IARC Monographs Research Articles

Use of mechanistic data in IARC evaluations

Consideration of mechanistic data has the potential to improve the analysis of both epidemiologic studies and cancer bioassays. IARC has a classification system in which mechanistic data can play a pivotal role. Since 1991, IARC has allowed an agent to be classified as carcinogenic to humans (Group 1) when there is less than sufficient evidence in humans but there is sufficient evidence in experimental animals and "strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity." Mechanistic evidence can also substitute for conventional cancer bioassays when there is less than sufficient evidence in experimental animals, just as mechanistic evidence can substitute for conventional epidemiologic studies when there is less than sufficient evidence in humans. The IARC Monographs have used mechanistic data to raise or lower a classification that would be otherwise based on epidemiologic studies and cancer bioassays only. Recently, the IARC Monographs have evaluated several agents where mechanistic data were pivotal to the overall evaluation: benzo[a]pyrene, carbon black and other poorly soluble particles, ingested nitrates and nitrites, and microcystin-LR. In evaluating mechanistic data, it is important to consider alternative mechanistic hypotheses, because an agent may induce tumors through multiple mechanisms.

Carcinogenic Food Contaminants

A large number of scientific studies and reviews have addressed the potential for dietary components to influence the risk of developing cancer. One topic of particular interest has been the impact of food contaminants. Two complementary programs, among others, have reviewed and synthesized information on the carcinogenic potential of food contaminants and judged the degree of evidence linking different food contaminants to the risk of cancer in humans. These programs, the International Agency for Research on Cancer's IARC Monographs on the Evaluation of Carcinogenic Risks to Humans and the US National Toxicology Program's Report of Carcinogens have reviewed hundreds of chemicals, mixtures, and natural products and then graded the cancer risk posed to humans. Contaminants with the highest level of evidence include aflatoxin, alcoholic beverages, 2,3,7,8-tetracholordibenzo-p-dioxin. Agents with a moderate level of evidence include acetaldehyde, polycyclic aromatic hydrocarbons, some nitrosamines, and yerba mate. Agents with a low level of evidence include bracken fern, fumonsin B1, ochratoxin, and others. This review presents a summary of the evidence for the carcinogenicity of these and other agents and the ranks provided by two important assessment programs.

Carcinogenic Hazards from Inhaled Carbon Black, Titanium Dioxide, and Talc not Containing Asbestos or Asbestiform Fibers: Recent Evaluations by an IARC Monographs Working Group

In February 2006, an IARC Monographs Working Group reevaluated the carcinogenic hazards to humans of carbon black, titanium dioxide, and talc, which belong to the group of poorly soluble, low-toxicity particles. The review of the relevant literature and the evaluations by the Working Group will be published in Volume 93 of the IARC Monographs series. This article summarizes the Working Group's conclusions. Epidemiological studies among workers in carbon black production and in the rubber industry provided inadequate evidence of carcinogenicity. The overall data from cancer studies in rodents exposed to carbon black provided sufficient evidence of carcinogenicity. The Working Group evaluated carbon black as possibly carcinogenic to humans, Group 2B. Reviewing the epidemiological studies in the titanium dioxide production industry, the Working Group concluded that there is inadequate evidence of carcinogenicity. Overall, the results from rodent cancer studies with titanium dioxide were considered to provide sufficient evidence. Titanium dioxide was evaluated as possibly carcinogenic to humans, Group 2B. Epidemiological studies on talc miners and millers provided inadequate evidence of carcinogenicity of inhaled talc not containing asbestos or asbestiform fibers. The evidence from rodent cancer studies was considered limited. The Working Group evaluated inhaled talc not containing asbestos or asbestiform fibers as not classifiable as to its carcinogenicity to humans, Group 3. The Working Group noted that prolonged exposure to inhaled particles at sufficiently high concentrations in experimental animals may lead to impairment of normal clearance mechanisms in the alveolar region of the lung, resulting in a continued buildup of particles that eventually leads to excessive lung burdens accompanied by chronic alveolar inflammation. The inflammatory response may give rise to increased generation of reactive oxygen species, cell injury, cell proliferation, fibrosis, induction of mutations, and, ultimately, cancer. Since many of these steps also occur in workers in dusty jobs, such as coal miners, data on cancer in animals obtained under conditions of impaired lung clearance were considered relevant to humans. In addition, impaired lung clearance in rodents exposed to ultrafine particles occurs at much lower mass concentrations than with fine particles, which adds to the human relevance.

