Target organs for carcinogenicity of chemicals and industrial exposures in humans: a review of results in the IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans.

Epidemiological observations indicate that cancers affecting different organs and systems in humans have different causes. At the descriptive level, cancer incidence and mortality rates exhibit patterns of geographic and temporal variation which are distinct and separate for each cancer site and even, at a given site, for different histological types (for instance, increasing squamous cell carcinoma of the lung and decreasing stomach cancer in most developed countries in recent decades). The existence of these distinct patterns in itself indicates that different causes are at the origin of cancers at different sites. Hence, it is of scientific and practical importance not only to identify agents that are carcinogenic to humans but also to specify as definitely as possible the target organ(s) of their action. This is done in the present review of results in the International Agency for Research on Cancer Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans.

Evaluation of the carcinogenicity of chemicals: a review of the Monograph Program of the International Agency for Research on Cancer (1971 to 1977).

In 1971 the International Agency for Research on Cancer initiated a program on the evaluation of the carcinogenic risk of chemicals to humans, which concentrated on the production of monographs on individual chemicals. A review of this ongoing program is presented here as a contribution to the discussion of primary prevention of cancer. A total of 368 chemicals were evaluated in the first 16 volumes of the International Agency for Research on Cancer monographs. For 26 chemicals (or industrial processes), a positive association between exposure and the occurrence of cancer in humans was observed. For 221 chemicals, some evidence of carcinogenicity was found in at least one species of experimental animals. However, no evaluation of the carcinogenic risk of these chemicals to humans was made, either because no epidemiological studies or case reports were available or because the results of available human studies were inconclusive. For the remaining 121 chemicals, the available data were inadequate for an evaluation of the presence or absence of a carcinogenic effect in experimental animals or humans. The criteria on which the carcinogenicity of chemicals to humans and/or experimental animals was assessed, from the initiation of this program in 1971 until 1977, have recently been revised and are briefly discussed.

Evaluation of the carcinogenic risks to humans associated with surgical implants and other foreign bodies - a report of an IARC Monographs Programme Meeting. International Agency for Research on Cancer.

A meeting was held within the International Agency for Research on Cancer (IARC) Programme on the Evaluation of Carcinogenic Risks to Humans of surgical implants and other foreign bodies. This meeting report summarises the types of materials considered, their wear and degradation, their cancer epidemiology in both humans and other animals, the published experimental carcinogenicity data and selected data on their toxic, including genotoxic, effects. Evaluations resulting in a classification of Group 2B (possibly carcinogenic to humans) were reached for: (1) polymeric implants prepared as thin smooth films [with the exception of poly(glycolic acid)]; (2) metallic implants prepared as thin smooth films; and (3) implanted foreign bodies consisting of metallic cobalt, metallic nickel and a particular alloy powder consisting of 66-67% nickel, 13-16% chromium and 7% iron. Group 3 classifications (not classifiable as to their carcinogenicity to humans) were made for: (1) organic polymeric materials as a group; (2) orthopaedic implants of complex composition and cardiac pacemakers; (3) silicone breast implants; (4) dental materials; and (5) ceramic implants.

An overview of phthalate ester carcinogenicity testing results: the past.

This paper presents a short review of the available carcinogenicity tests which have been carried out on various phthalate esters prior to the availability of the National Cancer Institute bioassay studies. All of these studies suffer from diverse limitations in design or reporting when compared to more recent experimental protocols and reports. There are three papers related to di(2-ethylhexyl) phthalate, one to di-n-butyl phthalate, two to butyl benzyl phthalate, one to ethyl phthalyl ethyl glycolate nd another to butyl phthalylbutyl glycolate (1).

Carcinogenicity evaluations and ongoing studies: the IARC databases.

Many thousands of chemicals are produced industrially and many more occur naturally. Information on the toxicology of these chemicals is often minimal or absent. The International Agency for Research on Cancer (IARC) has published evaluations of the carcinogenic risk to humans of over 700 chemicals, groups of chemicals, and complex mixtures as a regular series of monographs. A database has been created containing summaries of all the relevant epidemiological, animal carcinogenicity, and other relevant biological data for each chemical or mixture evaluated. Additional databases have been created for ongoing epidemiological studies of cancer in humans and for long-term carcinogenicity studies in rodents, as well as a database containing information on genotoxic and related effects of chemicals. Some of these databases have been published in print form. IARC now plans to publish them electronically, together with other databases, in the form of a CDROM (compact disk, read-only memory). The objective will be to make the entire IARC database of cancer information as widely available as possible in an integrated format conducive to efficient and combined exploitation of all the component databases.

