Jack: Hi all, in this lecture,
we'll continue our discussions
of the epidemiology of lung cancer
by discussing risk factors in tobacco carcinogenesis.
Our two main goals are to describe tobacco carcinogenesis
and to review studies of other lung cancer risk factors.
So to begin with, tobacco smoke contains
several carcinogenic chemicals.
These are divided into three main classes,
the polycyclic aromatic hydrocarbons,
nitrous amines, and heterocyclic amines.
These chemicals are taken up by the body
and cause DNA mutations and damage,
which leads to the cell division
that is responsible for lung cancers.
Tobacco smoke is a complex mixture
of more than 5,000 gases and compounds,
which has made it difficult to determine
exactly what these carcinogens are,
though many different epidemiologic studies
have elucidated these three main classes
as the ones responsible for cancers.
So in addition to these three carcinogen classes,
there's other chemical compounds that are present
that are highly inflammatory to lung tissues.
One of the primary ones is tobacco residue, or tar.
It's the common name given to the particular matter
of tobacco smoke without nicotine and water content.
So tar is a mixture, actually,
of thousands of compounds
resulting from the combustion
of tobacco and tobacco resins.
And it's estimated that lungs of a chronic smoker
of 20 or more cigarettes per day for 40 years
are exposed to 8 to 10 kilograms of tar.
So when it comes to lung cancer,
there are several synergistic risk factors.
So key risk factors are asbestos fibers,
radon, arsenic, cadmium, lead, dioxins,
genetic predisposition, and diet.
And in particular, all these exposures
can be responsible
for chronic inflammation in lung tissues,
and it's the inflammation that's responsible
for the increased risk of lung cancer.
So to begin with, or to touch upon one example,
radon is a key risk factor for lung cancer.
It's a colorless and odorless gas,
and it's capable of damaging DNA,
which can cause mutations
that can lead to carcinogenesis
and the development of lung cancer.
There have been several studies
that have pointed to radon
as a risk factor for lung cancer.
So in early ecological study of lung cancer in Maine,
estimates of radon levels in domestic water supplies
were found to be significantly correlated
with county rates of lung cancer across the states.
A study also found that exposure to radon in uranium miners
was found to be independently,
or was found to independently increase
the miner's risk of lung cancer.
Finally, the Iowa Radon Study
found a significant dose response and lung cancer risk
in women with communicative radon exposures
exceeding five picocuries,
which is the measure of exposure to radon.
So in 1994, the US EPA,
or the Environmental Protection Agency,
issued a warning that radon
could be the second most frequent cause of lung cancer,
after cigarette smoking.
And it's important to note or to remember
the discussion of Hill's criteria of causality,
that the determination
that radon is a significant risk factor,
that conclusion was only made
after looking at a number of independent studies
and seeing that their conclusions all pointed
to radon as a risk factor.
Next, to discuss another risk factor,
asbestos causes mesothelioma
and malignancy of the tissue surrounding the lung.
The etiologic link between mesothelioma
and asbestos exposure is well established
through numerous studies.
And the way that asbestos leads to lung inflammation
is that the inhaled fibers migrate
to the periphery of the lung
where they become trapped
and cause repetitive inflammatory events,
which lead to carcinogenesis.
It's also estimated those asbestos workers
with a history of chronic smoking
have eightfold higher lung cancer risk
than smokers who have not been exposed to asbestos.
In addition, asbestos-exposed male smokers
have roughly 50 times the lung cancer risk
of unexposed men who do not smoke.
And we see that from this figure here,
that smoking and asbestos exposure
really acts synergistically
to increase one's risk of lung cancer.
Next, wood smoke is another important risk factor
for lung cancer.
It contains a mixture of harmful chemicals
in the form of gases and particulate matter,
like carbon monoxide, ozone, nitrous oxides,
sulfur dioxide, volatile organic compounds,
dioxin, potential carcinogens,
and inhalable particles.
And certain of these compounds
are not only irritating and toxic,
but also potent carcinogens on their own.
It's been estimated that residential wood combustion
may account for up to 75%
of the exposure to particulate associated organics
and account for a significant fraction
of the cancer risk
in the upper respiratory tract of non-smokers.
Exposure to wood smoke
may increase the risk of lung cancer
via a mechanism similar to that of tobacco.
And the role of air pollution
in the genesis of lung cancer
was examined in a prospective cohort study
of more than one million American men and women
conducted by investigators
at the American Cancer Society.
These study results showed that for each 1% increase
in the the concentration of particles in the air
led to a 14% increase
in the risk of developing a lung cancer.
It's important to note, too,
that people can be exposed to wood smoke
and various sources of air pollution in different ways.
So in certain parts of the world,
wood and burning wood can be used to heat one's home,
and it's also a key way
that people in some countries
and communities will cook food.
So there's lots of exposure related to people who cook,
especially when there's wood-burning stoves
inside a house without proper ventilation.
So next, to briefly touch
upon chronic obstructive pulmonary disease, or COPD,
which causes three million deaths annually
in the world population,
it's a chronic inflammatory condition
and it increases the risk of lung cancer.
Other key risk factors for lung cancer
are dioxins and arsenic.
So dioxins are metabolized by a couple of liver enzymes
into compounds with carcinogenic potential
in lung cells and other tissues.
One study that looked at the population
of a town in Italy, Sevenso,
there was exposed to dioxin
after an industrial accident that occurred in 1976.
Then, after this accident,
lung cancer mortality among men
in high exposure zones was significantly increased.
