INTEGRATIVE COMPUTATIONAL

APPROACHES FOR EXPOSOME

ANALYSIS

Dr PATRIZIO ARRIGO
CNR INSTITUTE FOR MACROMOLECULAR STUDIES
EMAIL: arrigo@ge.ismac.cnr.it
 OUTLINE OF THE COURSE

The aim of this course is to offer a landscpe of ICT tools

and their integration in order to face the environmental
risk assessment taking into account different exposure
modality and duration

the course will initially consider separately the biological

aspects from the computational ones and then will analyze
their functional integration
 THE EXPOSOME: A GENERAL SURVEY
The term exposome was coined recently on the wake of OMIC
technologies. The exposome indicates the overall exposure of an organism
during his lifetime. The exposomic approach has been developed in a
human health perspective, however it could be extended to specific
ecological systems.
1. Determination of multiple low level exposures that co-occur in real life
conditions.

2. Analysis of contaminant impact on biological processes at

molecular,metabolic, cellular, developmental and organismic level.

3. Determination of critical level of overall exposure in different stage of

lifespan in order to develop policies to mitigate the risk of morbidity.
INFORMATIONAL FLOW IN ENVIRONMENTAL PUBLIC HEALTH

Engineering

Epidemiology

Toxicology
Public Health

4
 DIFFERENT TYPE OF EXPOSURE SOURCES
Social relations, Education

Exposome General Economical status, psychological and mental

stress Environmental context,climate
external
Radiation, Infectious diseases, Diet,lifestyle
Specific Chemical and environmental pollutants,
Occupational factor,medical operation
external

Metabolism,Hormones, body characteristics,physical

Internal activity endogenous microbiome, oxidative stress
products,ageing
DIFFERENT CLASS OF BIOMARKERS AND
SPECIFIC TECHNOLOGIES FOR SCREENING
Class of Biomarkers
General
Targeted
Sensor Technology
Imaging Technologies
(including mobile and video camera)
Improved conventional measurements
Available tools
Genomics, Transcriptomics, Proteomics,Metabolomics,
Epigenomics
Adductomics,Lipidomics, Immunomics
Environmental pollutants, physical activity,Stress, circadian Rithms
localization(GPS)
Behavior and experience,Stress,Diet,Physical activity
Exposure Matrices Dietary recall (interview about food
consuption in 24h)
DIFFERENCE BETWEEN EXPOSOME AND
ENVIROME
The two terms seem to be synonims,however they imply a subtle
difference
• The ENVIROME could be defined an holistic snapshot of the
whole multiscale exposure framework
• The EXPOSOME can be the analysis,in the time domain, of changes
in the holistic exposure framework
 EXTERNAL EXPOSOME (ECO-EXPOSOME AND
SOCIOEXPOSOME)
ECOEXPOSOME Definition From National Research Council USA:
Extension of exposure science from point of contact between stressor
and receptors inward into the organism and outward to th general
environment including ecosphere.
SOCIOEXPOSOME: The ensemble of social political and economical
components that could influence the exposure processes in order to
improve the collective awareness in the perspective to ameliorate the
environmental quality (sustainability)
 SOCIO-EXPOSOME

Data collection and analysis of information about the

Individual
Socoiexposome

subject in a panel in order to estimate the social

characteristics a population panel

Analysis of social political and economic forces

Local that can influence the exposure of a population

Analysis of factors that modify the social

Global organization and in which way they could
influence the exposure to hazards
 COMPLEXITY OF SOCIO ECONOMIC FACETS OF
EXPOSOME
Molecular
Individual Biomonitoring
Medical records

Official statistics
Epidemiological studies

Local Social environment al data

EcoExposome Physical environmental data
Political data

Governmental information
Global Corrporate data (economic)
Non profit civil organization
 PIONEERING PROJECTS FOCUSED ON AN
EXPOSOME PERSPECTIVE
• 2007 EPA project ToxCast: the aim of the project was the development of
HTS assay to screen the responses of a biological system suitable to
predict the adverse effects induced by chemical on human health
• 2012 EU FP-7 EXPOsOMICS is the first research program that has used
the term ‘exposome’ .The project was focused on the investigation of
environmental stress factors, both external and internal, that can trigger
adverse effects on human health
• 2015 EU Commission and personal care industries funded the SEURAT. The
aim of the project was the development of tools to replace the animal
testing of personal care ad cosmetic products
• 2016 EPA project ExpoCast that is a complement of ToxCast
KEY POINT OF RISK ASSESSMENT PROCESS

