For our Environment

German Environmental Survey and Specimen Bank and the use of the human biomonitoring data for risk assessment

RASS MSS Webinar - January 11, 2017

Marike Kolossa-Gehring, André Conrad, Petra Apel, Ulrike Fiddicke, Maria Rüther, Christine Schulz, Christa Schröter-Kermani, Gerda Schwedler

German Environment Agency (Umweltbundesamt)

Keeping an eye on chemicals

2

European Commission (2001): Global production of chemicals increased from 1 M t in 1930 to 400 M t in 2001. June 2015: Chemical Abstracts Service (CAS) assigned 100 Millionth CAS Registry Number®.

Chemical industry is Europe’s 3rd largest manufacturing industry.

Eurostat: about 30 M t of carcinogenic, mutagenic and reprotoxic chemicals produced in 2009. So

urc

e: C

C V

isio

n

0

100

200

300

400

500

600

700

800

0

1

2

3

4

5

6

1994 1997 2000 2003 2006 2009

Ge

rman

BPA

pro

du

ctio

n (

kt/y

)

BPA

in u

rin

e (

Me

dia

n in

µg

/L)

Why do we need HBM data? Bisphenol A production and human exposure

3

Data Source: German Environmental Specimen Bank (ESB)

Exposure quantifiable?

The German HBM System: Answering key questions concerning human exposure to chemicals

4

Variation in population?

(Risk groups, sources, etc.)

Regulation and voluntary measures sufficient?

Exposure health-

relevant?

German Environmental Survey - population- representative - ambient monitoring - interviews

German Environmental Specimen Bank - retrospective monitoring - time trends background exposure

Human Biomonitoring Commission at UBA

- HBM assessment

values

Cooperation for the promotion of HBM

- new analytical methods for chemicals of

interest

Sound HBM data for science and policy

Ulm (since 1997)

Halle/S. (since 1995)

Münster (since 1977)

Greifswald (since 1995)

German Environmental Survey (GerES)

Environmental Specimen Bank (ESB)

Survey Period Age Size

GerES I 1985 - 86 25 - 69 2,700

GerES II a

GerES II b 1990 - 92

25 - 69

6 - 14

4,000

730

GerES III 1997 - 99 18 - 69 4,800

GerES IV 2003 - 06 3 - 14 1,790

GerES V 2014 - 17 3 - 17 2,505

5

6

Instruments

GerES ESB

Study design and sample of GerES V

2,505 children and adolescents from 167 locations in Germany Age range: 3 to 17 Years Representative according to age, gender and community size. Randomly selected from the 2. wave of the KiGGS study (the German Health Interview and Examination Survey for Children and Adolescents),

conducted by the Robert Koch Institute (RKI)

Sou

rce:

Ro

ber

t K

och

Inst

itu

te

7

Environmental influences State of health

Exploration of associations

8

more than 2,000 pieces of information per child/adolescent

Drinking water

anorganic and organic compounds (from plastic pipes)

Indoor monitoring

- ultrafine particles, particulate matter PM2,5 and PAH

- house dust: „new“ plasticizers and flame retardants

- VOC and aldehydes

Noise

noise level , subjective annoyance

Integration of GIS data

Ambient monitoring

9

Source: mitev / Fotolia.com

Source: style photographs / Fotolia.com

Source: auris / Fotolia.com

Design of the German ESB (human samples)

Since 1997: regular standardized sampling at 4 locations approx. 120 healthy male and female adults (20 - 29 yrs.) in each city No specific exposure Urine (24 hrs.) Blood (whole blood, serum) Self-administered questionnaire Dental anamnesis

Cryo-archiving of samples: retrospective analyses

10

11 11

Biobanking

According to obligatory standard operation procedures (SOP)

