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J Natl Cancer Inst. Dec 21, 2011; 103(24): 1827–1839.
Published online Dec 12, 2011. doi:  10.1093/jnci/djr483
PMCID: PMC3243677
Preventable Exposures Associated With Human Cancers
Vincent James Cogliano,corresponding author Robert Baan, Kurt Straif, Yann Grosse, Béatrice Lauby-Secretan, Fatiha El Ghissassi, Véronique Bouvard, Lamia Benbrahim-Tallaa, Neela Guha, Crystal Freeman, Laurent Galichet, and Christopher P. Wild
Affiliation of authors: Section of IARC Monographs, International Agency for Research on Cancer, World Health Organization, Lyon, France (VJC, RB, KS, YG, BL-S, FEG, VB, LB-T, NG, CF, LG); Director, International Agency for Research on Cancer, World Health Organization, Lyon, France (CPW)
corresponding authorCorresponding author.
Correspondence to: Vincent James Cogliano, PhD, Section of IARC Monographs, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France (e-mail: imo/at/iarc.fr).
Received November 10, 2010; Revised October 13, 2011; Accepted October 14, 2011.
Information on the causes of cancer at specific sites is important to cancer control planners, cancer researchers, cancer patients, and the general public. The International Agency for Research on Cancer (IARC) Monograph series, which has classified human carcinogens for more than 40 years, recently completed a review to provide up-to-date information on the cancer sites associated with more than 100 carcinogenic agents. Based on IARC’s review, we listed the cancer sites associated with each agent and then rearranged this information to list the known and suspected causes of cancer at each site. We also summarized the rationale for classifications that were based on mechanistic data. This information, based on the forthcoming IARC Monographs Volume 100, offers insights into the current state-of-the-science of carcinogen identification. Use of mechanistic data to identify carcinogens is increasing, and epidemiological research is identifying additional carcinogens and cancer sites or confirming carcinogenic potential under conditions of lower exposure. Nevertheless, some common human cancers still have few (or no) identified causal agents.
Cancer includes many diseases, and the question often arises which exposures are associated with cancer of a specific organ or site. This information is important for rational planning of cancer control programs. It is also critical to the identification of potential confounding factors in the design and analysis of epidemiological studies and to the formulation of hypotheses concerning mechanistic pathways for experimental investigation. On a more personal level, patients and their families often wonder whether preventable environmental, occupational, dietary, or consumer exposures might have contributed to their disease. Information about exposures associated with cancer at specific sites is difficult to obtain because it is spread across hundreds of agent-specific assessments published by different health authorities at various times using different methods.
Recently, the International Agency for Research on Cancer (IARC) completed a review (1) of the more than 100 chemicals, occupations, physical agents, biological agents, and other agents that it has classified as carcinogenic to humans (Group 1; IARC classifies agents as carcinogenic to humans [Group 1], probably carcinogenic to humans [Group 2A], possibly carcinogenic to humans [Group 2B], not classifiable [Group 3], or probably not carcinogenic to humans [Group 4]) (2). To this end, IARC convened six Working Groups that included 160 scientists from 28 countries to critically review published epidemiological and experimental studies, to evaluate the carcinogenicity of each agent, to identify cancer sites where a causal association is established or credible, and to identify mechanistic events that are known or likely to be involved. This work will be published in 2011 as Volume 100 of the IARC Monographs (1), and summary information is already available (38). IARC's review provides up-to-date information on cancer sites associated with each human carcinogen.
There has been debate over the value of identifying cancer sites associated with an agent, with some scientists arguing that association with some cancer sites implies exclusion of a possible association with cancer at other sites (9,10). The crux of the matter is whether to regard a list of cancer sites restrictively, as a finite number of sites where carcinogenesis is possible, or expansively, as examples where strong evidence of an association exists at the time of evaluation (11). IARC has taken the expansive view, and its recent review provides information pertinent to this question.
In this article, we have brought together cancer site information on more than 100 human carcinogens identified through 40 years of IARC Monographs reviews, rearranged this information to list the known and suspected causes of cancer at various sites, and discussed some implications for the state-of-the-science of carcinogen identification. Other factors associated with an increased cancer risk not covered in the IARC Monographs, notably genetic traits, reproductive status, and some nutritional factors, are not included in this review.
