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LIFE12 ENV/GR/001040

Conference Title or Presentation Title 1Day, XX Month XXX, City, Country www.crome-life.eu

Cross-Mediterranean Environment and Health Network

CROME–LIFE

Participating Countries:

Greece, Italy, Slovenjia, Spain

Mapec meeting Pisa, 16/06/2016 www.crome-life.eu



Lead Beneficiary:

• Aristotele University of Thessaloniki (AUTH) - Greece

• AUTH coordinates the scientific/technical and administrative/financial aspects of

the project

The designated project manager is Prof. Dimosthenis Sarigiannis

Associated beneficiaries:

– Agencia Estatal Consejo Superior de Investigaciones Cientificas (CSIC) – Spain

– Principal investigator: Prof. Joan Grimalt

– Istituto Superiore di Sanità (ISS) – Italy - Principal investigator: Dr. Gemma

Calamandrei/Dr Alessandro Alimonti

– Jožef Stefan Institute (JSI) – Slovenija - Principal investigator: Prof. Milena

Horvat

CROME Participants



Conference Title or Presentation Title 3Day, XX Month XXX, City, Country www.crome-life.eu 3

from Wild, Int J Epidem 2012;41:24–32

THE CROME APPROACH




WHAT IS CROME ABOUT?

The project will build a prototype methodology for linking

environmental, biological and health data to draw

comprehensive and robust associations between

environmental stressors and human health.

Chemical pollutants: mercury and other neurotoxic metals, organic pollutants, PM

and PAH

Health effects: cancer risk and neurodevelopmental disorders

Cofactors: lifestyle, diet, socioeconomic status, health status, genetic vulnerability

CROME Interregional meeting Roma, ISS, 21/04/2016 www.crome-life.eu

Integrated analyses of old and new biomonitoring data:

recostructing exposures by measuring environmental

matrices, and exploiting exhisting data base




HOW IS CROME ORGANIZED?

• 1. Identify the gaps in knowledge in exhisting studies in environmental health:

sources of exposure, internal exposure, multiple exposures, diet, lifestyles,

habits, health outcome.

• 2. Develop a protocol to be applied to future studies of environmental epidemiology,

considering all the external factors that can influence the health of an individual

• 3. Assessing in a new biomonitoring targeted study the validity of the protocol

• 4. Disseminating and diffusing results with local authorities, citizen, stakeholder

• 5. Preparing guidelines to approach in a more integrated and realistic way the

environment-health association

• 6. Promoting new policies to protect the health of our children!




LIFE12 ENV/GR/01040

National

Institute

of Health,

Italy

Interregional Workshop 21 April 2016, Rome www. crome -

life.eu6

� National targeted environmental studies:•Case study Greece - Human Biomonitoring for Cr(VI) in Greece; Health effects of urban biomass combustion in Thessaloniki

•Case study Slovenia - Human Biomonitoring in general population in Slovenia

•Case study Italy - Human Biomonitoring in Italy (PROBE-adolescents)

•Case study Spain - Human Biomonitoring in Menorca and Catalona

�Common case study: CROME study which includes Greece, Italy, Slovenia (and Croatia), Spain: exposure to MeHg in children



LIFE12 ENV/GR/01040

National

Institute

of Health,

Italy


life.eu7

PROBE-adolescents (Italy) 500 adolescents , Latium Region

PROgramme for Biomonitoring of the Exposure, carried out in cooperation with

the National Association against Microcytemia during the annual screening for

thalassemia in schools. . Aim: to assess reference values

CROME

integration of HBM existing data

with environmental, health, lifestyle, etc., data (if existing)

CROME-LIFEA pilot demonstration of the exposome approach to assess the health burden

of environmental stressor (in particular chemical stressors), coupling HBM

values with environmental monitoring data and epidemiological observations

trough the use of PBTK and PBTD models.