Sampling Anamnesis

Sampling planning

Analyses Storage

Operated by Fraunhofer IBMT on behalf of the German Environment Agency

Source: Fraunhofer IBMT

Specimen regularly collected by the ESB

12

Spruce/Pine Beech/Poplar Earthworm Pigeon Deer

Zebra mussel Bream

Blue mussel Eelpout Herring gull

Soil

Suspended sediment

Human specimen

Environmental specimen

Whole blood/ Plasma

24 h sampling urine

Sources: Projektgruppe Trier (10), Fraunhofer IBMT (2), Fraunhofer IME (1), UBA (1)

German Initiative to further develop HBM

13

The German Chemical Industry Association (VCI)

Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety

German Environment Agency

development of new chemical-analytical HBM methods

HBM relevant

Chemicals

Federal Institute for Occupational Safety and Health (BAuA)

Federal Institute for Risk Assessment (BfR)

German Environment Agency (UBA)

Potential exposure of the general

population +

Potential health

relevance

Human biomonitoring & interview monitoring

first application of newly developed analytical methods

• Plasticiser: Hexamoll DINCH, DPHP,

ASE/ASEP („Mesamoll“), Tri(2-ethylhexyl) trimellitat TOTM, diethylhexylterephthalat DEHTP, Di-isononyladipat DINA, Di-2-ethylhexyladipat DEHA/DOHA

• Antioxidant: butylated hydroxy-toluene BHT

• Sun screens: 4-MBC, OMC , octisalate, octocrylene

• Biocides: CIT/MIT, climbazol

• Fragrances: geraniol, lysmeral, 7-hydroxycitronellal

• Polyurethane ingredients: TDI (2,4-TDI+ 2,6-TDI), MDI

• Technical solvents: NMP, NEP • Vulcanisator: 2-MBT • Glyphosate

Source: angellodeco / Fotolia.com

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15

The German Human Biomonitoring Commission

Protection of the health of the population who is exposed to chemical substances from the environment

by scientific assessment and derivation of guidance values: • Statistically derived Reference values

• Toxicologically/epidemiologically based Human Biomonitoring Values ( HBM I= alert value & HBM II = action value)

New HBM values for emerging substances, inventory of reference and HBM values in force, and working principles of the German Human Biomonitoring Commission. Int J Hyg Environ Health. 2016 Sep 17, DOI: 10.1016/j.ijheh.2016.09.007.2

0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0

Percentage [%] exceeding the TDI* value

DEHP - Diethylhexylphthalat

TDI*: 50 µg/(kg KG∙d)

DnBP - Di-n-butylphthalat

TDI*: 10 µg/(kg KG∙d)

DiBP - Di-iso-butylphthalat

TDI*: 10 µg/(kg KG∙d)

1.4

11.7

%

9.1

GerES IV: Identification of a possible impact on health I

* TDI: Tolerable Daily Intake

Phthalates metabolites in urine of children aged 3 to 14

16

GerES IV: Identification of a possible impact on health II

GerES (2003-2006): children aged 3 to 14

Weighting according to factors decribed by Earl Gray, US-EPA

Intake rates: daily intake related to volume calculated by Wittassek

85% Exceedance of TDI (DnBP)

to to to to to to to to to to to

up to

1%

14%

18%

13%

10%

7%

4% 3%

2% 2% 1%

4%

23%

0%

5%

10%

15%

20%

25%

5

>5

10

>10

15

>15

20

>20

25

>25

30

>30

35

>35

40

>40

45

>45

50

>50

55

>55

60

>60

Phthalate intake (µg/kg BW/d)

% o

f valu

es

weighted intake rates of 5 phthalates

17

18

Phthalates: decision on measures and control of success Exposure of the general population, children, GerES IV: single substances: exceedance of HBM-I or TDI by 2 % to 12 % per substance aggregate exposure: exceedance by more than 50 % Regulation: Several steps: toys for children, cosmetics, food Danish proposal to ban phthalates rejected Authorisation since 2/2015 Toxicology: reproductive toxicants Substances of Very High Concern DEHP, DnBP, BBzP: SVHC in 2008; DiBP: SVHC in 2010 HBM Values DEHP sum of metabolites 5oxo-MEHP and 5OH-MEHP in urine: Children, aged 6 - 13: HBM-I 500 µg/ l Women in childbearing age HBM-I 300 µg/ l Others HBM-I 750 µg/ l assessment of aggregate exposure required

