ing the resistance of the lining epithelium of the respiratory tract. These include aldehydes, various acids, and various of the oxides of nitrogen.

There are some aromatic amines found in the tar which are carcinogenic and have their action in the bladder.

There is a very toxic agent which has a direct toxic effect on living cells, acetonitrile.

RESEARCH ON SMOKING AS A POSSIBLE CAUSE OF CANCER

Mr. NATCHER. Dr. Endicott, can you tell me the research specifically that proves this?

Dr. ENDICOTT. That proves these are carcinogenic?

Mr. NATCHER. Yes.

Dr. ENDICOTT. Yes, sir; I can supply that for the record.

(The information follows:)

The section on smoking and health is submitted for inclusion in the record as a joint report from the National Cancer Institute and the Division of Environmental Health Sciences.

TOBACCO AND HEALTH (LUNG CANCER)

The evidence suggesting a role for cigarette smoking in the causation of pulmonary disease derives from three main areas of study.

1. Epidemiological data indicate that cigarette smokers are at increased risk to the development of lung cancer, bronchitis, and emphysema. A similar epidemiological association is seen in urban residents exposed to polluted city air. 2. Chemical analytical studies have established the presence of compounds in cigarette smoke which are (a) experimental laboratory carcinogens, (b) cocarcinogenic agents, and (c) chemical and physical irritants which can modify normal ciliary function and qualitatively and quantitatively alter the mucus secreted by the cells lining the respiratory tract.

3. Biological studies have shown that cigarette smoke condensate and certain of its fractions are capable of producing cancer in experimental animals when applied by skin painting techniques, injection techniques and direct installation in the respiratory tract.

Over twenty independent retrospective epidemiologic surveys have demonstrated an association between cigarette smoking and lung cancer in men. Two major prospective epidemiologic surveys have been undertaken, one in the United States and one in the United Kingdom and these latter two surveys have corroborated the findings of the retrospective studies in demonstrating this association. In assessing the increment of contribution of cigarette smoking to the total incidence of lung cancer as currently observed, it is necessary to recognize and evaluate other associations which fulfill the criteria for suspicion in lung cancer causation. The epidemiologic evidence describing an association between the exposure to general air pollution and lung cancer leaves little doubt that those who live in big cities, conurbations and industrial areas have a higher risk for lung cancer than those living in rural areas.

Further there have been identified a series of industrial and occupational factors which appear to have a causal role in the development of lung cancer. These include:

1. Arsenic

2. Asbestos

3. Beryllium

4. Chromium

5. Coal and gas

5. Nickel

7. Radioactive ores

On the basis of epidemiological association alone, cigarette smoking would appear to be the most potent of the environmental influences yet studied, although the multiplicity of factors associated with increased risk is at present a confounding factor in any attempt to arrive at a finite percentage contribution. The asso

ciation appears unequivocal and its causal implications are supportable; the latter particularly, in light of the most recent epidemiological findings indicating that cessation of smoking is associated with a reduction in the risk to lung cancer. From an analytical viewpoint, compounds belonging to chemical groups containing carcinogenic members have been identified. These include:

1. Carcinogenic polycyclic aromatic hydrocarbons

2. Carcinogenic heterocyclic compounds

3. Alkylating agents of both the nitrosamine and the lactone type

4. Radioactive elements

5. Trace metals

6. Free radicals

While not all of the individual members of each group listed above are carcinogenic, carcinogenic members have been identified in each.

Compounds belonging to the general group of carcinogens include:

1. Phenols and polyphenols

2. Aliphatic hydrocarbons

Compounds belonging to the group of irritants include:

1. Aldehydes

2. Acids

3. Oxides of nitrogen

Bioassay studies have been performed on total smoke condensate, as well as individual fractions of condensates with the production of skin cancer following painting, connective tissue tumors on injection and lung tumors following direct installation into the lung. It is to be recognized that these agents have been applied in concentrations significantly greater than those occurring under natural use of tobacco and by means of application other than smoking and inhalation. However, these agents have been applied under strict laboratory conditions, usually as a single agent exposure in contrast to the human situation where daily living results in exposure to a highly complex environment with multiple sources of carcinogens, cocarcinogens, and irritants.

The cocarcinogens in tobacco belonging to the group of phenols and polyphenols have been under laboratory conditions shown to be cocarcinogenic; i.e. they are capable of enhancing the action of a carcinogen so that concentrations of the latter which are incapable of producing cancers alone, are transformed or potentiated so that they achieve cancer producing levels. The cocarcinogenic compounds alone are incapable of inducing cancer.

Irritants though incapable of initiating cancer, facilitate the sequence of events which result in cancer induction by interfering with the normal flow of mucus covering the lining cells of the lung. Mucus flow is accomplished by the propulsive beat of whip-like processes on the cells lining the lung, called cilia. Ciliary action is significantly interfered with often to the point of total paralysis by cigarette smoke as well as certain of is constituents.

The following represents in summary form the components of the body of data suggesting a causal relationship between cigarette smoking and lung cancer. 1. An increased risk to lung cancer associated with cigarette smoking with the risk relatively proportional to the amount and duration of smoking.

