

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HBM in hotspots: strategy

» Targeted biomonitoring studies (Control group = populations in reference biomonitoring)

» Target = areas or population groups with a concern for environmental

pollution pressure

» Selection of hot spots: » Open call for cases

» Transparant and deliberative selection procedure

interaction between scientists, policy makers,

stakeholders and the public.

85 cases

5 cases

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HBM in hot spots

» 5 priorities:

» Area around non-ferro industry (Genk South)

» Area around shredder industry (Menen)

» High unexplained mortality rates in one specific region (Dendermonde)

» Chipboard industry (several locations)

» Chemical industry in harbour (Ghent canal zone)

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Results survey reference values

» Study population

Mothers of

newborns

Students Adults

N 255 210 204

Age(yr) Geometric mean(min.-max)

30,3 (18,2 – 42,4) 14,8 (13,8 – 16,3) 33,9 (21,4 – 40,6)

% male / female 0 / 100 57,6 / 42,4 47,1 / 52,9

% smokers 11,6 13,6 23,3

% higher education 61,5 56,0 (family) 77,5

% urban 61,6 36,7 48,5

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Results survey reference values

» Brominated flame retardants in serum of newborns (cord blood) and students (% > LOD)

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Partners

» Co-ordination: Prof. W. Bayens, K. Goeyens; VUB » Spokesmen: Prof. N. Van Larebeke; UGent

» Co-ordination biomonitoring: Prof. G. Schoeters, E. Den Hond, A. Colles, E.Govarts; Vito » Fiedwork: Dr. V. Nelen, E. Van de Mieroop; PIH » Social sciences: Prof. I. Loots, B. Morrens, H. Keune; UA » Nutrition: Prof. S. De Henauw, I. Sioen; UGent » Statistics: Prof. G. Molenberghs, L. Bruckers; UHasselt » Epidemiology: Prof. B. Nemery, T. Nawrot; KULeuven » Neurology (follow-up): Prof. M. Viaene, G. Vermeir; OPZGeel » Chemical analyses: Dr. A. Covaci; UA

» Ministry of health: D. Wildemeersch, H. Chovanova » Ministry of environment: K. Van Campenhout, C. Teughels

Documents

Current biomonitoring studies for FR; general information ... · Current human biomonitoring studies for FR; general information about setup of human ... hypothesis generation and