Sou

rce:

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illet

/ F

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lia.c

om

ESB time trend phthalates 1988 to 2015

1.0

10.0

100.0

1000.0

1985 1990 1995 2000 2005 2010 2015 2020

Me

dia

ne

co

nc

en

tra

tio

n [

ng

/ml]

Year of sampling

DnBP

DEHP

DiBP

BzBP

DiNP

toys

SVHC

cosmetics

authorization

- 85.6%

- 66.5%

- 95.5%

+ 56.3%

- 84.5%

Regulations …

toys

Exposure to metabolites of 4 SVHC has decreased by 67- 96%, they are still to be detected in every single sample. DINP increased by 56%.

DiBP SVHC

Measured by Holger Koch, IPA, and Thomas Göen, IPASUM

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20

N-Methyl-2-pyrrolidone (NMP) Use: Technical solvent Exposure of the general population: • by using paint and graffity remover, • indoors via paints and carpets Exposure pathway: inhalative, dermal Toxicology: a) specific metabolites in urine: 5-hydroxy-NMP (5-HNMP) and 2-hydroxy-N-methylsuccinimide(2-HMSI) b) reproductive toxicant Substance of Very High Concern (SVHC, 2011) HBM Values, sum of metabolites 5-HNMP + 2-HMSI in urine: Children: HBM-I = 10 mg/l, HBM-II = 30 mg/l Adults: HBM-I = 15 mg/l, HBM-II = 50 mg/l Substitute: N-Ethyl-2-pyrrolidone (NEP) CAVE: similiar toxicological profile assessment of aggregate exposure required

N O

CH3

BMUB/VCI-Cooperation

Sou

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Kad

my

/ Fo

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.co

m

Time trend of NMP-metabolites in 24h-urine

The internal exposure of the reprotoxic SVHC did not decline.

62.16 61.41 53.38 50.69 54.33 49.58 52.71 44.67 53.48

37.84 35.79 49.56 36.78

43.00 38.93

58.06

38.16

57.46

0

20

40

60

80

100

120

1991 1995 1999 2003 2006 2008 2010 2012 2014

%

Year of Sampling

Sum of NMP-Metabolites in human 24h-sampling urine

(1991 ≙ 100%)

2-HMNP 5-HNMP 5-HNMP values > LOQ 2-HMSI values > LOQ

Measured by Holger Koch, IPA

21

Time trend of NEP-metabolites in 24h-urine

The internal exposure of the reprotoxic substitute declines

70.65

37.64 49.80

95.00

34.50 21.66

47.68

18.19 33.98

29.35

23.17

64.31

24.37

26.11

12.54

13.36

22.20

27.68

0

20

40

60

80

100

120

1991 1995 1999 2003 2006 2008 2010 2012 2014

%

Year of Sampling

Sum of NEP-Metabolites in human 24h-sampling urine (1991 ≙ 100%)

5-HNEP 2-HESI 5-HNEP values > LOQ 2-HESI values > LOQ

22

Measured by Holger Koch, IPA

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Glyphosate Use: • Broad spectrum systemic herbicide • Used for crop desiccation Toxicology: IARC: probably carcinogenic to humans (Group 2A) EFSA: Acceptable Daily Intake (ADI) 0,5 mg/kg bw/d

Clarification by the different agencies is indispensable Exposure of the general population: • By food • Home use for gardening

Analytical method: GC-MS/MS, LOQ: 0.1 µg Glyphosate/L urine

[Gly]cine [phos]phon[ate]

Sou

rce:

oti

cki /

Th

inks

tock

Time trend glyphosate in 24h-urine

Fraction of quantifiable levels decreases after 2012? Result of changes in application?

