Biomarkers and measuring the internal exposome

John Cherrie

PDC Session: The exposome and exposure in the workplace

Let’s take a minute to think…

�  Work with the person next to you. �  How can you distinguish biomarkers of effect

from biomarkers of exposure? �  Why is this important?

Summary…

�  Conventional biomonitoring of single substances

�  Targeted biomonitoring of multiple substances

�  Omics and untargeted studies �  Half-life and toxicologically-relevant window

�  Timing of sample collection �  Biobanking

Isocyanates…

�  A study to assess the changes in control of exposure to hexamethylene diisocyanate (HDI) based paints used in vehicle spraying after an intervention �  Paint sprayers and managers invited to one of 32

Safety and Health Awareness Days (SHADs) �  Urinary biomonitoring for

Hexamethylene diamine (HDA) �  Before and after the intervention

Jones, K., Cocker, J., & Piney, M. (2013). Isocyanate exposure control in motor vehicle paint spraying: evidence from biological monitoring. The Annals of Occupational Hygiene, 57(2), 200–209.

SHADs study

Differences not statistically significant

90th percentile 0.6 µmol/mol creatinine

0.6 µmol/mol creatinine

2.8 µmol/mol creatinine

SHADs study

Differences not statistically significant

90th percentile 0.6 µmol/mol creatinine

0.5 µmol/mol creatinine

Multiple biomarker studies…

�  Phthalates, perfluoroalkyl acids, metals and organochlorines and reproductive function �  a priori concerns �  cross-sectional study (n=602) of male partners of

pregnant women �  Fifteen contaminants were detected in more than

70% of blood samples �  Twenty-two reproductive biomarkers assessed

Lenters et al. (2014). Phthalates, perfluoroalkyl acids, metals and organochlorines and reproductive function: a multipollutant assessment in Greenlandic, Polish and Ukrainian men. OEM, 1–10.

Biomarkers are often correlated…

Outcomes…

�  Over 300 exposure–outcome associations �  10 associations encompassing 8 outcomes �  Several associations were consistent across

the three study populations �  Positive associations between mercury and inhibin

B and cadmium and testosterone �  Inverse associations between DiNP metabolites

and testosterone and polychlorinated biphenyl-153 and progressive sperm motility

Omics…

�  Omics is biomonitoring for multiple analytes �  Exposure �  Health status �  Disease occurrence and progression related

�  Evaluated for… �  Individual genes, RNA expression

(transcriptomics), protienomics, metabolomics, epigenomics and more!

Coughlin, S. S. (2014). Toward a road map for global -omics: a primer on -omic technologies. American Journal of Epidemiology, 180(12), 1188–1195.

4/25/15 HEALS Kick-Off Meeting Paris 11

Methodologies �  Non–targeted approaches �  Targeted / Semi–targeted

approaches – list of potentially significant metabolites

�  Analytical tools: �  Nuclear Magnetic Spectroscopy (NMR) �  Liquid Chromatography Mass

Spectrometry (LC-MS) �  Gas Chromatography MS (GC-MS) �  And more…

EWAS…

�  Patel and colleagues carried out an Environment-Wide Association Study on Type 2 diabetes �  266 environmental factors �  Four NHANES cohorts each involving 500 – 3,300

subjects �  Identified they had a potential false-discovery rate

of 10 to 30%

Patel, C. J., Bhattacharya, J., & Butte, A. J. (2010). An Environment-Wide Association Study (EWAS) on Type 2 Diabetes Mellitus. PLoS ONE, 5(5), e10746.

Agnostic approaches to identify disease associations…

�  Genome-wide association studies (GWAS) �  Steve Rappaport has suggested a similar

Exposome-wide association (EWAS) paradigm �  Assumes we start with cases of disease and

compare the omics profile (or the exposome) with controls (case-control study design)

�  How stable are the biomarkers? �  Are these biomarkers of effect or exposure?

“Meet-in-the-middle” approaches to understanding causality… �  With biomarkers of effect and exposure, associations

strengthen judgments of causality

Vineis et al (2013). Advancing the application of omics-based biomarkers in environmental epidemiology. Environmental and Molecular Mutagenesis, 54(7), 461–467.

Prospective study

Assess links between environment and risk-predictive biomarkers

Nested case-control study of intermediate biomarkers biomarkers

Exposure Biomarkers of Exposure

Intermediate omic markers Disease

Timing of sample collection…

Timing of sample collection… �  Preconception in parents �  During pregnancy, particularly the first trimester �  Childhood, before and after 3 years of age �  Puberty �  Adulthood, particularly middle age �  During menopause in women (between the age

of 45 years and 55 years) �  After 65 years �  Post 80 – 85 years

Biobanking samples…

�  Omics analysis needs samples, which must be collected prospectively and stored indefinitely �  Often requires storage at very low temperature �  Along with associated metadata �  Rigorous protocols for sample handling �  Industrial scale processing �  Informed consent and research governance

Elliott et al (2008). The UK Biobank sample handling and storage protocol for the collection, processing and archiving of human blood and urine. International Journal of Epidemiology, 37(2), 234–244.

The future!

�  We don’t need to have all the answers today… �  Analytical technology constantly improving �  Providing we have good long-term storage

we should be able to analyse samples in the future