ELF MFs: Straif et al. Respond

Mild et al. suggest that we should have included magnetic fields at extremely low frequencies (ELF MFs) in our listing of occupational carcinogens (Siemiatycki et al. 2004). We acknowledge that ELF MFs have been classified as “possibly carcinogenic to humans” (Group 2B) by the Monographs Programme of the International Agency for Research on Cancer (IARC 2002) and that there is significant occupational exposure, thereby meeting our operational criterion for inclusion as a possible occupational carcinogen. However, the nature of the evidence that led to the IARC classification complicates the designation of ELF MFs as an occupational carcinogen. For our article (Siemiatycki et al. 2004), we drew on the evaluations of the IARC Monographs Programme. Each evaluation was based on data that were available at the time of the deliberations of the working group. We supplemented the evaluation by adding information on major occupational exposure circumstances and on the cancer sites affected. For some carcinogens, notably those evaluated recently, such information was explicitly mentioned in the published monograph, but for others it was based on our expert judgment. For ELF MFs, the IARC evaluation of “possibly carcinogenic” was founded on a determination that there was limited evidence of carcinogenicity in humans based on its effects on childhood leukemia and “inadequate evidence” in experimental animals (IARC 2002). In contrast with an earlier evaluation [National Institute of Environmental Health Sciences (NIEHS) 1998], the IARC Working Group considered that studies conducted among adults, at work or elsewhere, did not provide consistent enough and strong enough evidence to support an evaluation of carcinogenicity. There is no clear-cut way to classify an exposure that has only been demonstrated to be carcinogenic (albeit group 2B) in children, but also occurs among workers. Although we decided not to include ELF MFs in our tables of occupational carcinogens (Siemiatycki et al. 2004), we could have done so with a footnote to explain that the evidence supporting that evaluation was based on children. Mild et al. also discuss the evidence on the carcinogenic effects of ELF MFs that has arisen since 2002. Although we agree that some of these studies may substantially contribute to an evaluation of the carcinogenic effects of ELF MFs, it was not in the scope of our work to evaluate new information and update the evaluations on all of the agents reviewed. The World Health Organization (WHO) will be holding a meeting of an Environmental Health Criteria Task Group in October 2005; this task group will evaluate the health effects of ELF MFs (including cancer and noncancer outcomes). We anticipate that they will review the recent evidence in conjunction with the evaluation of the 2002 IARC Monograph. The WHO Environmental Health Criteria document on ELF MFs should be published shortly after this meeting.

Meeting report: summary of IARC monographs on formaldehyde, 2-butoxyethanol, and 1-tert-butoxy-2-propanol.

An international, interdisciplinary working group of expert scientists met in June 2004 to develop IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans (IARC Monographs) on formaldehyde, 2-butoxyethanol, and 1-tert-butoxy-2-propanol. Each IARC Monograph includes a critical review of the pertinent scientific literature and an evaluation of an agent’s potential to cause cancer in humans. After a thorough discussion of the epidemiologic, experimental, and other relevant data, the working group concluded that formaldehyde is carcinogenic to humans, based on sufficient evidence in humans and in experimental animals. In the epidemiologic studies, there was sufficient evidence that formaldehyde causes nasopharyngeal cancer, “strong but not sufficient” evidence of leukemia, and limited evidence of sinonasal cancer. The working group also concluded that 2-butoxyethanol and 1-tert-butoxy-2-propanol are not classifiable as to their carcinogenicity to humans, each having limited evidence in experimental animals and inadequate evidence in humans. These three evaluations and the supporting data will be-published as Volume 88 of the IARC Monographs.

Tobacco: science, policy and public health; Tobacco smoke and involuntary smoking (IARC Monographs, Volume 83).

Tobacco: science, policy and public health; Tobacco smoke and involuntary smoking (IARC Monographs, Volume 83).