2. The identification of compounds of cigarette smoke which are capable of a) producing cancer in experimental animals, b) acting as cocarcinogens, and c) interfering with ciliary action and mucus flow, as well as qualitatively and quantitatively altering the mucus secretion of the lining of the lung. This effect on cilia and mucus deprives the lung of its normal defense mechanism whereby the continuous flow of mucus from the outer portions of the lung to the throat prevents the local accumulation of inhaled materials. This dynamic condition deprives these agents of an opportunity to enter the cell and produce adverse effects. As noted above, there are other environmental experiences possessing similar associations, similar chemical, physical and physiological properties and similar tumor inducing properties.

There follows a limited bibliography with representative papers presenting data and reviewing several areas of evidence relating cigarette smoking to the causation of lung cancer.

Blacklock, J. W. S.: An experimental study of the pathological effects of cigarette condensate in the lungs with special reference to carcinogenesis. Brit. J. Cancer 15: 745-762 (1961).

Bock, F. G.; Moore, G. E.; Dowd, J. E. and Clark, P. C.: Carcinogenic activity of cigarette smoke condensate. Biological activity of refined tar from certain brands of cigarettes. J. amer. med. Ass. 181: 668-673 (1962).

Breslow, L.; Hoaglin, L.; Rasmussen, G. and Abrams, H. K.: Occupations and cigarette smoking as factors in lung cancer. Amer. J. Publ. Hlth. 44: 171-181 (1954).

Dean, G. Lung cancer among white South Africans. Brit. med. J. 2: 852-857 (1959)-Lung cancer among white South Africans: Report on a further study. Brit. med. J. 2: 1599-1605 (1961).

Doll, R. and Hill, A. B.: Smoking and carcinoma of the lung. Brit. med. J. 2: 739-748 (1950).-A study of the etiology of carcinoma of the lung. Brit. med. J. 2: 1271-1286 (1952).—The mortality of doctors in relation to their smoking habits. A preliminary report. Brit. med. J. 1: 1451-1455 (1954).—Lung cancer and other causes of death in relation to smoking. A second report on the mortality of British doctors. Brit. med. J. 2:1071-1081 (1956).

Druckrey, H.: Experimental investigations on the possible carcinogenic effects of tobacco smoking. Symposium on Chemical and Biological Problems Related to Smoking. Acta med. scand. 170: 24–42 (1961).

Eastcott, D. F.: The epidemiology of lung cancer in New Zealand. Lancet 1: 37-39 (1956).

Falk, H. L.; Tremer, H. M., and Kotin, P.: Effect of cigarette smoke and its constituents on ciliated mucus-secretory epithelium. J. nat. Cancer Inst. 23: 999-1012 (1959).

Gellhorn, A.: The Co-carcinogenic activity of cigarette tobacco tar. Cancer Res. 18: 510-517 (1958).

Hammond, E. C. and Horn, D.: The relationship between human smoking habits and death rates: A follow-up study of 187,766 men. J. amer. med. Ass. 155: 1316-1328 (1954).-Smoking and death rates-report on forty-four months of follow-up of 187,783 men. I. Total mortality. II. Death rates by cause. J. amer. med. Ass. 166: 1159–1172 and 1294–1308 (1958).

Kotin, P. and Falk, H. L.: The Role and Action of Environmental Agents in the Pathogenesis of Lung Cancer. II. Cigarette Smoke. Cancer 13 (2): 250-262,

1960.

Lilienfeld, A. M.: Emotional and other selected characteristics of cigarette smokers and non-smokers as related to epidemiological studies of lung cancer and other disease. J. nat. Cancer Inst. 22: 259–282 (1959).

Peacock, P. R.: Experimental cigarette smoking by domestic fowls. Brit. J. Cancer 9: 461 (1955) I. Cigarette smoking experiments. Rep. Brit. Emp. Cancer Cmpgn. 34: 287 (1956).-Cigarette smoking experiments. Rep. Brit. Emp. Cancer Cmpgn. 38: 525 (1960).

Radford, E. P. and Hunt, V. R.: Polonium 210: A violatile radioelement in cigarettes. Science 143: 247–249 (1963).

Roe, F. J. C. and Commins, B. T.: The carcinogenic effect of combinations of cigarette smoke condensate and extracts of particulate air pollutants obtained by filtration. Rep. Brit. Cancer Campgn. 41: 65-66 (1963).

Roe, F. J. C.; Salaman, M. H.; Cohen, J. and Burgan, J. G.: Incomplete carcinogens in cigarette smoke condensate: Tumour-promotion by a phenolic fraction. Brit. J. Cancer 13: 623-633 (1959).

Tokuhata, G. K. and Lilienfeld, A. M.: Familial aggregation of lung cancer in humans. J. nat. Cancer Inst. 30: 289-312 (1963).

Waller, R. E.: The role of 3:4-benzpyrene in the epidemiology of lung cancer. Acta Un. int. Cancer. 19: 486-487 (1963).

Mr. NATCHER. Why does not everyone who smokes get lung cancer? Dr. ENDICOTT. Of course, I don't know. This is a general observation with almost any form of cancer-causing agent-if you expose the population, the entire population, to a given cancer-causing agent only some of those exposed develop cancer.

