CARCINOGENS IN THE HUMAN ENVIRONMENT

By the second half of the 1960s, it had become evident that several physical, chemical, and biological agents could cause cancer in humans, as reviewed in Richard Doll’s book Prevention of Cancer: Pointers from Epidemiology in 1967. Alongside epidemiology, long-term experiments with animals (typically mice, rats, or hamsters) exposed to high doses of chemical substances, such as soot and coal tars, clearly showed the capacity of such substances to induce cancer. The two approaches – observations in humans and laboratory experiments with animals – to identify carcinogens, natural or man-made, were at the same time complementary and in “useful tension”. Epidemiology is based on direct evidence in humans, and hence it is the litmus test of carcinogenicity, but this very fact implies that several cancers due to a substance have already occurred. From a cancer prevention viewpoint, evidence from animal experiments is far preferable, as it enables the avoidance of exposure of humans to experimentally recognized carcinogens. The drawback is that what happens, or does not happen, in animals does not necessarily match what occurs in humans. Thus, in the mid-1960s, there was one striking discrepancy between epidemiological and experimental evidence: tobacco smoking could be clearly demonstrated to cause cancer in humans, but at the time no proof of carcinogenicity of tobacco smoke could be obtained in animal experiments.

Starting as early as 1969, IARC capitalized on the complementary nature of the two approaches rather than standing aside because of possible discordances. IARC developed two main long-term focus areas aimed at identifying carcinogens in the human environment: the IARC Monographs Programme, with its systematic reviews of all published epidemiological and experimental evidence of carcinogenicity of (initially) chemicals; and epidemiological studies on specific human exposures arising from occupation or the general environment. In addition, during IARC’s first two decades, several animal carcinogenicity experiments were conducted at the Agency (see “DDT and transplacental and transgenerational carcinogenesis”).

THE IARC MONOGRAPHS, A WORLD REFERENCE FOR ENVIRONMENTAL CARCINOGENS

A systematic approach to the evaluation of scientific evidence

After a preparatory phase, the Monographs Programme was launched in 1971–1972 at the initiative of and under the leadership of Lorenzo Tomatis (see “Lorenzo Tomatis, second IARC Director”). The aim was to develop an instrument capable of evaluating the best evidence available at a given time on carcinogenic agents, in order to provide a sound scientific basis for cancer prevention. Some reviews of the evidence of carcinogenicity had already been published, including Doll’s book Prevention of Cancer: Pointers from Epidemiology. However, two features made the IARC programme highly innovative: the systematic approach to examining and evaluating each agent by the same procedures, and the idea that the soundest way to reach the “truth” about the carcinogenicity of an agent is through open discussion and reciprocal cross-checking by leading experts. Given the imperfect nature of all human knowledge, the truth is always approximate, but it can be explicitly stated and qualified by the degree of confidence attached to the statement.

In practice, scientific judgement can be distorted by secondary interests and goals extraneous to, and interfering with, the primary goal of pursuing scientific, reasonable truth, such as financial incentives or advocacy standpoints. Hence, the experts chosen to participate in evaluations had to be as free as possible of such conflicting interests.

An evolving programme

To fit its purpose, the Monographs Programme needed to be evolutionary, in the dual sense of incorporating updates of the evidence when relevant new findings become available and of adapting the very criteria used to evaluate such evidence in line with the accruing knowledge about the underlying mechanisms of cancer development. Over more than 40 years, the programme has successfully maintained and strengthened these characteristics, becoming a key reference – often the key reference – in both scientific and public health contexts.

Public health measures and decisions were up to countries, but they needed a document that showed clearly that there was evidence, and it was the Monographs. – Ruggero Montesano, former IARC scientist

The initial selection of agents to be considered centred on chemicals, for several of which data on carcinogenicity had been accumulating. For each compound evaluated, a Monograph was to be prepared and published. From the colour of the cover, the volumes soon became known as the “Orange Books”.

The first volume of the IARC Monographs series was published in 1972. It covered evaluations of some inorganic substances (e.g. beryllium), chloroform, several aromatic amines, nitroso compounds, and natural products (including aflatoxins).

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Each Monograph was produced by a Working Group composed of the world’s leading experts, who met in Lyon for 7–10 days, with staff from IARC serving as the supporting secretariat. During the meeting, initial drafts prepared in advance by different Working Group members were discussed and repeatedly revised to reach the final text of the Monograph sections. Each Monograph reviewed in detail all available reports published in the scientific literature on the occurrence of and human exposure to the compound, studies of cancer in experimental animals and in humans, and other relevant biological data. A summary of the sections and an evaluation of whether the compound should be regarded as carcinogenic to humans concluded each Monograph.

The first two volumes, each containing several Monographs, were published in 1972 and 1973. They already concluded that several chemicals caused cancer in humans, among them aromatic amines, asbestos fibres of all kinds, and nickel. The evaluations were expressed in a narrative style with variable language as suited to each Working Group. Soon, the need emerged to introduce some measure of uniformity and a grading of the evidence of carcinogenicity, which sometimes appeared definite, sometimes was limited, and sometimes was simply absent. Accordingly, the short general Preamble that introduced each Monograph was expanded to provide procedural and writing guidance to the Working Groups. Suggestions from their experience and discussions in several ad hoc meetings consolidated the guide into formal criteria; the format adopted in 1987–1988 is essentially still used today (see “The IARC classification of carcinogens”).

