Working Group on Mechanisms of Carcinogenesis and the Evaluation of Carcinogenic Risks

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[CANCER RESEARCH 52, 2357-2361, April 15, 1992] Meeting Report Working Group on Mechanisms of Carcinogenesis and the Evaluation of Carcinogenic Risks

A working group of experts in carcinogenesis and related a higher category for the overall evaluation of carcinogenicity disciplines' was convened in Lyon, France, June 11-18, 1991, to humans than that resulting from carcinogenicity data alone. by the IARC2 in the context of its program of Monographs on Among the 729 overall evaluations made in the existing 53 the Evaluation of Carcinogenic Risks to Humans. The task of volumes of the Monographs series, other relevant data were the group was to advise the agency regarding whether and to used to upgrade the overall evaluation from Group 3 to Group what extent information concerning mechanisms of action of 2B for five agents (e.g., styrÃ¨ne, bleomycins). Such data were agents to which humans are exposed could be used to evaluate also used to upgrade the overall evaluation from Group 2B to their carcinogenic risk. Group 2A for 26 agents (e.g., epichlorohydrin, MOCA). In 1983, the IARC convened for the first time an ad hoc Background working group of experts to discuss the contributions of epi demiolÃ³gica! and experimental studies to understanding mech Groups of experts evaluating agents in the Monographs pro anisms of carcinogenesis and to advise IARC on the use of gram follow well-defined guidelines, developed during several short-term tests for the identification of carcinogens and on the consultative meetings, in formulating their evaluations. These possibility of classifying carcinogens according to their mecha guidelines are published as the "Preamble" to each volume of nism of action. That group concluded that such a classification monographs. The evaluations are of a qualitative nature and would be an important contribution to the prevention of human reflect the opinion of the expert group regarding whether the cancer, since it is possible that different classes of carcinogens available evidence shows that an agent has the inherent property with different mechanisms of action, exhibiting different bio of being a carcinogenic risk to humans. logical effects, could be controlled by specific, appropriate The evaluations are made in two steps: (a) on the basis of all methods. The group considered, however, that at that time published studies of cancer in humans following exposure to information was inadequate to permit an exhaustive or defini the agent in question, the evidence of carcinogenicity in humans tive classification of carcinogens according to mechanism of is classified as being either sufficient, limited, inadequate, or action (1). suggesting lack of carcinogenicity: evidence from long-term studies of carcinogenicity in animals exposed to the agent is The Meeting classified similarly; (b) an overall evaluation is made of the carcinogenicity of the agent to humans, on the basis of all the The purpose of the meeting convened in June 1991 was to information available, which results in classification of the examine whether data on mechanisms of action could be used agent into one of the following categories: carcinogenic to in classifying agents in the five categories described aboveâ€”1, humans (Group 1), probably carcinogenic to humans (Group 2A, 2B, 3, and 4. Specifically, the working group was to decide 2A), possibly carcinogenic to humans (Group 2B), not classifi whether an agent could be defined as causing cancer by a defined able as to its carcinogenicity to humans (Group 3), or probably mechanism and whether the identification of a causative mech not carcinogenic to humans (Group 4). anism would influence an overall evaluation of carcinogenicity This overall evaluation is based not only on the evaluations to humans or elucidate the extrapolation of results from exper of degrees of evidence for carcinogenicity in humans and in iments in animals to the human situation. experimental animals made in the first step but also on other Twenty-eight discussion papers on aspects related to mecha data considered to be relevant. These may include information nisms of carcinogenesis were prepared by members of the group concerning chemical properties, metabolism, and toxicity, par and circulated to all participants before the meeting to serve as ticularly its activity in short-term tests for genotoxicity. background information. At the meeting, the group met initially At present, an agent is classified as carcinogenic to humans in plenary, then in subgroups, and finally in plenary to prepare (Group 1) only if there is sufficient evidence from epidemiolog- a consensus report of their conclusions. The proceedings of the ical studies that it is carcinogenic, and an agent is classified as meeting will be published in the IARC Scientific Publications probably or possibly carcinogenic to humans (Groups 2A and series (2). 