An IARC evaluation of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans as risk factors in human carcinogenesis.

The International Agency for Research on Cancer (IARC) Monographs program reevaluated polychlorinated dibenzo-p-dioxins and evaluated polychlorinated dibenzofurans as possible carcinogenic hazards to humans in February 1997, using the most recent epidemiologic data on exposed human populations, experimental carcinogenicity bioassays in laboratory animals, and supporting evidence on relevant mechanisms of carcinogenesis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was evaluated as carcinogenic to humans (IARC group 1 classification) on the basis of limited evidence of carcinogenicity to humans derived from follow-up of workers who had been heavily exposed in industrial accidents and sufficient evidence of carcinogenicity in experimental animals. The evaluation also considered the following supporting evidence: TCDD is a multisite carcinogen in experimental animals and has been shown by several lines of evidence to act through a mechanism involving the aryl hydrocarbon receptor; this receptor is highly conserved in an evolutionary sense and functions the same way in humans as in experimental animals; tissue concentrations of TCDD are similar in heavily exposed human populations in which an increased overall cancer risk was observed and in exposed rats that developed tumors in carcinogenicity tests. Other polychlorinated dibenzo-p-dioxins, the nonchlorinated dibenzo-p-dioxin, and polychlorinated dibenzofurans were evaluated as not classifiable as to their carcinogenicity to humans (group 3).

Identification of carcinogens within the IARC monograph program.

Fewer than 50 chemicals, groups of chemicals, or mixtures have been causally linked with cancer in humans. Some 250 chemicals have, however, been found to be carcinogenic to rodents. Carcinogenic risk factors that have been identified for humans occur in clearly quantifiable exposure situations, but epidemiologic information on cancer in humans is missing or inadequate for the great majority of chemicals. Extrapolation of animal data to humans is complicated because long-term carcinogenicity studies on animals are carried out under simplified conditions, whereas humans are exposed to a multitude of exogenous and endogenous agents. Furthermore, the carcinogenic process includes multistage and multifactorial aspects, and human populations are genetically and physiologically heterogeneous. Although the science of carcinogenesis is making rapid progress in terms of understanding some of these processes and interactions, there is still a need to err on the side of safety and accept animal data as a warning signal for possible human effects.

[Identification of human carcinogenic risks in IARC monographs]. / Identification des facteurs cancérogènes pour l'homme dans les Monographies du CIRC.

For more than twenty years, the IARC has been evaluating the carcinogenic risk to humans of chemicals, groups of chemicals, complex mixtures, occupational exposures, behavioral and life-style exposures, biological agents, such as bacteria and viruses, and physical agents, such as radiation, on the basis of published studies of carcinogenicity in humans and laboratory animals. This paper includes the list established by IARC of substances carcinogenic to humans.

Occupational cancer in developing and newly industrialized countries.

Cancer is a worldwide public health problem, accounting for an increasing proportion of all deaths. It is the second leading cause of death in most of the industrialised world, and developing countries appear to be launched on a cancer epidemic, similar to that in industrialised countries. In developing countries, most cancer deaths are due to tumours of the stomach, oesophagus, lung, liver and uterine cervix; occupational cancers account for an undetermined number of these cases. Occupationally associated neoplasms may either be related directly to specific exposures within a workplace, e.g., bladder cancer in benzidine-exposed workers, or reflect indirect factors, including socioeconomic status and conditions of life. Asbestos-induced pneumoconiosis is recognised as an occupational disease in many developing countries, whereas asbestos-related malignancies draw less attention. The rising prevalence of cigarette smoking in these countries greatly magnifies the effect of asbestos in inducing lung cancer. Transplantation of industries from developed to developing countries is often accompanied by a reduction in the standard of working conditions. The rising unemployment in developing countries is unlikely to incite workers to claim better conditions.

Cancer etiology: agents causally associated with human cancer.