For each agent that IARC classifies as carcinogenic to humans, we compiled lists of the cancer sites for which we have “sufficient evidence” or “limited evidence” of an association in humans. For the purposes of this analysis, sufficient evidence in humans means that a causal relationship has been established and that chance, bias, and confounding could be ruled out with reasonable confidence, whereas limited evidence in humans means that a causal relationship was credible but that chance, bias, or confounding could not be ruled out with reasonable confidence (2). We took this information from the published summaries of IARC's review (38) and from the final drafts that the Working Groups developed for IARC Monographs Volume 100 (1).
To complete the list of cancer sites with limited evidence, we searched IARC Monographs Volumes 1–99 for agents that were classified as probably carcinogenic or possibly carcinogenic to humans. In most cases, the cancer site associations are clear and are based on the published summary and evaluation by the most recent Working Group that has classified an agent. For some agents with positive findings for several cancer sites, we made a judgment based on the IARC reviews about which cancer sites might be considered to have a credible causal relationship.
As we searched Volumes 1–99, we found earlier assessments of most carcinogens reviewed in Volume 100 (1). We identified the cancer sites with established causal relationships in the first volume in which an agent had been determined to be carcinogenic and compared these with the cancer sites that are currently considered to be established. After listing the cancer sites associated with each known or suspected carcinogen, we rearranged this information to list the known and suspected causes of cancer at each site, based on currently reviewed studies.
We first list the cancer sites that IARC associates with each agent that it classifies as carcinogenic to humans (Table 1). For each agent, we list cancer sites for which IARC judges that there is sufficient evidence of an association and sites for which IARC judges that there is limited evidence of an association in its review. In some cases, cancer sites are described with a high level of precision, most notably for some biological agents that often infect specific target cells within an organ.
Table 1
Table 1
Agents that the International Agency for Research on Cancer has classified as carcinogenic to humans and associated cancer sites
For several agents in Table 1, there is insufficient evidence for an association with any cancer sites in humans; these agents are classified as carcinogenic to humans because of strong mechanistic data and other information. Most of these agents occur in complex exposures for which it would be difficult for epidemiological studies to attribute causality to specific components; however, agent-specific biomarkers have been identified that associate them with tumor development in exposed humans. We separately list the agents that IARC classifies as carcinogenic to humans based on mechanistic or other relevant data, along with a summary of the rationale for each classification (Table 2).
Table 2
Table 2
Agents that the International Agency for Research on Cancer has classified as carcinogenic to humans based on mechanistic and other relevant data
In the next table (Table 3), we list the cancer sites that IARC associates with the agents that it classifies as probably carcinogenic or possibly carcinogenic to humans. It must be stressed that several of these evaluations are many years old and that subsequent research may support a different classification today. For example, in Supplement 7 (12), IARC listed 18 agents as having limited evidence of carcinogenicity in humans. Of these, 12 agents have been reevaluated and there is now sufficient evidence to consider five of them to be carcinogenic (beryllium and its compounds, cadmium and its compounds, crystalline silica dust, formaldehyde, and phenacetin), limited evidence for four (chloramphenicol, creosotes, ethylene oxide, and polychlorophenols), and “inadequate evidence” for three (acrylonitrile, diethyl sulfate, and phenytoin; here, inadequate evidence means that the available studies do not show the presence or absence of a causal association) (2).
Table 3
Table 3
Agents that the International Agency for Research on Cancer has classified as probably carcinogenic or possibly carcinogenic to humans and associated cancer sites
The last table (Table 4) combines the IARC information from Tables 1 and and33 by cancer site rather than by agent. To accommodate the different degrees of precision with which cancer sites have been identified (eg, “liver cancer” for one agent and “hepatocellular carcinoma” for another), we have used designations that are more general in nature (liver cancer in this example) in Table 4. Information about specific histological types is presented in Tables 1 and and33.
Table 4
Table 4
Preventable exposures associated with human cancers, as identified by the International Agency for Research on Cancer*
Tables 1–4 summarize and update some major conclusions from the first 40 years of IARC Monographs. To these, one might add other consensus findings for dietary and nutritional factors, including red meat and processed meat (convincing evidence for colorectal cancer), β-carotene (lung cancer), body fatness (breast, colorectal, endometrium, kidney, esophageal, and pancreatic cancers), abdominal fatness (colorectal cancer), and adult attained height (breast and colorectal cancers) (13).
From Tables 1–4, we might also gain new insights into the state-of-the-science of carcinogen identification. We discuss five major themes below.