2B) if there is limited evidence of carcinogenicity in humans The consensus report consists of four sections. After a brief and/or sufficient evidence of carcinogenicity in experimental discussion of the multistage, multifactorial nature of carcino animals. These classifications are usually unaffected by infor genesis, possible mechanisms involved in carcinogenesis are mation which may be available from data other than those on described, under the broad headings of genotoxicity, cell prolif carcinogenicity. Thus, any agent that increases the incidence of eration, and receptor mechanisms. Various putative factors that malignant tumors is considered to be carcinogenic, independ influence the strain and species variability of the response to a ently of its mode of action. carcinogen and that may affect multistage mechanisms are Data other than those on carcinogenicity have already been reviewed under toxicokinetics, DNA repair mechanisms, inter used in making overall evaluations of carcinogenicity to hu cellular communication, immune defects and immunosuppres- mans, mainly resulting in an assignment to a category denoting sion, and the role of sex hormones. The third section comprises a discussion of the ways in which Received 9/23/91; accepted 2/10/92. 1See "Appendix" for list of participants. mechanisms of action of carcinogens can be identified, based 2The abbreviations used are: IARC, International Agency for Research on upon the contributions of epidemiolÃ³gica! studies, of long-term Cancer; MOCA, 4,4'-methylene bis(2-chloroaniline). carcinogenesis studies, of medium-term carcinogenicity assays, 2357

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1992 American Association for Cancer Research. MEETING REPORT and of other related mechanistic data, including structure- action. Multistage models particularly in skin, liver, and bladder activity relationships, toxicokinetics, and assays for genotoxic- are also available. ity. The final section proposes principles and procedures for Transgenic animals may be used to understand the conse using information on mechanisms in evaluating carcinogenic quences of the introduction of specific protooncogenes and risk to humans. activated oncogenes into certain tissues. Although few experi ments have been reported on the effects of environmental agents Contribution of EpidemiolÃ³gica! Studies on such animals, it is anticipated that such studies may even tually clarify the specific molecular effects of many agents on Epidemiological research has focused on the identification of mutagenesis and carcinogenesis. exposures that increase or decrease the risk of cancer. In some instances, such evidence has led to specific hypotheses about Contribution of Medium-Term Studies mechanisms of action. The most important of these, and which followed to a certain extent the hypothesis, first formulated on Medium-term assays for carcinogenicity are based mainly on the basis of experimental observations, is the multistage model the detection of preneoplastic lesions, particularly in rat liver. formulated to account for epidemiological observations that It is suggested that these focal lesions, characterized as pheno- cancer incidence was related to dose and duration of exposure typically altered cell populations, represent early stages in a and age at first exposure to specific agents. Other hypotheses biological continuum which may eventually lead to benign and/ based on both epidemiological evidence and other findings are or malignant neoplasms. that the immune system plays a role in carcinogenesis in that The phenotype of the preneoplastic lesion is not uniform, immunosuppression may allow the expression of virally induced and an accurate subclassification of different types of lesions in cancers that would otherwise be eliminated immunologically, particular with regard to their reversibility or persistence is that cell proliferation produced by hormones may be of rele imperative. In rodent liver, the focal lesions may have clonal vance in the etiology of hormonal cancers, and that genetic origins; but there may also be simultaneous alterations of many susceptibility to cancer may be the inheritance of one of the hepatocytes in larger cell populations rather than repeated changes involved in multistage carcinogenesis. clonal selection in the progressive development of phenotypic Epidemiological data relating cancer to specific risk factors heterogeneity during hepatocarcinogenesis. Sequential altera may thus provide information about the time of action of the tions in the morphological and biochemical phenotype are factor (i.e., whether early or late in the process of carcinogene