Addendum

October 27, 1996

In mid-October, tobacco stocks took a hit on the New York Stock exchange, on the announcement that a team of researchers had found the exact mechanism by which smoking "causes lung cancer". Tobacco industry executives were even reported, by the Wall Street Journal, to be ready to concede that there was a direct cause and effect relationship between smoking and lung cancer.

All of this panic was based upon a single article, published in Science magazine under the title, "preferential Formation of Benzo[a]pyrene Adducts at Lung Cancer Mutational Hotspots in P53", and authored by Dennisenko, Pao and Tang. Apparently, nobody read the original article with a critical eye because, if they had done so, it would be apparent, to put it charitably, that the study described in the article is underwhelming.

The authors of the article start out by pointing out that, in about 60% of lung cancer cases, there is mutational damage to the p53 gene, the so-called "guardian angel gene", which is thought by some to prevent cancer from developing. This is another way of saying, of course, that in 40% of lung cancer cases, there is no damage to the gene, meaning that people can get lung cancer even if their p53 genes are in perfect condition.

The authors did not study any actual human lung cancers. Rather, they studied cultured human cells. They exposed these cells to a "metabolite" of benzo(a)pyrene (BAP), benzo(a)pyrene diolepoxide (BAPDE). They then tested the cells for mutational damage, and claim to have found mutations at certain locations on the genes, similar to the ones found in 60% of lung cancer cases.

Before going any further, let's look at that word "metabolite". A metabolite is a substance produced by the process of metabolism in the human body. Metabolisis takes place in the gut and the liver, and the products of metabolisis flow into the bloodstream where they reach the lungs, during the process of re-oxygenation. BAP is a ubiquitous substance, produced by the combustion of vegetation and fossil fuels, and by burnt food. Earlier studies have shown that better than 90% of the BAP consumed by humans, even human smokers, comes from the food supply. The authors of the study apparently concede that BAP, in and of itself is not terribly carcinogenic (although, like any irritating substance, it will produce skin cancers in specially bred "nude mice"); it must be converted to BAPDE. There is no evidence that the lungs, themselves, can metabolize BAP into BAPDE. Even if they could, the amount of BAP reaching the lungs from cigarette smoke is dwarfed by the amount reaching the lungs in the blood supply (and already metabolized into BAPDE) from consumption of burnt food. Thus, at the outset, the study appears flawed. However, it gets worse!

Not having any humans to work with, the authors of the study compared the mutations which they had induced with specimens of DNA taken from a gene data base, compiled by others. Now, if the goal of the study was to prove that BAP from smoking causes lung cancer (and that was, indeed, the goal), it would seem to be scientifically necessary to compare the genes of smokers who fall victim to lung cancer with those of non-smokers who fall victim to the disease. Such a comparison would show whether lung cancer in smokers has a different etiology (cause) than in non-smokers.

The authors of the study, however, deliberately excluded from the study any DNA samples obtained from non-smokers or from "radon associated cancers". They did not say how they knew whether any particular samples came from non-smokers or were "radon associated"; apparently they took the word of the people who complied the data base. The point is, however, that while all experiments should always be controlled, these authors deliberately threw out the controls!

The authors make the astonishing statement that "This study provides a direct link between a defined cigarette smoke carcinogen and human cancer mutations". I say "astonishing", because the study dealt with BAPDE, not BAP, and there is no BAPDE in cigarette smoke. Thus, at best, the study could claim only an "indirect link". But, because the of the failure to take into account the BAP consumed in food, it isn't possible to claim even an "indirect link". The study could just as well be said to prove an indirect link between the consumption of burnt food and lung cancer. However, it doesn't prove even that, because (a) it does not explain lung cancer in the 40% of victims who have no p53 gene damage and (b) the authors compared their results with DNA samples which they selectively picked and chose, throwing out which they deemed to be "radon associated" or from non-smokers (free translation: throwing out those that would not have validated their conclusions).