Increased Use of Mechanistic Data
The use of mechanistic data to identify carcinogens is accelerating. Initially, IARC would classify an agent as carcinogenic to humans only when there was sufficient evidence in humans to support a causal association (14). Scientific understanding of the mechanisms of carcinogenesis, accompanied by the development of assays for studying mechanistic events involved in carcinogenesis, have given researchers new ways of establishing whether an agent is carcinogenic. Since 1991, IARC has allowed an agent to be classified as carcinogenic to humans if there is sufficient evidence in animal models and “strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity” [(15); sufficient evidence in animal models here means that a causal relationship has been established through an increased incidence of benign and malignant neoplasms in two or more species or independent studies, or in a single study to an unusual degree with regard to incidence, site, type of tumor, age at onset, or at multiple sites]. Under IARC's approach, classifications based on strong mechanistic evidence in exposed humans and classifications based on sufficient evidence from epidemiological studies of cancer in humans have been given similar confidence (2).
Some scientists would prefer that IARC be more conservative in classifying carcinogens based on mechanistic evidence. This alternative view holds that conclusions about the etiology of human cancers that are based on mechanistic evidence (in exposed humans [eg, biomarkers in a molecular epidemiological study], in human cell lines, in animals, or in animal cell lines) generally lack the certainty of conclusions based on epidemiological studies. Nevertheless, IARC's approach for using information on mechanisms of carcinogenesis has since been adopted by several national programs that identify suspected carcinogens (1618). Its classification system makes clear which Group 1 classifications are based on sufficient evidence of cancer in humans and which rely on strong mechanistic evidence. Most classifications based on mechanistic data have occurred during the past few years (see Table 2). A few examples are discussed here.
Studies reviewed in 1997, in Volume 69 (19), showed that 2,3,7,8-tetrachlorodibenzo-para-dioxin binds to the aryl hydrocarbon receptor, which functions similarly in humans and experimental animals and signals a sequence of events that lead to changes in gene expression, cell replication, and inhibition of apoptosis. At that time, this mechanistic information led to the classification of this compound as a human carcinogen. When it was reviewed in Volume 100 (1), this compound was determined to also have sufficient epidemiological evidence to be considered carcinogenic to humans. This is the first carcinogen that was initially classified based on mechanistic data and subsequently by sufficient evidence from epidemiological studies. This example highlights the ability of mechanistic information to provide early robust evidence of carcinogenicity (8).
Plants of the genus Aristolochia were first evaluated in 2002, in Volume 82 (20), after a series of case reports from the 1990s had described rapidly progressing end-stage renal disease following ingestion of medicinal herbs derived from these plants. At the time, it was impossible to identify specific causal agents. When plants of the genus Aristolochia were reevaluated 6 years later in Volume 100 (1), mechanistic evidence of aristolochic acid–specific A:T→T:A transversions in the TP53 tumor suppressor gene in renal disease patients led to the identification of aristolochic acid as the causal agent (3). It is encouraging to think that other carcinogens in the general environment might be identified with similar speed and confidence.
Acetaldehyde associated with consumption of alcoholic beverages is the first example of a classification based on genetic epidemiological studies of metabolic enzyme activity. Alcohol is metabolized by the enzyme alcohol dehydrogenase to acetaldehyde, which in turn is metabolized by the enzyme aldehyde dehydrogenase. Studies of a polymorphism of aldehyde dehydrogenase showed that populations with a less active form of this enzyme accumulate acetaldehyde and have a substantially higher risk for cancers of the esophagus and of the upper aerodigestive tract (7). The information from genetic epidemiology studies does not fully explain the carcinogenicity of alcoholic beverages. Relationships between internal ethanol and acetaldehyde concentrations and other factors that may contribute to cancers associated with the consumption of alcoholic beverages continue to be explored.
Mechanistic information also aids in the very definition of the agents that are classified. Ingested nitrate or nitrite is probably carcinogenic under conditions that result in endogenous nitrosation, and shiftwork that involves circadian disruption has also been classified as probably carcinogenic (see Table 3). Endogenous nitrosation and circadian disruption mark the first uses of a mechanistic event in the wording of an evaluation statement. It is not hard to envision that further research may lead to evaluations of broader classes of agents that induce endogenous nitrosation or circadian disruption.
More Cancer Sites per Carcinogen
Further research often finds additional cancer sites. Among the 87 agents that had been causally associated with one or more cancer sites before Volume 100 (1), 25 are now associated with additional cancer sites with sufficient evidence and 13 more are associated with new sites with limited evidence (see Table 1). These new findings provide a compelling reason to regard every list of cancer sites as a work in progress, which may be amended if subsequent research provides strong evidence of additional cancer sites.