Comparison of Carcinogen Hazard Characterisation Based on Animal Studies and Epidemiology

Recently we have described a simple method for quantitative risk assessment of non-threshold carcinogens based on the dose descriptor T25. In the present report quantitative hazard estimates calculated with the T25 method have been compared with results obtained using quantitative methods based on epidemiological studies. "Known" and "Likely/Probably" human carcinogens were identified from the US EPA database IRIS. In cases were the hazard characterisation was performed on the basis of epidemiological studies, the IARC monographs were used to identify animal studies by oral or inhalation exposure suitable for hazard characterisation by the T25 method. Six agents were identified: benzene, benzidine, 1,3-butadiene, cadmium, nickel subsulfide and vinyl chloride for which US EPA had made their hazard estimation based on epidemiological data. Animal data suitable for hazard characterisation were also available. For comparing hazard characterizations based on epidemiological and animal data, it was pragmatically decided to do this by comparing the chronic doses expressed as those representing a lifetime cancer hazard of 10(-3). In all cases the difference between the chronic doses determined from animal studies by the T25 method differed from those determined from epidemiological studies by a factor of less than three. Although a limited number of carcinogens were studied, the results demonstrate a very good agreement between the hazard characterisation based on epidemiological data and animal experiments over a range of more than 10(4).

Guest editors' introduction: Is EMF a potential environmental risk for children?

BioelectromagneticsVolume 26, Issue S7 p. S2-S4 Guest EditorialFree Access Guest editors' introduction: Is EMF a potential environmental risk for children? Mike Repacholi, Corresponding Author Mike Repacholi [email protected] Radiation and Environmental Health World Health Organization Geneva, SwitzerlandRadiation and Environmental Health, World Health Organization, 21 Avenue Appia, CH-1211 Geneva 27, Switzerland.Search for more papers by this authorRichard Saunders, Richard Saunders Radiation and Environmental Health World Health Organization Geneva, SwitzerlandSearch for more papers by this authorEmilie van Deventer, Emilie van Deventer Radiation and Environmental Health World Health Organization Geneva, SwitzerlandSearch for more papers by this authorLeeka Kheifets, Leeka Kheifets School of Public Health University of California Los Angeles, CaliforniaSearch for more papers by this author Mike Repacholi, Corresponding Author Mike Repacholi [email protected] Radiation and Environmental Health World Health Organization Geneva, SwitzerlandRadiation and Environmental Health, World Health Organization, 21 Avenue Appia, CH-1211 Geneva 27, Switzerland.Search for more papers by this authorRichard Saunders, Richard Saunders Radiation and Environmental Health World Health Organization Geneva, SwitzerlandSearch for more papers by this authorEmilie van Deventer, Emilie van Deventer Radiation and Environmental Health World Health Organization Geneva, SwitzerlandSearch for more papers by this authorLeeka Kheifets, Leeka Kheifets School of Public Health University of California Los Angeles, CaliforniaSearch for more papers by this author First published: 10 October 2005 https://doi.org/10.1002/bem.20157Citations: 13AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES AGNIR. 2003. Independent Advisory Group on Non-Ionizing Radiation. Health effects from radiofrequency electromagnetic fields. Documents of the NRPB 14(2): 177. COST281. 2002. European Cooperation in the Field of Scientific and Technical Research Workshop on “Mobile communication and children”. See: www.cost281.org/. HCN. 2002. Health Council of the Netherlands. Report on “Mobile phones: An evaluation of the health effects”. See http://www.gr.nl/. IARC. 2002. International Agency for Research on Cancer. Non-ionizing radiation, Part 1: Static and extremely low frequency electric and magnetic fields, Vol. 80. IARC monographs on the evaluation of carcinogenic risks to humans. Lyon: IARC Press. 429p. ICNIRP. 1998. International Commission on Non-Ionizing Radiation Protection. Guidelines for limiting exposure to time-varying electric, magnetic, and electromagnetic fields (up to 300 GHz). Health Physics 74(4): 494– 522. IEGMP. 2000. Independent Expert Group on Mobile Phones. Report “Mobile Phones and Health” .See: www.iegmp.org.uk/. Kheifets L, Repacholi M, Saunders R, van Deventer E. 2005. Sensitivity of children to electromagnetic fields. Pediatrics 116: e303– e313. NRPB. 2004. National Radiological Protection Board. Review of the scientific evidence limiting exposure to electromagnetic fields (0–300 GHz). Documents of the NRPB 15(3): 215. Citing Literature Volume26, IssueS72005Pages S2-S4 ReferencesRelatedInformation

The science and practice of carcinogen identification and evaluation.

