How do we judge what causes cancer? the meat controversy

The fact that obesity and the intake of processed meat are considered “carcinogenic to humans” – according to the criteria used by the International Agency for Research on Cancer (IARC) and/or the World Cancer Research Fund (WCRF) – may look disconcerting to many, and calls for an explanation of how the conception of causality has developed in medicine in the last 50 years. In this evolution IARC itself has played a pivotal role, as testified by the recent publication of a volume on its history, and the long series of Monographs on the carcinogenicity of specified agents to humans. The gold standard of causality in medicine since the 1940s has been the randomized clinical trial (RCT), used to test pharmaceutical drugs and other interventions intended to be beneficial. The emphasis of RCTs is on single agents as causal factors (medical treatments or otherwise “actionable” agents). This can be aligned with the microbiological tradition, in particular the criteria for the identification of pathogenic micro-organisms developed by Henle and Koch in the 18 and 19 centuries. According to these criteria, an agent was a cause of disease if it was always present in the diseased individuals, it was always absent in the healthy subjects and the disease could be reproduced by inoculation in animals. The first RCTs were on antibiotics, i.e. antimicrobial agents, to affirm the relationship between the successes of microbiology and the development of a powerful strategy to investigate drugs. Also the early years of research on chemical carcinogenesis entertained the idea of most cancer cases being attributable to single causal agents. That was, however, abandoned already in the 1950s mainly due to epidemiological studies demonstrating then-inexplicable marked differences in cancer incidence between communities worldwide. The idea of a single causal agent, applicable perhaps to smoking and a few like agents, may still be at the heart of community thinking about cancer causation generally, and may be at the basis of recent misunderstandings concerning the classification of processed meat. When tobacco smoking was found to be carcinogenic by sound epidemiological research in the 1950s, the tobacco industry asked for more than evidence of an association, specifying RCTs as the gold standard. Of course RCTs could not be undertaken for ethical reasons (we cannot knowingly expose humans to putative hazardous agents). To develop a sound response to this claim from the tobacco industry, the English statistician Sir Austin Bradford Hill modified HenleKoch’s criteria to apply them to non-infectious diseases such as cancer. The guidelines developed by Bradford Hill and used in a modified version also in the US Surgeon General reports on tobacco smoking – date back to the English philosophy of science developed in particular by John Stuart Mill and founded on concepts such as consistency of observations in different populations, strength of the statistical association between exposure and risk of disease, the presence of a quantitative relationship between level of exposure and quantification of the risk and the biological plausibility of a causal association (based for example on knowledge of intermediate mechanisms or work in animals and in vitro systems). It is with similar criteria that IARC Working Groups have come to the conclusion that chemicals or other exposures are “carcinogenic to humans”. While for many of these the causal nature of the association with cancer is obvious because of the strong increase in risk, for example asbestos and mesothelioma or aromatic amines and bladder cancer, for other exposures the conclusions of IARC have been more controversial, usually showing that the critics have little understanding of current concepts of causality in medicine. One of the Henle-Koch’s criteria was the idea of necessary cause, meaning that the disease will not appear in those unexposed to the agent in question: for example, the Ebola virus is necessary to develop the disease known as Ebola. However, the public usually does not appreciate that cancer and other non-infectious diseases are often due to a combination of factors, none of which is sufficient nor necessary. Cancer is multifactorial, that is it arises because exposure to several agents together with certain biological processes (including for example DNA damage or cell proliferation as explained below) constitute a pathway leading to malignancy. Multiple agents are involved almost by definition. Being obese or eating red meat do not necessarily lead to cancer, and in fact the causal association with cancer is weak (meaning a mathematically small increase in risk) but well established. We know only one necessary cause for cancer (i.e. an agent without which a certain type of cancer would not occur), that not by chance is an infectious agent, human papilloma virus (HPV) for cervical cancer (in this particular case we also have the equivalent of RCT evidence through vaccination). For non-infectious diseases, the vast majority of known causal agents belong to the category of non-necessary causes, such as tobacco smoking, asbestos, high blood pressure, high cholesterol and so on. Thus everyone is aware when a lifelong never smoker is diagnosed with lung cancer. Just to give some figures, the lifetime risk of lung cancer in a non-smoker is 1% and in a heavy smoker it is 25%; the lifetime risk of myocardial infarction or other cardiovascular diseases in people without other risk factors but with a cholesterol/HDL ratio greater than 6 is 19%, compared to 16% in those with a normal ratio (up to the age of 75); the risk of colorectal cancer in frequent red meat eaters is 6% vs. 5% in moderate eaters. Following the historical evolution described above, cancer causation is now understood as the complex interplay of numerous agents and biological response patterns that act E di to ri al