The exposome

John Cherrie

PDC Session: The exposome and exposure in the workplace

Summary…

�  Cholera and Snow �  Causation: from exposure to disease �  Why is causation important? �  How do we decide an association is causal? �  Success and failure �  The exposome, a new paradigm �  Inside and outside �  How to discover causal relationships?

Cholera…

�  In the early part of the 19th Century people believed cholera and other diseases were caused by a miasma

�  Miasma theory made sense to the sanitary reformers

�  However, Contagion or germ theory ultimately made more sense

John Snow (1813 – 58)

�  Cholera outbreak in London in 1854

�  Snow recorded the location of deaths related to cholera

�  The majority were clustered around one public water pump in Broad Street, Soho

�  He convinced officials to remove the handle to the pump

Anesthesia…

�  Snow also pioneered the use of anesthetics

Professor Sir James Young Simpson

http://www.rsc.org/chemistryworld/podcast/CIIEcompounds/transcripts/chloroform.asp

Causation…

�  A cause of a disease is an event, condition, characteristic, or combination of these factors that plays an important role in producing the disease

�  A cause could be sufficient or necessary �  Necessary = must be present for the disease to

occur �  Sufficient = inevitably produces or initiates a

disease

Populations and people…

�  Identification of necessary causes of disease in individuals is practicable

�  Identification of sufficient causes is more difficult

�  Identification of sufficient causes for individuals for multicausal diseases is not possible

�  Epidemiology solves this problem by dealing with populations Rose, G. (1985). Sick individuals and sick populations. International Journal of Epidemiology, 14(1), 32–38.

Tuberculosis…

Susceptible host Infection Tuberculosis

Risk factors Disease mechanisms

Exposure to bacteria

Genetic factors

Poverty Crowded housing

Malnutrition

Tissue invasion

Causal inference from associations…

AB Hill. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–300.

Sir Austin Bradford–Hill

Methodological questions

Evidence questions

Could selection or measurement bias cause the association?

Is there a relationship between exposure and biological response?

Could it be due to confounding?

Is an association biologically plausible?

Could it be due to chance?

Is there a strong relationship?

In 1965 Hill proposed nine criteria to judge the scientific evidence for disease causality.

Some guidelines for causation… Temporal relationship Does the presumed cause precede the disease?

Exposure-response relationship

Does varying exposure result in varying amounts of disease?

Strength of association Does the exposure raise the incidence of the disease?

Specificity Does the exposure cause specific diseases and are the diseases associated with a limited number of exposures?

Consistency Is the association consistent across studies and population sub-groups?

Experimental confirmation Does manipulating the level of exposure vary the disease experience?

Biological plausibility Is the mechanism of action understood?

Asbestos and cancer

�  Earliest suspicions about cancer in the 1930s

�  The link between asbestos and lung cancer was made in 1955 by Richard Doll �  Later confirmed in several epidemiological studies

�  In 1960 Chris Wagner noted high incidence of mesothelioma in the crocidolite mines in South Africa �  Also confirmed in epidemiological studies

http://www.sciencemuseum.org.uk/broughttolife/people/richarddoll.aspx

Causation and mesothelioma Temporal relationship Exposure precedes diagnosis of disease by on average 40

years Exposure-response relationship

Increasing exposure in a population increases the incidence

Strength of association For crocidolite and amosite there is a clear association, less clear for chrysotile

Specificity Asbestos causes several cancers, including mesothelioma. There is limited evidence for other causes of mesothelioma.

Consistency The associations are reasonably consistent across studies

Experimental confirmation

Animal experiments confirm that fibres can cause pleural tumours

Biological plausibility The mechanism of causation is not fully understood, but it is plausible that fibres could cause mesothelioma

Surely our genes explain everything? �  Phenylketonuria (PKU) is a rare genetic condition

�  the body can’t break down phenylalanine, which builds up in the blood and brain. High levels of phenylalanine can damage the brain

�  Brain damage can be prevented with a special low-protein diet

�  Death from a car accident �  For example from drunk driving �  Perhaps the person has a genetic

trait that results in a predisposition to alcoholism

Rothman, K., & Greenland, S. (2005). Causation and causal inference in epidemiology. American Journal of Public Health. http://doi.org/10.2105/AJPH.2004.059204

The Barker hypothesis…

�  The environment of the foetus and infant, determined by the mother's nutrition and the baby's exposure to infection after birth, determines the pathologies of later life

�  The "foetal programming” hypothesis

Prof David Barker Barker, D. J. P. (2012). Developmental origins of chronic disease. Public Health, 126(3), 185–189.