The Monographs Programme had started with the general title of IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man (“man” became “humans” in 1978). Recognizing the high quality of the programme, several leading scientists had argued that it should not be limited to individual chemicals but expanded to (in Richard Peto’s words) “see chemical carcinogens, lifestyle factors, and chronic infections as being separately important, placing cancer causes in a more balanced perspective.” Since its reshaping in 1987–1988, the series has been called the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, to denote the much-enlarged scope of the programme, covering physical, chemical, and biological agents as well as mixtures of compounds (like tobacco smoke) and circumstances not specifiable more precisely (like some occupations). This breadth has led to many important evaluations by the IARC Monographs Programme, for example of infectious agents including viruses (e.g. hepatitis B and C viruses, human papillomaviruses), bacteria (e.g. Helicobacter pylori), and parasites (e.g. Schistosoma mansoni) and of physical agents including ultraviolet radiation and radon.

I was impressed by the thoroughness of the Monographs Programme. It provided an international gold standard for the process, assessment criteria, and presentation of the assessed carcinogenicity of specified exposures. – Tony McMichael, former chair, IARC Scientific Council

Two other major adaptations have taken place over the years. First, taking into account the increasing knowledge about mechanisms through which an agent like a chemical or a virus can induce cancer, mechanistic data have been given increased weight in assessing whether an agent is carcinogenic. Several chemicals have been classified as carcinogenic to humans when the direct epidemiological evidence was insufficient but there was strong evidence in exposed humans that the agent acts through a known relevant mechanism of carcinogenesis. (For example, the molecules of some dyes are metabolized in the human body to benzidine, a molecule for which there is direct epidemiological evidence of carcinogenicity.) For almost all of these agents, there was, in addition, sufficient evidence of carcinogenicity in animals.

Second, the roles of the participants at Monographs meetings have been better specified. Working Group members are responsible for the critical reviews and evaluations that are developed during the meeting. Invited specialists and representatives of national and international health agencies contribute their expertise but do not serve as meeting chair or subgroup chair, draft text, or participate in the evaluations. A limited number of observers, for example from industry or nongovernmental organizations, with relevant scientific credentials may be admitted under well-defined guidelines on the restrictions on their participation. IARC staff act as the supporting secretariat, serving as rapporteurs and participating in all discussions.

A recent addition to the programme is Volume 100 of the Monographs series, which consists of six books summarizing the most up-to-date evidence for the 110 agents previously classified in Group 1 (carcinogenic to humans). Volumes 100A to 100F cover pharmaceuticals; biological agents; arsenic, metals, fibres, and dusts; radiation (ionizing and non-ionizing); personal habits and indoor combustions; and chemical agents and related occupations. These summaries include an assessment of the specific organs for which sufficient evidence is available that an agent induces cancer, with the proviso that when an agent is shown to be carcinogenic for some organs it cannot be excluded that other organs might be affected as well.

The six-book boxed set of IARC Monographs, Volume 100: A Review of Human Carcinogens.

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Vincent Cogliano, head of the Monographs Programme from 2003 to 2010, coordinated the operation of the Working Groups evaluating the evidence and the production of the Volume 100 books. Cogliano joins Lorenzo Tomatis, Harri Vainio, and Jerry Rice as one of the group of people who have led the Monographs Programme for extended periods over its history.

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EPIDEMIOLOGICAL STUDIES

Since the very beginning, IARC has engaged in a variety of epidemiological studies of possible carcinogens in the general, home, and occupational environments. These studies took different forms in different contexts.

Cancer hotspots

A first type of epidemiological study consisted of building on the suggestions, often coming from clinical observations or crudely recorded data on a geographical basis, that there were hotspots of cancer incidence in areas where some characteristic exposure was reported as common. Most often this occurred in developing countries, and IARC established collaborations in those areas with local health professionals who provided, directly and via official government channels, scientific support to mount rigorous epidemiological and laboratory investigations designed to put the suggestions to the test. Significant results were soon obtained, of value locally for the populations concerned and also of broader significance for the knowledge of new carcinogens.

Early examples of potent environmental contaminants stand out: aflatoxin inducing primary liver cancer by the alimentary route (see “Aflatoxin and primary liver cancer”) and erionite mineral fibres inducing mesothelioma by the respiratory route (see “Erionite mineral fibres and mesothelioma”). These two cases offer examples of ways that may lead to the identification of new environmental carcinogens. For aflatoxin, the evidence of carcinogenicity in animals, from accidental ingestion of contaminated food by poultry and rainbow trout, followed by experiments in rodents, inspired the epidemiological studies in human populations. For erionite, the process went in the other direction: the epidemiological findings prompted the subsequent laboratory experiments in rodents.