associated with increasing cell proliferation, from early lesions sis) or whether the observed effect is caused by more than one through intermediate cell populations to adenomas. The meta agent in accordance with some model of interaction. The group bolic aberrations that characterize preneoplastic hepatic lesions concluded that the inferences that can be drawn about mecha appear to be closely related to the mechanism of neoplastic nism of action from such information are not useful (within the conversion of the hepatocytes. framework of current knowledge) in contributing to the evi dence for or against a carcinogenic risk to humans. Contribution of Other Data on Mechanisms Techniques for detecting cellular and molecular alterations which may be involved in carcinogenesis are now being used in Several types of data can have a bearing on evaluating mech epidemiological studies, however, to provide more detailed anism^) of action of a carcinogen. These range from consider information concerning mechanisms. The ability to measure ations of the structure through to the measurement of specific exposures more sensitively and to identify tumors carrying cancer-related mutations in tissues of exposed humans. specific genetic changes may greatly increase the ability of Structure-activity relationships can be used to predict electro- epidemiologists to detect low cancer risks. When enough is philic carcinogens, including the sites and extent of interactions known about the predictive significance for cancer in humans with DNA. A further extension is the possible recognition of of measurable biological effects of potential carcinogens, it those substituents within an electrophilic carcinogen that are should become possible to use epidemiological data based on associated with its carcinogenicity, and it is sometimes possible such measurements in evaluating carcinogenicity. to recognize features in a molecule that will act against the expression of an electrophilic substituent. Directions of current Contribution of Long-Term Carcinogenesis Studies research in this field include how best to derive structure-activity relationships for validated surrogate end points for which data Carcinogens are considered to be agents that lead to a signif can be accrued rapidly. icant increase in the incidence of malignant neoplasms of one Information concerning the uptake, distribution, metabolism, or more histological types in exposed animals, as compared and excretion of a carcinogen provides support for the interpre with an appropriate control group, regardless of mode of action. tation of hypotheses of mechanism. Determinations of concen Included are agents that induce uncommon neoplasms or induce tration and time patterns of a carcinogen or its metabolites in common neoplasms earlier or in greater numbers than usual. target tissues can help in evaluating quantitative relationships In certain cases, "neoplasm" may include a combination of both between tissue dose and carcinogenic effect. For carcinogens benign and malignant tumors when they originate in the same that require conversion to a reactive metabolite, studies that organ from the same cell type. elucidate the pathways and reactions can be important in estab The results of such studies provide some information useful lishing mechanisms of action. Toxicokinetic factors may be the for postulating mechanisms of action. For instance, the occur underlying cause of, or contributing factors to, observed differ rence of uncommon neoplasms in multiple organs and species ences in cell-, tissue-, sex-, or species-specific differences in can give an indication of a genotoxic action, but exceptions carcinogenic effects. Quantitative and qualitative differences in may be found. The latency of tumor induction and shape of the human carcinogenic risk may be due to genetic polymorphism dose-response curve may also give insight into the stage of in biotransformation pathways. 2358

The contribution of short-term tests for genotoxicity to un can be considered supportive evidence for a proposed mecha derstanding mechanisms of action of carcinogens is implicit nism of carcinogenic action. from the role of genetic events in the development of cancer. The genetic changes that are implicated in carcinogenesis in Proposed Principles and Procedures for Using Information clude the induction of point mutations, deletions, insertions, on Mechanisms in Evaluating Carcinogenic Risks to gene amplification, chromosomal rearrangements, and numer Humans ical chromosomal mutations (aneuploidy). Knowledge that an agent that induces any of these effects is active in vivo, partic Developments in the understanding of carcinogenicity have ularly in the tissue subject to carcinogenesis, enhances confi several important implications for evaluating agents within the dence that the genetic effects