Some additional cancer sites may be of greater public health importance than the first sites identified for an agent. Alcohol consumption, for example, has been strongly associated with cancers of the liver and upper aerodigestive tract for a long time. Volume 96 (21) added associations with breast cancer and colorectal cancer, two of the most common cancers worldwide in terms of incidence and mortality. Thus, alcohol consumption appears to contribute substantially more to the worldwide cancer burden than was previously thought (22), although light to moderate alcohol consumption has been associated with some benefits related to heart disease, stroke, and diabetes (benefits that are reversed with occasional or regular heavy drinking) (23).
Another implication of the identification of additional cancer sites is that many agents cause cancer via multiple mechanistic pathways. For example, the recent addition, in Volume 100 (1), of leukemia (particularly myeloid leukemia) as a formaldehyde-associated malignancy has encouraged researchers to investigate a broader range of mechanisms than before, when formaldehyde research was focused on cancers of the upper respiratory tract. Similar implications follow from the new associations between non-Hodgkin lymphoma and hepatitis B and C viruses, which infect hundreds of millions of people worldwide.
Simultaneous consideration of agents that act at the same cancer site can suggest new research hypotheses. For example, does the association of ovarian cancer with talc-based body powder and asbestos suggest that a physical mechanism can induce this cancer in some cases? Is the limited association of hepatitis B virus with non-Hodgkin lymphoma stronger now that there is sufficient evidence of a strong association with hepatitis C virus? Is there a mechanistic pathway to link salted fish consumption and Epstein–Barr virus in the development of nasopharyngeal and stomach cancer because both of these cancers have been associated with both of these agents?
More Sensitive Indications of Carcinogenic Potential
Further research has confirmed carcinogenic potential under conditions of lower exposure. Some old evaluations explicitly restricted their applicability to a small set of high-exposure conditions. For example, IARC's 1973 asbestos classification in Volume 2 (24) was based on studies of miners and millers and explicitly ruled out risks from other exposures. Volume 100 (1), however, cites a growing body of studies that indicate increased risks of lung cancer and mesothelioma from environmental exposures to asbestos. Similarly, the California Environmental Protection Agency restricted its 1988 listing of alcoholic beverages as carcinogenic only “when associated with alcohol abuse” (25). Some subsequent studies, however, have shown that moderate alcohol consumption statistically significantly increases breast cancer risk (22). Even without an explicit restriction, there is sometimes a tendency to recognize carcinogenic potential only in circumstances that have been well studied. For example, IARC's 1988 radon classification in Volume 43 (26) was based on studies of underground miners, and debate ensued about whether radon in homes poses a hazard. Volume 100 (1) finds that studies of residential exposure alone provide sufficient evidence of lung cancer. Similarly, the carcinogenicity of secondhand tobacco smoke was confirmed several decades after the carcinogenicity of tobacco smoke was established in smokers, whereas today it is well accepted [Volume 83; (27)].
These examples suggest that it might be prudent to be more circumspect about statements that limit a cancer hazard only to the high-exposure conditions that have been studied. Although this practice is sometimes defended as describing where the data exist, it can and has delayed recognition of carcinogenic potential in other circumstances. It is difficult for epidemiological studies to detect a cancer hazard when exposures occur mostly at lower levels, such as additives or contaminants of food, water, air, or consumer products. Epidemiological and experimental studies of high-exposure conditions often provide the first evidence of a hazard that applies to lower exposures as well.
A Growing List of New Carcinogens
New research continues to find additional human carcinogens. During the decades ending in 1980, 1990, 2000, and 2010, respectively, there were 23, 27, 24, and 25 agents classified as carcinogenic to humans for the first time, and 11 more were so classified in Volume 100 [(1); see Table 1]. Some designations of new carcinogens were not based on conclusions found first in the Monographs but reflected the expansion of the IARC program to include additional types of agent already known to be carcinogenic. For example, tobacco smoking and alcoholic beverages were evaluated for the first time during 1986–1988, biological agents during 1994–1997, and ionizing radiation during 2000–2001, many decades after these agents had been recognized as human carcinogens.
The diversity of carcinogenic agents that have been identified more recently puts these “bursts” of new classifications in perspective. New carcinogenic agents from Volumes 90–99 (21,2836) have included 10 additional human papillomavirus types, estrogen–progestogen menopausal therapy, benzo[a]pyrene, indoor coal emissions, ethanol in alcoholic beverages, 1,3-butadiene, dyes metabolized to benzidine, 4,4′-methylenebis(2-chloroaniline), and ortho-toluidine (see Table 1). Except for indoor coal emissions and ethanol, which had not been evaluated before, these agents had been classified as probably carcinogenic or possibly carcinogenic, indicating that continued research on suspected carcinogens can lead to a more definitive classification.