The Dutch Hunger Winter…

�  In 1944 the German occupation limited food in the west of the Netherlands

�  Pregnant women also affected �  Children exposed during early gestation

experienced in later life elevated rates of obesity, altered lipid profiles, cardiovascular disease, and accelerated cognitive ageing compared to others born at that time

Schulz, L.C. (2010). The Dutch Hunger Winter and the developmental origins of health and disease. PNAS, 107(39), 16757–16758.

Multi-causality… �  A disease can be caused by more than one

mechanism, and each causal pathway involves the joint action of a number of component causes

�  A cause may be neither necessary nor sufficient for the disease, but it’s removal will reduce the incidence of disease

Causal path 1 Causal path 3 Causal path 2

Adding up all the causes… �  Adding the proportion of disease from each

cause results in more than 100% �  Attributable Fraction (AF) is the proportion of a

disease in a specific population that would be eliminated if people were unexposed…

€

AF = (1−1/RR)

€

AF = (Ie − In ) /Ie

Asbestos and smoking…

�  Asbestos and smoking both cause lung cancer… �  AF for smoking is

around 90% �  AF asbestos is

around 80% �  AF for smoking

and asbestos is 98%

Death rate (per 100,000)

Non-smoker

Smoker

No asbestos 11 123 Asbestos 58 602

Age-standardized lung cancer rates

Hammond EC, Selikoff IJ, Seidman H. Asbestos exposure, cigarette smoking and death rates. Ann N Y Acad Sci 1979;330:473-90.

How successful have we been?

�  Confirmation of a hazard �  Recent epidemiological studies of benzene in

relation to hematological malignancies �  Understanding of the relationship between

exposure and disease �  Diesel engine exhaust particulate and lung cancer

�  Discovery of unknown causes �  Breast cancer and shift work involving night work

Two-thirds of the deaths in the world are caused by noncommunicable diseases, especially cancer and cardiovascular disease

Only about 10% of this mortality attributed to genetic variation

The exposome is composed of every exposure to which an individual is subjected from conception to death.

Chris Wild

Steve Rappaport

Unknown

Airborne particles

Smoking

High blood sugar

High sodium

Alcohol

High cholesterol Lead Drugs

Ozone Low vit A

Low iron Radon Low

zinc

Rappaport, S. M., Barupal, D. K., Wishart, D., Vineis, P., & Scalbert, A. (2014). The Blood Exposome and Its Role in Discovering Causes of Disease. Environmental Health Perspectives, 1–6.

The Exposome…

The exposome is composed of every exposure to which an individual is subjected from conception to death.

Wild, C. P. (2012). The exposome: from concept to utility. International Journal of Epidemiology, 41(1), 24–32.

It comprises: §  processes internal to the body such as

metabolism, gut microflora, inflammation… §  external exposures including infectious agents, chemical

contaminants, diet… §  social, economic and psychological influences.

Chris Wild

Bottom-up or Top-down

van Tongeren, M., & Cherrie, J. (2012). An Integrated Approach to the Exposome. Environmental Health Perspectives, 120(3), a103–a104.

Or a more use a more integrated approach?

Critical life stages

Wild, C. P. (2012).

Big guns…

�  In Europe �  The EU has funded three large studies: Helix,

Exposomics and HEALS �  In the USA

�  The NIEHS has a developing programme of exposome research, e.g. the HERCULES Project

�  Total Worker Health from NIOSH

A new paradigm…

�  Chance has played an important part in the discovery of many (most) causes of disease

�  A more systematic “agnostic” approach may help uncover new causes

�  Requires a different approach to epidemiological study

�  How relevant is it for workplace exposures?

Acknowledgement…

The HEALS project has received funding from the European Union’s Seventh Programme for research, technological development and demonstration under grant agreement No 603946.