Several national and international health agencies have established programs with the aim of identifying agents and exposures that cause cancer in humans. Carcinogen identification is an activity grounded in the scientific evaluation of the results of human epidemiologic studies, long-term bioassays in experimental animals, and other data relevant to an evaluation of carcinogenicity and its mechanisms. In this commentary, after a brief discussion of the science basis common to the evaluation of carcinogens across different programs, we discuss in more detail the principles and procedures currently used by the IARC Monographs program.

Betel quid without tobacco as a risk factor for oral precancers

The IARC monographs recently classified chewing betel quid without tobacco as a human carcinogen. Several studies in Taiwan have reported that betel quid without tobacco may increase the risk of oral precancers such as oral leukoplakia and oral submucous fibrosis. However in India, since most betel quid chewers prefer to add tobacco to the quid, the independent effect of betel quid on the risk of oral precancers is difficult to assess and has not yet been fully explored. We conducted a large case-control study in Kerala, India, including 927 oral leukoplakia cases, 170 oral submucous fibrosis cases, 100 erythroplakia cases, 115 multiple oral precancer cases and 47,773 controls. The focus of this reanalysis is on the minority of individuals who chewed betel quid without tobacco. Among nonsmokers and nondrinkers, chewing betel quid without tobacco conferred ORs of 22.2 (95%CI=11.3, 43.7) for oral leukoplakia, 56.2 (95%CI=21.8, 144.8) for oral submucous fibrosis, 29.0 (95%CI=5.63, 149.5) for erythroplakia and 28.3 (95%CI=6.88, 116.7) for multiple oral precancers, after adjustment for age, sex, education and BMI. Dose-response relationships were observed for both the frequency and duration of betel quid chewing without tobacco on the risk of oral precancers. In conclusion, our study supports the hypothesis that chewing betel quid without tobacco elevates the risks of various oral precancers.

Global Development

SFDA Approves Tumor Necrosis Therapy for Marketing in China. Agilent Collaborates with Battelle Memorial Institute in Artificial Neural Network Technology. IARC Monographs Program Finds Betel-Quid and Areca-Nut Chewing Carcinogenic to Humans.

Exposure to residential radon causes lung cancer. For the proposition.

Exposure to residential radon causes lung cancer. For the proposition.

Integrity of the Conduct of the IARC Monographs Program

Integrity of the Conduct of the IARC Monographs Program

IARC Monographs, Industry lnfluence, and upgrading, Downgrading, and Under-grading Chemicals: A Personal Point of View

<i>IARC Monographs</i>, Industry lnfluence, and upgrading, Downgrading, and Under-grading Chemicals: A Personal Point of View

Letter to IARC Monographs Program Chief Jerry M. Rice

Letter to IARC Monographs Program Chief Jerry M. Rice

The IARC monographs program: changing attitudes towards public health.

From its outset, the International Agency for Research on Cancer's (IARC's) program for the evaluation of carcinogenic risks for humans had to resist strong direct and indirect pressures from various sources to protect its independence. External experts for Monographs working groups were selected on the basis of competence and the absence of conflicts of interest. The IARC did not use unpublished or confidential data, so readers could access the original information and thus follow the groups' reasoning. The strength of the original program lay in its scientific integrity and its transparency. Since 1994, however, the IARC appears to have attributed less importance to public health-oriented research and primary prevention, and the Monographs program seems to have lost some of its independence. Criteria for evaluating carcinogenicity related to mechanism(s) of action are not necessarily used as originally intended, to ensure better protection of public health. Evidence for carcinogenicity provided by the results of experimental bioassays has been disregarded on the basis of only suggested mechanistic hypotheses. If tests show those hypotheses to be incorrect, or if they do not account adequately for the wide range of susceptibility in humans, serious consequences for public health may follow.