of the agent are important in the IARC Monographs program. process by which it induces cancer. Judgment, however, is both The group recommended that information concerning pos critical and central to interpreting data on genotoxicity. For sible mechanisms of carcinogenic action should be summarized example, an unstable alkylating agent may induce mutations when appropriate data were available. They outlined a number and tumors at the site of contact in mammals (e.g., the skin of steps to use when evaluating carcinogenic risk. after painting, the nose after inhalation, the stomach after Mechanisms may be understood at many different levels. The gavage) yet be systematically inactive at other sites due to rapid group proposed four descriptive dimensions for considering hydrolysis or metabolic detoxification. Thus, negative results such data: (a) evidence of genotoxicity (i.e., structural change obtained in tests for cytogenetic changes in mouse bone marrow at the level of the gene), (b) evidence of effects on the expression cannot be used to assess whether a direct mutagenic mechanism of relevant genes (i.e., functional changes at the intracellular is important in the induction of nasal tumors after inhalation. level), (c) evidence of relevant effects on cell behavior (i.e., Particular DNA lesions and particular resultant genetic morphological or behavioral changes at the cellular or tissue changes have been associated with the carcinogenesis of some level), and (d) evidence of time and dose relationships of agents. Measurement of such events can help to rationalize carcinogenic effects and interactions between agents. These carcinogenic potency in different species or organotropism dimensions are not mutually exclusive and an agent may have within a species or to extrapolate to humans a carcinogenic effects on several or all dimensions. Thus, the action of an effect observed in experimental animals. Evidence of DNA agent on the expression of relevant genes could be summarized damage, DNA repair, adducts between DNA and proteins, and under both the first and the second dimension if it were known chromosomal changes in people exposed to known carcinogens with reasonable certainty that those effects resulted from gen indicates that some of these end points might be used to predict otoxicity. Because different agents act by different mechanisms, carcinogenic risk. Stable genetic changes, such as chromosomal the relevance and importance of each of these levels are de rearrangements, deletions, and point mutations, are highly rel pendent on the agent and tumor site that are being considered. evant, since they are known to be related to carcinogenesis. The group proposed that the strength of the evidence that a particular mechanism of carcinogenesis is or is not operating Any generalization about the carcinogenicity or lack of car- be evaluated, using terms such as "weak," "moderate," and cinogenicity of an agent on the basis of results from short-term "strong." Development of operational guidelines for making tests for genetic effects must, however, be tempered with cau tion. Although there are well-established tests for gene muta such evaluations might be difficult because of the diversity of the phenomena involved; however, each working group would tions, many of those for chromosomal rearrangements and assess the available data with regard to the relevance, reproduc- damage have low sensitivity, and generally available assays for ibility, and sensitivity of the methods used. gene amplification do not exist. So, while an agent can be In assessing the relevance of the available data concerning concluded to be genotoxic on the basis of its chemical structure mechanisms to the evaluation of the carcinogenic risk of an and its activity in an established short-term test, conclusions of agent to humans, a number of issues are pertinent: (a) evidence nongenotoxicity must be made only on the basis of a wide range that the effect lies in the chain of events linking the agent with of tests. cancer, (b) relevance of the test system to human responses, (c) The genotoxic status of a known carcinogen that is inactive similarity of the end point of the test system to the human in such short-term tests is difficult to evaluate. Since it is a target cells (although the validity of the end point can override carcinogen, it is evident that a genetic change in the target this consideration), (