LIFE12 ENV/GR/01040


life.eu8

- extreme values were excluded

(by the box plot criterium)

- values under the LoD were

included as the ½ LoD

Reference Values in blood

Livelli di metalli in 500 adolescenti Regione Lazio

Element GM 50th 5th 95th

As 0.71 0.75 0.13 2.95

Cd 0.29 0.30 0.13 0.60

Co 0.09 0.09 0.03 0.30

Cr 0.31 0.30 0.09 1.25

Hg 0.78 0.83 0.27 2.04

Ir * 6.71 6.84 2.50 15.0

Mn 7.22 7.46 3.36 16.0

Mo 1.11 1.10 0.54 2.39

Ni 0.94 1.02 0.18 2.60

Pb 9.60 9.55 4.13 21.6

Pd* 21.3 22.1 7.50 38.6

Pt* 10.9 10.9 5.16 23.9

Rh* 21.2 22.1 7.50 35.6

Sb 0.37 0.39 0.17 0.79

Sn 0.57 0.56 0.18 1.52

Tl 0.04 0.04 0.02 0.09

U* 5.09 4.85 2.26 14.3

V 0.07 0.08 0.03 0.17

W 0.03 0.03 0.01 0.08(µg/L; when *, in ng/L)




LIFE12 ENV/GR/01040

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Collection of data from the questionnaire

Categories Total (%)AREA

1 2 3 4Factors

452 (100) 89 (19.7) 160 (35.4) 131 (29) 72 (15.9)

Gender M 210 (46.5) 50 (56.2) 68 (42.5) 53 (40.5) 39 (54.2)

F 242 (53.5) 39 (43.8) 92 (57.5) 78 (59.5) 33 (45.8)

SES-F low 104 (27.9) 29 (39.2) 32 (24.1) 30 (28) 13 (22)

medium 157 (42.1) 19 (25.7) 68 (51.1) 45 (42.1) 25 (42.4)

high 112 (30) 26 (35.1) 33 (24.8) 32 (29.9) 21 (35.6)

S-H smoke no 181 (49.9) 40 (56.3) 52 (40.9) 60 (54.1) 29 (53.7)

home 93 (25.6) 17 (23.9) 40 (31.5) 23 (20.7) 13 (24.1)

outdoor 89 (24.5) 14 (19.7) 35 (27.6) 28 (25.2) 12 (22.2)

FISH never 24 (6.5) 7 (10.0) 3 (2.17) 9 (8.7) 5 (8.6)

1/week 265 (71.6) 50 (71.4) 107 (77.5) 69 (66.3) 39 (67.2)

>=2/week 81 (21.9) 13 (18.6) 28 (20.3) 26 (25.0) 14 (24.1)

MILK never 7 (1.7) 1 (1.2) 2 (1.3) 3 (2.6) 1 (1.5)

1-3/week 99 (24.1) 21 (25.6) 30 (20.3) 28 (24.3) 20 (30.8)

4-6/week 63 (15.4) 14 (17.1) 17 (11.5) 26 (22.6) 5 (9.2)

7/week 241 (58.8) 46 (56.1) 99 (66.9) 58 (50.4) 38 (58.5)




LIFE12 ENV/GR/01040

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Institute

of Health,

Italy


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a - German Federal Environment Agency, 2008; adolescents aged 11-14

b - Health Canada, 2010; children aged 12-19

c - Fourth National Report on Human Exposure to Environmental Chemicals, CDC, 2009;

children aged 12-19

d – FLESH II, adolescents aged 14-15

e - PROBE survey, adolescents aged 13-15

Comparisons�

Blood metals (µµµµg/L), GM

Metal GerES IV a Health Canada b NHANES c FLESH II d PROBE e

M F M F

As 0.58 0.61 0.71 0.72

Cd 0.14 0.16 0.18 <0.14 0.21 0.29 0.29

Hg 0.26 0.29 0.33 0.49 0.77 0.78

Mn 9.44 10.6 9.66 7.24 7.22

Mo 0.70 0.65 1.10 1.11

Ni 0.62 0.63 1.25 0.94 0.94

Pb 14.5 8.8 7.1 <0.42 14.8 9.60 8.75




LIFE12 ENV/GR/01040

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of Health,

Italy


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Element SexBraces/

FillingsPiercing Traffic

Second-

hand

smoking

Fish SES

As 0.0025 0.004 0.0005 0.0095

Cd 0.004

Cr 0.011 0.018

Hg 0.0374 0.018 0.0043

Ni 0.0367

Pb 0.000 0.0026 0.015

Pd* 0.030

(K-W or M-W test, p-values)

