Angel H Roffo: the forgotten father of experimental tobacco carcinogenesis.

Angel Honorio Roffo of Argentina (1882-1947) was one of the first to publish detailed accounts of animal experiments demonstrating the production of tumours by tobacco tars. As founding director of the Instituto de Medicina Experimental para el Estudio yTratamiento del Cancer, established in 1922 in Buenos Aires, he was able to examine and treat a large population of cancer patients, from whom he had learned by the end of the 1920s that smoking was a cause of many kinds of cancer. (1) During the next decade and into the early 1940s he published a series of ambitious papers pioneering the field of experimental tobacco carcinogenesis, blending experimental, clinical and statistical reasoning with a strong sense that many of the world's most common cancers could be prevented. Using a number of different experimental methods, Roffo showed that cancers all along the "smoking highway" (lips, tongue, throat, cheek, bronchial passages, etc.) must be caused by exposure to tars released in the course of smoking; he was also one of the first to realize that smoking could cause bladder cancer. Roffo's work is interesting for a number of different reasons. For one thing, there is his defence of the use of experiments to investigate tobacco carcinogenesis--as if clinical observations had already proved the point. In 1931, writing in the Zeitschrift fur Krebsforschung (he published much of his work in German), he noted that while there were cases in which tobacco was clearly to blame for the onset of certain malignancies (from clinical observations) it was nonetheless useful to document the phenomenon more generally by animal experiments. (2) Reasoning by analogy from the production of cancer using coal tars, he argued that the carcinogens in tobacco smoke must be the complex, tarry, polycyclic aromatic hydrocarbons, rather than the (chemically simpler) inorganic constituents or the alkaloid nicotine. To test this hypothesis, Roffo separated tobacco smoke into three separate distillation products, which he rubbed onto the ears of three groups of 10 rabbits each. He found that the tarry fractions produced cancers but that when nicotine alone was applied no cancers were produced, no matter how long he waited. The same (no cancerous effect) was true from the various inorganic components he had isolated from smoke, including salts such as ammonium chloride but also carbon monoxide and carbon dioxide. (2) Roffo ran many similar tests using different methods of preparing tobacco extracts, different fractions of tobacco tars, and different species of test animals. He never seems to have doubted the role of tobacco, and by the end of his career was able to claim, based on hundreds of his own published papers, that tobacco was the major cause of lung cancer, that tar rather than nicotine was the primary culprit, and that polycyclic aromatic hydrocarbons were the principal carcinogenic agents. Among these last-mentioned compounds was 1:2 benzopyrene--the subject of the paper reproduced here (3)--which Roffo was apparently the first to identify in tobacco smoke (on the basis of spectrographic signatures). (4,5) Roffo also concluded that blonde tobacco was more dangerous than black--from having higher quantities of tars--and that the most dangerous were Turkish, Egyptian, and Kentucky tobaccos. (3,6) He also showed that cancers could be induced in experimental animals even by using nicotine-flee tobacco, meaning that it must be the tar, rather than the nicotine, that was causing cancer. Tar was not a trivial component of tobacco smoke: Roffo calculated that smokers could inhale as much as 4 kg of tobacco tar in 10 years of smoking. (4) Roffo had access to a very large pool of cancer patients at his institute in Buenos Aires and used this to explore cancer causation on a statistical basis. (7) In 1934, he described how 302 of his 500 skin cancer patients had presented with malignancies of the nose, the body part most directly exposed to the sun. …