(1) Occupatio& Cancer

Since the observation in 1775 that the incidence of scrotal cancer

was unusually high in chimney sweeps, our knowledge of environmental cancer
in man has been chiefly based on studies of occupational groups with unusually
high cancer rates,
response, and relation of types of cancer to environmental agents has been
based on detailed studies of occupational cancer,
on the environmental aspects of lung cancer have been obtained in the general
population with investigation of such factors  as cigarette smoking and air
pollution as causal agents.  A partial list of occupations as they pertain
to cancer of the lung fallows:

Our knowledge of such factors as latent period, dose

More recently, similar data

Radioactive or mining and smelting
Coke oven operators
Gas works operators
Chromium ore refining
Nickel ore refining
Asbestos mining and use
Welders, Steam fitters, Short order cooks,

Crane operators, Foundry workers

At present, occupational cancer offers two additional unique

opportunities for research. (I) The growth in number, efficiency, and
reliability of hospital cancer registries, state tumor registries, as well
as a most laudable spirit of willingness and cooperation on the part of
industry (private corporations as well as nationwide trade associations )
makes it now appear feasible to determine the actual contribution of occupa-
tional cancer to the total cancer spectrum in the United States. The increment
represented by occupationally determined or occupationally caused cancers
may be as little as 2 to 5% or as much as 35 to 5G$*
we are awe of this and since correction of occupational cancer environments
has thus far been the most effective means of cancer control, a long-term
study to determine its actual significance seems timely and important,
Further, the study will inevitably contribute to our more accurately assessing
the role of non-occupational environmental factors and cancer. (2) The
second opportunity provided by studies in occupational cancer is that persons
at higher risk to cancer of any site because of occupational experience make
up prime population groups for fundamental studies on the pro-neoplastic and
pre-neoplastic states, The farmer term describes individuals at higher risk
to cancer because of the specific environment in which they mrk;  the latter
describes individuals who in addition to being in a high risk environment
have certain pathological or other biological stigmata irdicating the earliest
stages of tissue reactions including benign lesions which may progress to
overt cancer.  Such patients can be studied using such recent, inportant, and
relevant techniques of cytogenetics (chromosomal studies for the presence of
abnormalities which may herald an oncoming cancer), biochemistry in which
metabolic abnormalities in target organ sites may be identified by enzymes
and other protein studies, and histopathological, histochemical and electron
microscopic studies of cells from organ or organ systems at high risk.

We do not 'know.

Because

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(2) Double Primary

An exciting and potentially very useful tool in studying the

causes of cancer is the growing recognition and supporting evidence that
a person with a previously diagnosed, successfully treated cancer is at
greater risk to a second, independent primary cancer than appropriate
controls,  Recently,  the successful treatment of cancer has permitted
patients to survive long enough to develop a second cancer,
of a second tumor is of critical importance as it may well indicate a
systemic factgr in susceptfbility to cancer induction.  Though thls has
long-beck suspected, this appears to be the first time we have the avail-
ability of model systems to study this important problem,  For example,
a patient with oral cancer who has been treated and cured is perhaps at
fifty times the risk to esophageal cancer compared to appropriately selected
controls. Similarly, iFcreased ____ risk to visceral cancer (cancer of internal
organs) has been observed in patients with cancer in sE6 =-€he skin.
Associations of this kind permit the use of these gtients for fundamental
biochemical, physiolugical, and pharmacological studies of the pro-malignant
or pre-malignant state a8 noted above under occupational cancer.

(3)

This development

I _._--

Metabulic Approach to Epidemiolugic Observations on Selected Populations

Just as it has been long known that during an epidemic of an

infectious disease not all of the exposed population succumbs, so in high
risk cancer environments not all of the exposed develop cancer,  For
infectious diseases, an Fmmunologic basis for patterns of residence and
susceptibility appear to aca unt for the epidemiologic observations,
neoplastic disease, a possible explanation may reside in the capability of
the host to met-uze, detmify and excrete environmental carcinogens,
Specifically, one my ask,'%?hy by far do mast of those two-pack-a-day, twenty-
year cigarette smokers not develop lung cancer?"
complex and certainly involves  such factors as intensity and duration of
exposure (dose), age at onset of exposure, and frequency of intervals of
exposure as well as host factors which appear to be operative in establishing
"susceptibility" and "resistance."  Pertinent and relative to this is the
observation that populations migrating from country to country as well as
from rural to urban areas significantly alter their risk to cancer of
virtually all sites,
and mortality rates of the country to which they have immigrated,
others, they retain the pattern of the country from wbich they emigrated,
This can be manifested by eitkr an increase or decrease in risk to cancer
of a certain, specific site.