The results of this study
support the continued evaluation of dioxin
as a lung carcinogen
and underscore the need to also study interactions
with tobacco and other risk factors.
Longterm exposure to low levels
of arsenic in drinking water
have been linked to human health risks
associated with cancer at multiple sites,
including the lung, bladder, and skin.
Studies have shown that the malignant transformation
of mammalian cells by inorganic arsenic occurs
and that arsenic exposure is both mutagenic
and carcinogenic in humans.
A study in Chile over the course of 50 years
looking at a population exposed
to arsenic contaminated drinking water,
it was shown that toxic arsenic exposure
greatly increased lung cancer risk
when exposure occurred in utero or early in life.
Another key risk factor
is environmental tobacco smoke,
or secondhand smoke.
We see that environmental tobacco smoke
inhaled by non-smokers has higher levels
of nitrosamines and smaller particle sizes,
leading to easier deposition within the bronchial tree.
Approximately one-third of lung cancer in non-smokers
results from passive exposure
to secondhand cigarette smoke,
and environmental tobacco smoke or secondhand smoke
increases the risk of heart attacks
and myocardial infraction in adults,
and is also linked to various conditions in children,
including sudden infant death syndrome,
ear infections, and asthmatic effects.
To turn slightly from the risk factors
we've been discussing,
we'll next discuss the Japanese smoking paradox.
So the Japanese smoking paradox stems
from discrepancies in lung cancer rates
in Japan versus the US.
Despite the fact that the prevalence
of chronic cigarette smoking among Japanese men
is approximately twice that of American men,
their lung cancer rates are substantially lower.
An early international case-control study
of smoking and lung cancer in Japan and the United States
found that the relative risk
of lung cancer development among chronic smokers
is tenfold higher in US men
compared to Japanese men.
Japanese smokers are exposed to lower concentrations
of carcinogens in their cigarettes
because tobacco blends used
in formulating cigarettes differ in the US and Japan,
and most Japanese cigarettes
are made with charcoal filters
that more effectively filter out
nitrates and nitrous amines.
We also see that one reason behind this paradox
might be because Japanese men
begin smoking at a later age than American men,
by two to three years on average,
and that Japanese men are exposed
to other risk factors at lower rates than American men.
So for example,
Japanese men consume less alcohol than American men,
they consume less fat in their diets than Americans,
and they have a high level of fish consumption.
In fact, Japan has one of the highest annual levels
of fish consumption in the world,
consuming about 70 kilograms of fish per capita,
which is more than fourfold higher than the US level.
A case control study conducted in 2001
found that consumption of cooked or raw fish
reduced the risk of lung cancer
in both men and women by about 50% in Japan.
Since eating fresh fish
provides an excellent source
of complex polyunsaturated fatty acids
and then have potent anti-inflammatory effects,
it's possible that regular fish consumption
by Japanese smokers inhibits
or delays lung carcinogenesis by tobacco smoke.
Next, we see that certain viruses
have been implicated in lung carcinogenesis
by virtue of their presence in lung cancer specimens.
So we know that chronic lung infections
due to certain viruses can cause lung cancer in animals.
For example, JSRV, which is a kind of sheep retrovirus,
causes pulmonary adenocarcinoma in sheep.
Among viruses that have been found
in human lung cancer specimens,
we see that there have been human papillomavirus strains,
JC-virus, simian virus-40, BK virus,
and cytomegalovirus.
While these viruses have been found in samples,
the role of viral infection
in human lung cancer development
has not been definitively proven.
It's highly likely that acute viral infection
present at the time of lung cancer diagnosis
is an effect of the lower susceptibility
of such patients rather than the cause
of a protracted course of carcinogenesis over many years.
Genetic studies have also identified genetic polymorphisms
and mutant forms of genes that regulate key mechanisms
of lung carcinogenesis.
So we see that, among genes
that are potentially implicated in lung carcinogenesis,
there are lungs that regulate the cell cycle
and cell division, genes that control DNA repair enzymes,
genes that play a role in the inflammatory cascade,
and genes that modulate phase 1
and phase 2 liver enzymes.
Finally, we will turn to discuss cyclooxygenase-2,
or COX-2, which we begin discussing in this lecture
though it will continue to play a role
throughout this course, as it's a really key factor
in the inflammatory cascade
in multiple tissues of the body.
So it was first suggested that chronic inflammation
leads to cancer development
by a German pathologist in 1863.
Then, more than 100 years later, by 1989,
an inducible enzyme called cyclooxygenase-2,
or COX-2, was discovered
by various scientists.
In 1991, the human version of the gene was cloned,
and it's been found that this gene, COX-2,
is normally silent in non-inflamed tissues.
But when stimulated by inflammatory factors
like those in tobacco smoke,
COX-2 transcription is triggered
leading to the enzymatic conversion of a specific acid
into molecules called prostaglandins
that are highly inflammatory.
So it was really the discovery
of this COX-2 gene that led to the interest
in the causal link between inflammation and cancer.
So after this gene was discovered,
a huge volume of cohesive scientific evidence
from molecular animal and human investigations
support the hypothesis
that sustained induction of COX-2
and upregulation of the prostaglandin cascade
by chronic exposure to inflammatory agents
promotes the development of cancer,
including cancer of the lungs.
Finally, there is evidence that chronic exposure
to many highly inflammatory constituents of cigarette smoke
promotes lung carcinogenesis, and reciprocally,
the blockade of the process has strong potential
for cancer prevention and therapy.