INSTITUTE OF OCCUPATIONAL MEDICINE . Edinburgh . UK www.iom-world.org

Cancer and work

John CherrieI want

to

ELIMINATE

workplace

cancer

Summary…

• Europe’s dirtiest factory• What is cancer?• Workplace cancers• How do we identify carcinogens?• Toxicology• Epidemiology

• Causality• The International Agency for Research on

Cancer (IARC)

Europe’s dirtiest factory…

• Malcolm Carhart died from lung cancer

• Fred Richards had bladder cancer and survived

• 300 other men who worked at the Phurnacite plant in South Wales had their health damaged by their work Mr Fred Richards

This was a coal carbonization plant

Mortality in the plant…

• We carried out a mortality study in the plant in 1987• 17 year follow-up• 620 men included

• Increased cancer mortality• Lung – about 1.5x the expected numbers• Stomach – 1.6x• Prostate – 1.5x• Bladder – 2.7x

• Non-melanoma skin cancer commonly reported

What is cancer?• Diseases where abnormal cells

divide without control and are able to invade other tissues• Cancer cells can spread through the blood

and lymph systems

• The difference between a benign and a malignant tumour is the process of metastasis

• There are more than 100 different types of cancer

• Cancers are named according to the tissue where they originate, e.g. bladder cancer

Mutations…

• Normal cells grow by division• Mechanism controlled by

our genes

• In a very small number of instances a cell may be damaged• And cannot be repaired

• These cells should “self-destruct”• A process known as apoptosis

Mutations…

• Cells may accumulate genetic transformations

• Typically several mutations are needed to cause cells to proliferate• Grow uncontrollably

• This results in a mass of identical cells forming• This is a tumour• … but it may be benign!

Metastasis…

• Two additional things characterise malignant tumours:

• Local invasion• Metastasis

Main types of cancer…• Carcinoma - begins in the skin or tissues around

internal organs• Sarcoma - cancer that begins in bone, cartilage, fat,

muscle, blood vessels, or other connective or supportive tissue

• Leukemia - cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced and enter the blood

• Lymphoma and myeloma - cancers that begin in the cells of the immune system

• Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord

Workplace cancers…

• For most individual cancers it is not possible to be certain of the cause• Multi-causal• Long latency, typically 40 years for carcinomas• 20 years for leukaemia

• Most cancers are caused by the lifestyle we choose

• Some cancers are known to be associated with work or workplace exposures• e.g. lung cancer and diesel exhaust particulate

Key workplace carcinogens…

• There are more than 20 types of cancer that have been linked to work…

• Main occupational cancers in Britain are lung, mesothelioma, non-melanoma skin cancer (NMSC) and breast cancer

Bladder, Bone,Brain, Breast, Cervix, Kidney, Larynx, Leukaemia, Liver, Lung, Lympho-haematopoietic, Melanoma (eye), Mesothelioma,Multiple myeloma, Nasopharynx, NHL, NMSC, Oesophagus,Ovary, Pancreas, Sinonasal, Soft Tissue Sarcoma, Stomach, Thyroid

Identifying carcinogens?

• Epidemiology• Studies of working populations• Likely to be many other exposures present in the

workplace(s) and differences in the lifestyle of individuals

• Studies need to have exposure over many decades

• Toxicology• Experimental studies involving animals or cells,

where the dose is controlled• May be relatively short-term or may last two or

three years

Risk and associations…

• Risk is the likelihood of an individual developing a disease

• Epidemiology measures risk• A risk factor is a characteristic associated

with a disease• Exposure to a specific agent may be a risk

factor• Gender, age, dietary habits etc may also

be risk factors• Epidemiology identifies associations

between risk factors and disease

Incidence prevalence and death…

• Incidence is the rate of new cases of a disease• generally reported as the number of new

cases in a period, e.g. per year• more meaningful when reported as a fraction

of the population at risk, e.g., per 100,000 or per million

• Prevalence is the number of cases alive with the disease during a period of time (period prevalence)

• Death (= mortality)…Incidence

DeathPrevalence

Relative Risk and Standardised Mortality Ratio…• Results from a epidemiological study

in a factory are generally expressed as a Standardised Mortality Ratio (SMR)• Ratio of observed to expected mortality • Standardised for age and gender

• Relative Risk (RR) is the ratio of the disease rate in exposed persons compared to unexposed persons

Attributable fraction …

• Attributable Fraction is the proportion of a disease in a specific population that would be eliminated if people were unexposed

• So AF smoking is around 90%

• AF asbestos is around 80%€

AF = (1−1/RR)

€

AF = (Ie − In ) /Ie

Death rate (per 100,000)

Non-smoker

Smoker

No asbestos 11 123

Asbestos 58 602

Age-standardized lung cancer death rates

Hammond EC, Selikoff IJ, Seidman H. Asbestos exposure, cigarette smoking and death rates. Ann N Y Acad

Sci 1979;330:473-90.

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

Heterogeneity of lung cancer findings…

Asbestos toxicology studies…• Gardiner (1942) found that “on grinding …

they do not become more irritating but practically loose their power to provoke tissue reaction”

• Vorwald et al (1951) found that “The duration of exposure needed to develop an pulmonary reaction … is inversely proportional to the concentration of long fibres…”

• 1960s Merle Stanton at the National Cancer Institute studied mesothelioma induction by fibres using an implantation technique onto the pleura

21

Further toxicity studies have shown…

• Fibres are harmful because…• they are thin (d < 3m)• they are long (l > 5mm) and • because of their shape (l/d > 3) • and they persist in the lung

However…

• Animals are not humans!• Inhalation toxicity studies are often

carried out with small groups of animals at very high air concentrations• Danger of unrepresentative findings from

overloading the lungs

• Toxicity studies now often carried out with cellular systems • in vitro versus in vivo

• Toxicity data not a good indicator of risk

Guidelines for Judging Causality

• Strength of Association• Consistency

• Are results “similar” across studies

• Specificity• An exposure gives a single outcome

• Temporality• Biological gradient

• Response related to magnitude of exposure

• Plausibility• Coherence• Experiment• Analogy

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

Sir Austin Bradford–Hill

IARC monograph programme…• The International Agency for Research on

Cancer (IARC) Monographs published since 1971• Chemicals • Complex mixtures • Occupational exposures • Physical and biological agents • Lifestyle factors

• More than 900 agents have been evaluated • A source of scientific information on potential

carcinogens and support for prevention

The IARC Monographs…

• The International Agency for Research on Cancer (IARC) classify carcinogens as:• Group 1: The agent is carcinogenic to humans• Group 2A: The agent is probably carcinogenic to

humans• Group 2B: The agent is possibly carcinogenic to

humans• Group 3: The agent is not classifiable as to its

carcinogenicity to humans• Group 4: The agent is probably not carcinogenic

to humans

http://monographs.iarc.fr

Summary…

• Cancer is a multitude of different diseases, each with a variety of potential causes

• Many exposures in the workplace can cause cancer

• Epidemiology and Toxicology allow us to identify causal associations between exposures and specific cancers

• Risks are best quantified by epidemiology• IARC provides a reliable assessment of

human carcinogenicity