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% o

f co

nce

ntr

atio

ns

of

at le

ast

LOQ

(0

.1 µ

g/L

)

0

10

20

30

40

50

60

70

80

90

100

2001 2003 2005 2007 2009 2011 2012 2013 2014 2015

Source: Conrad, Schröter-Kermani, Hoppe, Rüther, Pieper, Kolossa-Gehring (2016): Glyphosate in German adults – Time trend (2001 to 2015) of human exposure to a widely used herbicide, International Journal of Hygiene and Environmental Health, Volume 220, Issue 1 http://dx.doi.org/10.1016/j.ijheh.2016.09.016

Sex-related differences in exposure? Analysis of population-representative GerES V samples

Time trend glyphosate: differences male/female

25

0

10

20

30

40

50

60

70

80

90

100

2001 2003 2005 2007 2009 2011 2012 2013 2014 2015

% o

f co

nce

ntr

atio

ns

of

at le

ast

LOQ

(0

.1 µ

g/L

)

Source: Conrad, Schröter-Kermani, Hoppe, Rüther, Pieper, Kolossa-Gehring (2016): Glyphosate in German adults – Time trend (2001 to 2015) of human exposure to a widely used herbicide, International Journal of Hygiene and Environmental Health, Volume 220, Issue 1 http://dx.doi.org/10.1016/j.ijheh.2016.09.016

0

25

50

75

100

be

ta-H

CH

DD

E

PC

B 1

38

PC

B 1

53

PC

B 1

80

2,4

-DC

P

PC

P

1-O

H-P

yre

n

1-O

H-P

he

n.

Bis

ph

en

ol-

A

Mn

BP

MiB

P

MB

zP

ME

HP

OH

-MiN

P

oxo

-MiN

P

cx-M

iNP

Valu

es a

bo

ve L

OQ

[%

]

HBM Data from the German Environmental Survey GerES IV (2003-2006)

Multiple exposure in children: endocrine disruptors

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Multiple exposure - conclusions

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People are exposed to a large number of chemicals

Exposure consists of several chemicals with the same mode of action or affecting the same target organ HBM reveals co-exposures HBM helps to describe typical exposure situations HBM demonstrates that single substance assessment does not reflect realistic exposure scenarios

Policy advice: the example of mercury

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Children

Adults

Number of teeth with amalgam fillings

0 2 4 6 8 10 12 14 16 18

Re

lati

ve c

han

ge o

f H

g in

uri

ne

(95

%-C

I)

100 %

200 %

300 %

GerES II (1990/92)

Official recommendation of the Federal Health Office (1992): “The use of dental amalgam should be considered very cautiously for children under the age of 6.”

Reduction in amalgam use (as observed in GerES)

29

GerES No tooth 1 tooth 2 or more teeth

II (1990/92) 37% 10% 53%

IV (2003/06) 92% 3% 5%

Exceedance of HBM assessment values for Hg (in %)

Mercury – Reduction in amalgam use (ESB)

30

Par

tici

pan

ts w

ith

am

alga

m f

illin

gs (

in %

)

Münster (West)

Mercury – multivariate analysis (ESB)

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Contribution to Hg amount in 24h-urine (ng)

Source: Schulz, Rüdel, Uhlig, Hettwer, Kaltenbach (2015): Comparative examination of the human and environmental mercury exposure based on monitoring data derived from the German Environmental Specimen Bank (ESB) https://www.umweltprobenbank.de/upb_static/fck/download/Endbericht_Integrierte_Bewertung_Hg_2015_08_10_Web.pdf [in German]

Mercury - conclusions

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Internal mercury exposure decreased substantially in Germany.

Dental amalgam is a main exposure determinant.

As the use of dental amalgam has decreased, exposure via food became relatively more important.