Cancer is a multifactorial and multistage process, the exact mechanisms of which are still only partially known. However, even in the absence of a complete understanding of the process of carcinogenesis, we have been able to identify several factors which modify the risk of tumour development in humans. These include both endogenous and environmental factors, ranging from exposure to a single identified chemical to the occupations we follow in order to make our living. Cancer prevention strategies may differ in different parts of the world. In Europe, lung cancer is responsible for about one fourth of all cancer deaths and most of it could be prevented by eliminating tobacco smoking. Other exposures that can be controlled include occupational exposures to agents known to cause cancer at sites such as lung, bladder, paranasal sinuses, leukaemia, lymphoma and liver, as well as exposure to sunlight, known to be associated with both non-melanocytic and melanocytic skin cancer. Liver cancer is a common cancer in other regions of the world where hepatitis B virus (HBV) infection is endemic; in these areas, fungal contamination of food is also common. While immunization against HBV may be the method of choice in the long run, reduction of exposure to aflatoxins might be a more useful intermediate goal in primary prevention because of the strong interaction between hepatitis B and aflatoxin exposure on liver cancer risk. To date, few chemical agents have been proved to be of etiological relevance to cancer in humans at sites such as the breast (with the exception of oestrogenic hormones), ovary, colon-rectum and prostate.(ABSTRACT TRUNCATED AT 250 WORDS)

Human cytogenetic damage as a predictor of cancer risk.

The human cytogenetic assays presently available for biomonitoring are still inadequate for use in routine surveillance procedures and they must be applied with care. Knowledge of the effects of the agents concerned in experimental systems is a prerequisite, and confounding factors should be assessed. Consequently, the methods are useful and informative under carefully selected conditions and can indicate agents and exposures that are capable of causing chromosomal damage in humans, hinting at possible human cancer risk. Established and potential human carcinogens have frequently been shown to induce chromosomal aberrations in humans in vivo. It is also well documented that chromosomal rearrangements play an important role in the development of neoplasia. These combined lines of evidence suggest that structural chromosomal aberration in vivo has advantages over other cytogenetic end-points in predicting potential human cancer risk. Preliminary findings in a prospective follow-up study suggest that subjects with a high percentage of structural chromosomal aberrations but not sister chromatid exchanges may be at elevated risk for cancer.

Data on the carcinogenicity of chemicals in the IARC Monographs programme.

Data were extracted from IARC Monographs volumes 1-38 on chemicals and exposures for which some data on carcinogenicity in humans, or sufficient evidence of carcinogenicity in experimental animals existed. In all, 288 chemicals, industrial processes and complex mixtures fulfilled these criteria. For 30 chemicals or mixtures of chemicals, and nine industrial processes, there was sufficient evidence of carcinogenicity in humans; and for 63 chemicals and mixtures of chemicals and for five industrial processes, there was evidence that these exposures were probably carcinogenic to humans. For 61 chemicals or groups of chemicals and six industrial processes or occupations, no evaluation of carcinogenicity to humans could be made. For 115 chemicals there is sufficient evidence of carcinogenicity to experimental animals, but no epidemiological data are available. Publications not earlier referred to on the carcinogenicity of these chemicals and exposures were found for approximately 70. A call is made for further information on these exposures with a view to updating the IARC Monographs.

Tumors of the nervous system in carcinogenic hazard identification.

In the absence of adequate data on humans, it is biologically plausible and prudent to regard agents and mixtures for which there is sufficient evidence of carcinogenicity in experimental animals, usually rats and mice, as if they presented a carcinogenic risk to humans. Prediction of cancer sites in humans from bioassay data in rodents is much less certain, however, regardless of organ or tissue. For tumors of the nervous system, there is practically no basis for judging the validity of such predictions, as only ionizing radiation is known to cause tumors of the central nervous system (CNS) in humans. Brain tumors are relatively uncommon findings in bioassays and are rare in untreated rodents, even in rats, which appear to be the most susceptible species. However, CNS tumors have been readily induced in rodents by systemic exposures to some chemicals, notably N-nitrosoalkylureas and other alkylating agents and certain alkyl hydrazine derivatives. CNS tumors in rodents have played a significant role in carcinogenic hazard evaluations of several other chemicals, including acrylonitrile, ethylene oxide, and acrylamide, and have been implicated as part of the tumor spectrum induced by vinyl chloride and certain inorganic lead compounds. In some of these evaluations, it is not certain that all tumors diagnosed as primary brain tumors were correctly identified. Diagnostic difficulties have been presented by undifferentiated small-cell tumors that may invade the brain, including carcinomas of the nasal cavity and undifferentiated schwannomas arising in cranial nerve ganglia, and by the difficulty of reliably distinguishing between focal reactive gliosis and early glial neoplasms. The most striking experimental finding regarding the induction by chemicals of tumors of the nervous system is the dramatically greater susceptibility of the fetal and neonatal nervous system to some carcinogens, as compared with the susceptibility of the nervous system in adults of the same species.