• Hazard Identification: characterization of adverse environmental or health effects

triggered by a specific stressor
• Dose-response assessment: Estimate the probability that the exposure to a
specific dose range of a chemical can induce an adverse effect on environment
or health.
• Exposure Assessment Determination of doses and time of exposure in which a
population in incurred
• Risk Characterization Analysis of the risk type and magnitude on the basis of
actual exposure conditions. Determination of mitigation reducing the impact of
each actual stress factors and, conversely, the increase of risk due to the each
stress factor
 OVERVIEW OF EXPOSURE SCIENCE
Epidemiological aspects of exposure

Environmenntal monitoring Toxicological aspects of

Exposure exposure
Medium INTERNAL
Environmental EXPOSURE TARGET
Source of distribution (Air,water,food & EXTERNAL (Absorbed,intake EXPOSURE (genes, ALTERED
Pollutants drink, consumer exposure proteins, cells,
context products, amount, level in OUTCOME
tissues and organs)
(water,air, soil) pharmaceuticals biofluids
)
 RELATIONSHIP BETWEEN AEP AND AOP

Justin G. Teeguarden; Yu-Mei Tan; Stephen W. Edwards; Jeremy A. Leonard; Kim A. Anderson; Richard A. Corley;
Molly L. Kile; Staci M. Simonich; David Stone; Robert L. Tanguay; Katrina M. Waters; Stacey L. Harper;
David E. Williams; Environ. Sci. Technol. 2016, 50, 4579-4586.DOI: 10.1021/acs.est.5b05311
Copyright © 2016 American Chemical Society
 EXPOSOME
Environmental Monitoring

EXPERIMENTAL Personal monitoring

Biomonitoring
Exposure
Assessment
Far-field exposure models

COMPUTATIONAL
Pharmacokinetic
Near-field exposure models

Reverse toxicokinetic
Dynamical models models
 IN SILICO AND WET LAB INFORMATION A FOR
TOXICOLOGICAL ASPECTSEXPOSOME
Pharmacokinetic
models
Computational ADME models
Models
ChemoInformatics
Docking models
Virtual Cell
QSAR models
Model
Population System Biology
Model models Virtual Tissue
Toxicology Model
Experimental Assay Pharmacokineti
c Assay
Cell-free assay
& Cell based
assay
Molecular
epidemiology Organ based
assay
 MULTISCALE RESPONSES TO EXPOSURE
• Structural
• Inflammation deficit
• Tissue necrosis • Functional
• Hyperplasia deficit
• Hypertrophy • Diseases

Interaction Tissue and

External Internal target with Cell organ Outcome
exposure exposure exposure biomolecule response response
s

• Covalent binding • Viability

• Receptor–ligand binding
• Protein peroxidation
• Inhibition of protein
function
• Protein stability
modification
• Apoptosis
• Necrosis
• Proliferation
• Differentiation
• Gene expression
• Enzyme induction or inhibition
 THE EXPOSURE ALIGNMENT
The exposure alignment indicates the compartison of biological response across different
experimental systems in order to evaluate the concordance and consistency of exposure-
response relationship.
Protein Binding
Cell Free Degradation
Loss of Functionality

Cell Culture Metabolism,Uptake

Pasrticle Size,solubility, Consistent
agglomeration esxposure
Air-liquid metrics
interface Chemical-physics characterization For muliscale
of stressors
alignment
Organ-on-a chip Molecular information
Metabolic information
Phramacokinetic information
Animal Model
Biokinetic data (ADME)

Human
Biokinetic data (ADME)
 PIVOTAL APPLICATIONS FOR EXPOSURE
SCIENCE

• Alignment exposures between test systems and human

• Improving exposure assessment for epidemiological sudies
• Exposure-based screening and priority-setting
• Identify new chemical exposures for toxicity testing
• Predicting exposure to support registrationand use of chemicals
• Identifying, evaluating and mitigating sources of exposure
• Assessing cumulative exposure and exposure to mixtures
 DEFINITION OF MAIN TYPE OF EXPOSURE FOR
COMPUTATIONAL ASSESSMENT
• Near-field chemical exposure: is the environmental stress resulting from the
release or use of chemicals in proximity of a subject. This definition encompasses the direct
skin contact (cosmetics, sunscreens etc), the inhalation (tobacco smoke etc) and ingestion
(drugs) The exposure can be due to an intentional use (cosmetic) or due to an accidental
release of chemical pollutants near an individual Indoor pollution is near-field exposure.