Source: marcel / Fotolia.com

Aims

• Preparation and conduct of a feasibility study • Harmonization of methods, questionnaires, quality assurance, … • Measurement of comparable results • Building up network & infrastructur • Use of HBM for improving policy

HBM in the EU: preparatory phase and pilot study

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DEMOCOPHES: exposure of children to DEHP

Sweden

Germany

Luxembourg

Switzerland

Slowenia

Belgium

Denmark

Ireland

ALL

Cyprus

Slovakia

Portugal

Spain

Poland

Czech Republic

Hungary

Rumania

United Kingdom

0 10 20 30 40 50 60 70 80 90 100

DEHP-metabolite im urine (µg/L) , adjusted to creatinin, age and gender

p < 0.001

p < 0.001

p < 0.001

p < 0.001

p < 0.001

p < 0.001

p = 0.001

p = 0.54

p = 0.21

p = 0.004

p = 0.009

p < 0.001

p = 0.96

p < 0.001

p < 0.001

p < 0.001

p < 0.001

1,7% > HBM I

HBM I:

300 µg/L (mothers)

500 µg/L (children) ∑(OH-MEHP, oxo-MEHP)

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Answer open policy relevant questions as defined by EU

Services and partner countries

Bridge the gap between science and

policy

Give policy makers a fast and easy access to results and

data

Sou

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(map

of

Euro

pe)

: © U

ser:

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2.5

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an ambitious EU research programme designed especially to answer policy

relevant questions

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(map

of

Euro

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: © U

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2.5

Who we are - the HBM4EU partners

22 EU Member States 3 Associated States, Switzerland, and EEA (3 candidates to join in later) 107 Partners 38 Grant Signatories Financial volume: ~ 74 M € Management Board Member

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Prioritization process

38

EU level

JRC scientific and technical support

EEA

environment data, information, assessment

ECHA REACH regulation

EFSA risk assessment for food and feed

ENV

chemicals legislation

(e.g. REACH), air/water pollution,

noise

SANTE food

contaminant, pesticides,

biocides, EDs

EMPL worker safety,

exposure to chemicals

GROW product safety,

cosmetics, REACH

RTD R&I framework programme

Prioritization process

39

National Hub

German HBM Commission

Experts

Public institutions

and agencies with HBM expertise

Source: David Liuzzo, derivative work: MichaelBueker [CC BY-SA 3.0], via Wikimedia Commons

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Nat

ion

al a

nd

EU

Sta

keh

old

ers

; A

dvi

sory

Bo

ard

Pillar 1: Science to Policy

WP4: Prioritisation and input to the annual work plan

WP6: Sustainability and capacity building

WP5: Translation of results into policy

WP7: Survey design and fieldwork preparation

WP8: Targeted field work surveys and alignment at EU level

WP9: Laboratory analysis and quality assurance

WP10: Data management and analysis

Pillar 2: European HBM Platform Pillar 3: Exposure and Health

WP13: Establishing exposure health relationships

WP14: Effect Biomarkers

WP12: From HBM to exposure

WP11: Linking HBM, health studies, and registers

WP15: Mixtures, HBM and human health risks

WP16: Emerging Chemicals

WP2: Knowledge Hub

WP1: Programme management and coordination

Scientific and Administrative Management

WP3: Internal Calls WP17: Ethics Requirements

Activities on mixtures in HBM4EU

• Identification of most relevant chemical mixtures for risk assessment - development of aggregated mixture indicators - integration of various approaches and conventions of countries - database of existing HBM mixture data • Joint survey on HBM mixtures in 3-5 countries, and apply overarching analysis across priority substances to get aggregated HBM profiles - study populations enrolled based on exposure gradient

- priority substances and pesticides (due to EU/EFSA approach)

• Identification of mixture health effects - close co-operation with ongoing EU projects - liaison with EFSA activities - use and/or development of effect markers

16

Conclusions

42

The human exposure to various chemicals is a key aspect of environmental health. • Evidence of toxicologically relevant properties alone does not

automatically reduced use and exposure • Safe or at least better substitutes can be identified • Regulation supports reduction of exposure • Control of the success of regulatory measures is necessary • Admission to SVHC list does not automatically decrease

human exposure • HBM helps to set priorities • Health risk assessment needs to include aggregate exposure

HBM helps bridging the gap between science and policy making

www.umweltprobenbank.de

Supporting policy, but also the public …

43

www.uba.de/geres

Thank you very much for your attention.

Funding by the German Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (BMUB) is gratefully acknowledged.

marike.kolossa@uba.de