The group suggested a number of situations in which relevant Harri Vainic? information concerning mechanisms could be used in evaluating Elisabeth Heseltine* carcinogenic risk to humans: (a) such information may confirm Douglas McGregor the level of classification indicated by data from epidemiolÃ³gica! Lorenzo Tomatis and/or experimental carcinogenicity studies; (b) strong evi Julian Wilbourn dence for a mechanism of action that is relevant to carcinogen International Agency for Research on Cancer icity in humans could justify "upgrading" of the overall evalu 150 cours Albert Thomas ation for a particular agent; (c) an overall evaluation of human 69372 Lyon Cedex 08 France cancer hazard based on the results of experimental carcinogen icity tests could be "downgraded" by strong evidence that the mechanism responsible for tumor growth in experimental ani Appendix mals does not occur in humans. In keeping with the goal of public health, priority must be given to the demonstration that Members the mechanism is not operative to humans. Obviously, the J. Ashby, Central Toxicology Laboratory, Imperial Chemical Indus absence of data on mechanisms would not influence evaluations tries, PLC, Alderley Park, Nr Macclesfield. Cheshire SK10 4TJ, United of human carcinogenic hazard based on epidemiological or Kingdom. experimental carcinogenicity data. P. Bulinaseli. Department of Cytopathology, Institute for Experi The group considered that increasing inclusion of data on mental Pathology, German Cancer Research Centre, Im Neuenheimer mechanisms of carcinogenic action might necessitate modifi Feld 280, 6900 Heidelberg 1, Germany. cation of the criteria for placing agents in the different IARC J. C. Barrett, Laboratory of Molecular Carcinogenesis, National categories. Although it may not now, or in the future, be Institute of Environmental Health Sciences, PO Box 12233, Research possible to prescribe exhaustive criteria for entry into each Triangle Park, NC 27709. V. Beral, Cancer Epidemiology Unit, Imperial Cancer Research category, the group sought to identify those circumstances Fund, University of Oxford, Gibson Building, The Radcliffe Infirmary, which, currently, would be the most likely to engender Oxford OX2 6HE, United Kingdom. alternatives. J. L. Bos, Laboratory of Physiological Chemistry, Vondeeaan 24a, An agent is currently placed in Group 1 when there is 3521 GG Utrecht, The Netherlands. sufficient evidence of carcinogenicity in humans. This actually P. Brandt-Rauf, Division of Environmental Sciences, Department of meant that, until now, an agent could not be assigned to Group Medicine and Comprehensive Cancer Center, Columbia University, 60 1 unless statistically significant increases in relative risks had Haven Avenue, B-l, New York City, NY 10032. been observed in exposed humans. Very low relative risks were B. E. Butterworth, Chemical Industry Institute of Toxicology, P.O. thus, in practice, excluded. The category could be extended to Box 12137, Research Triangle Park, NC 27709. include agents for which the evidence of carcinogenicity in B. A. Bridges, Medical Research Council Cell Mutation Unit, Uni humans is less than sufficient but for which there is sufficient versity of Sussex, Falmer, Brighton BN1 9RR, United Kingdom. N. Day, Medical Research Council Biostatistics Unit, 5 Shaftesbury evidence of carcinogenicity in experimental animals and strong Road, Cambridge CB2 2BW, United Kingdom. evidence in exposed humans that the agent acts through a E. Dybing, Department of Environmental Medicine, National Insti relevant mechanism of carcinogenesis. tute of Public Health, Geitmyrsveien 75, 0462 Oslo, Norway. Currently, agents are categorized into Group 3 when there R. A. Griesemer, Division of Toxicology Research and Testing, are no or inadequate epidemiological data on carcinogenicity National Toxicology Program, National Institute of Environmental in humans and less than sufficient evidence of carcinogenicity Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709. in experimental animals. This category could be extended to C. Harris, Laboratory of Human Carcinogenesis, Division of Cancer include agents for which there is sufficient evidence of carcin Etiology, National Cancer Institute, National Institutes of Health, ogenicity in experimental animals and strong evidence that the Building 37, Room 2C-01, Bethesda, MD 20892. mechanism of carcinogenicity in animals does not operate in K. Hemminki, Center for Nutrition and Toxicology, Novum, 141 57 Huddinge, Sweden. humans. D. G. Hoel, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709. J. E. Huff, National Institute of Environmental Health Sciences, Conclusion P.O. Box 12233, Research Triangle Park, NC 27709. T. Key, Cancer Epidemiology Unit, Imperial Cancer Research Fund, University of Oxford, Gibson Building, the Radcliffe Infirmary, Oxford As the range of data on mechanisms of action of carcinogens OX2 6HE, United Kingdom. increases, so the set of possible configurations of the substantive J. Kinlen, Cancer Epidemiology Unit, 15 George Square, Edinburgh types of evidence available (epidemiological, experimental car EH8 9JZ, Scotland, United Kindgom. cinogenesis, and information on mechanisms) will increase. At D. Krewski, Environmental