If we understood this I think that this in itself might be one of the most important breakthroughs that could be made, but I don't know why.

Mr. NATCHER. Is it not likely that there are other factors which play a role in the disease?

Dr. ENDICOTT. In lung cancer?

Mr. NATCHER. Yes.

Dr. ENDICOTT. Oh, yes, sir. I have mentioned several of them. For

example, we have a study in progress in the Colorado Plateau amongst uranium miners. There is a substantial increase in risk of lung cancer if you mine radioactive ores.

In improperly controlled chromate industries where chromate dust is around it is increased.

I mentioned the coking process.

In the process of cracking petroleum for the preparation of gasoline or refining petroleum for various purposes, unless this process is very carefully contained there is a major risk.

There was a group of Japanese who worked on the manufacture of mustard gas before and during World War II, and there is a very high incidence of lung cancer among workers in that factory. Therefore the answer is yes, sir, there are many causes.

VIRUSES AND LUNG CANCER

Mr. NATCHER. Is it possible that viruses play a very important role, too?

Dr. ENDICOTT. It is possible, and there are those who have speculated that part of the increase in lung cancer might be attributed to epidemics of influenza which occurred around the time of World War I. However, this does not fit the pattern of distribution of the disease as we see it today.

Mr. NATCHER. In addition to the influenza we had back during World War I, do we have other lung infections which might play a major role, too?

Dr. ENDICOTT. This is entirely possible.

I was going to turn to Dr. Kotin, who is on my staff and moving to Carolina to head up the environmental health center, because he has had so much experience and done so much research in the field.

He did an interesting piece of research a few years ago in which he succeeded in producing cancer by adding or superimposing an influenza infection on exposure to chemical carcinogens which, without the influenza, did not produce the cancer in animals. That was probably the first work of that sort.

Mr. NATCHER. You might want to turn to Dr. Kotin.

Do you want to add anything further?

Dr. KOTIN. The role of viruses?

Mr. NATCHER. Any previous lung infections as far as playing a major part.

Dr. KOTIN. I don't know that we can say a major part but certainly we do know lungs that have some prior abnormalities as a result of the disease are more prone to localized chemical carcinogens to react with them and therefore are more likely to have a cancer develop than a lung similar in every other way except for the fact he doesn't have this lung infection.

Mr. NATCHER. Let me ask you the same question I asked Dr. Endicott.

Do you know what causes lung cancer?

Dr. KOTIN. I know agents that are associated with increased risk in lung cancer. There is a series of environmental experiences which when participated in by the population, or segments of the population, results in their having a greater likelihood of developing lung cancer.

At the cellular level, the actual mechanics involved in alteration of the cells, as Dr. Endicott points out, we don't know this.

However, we do know that the environmental agents which are associated in the increased risk for lung cancer are substantively important.

Development of a cancer is the development of a series of sequential events. We know in those instances where we have been successful in modifying the environment or removing the environment, or moving people from the environment, that a reduction of the risk has been brought about. The cause-effect relationship is one of the links in the chain.

RELATIVE EMPHASIS GIVEN TO TOBACCO AS CAUSE OF LUNG CANCER

Mr. NATCHER. Dr. Kotin, are you and Dr. Endicott and others pointing your finger at these other elements which might enter into it as well as tobacco or are you just confining your attention to tobacco and saying that tobacco causes lung cancer?

Dr. KOTIN. I assure you that tobacco represents only one segment of a very broad approach.

As you pointed out so very importantly, the attack rate, even in the class of smokers who presumably have smoked long enough to enter this category, is a very low one relatively speaking. One has to assume that other factors are operating in sequence which ultimately develops in a cancer.

To approach any one agent, Dr. Endicott mentioned the high risk asociated with chromate exposure, coking operations, radioactivity, these other experiences themselves all are factors which we know can cause an increased risk in lung cancer and we are trying to see where they fit into the overall national pattern of the disease.

Certainly we are concerning ourselves with virtually all areas that have some degree of suspicion in terms of contributing to the problem.

NUMBER OF DEATHS FROM LUNG CANCER

Mr. NATCHER. I believe you and Dr. Kotin, Dr. Endicott, would agree with me that it is true that only a relatively small number of smokers actually get lung cancer. Is that true?

Dr. KOTIN. If I may say, by far the greater number of smokers do not get lung cancer.

Dr. ENDICOTT. 50,000 is a pretty large number of deaths. This year I anticipate there will be 53,000 deaths deaths from lung cancer, not all attributable to cigarettes but certainly a substantial part of it; 50,000 is a small number compared to the number of people who smoke, but 50,000 deaths is not a small number.

Mr. NATCHER. You say that 50,000 who died, those you have just mentioned, died as a result of lung cancer which was brought about as a result of smoking. Is that right, Doctor?

Dr. ENDICOTT. No, sir, that is not what I said. I said there will be 53.000 deaths of lung cancer this year as far as we can best estimate. Out of that group a percentage will never have smoked. Perhaps on the order of 10 percent of the patients who die of lung cancer this year will never have smoked in their lives.