Differences




LIFE12 ENV/GR/01040

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Institute

of Health,

Italy


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0

5

10

15

20

25

As Cd Cr Hg Mn Mo Ni Pt W

ug

/Lit

er No fish

Fish=1

Fish =2

Fish=3

Association between HBM concentration and fish/week




LIFE12 ENV/GR/01040

National

Institute

of Health,

Italy


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0

1

2

3

4

5

6

7

8

9

Cd Cr Mn Mo Ni Sb U

ug

/Lit

er No milk

Milk =1

Milk =2

Milk =3

Association between HBM concentration and milk/week




LIFE12 ENV/GR/01040

National

Institute

of Health,

Italy


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Metal 1 2 3 4

As

Cd

Co - - - -

Cr -

Hg - -

Ir

Mn

Mo

Ni - -

Pb -

Pd - - - -

Pt

Rh - -

Sb

Sn

Tl -

U -

V

W - - - -

- : no differences

: significant differences (p< 0.05)

Differences among the areas

(K-W test for independent samples)

Four areas: Rome (1)

Viterbo (2)

Fontenuova (3)

Monterotondo (4)




LIFE12 ENV/GR/01040

National

Institute

of Health,

Italy


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2

1

3

4

As Hg V

Rome (1) Viterbo (2) Fontenuova (3) Monterotondo (4)




3

2

1

4

LIFE12 ENV/GR/01040

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of Health,

Italy


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Mn

Urban areas

Ni Pb




LIFE12 ENV/GR/01040

National

Institute

of Health,

Italy


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y = 0.06x + 31.17

R2 = 0.06

29

30

31

32

33

34

35

36

0 5 10 15 20 25 30

Mn concentration in blood (ug/Liter)

PM10 concentration (ug/m3)

PM10 vs. Mn in blood



LIFE12 ENV/GR/01040

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Institute

of Health,

Italy


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GLM model results: significant associations

Dependent

VariableFish Milk

Land

cover

Fish +

Milk

Fish +

Land

cover

Milk +

Land

cover

Fish +

Milk +

Land

cover

Cr p = 0.000 p = 0.000 p = 0.000 p = 0.000

Ni p = 0.030

Pt p = 0.038

Hg p = 0.005




CROME Cross Mediterranean study

• Aims: to assess the long-term effects of early chemical exposure on

neuropsychological functions at 6-7 years;

• Slovenia, Greece and Croatia:

– follow up of the PHIME cohort;

– urine, blood, hair and saliva sampling;

– neuropsychological testing WISC IV (6-8 years of age)

– metal exposure and gene polymorphism analyses (SNPs)

• Italy:

– Follow up of the NACII in collaboration with University of Udine and Child

health IRCC Burlo Garofolo, Trieste

– Complete neuropsychological testing (7 years of age)

– measurement of chemical exposures (neurotoxic metals and

organophosphate insecticides) and genetic analysis to evidence markers of

individual susceptibility

• Spain:

– A comparative cohort to be established in Menorca




HEALTH OUTCOME: NEURODEVELOPMENTAL DISORDERS

disabilities in brain functioning that affect a child’s behaviour, social

competencies, memory, or ability to learn. They include mental

retardation, learning disabilities, ADHD, autism spectrum disorders

(ASDs)

HEALTH OUTCOME: NEURODEVELOPMENTAL DISORDERS

disabilities in brain functioning that affect a child’s behaviour, social

competencies, memory, or ability to learn. They include mental

retardation, learning disabilities, ADHD, autism spectrum disorders

(ASDs)

Characterized by:

•Early onset

•Male sex more affected

•Increasing prevalence rates in the

last two decades

• Significant heritability

20CROME Interregional meeting Roma, ISS, 21/04/2016 www.crome-life.eu Mapec meeting Pisa, 16/06/2016 www.crome-life.eu



21

ADHD

What

causes

autism???