• Far-field chemical exposure: The stress results from a release or use distal from the
subject . Food and water could be contamined by chemicals spreaded in environment far
from the subject.

• Aggregate exposure: Is the overall exposure to a given substance derived by multiple

pollutant sources and pathways
 PERSONALIZED EXPOSURE ASSESSMENT

• Determination of indivual exposure

taking into account spatial and
temporal variations. The screening can be carried out inside or
outside the body.
• Portable sensors array are under development to meaure multiple
pollutants.
• Mobility-based exposure assessment use personal devices with
geolocalization (Remote sensing) to determine the where and when
people
• Consumer products information and related repository combined with
 TARGETED AND NON-TARGETED CHEMICAL
EXPOSURE ASSESSEMENT
• Targeted Analysis It is carried out only on selected chemicals for which
standard and methods are well established. The screening techniques are
consolidated (MS,HPLC, NMR and so on). This approach is limited by the
availability of standards for chemical pollutants.
• Non targeted approach provides qualitative information about a large
portion of uncharacterised components of exposome including
endogenous metabolites macromolecules and exogenous chemicals,
metabolites and so on. This approach cannot yet allow to correlate the
presence of an analyte with a clinically relevant effect.
 CONSTRAINS IN EXPOSOME DECISION MAKING
SYSTEMS
• Large variability among the screening data influenced by limited to
multsource and multiroute assessment in longitudinal studies at population
level. Data uncertainty, sensitivity combined with variability can give an
estimate of exposure capable to induce an effect outside of reliable range
• Balance between quality of exposure data and the cost of data acquisition
• The context in which the exposure assessment is formulated and for which
the decision must be assumed.
• Contamination of samples collected without information about exposure
intake or lacking of temporal resolution (sampling in the time space)
 EXPOSOME CONCEPTUAL STRUCTURE

CENTRAL CONCEPT

Published in: Carolyn J. Mattingly; Thomas E. McKone; Michael A. Callahan; Judith A. Blake;
Elaine A. Cohen Hubal; Environ. Sci. Technol. 2012, 46, 3046-3053.DOI: 10.1021/es2033857
Copyright © 2012 American Chemical Society
 A WORKFLOW FOR SITE BASED EXPOSURE
ASSESSMENT
Exposure
Characterization of cleanup
Targeted Chemicals mitigation
Environmental Analysis
Hazard
context
Dose-response
Assessement
Non targeted
Analysis Identification of
new chemicals Risk
Assesement

Experimetal identification Collection of

of bioactive chemicals toxicity data

Identify exposures from

epidemiolgical & omic
studies
 WORKFLOW FOR CHEMICAL BASED EXPOSURE
ASSESSMENT

Search of analogues Toxicity data of

using physicochemical best analogues Point pf*
properties and structure Departure

Chemical of
interest Refined
PoD
Tune the pharmacokinetic
and bioctivity of chemical
under investigation
HTS in vitro assay
(omic data) Health Reference
Value

The point of departure (PoD )s defined as the point of dose-response curve corresponding to minimal effect or
no effect
 EXPOSOME AND BIG DATA

MULTI -OMIC
DATA

GEOLOGICAL &
CLIMATOLOGICAL
DATA EPIDEMIOLOGICAL DATA

• EXPOSOME

ENVIRONMENTAL
SOCIO DATA
ECONOMIC DATA
ELEMENTS REQUIRED TO ESTIMATE THE ASSOCIATION
OF HEALTH EFFECTS AND COMPONENTS,PATHWAYS
AND MECHANISM OF ACTION
• Temporality: The relation between exposure and the effect on health in thee timeme domain is not easy
to identify. The sequence of elementary events cannot be completely clarified.
• Strenght of Association: The magnitude of the effect is important however it is not always
discriminative
• Consistency: The reproducibilty of results is a key point. Inconsistent results could be related to
specific assay perfomance and also in domai applicability.Incosistendt outtcome can imply causal
relations
• Plausibility: Determination if a proposed mechanism agrees with current knwoledge. The plausibility is
heavily dependent on the state of art
• Specificity: It indicate a specific relationship between a single exposure and diesease
• Coherence: It is an elemento of plausibility. It takes into account the complimentarity of different proof
of cause and effect. It can be estimated across different levels of organization (vertical coherence) or
taking into account diffeerentt effect at the same level of organization (horizontal coherence)
 EXPOSOME REFERENCES
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