In

-- __

The explanation is most

For cancers of some sites, they adopt the risk pattern

For

       I believe we are ready to investigate the possible metabolic bases
for these differences in susceptibility and alterations in risk, Environmental
carcinogens do not differ essentially from other environmental, toxic agents
in that they too have to undergo metabolic change in the body either for the

3

theoretical. possibility of &ificiSl;lly buffering or protecting tihe various
organs against enzyme-neutralizing or enzyme-destroying environmental sub-
stances, or conversely, artificially stimifiating enzyme systems so that they

I 7,J t,
L.-
[*c LF'

Chemical carcinogens  m introduced into the general environment

,;/ut i ~ 7' as constitutents of coaplex mixtureso

' <. %";,&. &).nltaneouslyr In cigarette smoke, aubexhaust, industrial effluents,
      and polluted urban air, for example, in addition to the carcinogens,  numerous
     structurally-related non-carcinogenic compounds are wudly enitted into the
        environment as part of tbe pollutant mixtureD  These combinations of related
     compounds (Isomers - same chemical composition but structurally different; and
    Analogues - similm but not identical in chemical composition and structure)
       reaet with one another as well as with the host systen they are attacking,
     It has been shown that carcinogenic potency of these environmental. agents is

Several carcinogenic agents are present

Jl <J< -4
L' Lw 4

\

4

significantly related to the ratio of these various comgounds to one another,
Experimentally, it has been possible, through purposefully altering the
ratio of these compounds to one another, to eliminate carcinogenic potency
without the necessity of laboriously eliminating the carcinogenic consti-
tuents of a mixture,
The hplications for this in the control of sources of environmental carcino-
gens are great, The mechanism of the"anticarcinugenic effect" is not
completely understood though we have learned more about it in the last fex
years than the preceding decades,
ultimate goal in terms of cancer control is the ability to intentionally
alter and control ratios of the various compounds to one another to make
sources of carcinogens less hazardous or completely free of hazard,  One
can only guess whether "safe polluted urban air" or "a safe cigarette" is
possible.
better than a 50-50 chance that this is so, the approach suggested here is
promising,
fruitful approach for the study of basic mechanisms as well as application
to cancer control in those organ or organ systems that are targets for
environmental carcinogens which may be buffered or protected using the
anbicarcinogenesis principle,

In essence, the carcinogens in the environment are drowned,

This area is ripe for exploitation,

Its

If this is a tenable hypothesis, and I would guess that there is

From a host viewpoint, anticarcinogenesis is also a potentially

(5)

Familial €lancer and Association of Cancer and Congenital Abnormalities

The role of genetics or heredity in the Mendelian sense in suscep-

tibility to cancer is really unknown; nevertheless,  several recent observations
can contribute to our ability to assess the role of inheritance through the
study of defined populatians with unique patterns of cancer incidence,

It has been shown that fur cancer of specific sites, certain

families have higher rates than expected.
bladder has been shown to occur at a fantastically higher rate in several
melnbers of a few families whose genealogies have been s-txldied.
these families have abnormalities in the metabolism of an amino acid,
tryptophane, which in experimental studies has been shown to be concerned
with the pathogenesis of urinary bladder cancer.
of "errors in metabolism" in relation to cancer is unknown.  It may be of
overwhelming significance or quite unimportant.
instance that major errors in metabolism can result in such non-cancerous
disease as phenylketonuria and galactosemia, cystinuria, etc,
is:
or fat metabolism be manifested over the long period by susceptibility to
cancer?"
of designing experiments predicated on epidemiologic and biometric obser-
vations can assure meaningful studies of the role of genetic factors  in
cancer at this time,

For instance, cancer of the urinary

Further,

The extent and universality

Nevertheless, we know for

The question

"Could the lower, more subtle level of errors in amino acid, carbohydrate,
  The ability to study large populations and the more recent capability

It has been shown that the congenital abnomlity, mngolism, is

associated with an increased risk to leukemia in children (Down's Syndrome).
More recently studies have shown that a whole series of congenital abnor-
malities are associated with increased 3;"isk to other cancers, as for exmple,
Wilm's tumor of the kidney.

One may ask if indeed congenital abnomHties

5

and cancer are the results of the same environmental agents with different
clinical manifestations since, in the former, it is the embryo and fetus that
are attacked while in the latter, it is the fully developed individual.  A
new approach to the study of cancer causation, therefore, appears feasible
for it is known that if two diseases appear to be etiologically related the
more that we learn about one, the more we inevitably knuw about the second.
Controlled experimental and laboratory studies and populations  in this area
can now be undertaken.

(6) Natural Product Carcinogenesis

-

        It is understandable that a society investigating disease patterns
wfiich appear temporally related to man-made changes in the environment would
assume that the recent changes may be responsible for the new or unique
patterns,  We have recently become aware, however, of the ever-growing
importance of environmental carcinogens that are the product of natural agents.
These include certain botanical substances and food stuffs as well as
what may be more important at present, infectious agents such as fungi.
These latter agents produce the mcst potent chemical carcinogens we know,
They are worldwide in their distribution and, more important perhaps, they
begin to offer a partial explanation for historically unique cancer patterns
in non-industrial or underdeveloped parts of the world, The actual combination
of natural product carcinogens to the total cancer spectrum in the United
States is unknown,
States and the recent experience with cancer of the liver in trout appears
to be atOributable to a natural product contaminating synthetic diets used
in the feeding of fish in commercial hatcheries.
to devote as much attention to these natural products as we do to man-made
carcinogens.

Suffice it to say, they have been identified in th  United

It now appears Fmperative

Investigations in the foregoing areas require close and intense cooperation
between the National Cancer Institute and a virhually unlimited number of
universities, research institutes, and laboratories in private industry,
The central role of the National Cancer Institute is apparent in view of its
accessibility to vital records primarily located in government bureaus  as
well as its accessibility to industry on a nationwide basis, These records
provide much of the required base for epidemiological and biometric studies,

The implementation of these studies would, of course,  have to be on a basis
of successive phases and would probably require as long as a decade for the
benefits to be measured in terms of hopefully reducing cancer risks, rates,
as well as increasing survival.

4/8/66