Estimation of the proportion of the worldwide cancer burden represented by these agents is outside the scope of the IARC Monographs or of this review. Although tobacco, diet, infectious agents, and estrogenic compounds are responsible for a substantial fraction of cancers at some sites, it is also likely that many human carcinogens remain to be identified. This is suggested by the continuing identification of carcinogenic agents throughout the 40-year history of the IARC Monographs, by mechanistic understanding that many cancers are caused by multiple factors acting jointly, and by the large number of probable and possible carcinogens identified by experimental studies. A recent review identified more than 200 chemicals that induce mammary gland tumors in experimental animals (37). Most of these have been classified by IARC as carcinogenic, probably carcinogenic, or possibly carcinogenic to humans, but there were too few women in the epidemiological studies to permit conclusions about their potential to cause breast cancer. Better linkage between experimental results and human carcinogenicity should lead to the identification of human carcinogens on the basis of experimental results.
Some occupations classified as carcinogenic to humans have had subsequent reviews attribute their carcinogenicity to specific chemical or physical agents. These include chromate production and nickel refining, whose carcinogenicity is now attributed to chromium (VI) and nickel compounds, respectively (see Table 1). Other examples are boot and shoe manufacture and repair (respiratory tract cancers are now attributed to leather dust; and leukemia, to benzene), furniture and cabinet making (respiratory cancers from wood dust), and chimney sweeping (lung and skin cancers from soot). These and other occupations should be regarded as carcinogenic to humans whenever there is exposure to the carcinogenic agents identified in those workplaces. Attributing carcinogenicity to specific agents helps national agencies develop regulations to prevent exposure to these agents wherever they are found, in the workplace or in the general environment.
Remaining Research Needs
Some common human cancers have few (or no) identified causal agents. There are wide disparities in the number of agents that are causally associated with the more common human cancers (see Table 4). In 2008, the 10 most frequent cancers worldwide (in both sexes combined) were cancers of the breast, prostate, lung, colorectum, cervix, stomach, liver, uterus, esophagus, and ovary (38). For several of these cancer sites, only a few causal factors have been identified, and none has been found for prostate cancer. A few less-prevalent cancers do not appear in these tables, for example, those of the small intestine, thymus, heart, and endocrine glands other than the thyroid and salivary glands. There is a need for etiological research to identify additional causal factors for common and uncommon human cancers.
IARC's review of human carcinogens, to be published in six parts in 2011(1), will include full Monographs on the more than 100 agents classified by IARC as carcinogenic to humans. These Monographs critically review the epidemiological studies, cancer bioassays in animals, and information on toxicokinetics and mechanisms of carcinogenesis.
Subsequent workshops will synthesize this information for related scientific publications. An analysis of tumor concordance between humans and experimental animals will explore the predictive value of animal tumors and identify human cancers for which currently there are not good animal models. This analysis could encourage development of predictive mechanistic models for these cancers. A review of mechanisms involved in human carcinogenesis will synthesize information on mechanistic events that are known to be or likely to be involved in human carcinogenesis. It will also suggest populations and developmental stages that may be especially susceptible to certain mechanistic events, as well as identify biomarkers that could be incorporated into future epidemiological study designs. The ultimate objective is to facilitate the identification of carcinogens based on mechanistic information in the absence of cancer studies in animals or in humans.
Every Group 1 agent can be considered to represent cancers that might have been prevented had scientists been able to predict cancer hazards earlier or had public health authorities been willing to act more quickly when scientific information became available. Volume 100 (1) of the IARC Monographs will be a bridge from epidemiological studies that identify carcinogens after decades of human exposure to experimental studies that can screen suspected carcinogens before humans are exposed. The information in this article, together with the more detailed Monographs that IARC will publish in Volume 100, should stimulate researchers worldwide to create links between epidemiological and experimental results and lead to more rapid and more confident identification of carcinogens.
Funding
This work was supported by the International Agency for Research on Cancer; the National Cancer Institute at the National Institutes of Health (CA033193); the European Commission Directorate-General for Employment, Social Affairs and Equal Opportunities (VS/2010/0211); and the National Institute of Environmental Health Sciences at the National Institutes of Health.
Footnotes
This review does not necessarily reflect the views of these agencies.
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