The IARC Monographs Program: Changing Attitudes towards Public Health

The IARC Monographs Program: Changing Attitudes towards Public Health

Carcinogenic risks of silica and coal dust to humans — International rating by volume 68 of the IARC monographs (1997) — Part 2. Abstracts of epidemiological reports on silica and coal dust

Carcinogenic risks of silica and coal dust to humans — International rating by volume 68 of the IARC monographs (1997) — Part 2. Abstracts of epidemiological reports on silica and coal dust

1,3-Butadiene, isoprene and chloroprene: reviews by the IARC monographs programme, outstanding issues, and research priorities in epidemiology

1,3-Butadiene, isoprene and chloroprene have all been evaluated more than once by the IARC Monographs Programme on the Evaluation of Carcinogenic Risks to Humans, most recently in February 1998 (Volume 71). Summaries are available on-line at http://monographs.iarc.fr. 1,3-Butadiene is currently classified in Group 2A ( probably carcinogenic to humans), on the basis of limited evidence for increased occupational cancer risk in humans plus sufficient evidence of carcinogenicity at multiple organ sites in rats and especially in mice exposed by inhalation. Four epidemiologic studies are available on cancer risk among workers exposed to 1,3-butadiene, one large study among styrene-butadiene rubber (SBR) workers, and one large and two small studies among 1,3-butadiene production workers. The results of the study of SBR workers suggest an association between butadiene exposure and leukaemia risk, which is consistent with the results of the large study of production workers. This latter study also suggested an increased risk of lymphoreticulosarcoma (ICD-8, 200). The major factors hampering the assessment of the available results are (i) possible misclassification of lymphoid and haematopoietic neoplasms, (ii) limitations in the assessment of past exposure (with the exception of the study of SBR workers) and (iii) a potential confounding effect of agents other than butadiene. Future research priorities include (i) the incorporation of newly developed biomarkers of exposure, (ii) the possible application of intermediate biomarkers, (iii) the replication of the study among SBR workers, possibly in Europe, and (iv) reanalysis of existing data in light of revisions of the classifications of leukaemias and lymphomas in the International Classification of Diseases for Oncology, Third Edition (2000). Isoprene is classified in Group 2B ( possibly carcinogenic to humans), on the basis of sufficient evidence for carcinogenicity at multiple organ sites in both mice and rats, especially male mice, exposed by inhalation. No epidemiologic studies are available on cancer risk from occupational exposure to isoprene. Such studies could be conducted within the framework of existing or future studies of SBR workers, assuming that isoprene exposure can be disentangled from butadiene and styrene exposure. Chloroprene is classified in Group 2B on the basis of sufficient evidence for carcinogenicity at multiple organ sites in both mice and rats exposed by inhalation. Studies of chloroprene exposed workers now include chemical workers from the United States, China and Armenia as well as shoe workers from Russia. The results of the studies from China, Armenia and Russia suggest an excess risk of liver cancer. The risk of other neoplasms was not consistently increased. Limitations of available studies include possible bias from cohort enumeration, follow-up, and choice of reference population. In most studies the exposure assessment was poor, the possible confounding effect of co-exposures was not addressed and the statistical power was low. The pathology of the cases of liver cancer should be reviewed. Future research priorities include a replication of available studies in well-defined populations and the development of biomarkers of exposure.

Rodent carcinogenicity tests need be no longer than 18 months: an analysis based on 210 chemicals in the IARC Monographs

The IARC Monographs (Vols 1–70) were studied to determine the time of onset of treatment-related tumorigenicity in long-term rodent studies for chemicals classified by IARC as having sufficient evidence of carcinogenicity in animals. The analysis excluded studies on metals and their salts, studies on particulates, studies by parenteral routes of administration that resulted in tumours only at the site of exposure, and studies that did not approximate to the current standard long-term rodent carcinogenicity bioassay, for instance transplacental or multigeneration studies, initiator-promoter studies, lung tumour assays in Strain A mice and studies in newborn animals. Data from a total of 210 chemicals revealed that, overall, evidence of treatment-related tumorigenicity was first apparent within 12 months for 66% of the chemicals and for only 7% were studies of longer than 18 months necessary. All IARC Group 1 chemicals were detected in animals within 18 months, and most within 12 months. Most of the tumour types that required more than 18 months for detection were of dubious relevance to human risk assessment. Termination of rodent carcinogenicity studies at 18 months or earlier would greatly reduce the complications that arise in interpreting the findings in aged animals which often have defective hepatic or renal function and would also markedly reduce the time required for histopathological examination of dozens of tissues taken from the approximately 500 animals routinely employed in these studies.