Health Center, Health and Welfare Canada, Tunney's Pasture, Ottawa K1A O12, Canada. the same time, inclusion in human studies of measures related to mechanisms (e.g., molecular dosimetry and definition of B. Lambert, Department of Clinical Genetics, Karolinska Institute cancer subtypes according to the presence of critical mutations) and Hospital, P.O. Box 60500, 10401 Stockholm, Sweden. will increase the scope and sensitivity of epidemiological re G. W. Lucier, National Institute of Environmental Health Sciences, search. It is therefore likely that information on mechanisms P.O. Box 12233, Research Triangle Park, NC 27709. P. N. Magee, 12 Lancaster Road. London SWI9 5DD, United will contribute both by extending the range of relevant data and Kingdom (Chairman). by broadening the scope of epidemiological studies. B. McKnight, Department of Biostatistics SC-32, University of Washington, Seattle, WA 98195. 3To whom requests for reprints should be addressed. A. J. McMichael, Department of Community Medicine, University 4 Present address: 'Lajarthe,' Saint-LÃ«on-sur-VÃ©zÃ¨re,24290 Montignac. of Adelaide, North Terrace, Adelaide, SA 5000, Australia (Vice- France. Chairman). 2360

S. Nesnow, Carcinogenesis and Metabolism Branch, U.S. Environ D. G. Zaridze, Institute of Carcinogenesis, All-Union Cancer Re mental Protection Agency, MD-68, Research Triangle Park, NC 27711. search Centre, USSR Academy of Medical Sciences, Kashirskoye F. Perera, Cancer Center, Institute of Cancer Research, College of Shosse 24, 115478 Moscow, USSR. Physicians and Surgeons, Columbia University, 701 West 168th Street, New York City, NY 10032. Representatives/Observers J. Peto, Section of Epidemiology, Block D, Institute of Cancer American Industrial Health Council: D.H. Hughes, Procter & Gam Research, Royal Cancer Hospital, 15 Cotswold Road, Belmont, Surrey ble Company, Ivorydale Technical Center, 5299 Grove Avenue, Cincin SN2 5NG, United Kingdom. nati, OH 45217. D. H. Phillips, Haddow Laboratories, Institute of Cancer Research, European Chemical Industry Ecology and Toxicology Centre: M. A. Royal Cancer Hospital, 15 Cotswold Road, Belmont, Surrey SN2 5NG, Martens, Monsanto, 270 avenue de Tervuren, 1150 Brussels, Belgium. United Kingdom. Unable to Attend. O. M011er Jensen, Danish Cancer Registry, Box C. Ramel, Wallenberg Laboratory, University of Stockholm, 10691 839, 2100 Copenhagen 0, Denmark. J. K. Reddy, Medical School, Stockholm, Sweden. Northwestern University, Ward Memorial Building, 303 East Chicago H. S. Rosenkranz, Department of Environmental and Occupational Avenue, Chicago, IL 60611. Health, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh PA 15261. IARC Secretariat T. Shirai, Department of Pathology, Medical School, Nagoya City A. Aitio, Helsinki D. McGregor University, Nagoya 467, Japan. B. Armstrong R. Montesano S. M. Sieber, Division of Cancer Etiology, National Cancer Institute, H. Bartsch C. Partensky National Institutes of Health, Building 31, Room 11A03, Bethesda, P. Boffetta I. Peterschmitt MD 20892. P. Boyle R. Saracci M. Sorsa, Institute of Occupational Health, Topeliuksenkatu 41 a J.R.P. Cabrai E. Smith, Geneva A, 00250 Helsinki, Finland. B. W. Stewart, Children's Leukaemia and Cancer Research Unit, E. Cardis D. Shuker The Prince of Wales Children's Hospital, High Street, Randwick, NSW E. Heseltine L. Tomatis V. Krutovskikh H. Vainio 2031, Australia. G. Lenoir J. Wilbourn J. A. Swenberg, Program of Molecular Carcinogenesis and Mutage- C. Malaveille H. Yamasaki nesis, University of North Carolina, Chapel Hill, NC 27599. E. Matos S. Swierenga, Drugs Directorate, Health and Welfare Canada, Tun- ney's Pasture, Ottawa, Ontario K1A OL2, Canada. P. Vineis, Unit of Cancer Epidemiology, Department of Biomedicai References Science and Human Oncology, via Santena 7, 10126 Turin, Italy. 1. Approaches to Classifying Chemical Carcinogens according to Mechanism J. Wahrendorf, Institute of Epidemiology and Biometry, German of Action. Joint International Agency for Research on Cancer/IPCS/CEC Cancer Research Centre, Im Neuenheimer Feld 280. 6900 Heidelberg, Working Group Report, internal technical report 83/001. Lyon, France: Germany. International Agency for Research on Cancer, 1983. 2. Vainio. H., Magee, P. N., McGregor, D., and McMichael, A. J. (eds.). G. M. Williams, American Health Foundation, Dana Road, Valhalla, Mechanisms of Carcinogenesis in Risk Evaluation, scientific publications NY 10595. 116. Lyon, France: International Agency for Research on Cancer, in press.

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1992 American Association for Cancer Research. Working Group on Mechanisms of Carcinogenesis and the Evaluation of Carcinogenic Risks

Harri Vainio, Elisabeth Heseltine, Douglas McGregor, et al.

Cancer Res 1992;52:2357-2361.

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