ASD




Mercury (Hg)

• Routes of exposure

– Ingestion/ inhalation: >90% absorption

– Dermal: well absorbed; % depends on contact time

• Sources of exposure

– Primarily via ingestion of methyl mercury from fish

– Occupational exposures to other forms

– Some via inhalation

• Key Toxicities

– CNS; neurodevelopmental




EPA Reference Dose for

Chronic Oral Exposure

(RfD):

0.1 µµµµg/kg/bw

Calculated on the basis of

neuropsychological

effects in 7-year children

following prenatal

exposure (maternal blood

and hair)




Key Data on Mercury Neurobehavioural Toxicity

Hundreds of research papers have demonstrated mercury neurotoxicity

• Epidemic poisonings:

– Minamata

– Iraq

• Key epidemiological studies 1990’s:

– Faroe Islands;

– Seychelles Islands;

– New Zealand

– UK (Alpacs study)


Dati contrastanti! Effetti avversi Hg

in Faroe, nessun effetto Seichelles,

effetti positivi legati al consumo di

pesce in U




Faroe Study

• Study Overview

– >900 children

– Battery of neurodevelopmental/behaviour tests at several ages (18 months to 12 years)

– Mercury exposure from whale and fish

• Levels ranged from < 0.1- over 2 ppm

– Exposure measured by cord blood and hair

• Hair= 4.3 ppm

Deficits in several neurodevelopmentalendpoints observed:

�Effects subtle but significant�Cognitive function; neonatal neurological status; �Cardiovascular; post natal effects�Observed at several ages�Co-exposure to other chemicals: PCBs

�Effect still observed when controlled for !


MAIN RESULTS



Seichelles study

� Study overview

� >700 children, to 9 years of age

� Mercury in fish ranged from < 0.1 ppm- about 2 ppm, with average about

0.3 ppm

� Somewhat different battery of tests used: language; memory; motor;

cognitive; behavioral

� Measure of exposure: maternal hair: 6 ppm

“No evidence of neurodevelopmental

risk from prenatal methylmercury

exposure”.

•Differences from the Faroe study

explained on the basis of:

•absence of other contaminants’

exposure

•different nutritional factors

•life style

MAIN RESULTS




Mercury in the Mediterranean:

The distribution of mercury mineral

belts and most productive Hg mines

Drivers for Cross mediterranean study

CROME Interregional meeting Roma, ISS, 21/04/2016 www.crome-life.eu Mapec meeting Pisa, 16/06/2016 www.crome-life.eu



Drivers for Cross mediterranean study

• Mercury in fish in the Mediterranean is among the higher in the world

oceans

0

1,0

2,0

3,0

4,0

5,0

0 100 200 300 400

Body weight (kg)

Atlantic

Mediterranean

Total Hg in Thunnus thynnus

Concentration

(mg/kg, FW)

0 20 40 60

Body weight (g)

0

0,1

0,2

0,3

0,4

0,5

Concentration

(mg/kg, FW)

Total Hg in Sardina pilchardus

Mediterranean

Atlantic




PHIME – MEDITERRANEAN STUDY

AREAS

MERCURY MINING

Eastern Aegean CohortNorthern Adriatic Cohort I and II




Italy: Study design

Pregnancy Birth 18 months 3 years New assessment

at 6-7 years

Hg cord blood

Maternal blood

Maternal hair and urine Hg in Child’s urine and hair

Neurotoxic metals and OP pest

in childrens’ urine and hair

Genome-wide analysis in saliva

Neuropsychological assessment

Information on life style, dietary habits, environmental exposures




Cross-Mediterranean study

Data di esposizione ambientale resi disponibili dallo studio PHIME:

• Smoking behavior throughout the pregnancy,

• dental visits and new/replaced dental fillings throughout the pregnancy,

• detailed nutritional data: including different fish species and origin of a specific food

item (locally grown/caught or bought in the supermarket/local market).

• residential area: vicinity of industry, highways and different roads, railway station,

airport;

• potential occupational exposure to lead, mercury, gold and other metals, chromium,

pigments, PCBs, solvents, radioactive isotopes, amalgams

• general data on occupation

Altri dati derivati dal questionario compilati dai genitori:

• pregnancy history: mother’s age at delivery, BMI before pregnancy, weight gain

increase, health status and health records, type of delivery and delivery implications if

any;

• data on child: sex, birth weight and length, weight and length at 18 months,

breastfeeding history (any vs. none), duration and exclusiveness up to 4 months,

daycare attendance at 18 months, duration of the intake of fresh and homogenized

fish up to 18 months; health implications;

• socio-economic status data




PREVIOUS RESULTS




Results

18 months and 3 years

Chemical exposure:

• Strong correlation between consumption of different types of fish during pregnancy and total HG

levels in maternal hair (0.31< r < 0.43; p < 0.001) and cord blood (0.27< r < 0.51; p < 0.001);

• No major effects of total Hg levels in hair and cord blood at birth and neuropsychological

performances small but positive association between cord blood Hg and motor scores.

Life style factors:

• No correlation with fish intake during pregnancy and child neurodevelopment in the different

domains of the Bayley scales;

• Positive association between maternal IQ and child’s cognitive and motor scores.




Preliminary results 7 years

Chemical exposure:

Significant correlation between fish consumption during pregnancy

and breastfeeding by the mother and total Hg levels in child’s urine

No significant effects of total Hg levels in urine on the different

behavioral functions scored

Positive effect of Hg on some neuropsychological test

Adverse effect of manganese as measured in child's hair on the five

Wisc-II score, with statistically significant decrement of the general

IQ and of verbal comprehension.

Life style factors:

Positive effects on child neuropsychological scores of:

1) fish consumption, 2) maternal IQ and educational level of the

parents




In absence of significant impairments of behavioral functions

at different ages, the results highlight the complex interaction

between environmental exposures, life style and dietary

factors, and age at testing. They support the usefulness of the

integrated CROME approach in risk modelling.

These preliminary analyses confirm the results of other large

epidemiological studies on the neurobehavioural toxicity of

prenatal/neonatal mercury exposure at low doses.


ADDED VALUE OF THE CROME COMMON STUDY

Longitudinal analysis of neuropsychological maturation, to

detect delayed effects and the modification of the health

outcome (individual trajectory);

Repeated biomonitoring at different developmental stages to

capture the temporal dimension of the exposure




Next steps in CROME

• ISS will be responsible for preparing guidelines, including an integrated protocol of study of

health-environment association and a set of reccomendations to reduce the impact of

environmental contaminants on children’s health.

• The main goal is increasing awareness in the local and national health authorities on the risk

represented by chemical pollutants in the food chain, and promoting policies to protect the health

of the EU citizens, with specific attention to at-risk areas.

• The study protocol validated in CROME could be translated to future HBM initiatives, to implement

an integrated approach that takes into account the multeplicity of environmental factors potentially

impacting on human health

PREVENTION




ACKNOWLEDGEMENTS

• Flavia Chiarotti1, Fiorino Mirabella1, Aldina Venerosi1, Anna Pino1, Beatrice

Bocca1, Alessandro Alimonti1, Luca Ronfani 2, Liza Vecchi Brumatti 2,

Marika Mariuz 3, Valentina Rosolen 4, Fabio Barbone5

1Istituto Superiore di Sanita', Roma ITALY; 2Institute for Maternal and Child

Health - IRCCS "Burlo Garofolo" - Trieste, ITALY; 3DSMB, University of

Udine, and Central Health Directorate, Friuli Venezia Giulia Region, ITALY; 4DSMB, University of Udine, Udine, ITALY; 5DSMB, University of Udine and

DSM University of Trieste, Trieste, ITALY

• Neuropsychological scoring and biological analyses : Maura Bin 1, Veronica

Tognin1, Francesca Faletra1, Elisa Piscianz 2, Erica Valencic 1, Claudia

Loganes 2, Emmanouil Athanasakis 3 ; 1Institute for Maternal and Child

Health - IRCCS "Burlo Garofolo" - Trieste; 2DSMB, University of Udine,

and Central Health Directorate, Friuli Venezia Giulia Region; 3DSV,

University of Trieste

• The CROME partners for their invaluable contribution and expertise

• All the children and families of the NAC-II cohort who participated to the

study


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