Document Z8nv4k9B6JZ5YL5kGgQGyb4ZO

Organization Resources Counselors. Inc. 1625 I Street. N.W. Washington, D. C. 20006 (202) 872-1080 Cable Address: ORESCON Memorandum November 22, 1977 TO: ORC Group Members ORC Physicians Group FROM : B. K. Ewon The attached is for your information. Please send any comments you may have on the statement on Criteria concerning the carcinogen regulation to my attention. ALCOA0004598 General Criteria for Assessing the Evidence for Carcinogenicity of Chemical Substances: Report of the Subcommittee on Environmental Carcinogenesis, National Cancer Advisory Board1*2 - I A. INTRODUCTION The National Cancer Institute of the United States is frequently asked to advise on the possible carcinogenic bazarusof substances that might be introduced into, or already exist in, the human environment. On Septem ber 19, 1975, National Cancer Program Director Dr. Frank Rauscher, therefore, asked the National Cancer Advisory Board Subcommittee on Environmental Carci nogenesis to develop general criteria for use in the assessment of whether specific environmental agents constitute a carcinogenic hazard in humans. * This docu ment represents this Subcommittee's current formula tion of these criteria. The criteria adopted are based upon those generally used in the application of the scientific method to any question. In assembling these criteria, the Subcommittee recognizes that at present there is no simple and universal definition of either carcinogenesis or neoplasia. The criteria which are de scribed are general guidelines and no rigid, universal criteria. The complexity of the problem dictates that the evaluation of the potential human hazards of a given agent must be individualized in terms of the chemical and metabolic aspects of that agent, its intended use(s), the data available at the time that the decision must be made, and other factors pertinent to the case under consideration. Each case must be considered on its own and the criteria appropriate for one agent may not necessarily apply to another. . : - y; For purposes of clarity, the general criteria have been classified into three groups in terms of the sources of the data: 1) criteria from human studies; 2) criteria from animal bioassays; 3) criteria from in vitro or short-term tests. This does not imply that human carcinogens are distinct from animal carcinogens. Nor does it imply that carcinogens can be identified absolutely by any of the currendy available in vitro or short-term tests. Since the extrapolation of data from experimental animal systems to the human is a problem separate from that of estab lishing the validity of the experimental animal data, the problem of extrapolation is dealt with separately (see Section E) in this document. A major source of data on carcinogenicity comes from bioassays in experimental animals. Experience has indi cated that, with one or two possible exceptions, com pounds that are carcinogenic in humans are also carci nogenic in one or more experimental animal bioassay systems. In addition, several compounds first detected as carcinogens in experimental animals were later found to cause human cancer. Demonstration`that a com pound is carcinogenic in animals should, therefore, be considered evidence that it is likely to be carcinogenic in humans, unless there is strong evidence in humans to the contrary. In this document the term "carcinogen" is used in its broad sense, because in most of the current human epidemiologic approaches and certain animal bioassays it is not possible to differentiate clearly between iniuating agents, promoting agents, and certain modifying factors. Any factor or combination of factors which increases the risk of cancer in humans is of concern regardless of its mechanism of action. The criteria listed here apply only to chemical agents. Criteria for the induction of neoplasms by physical agents or by the direct action of viruses have not been considered in this report. . This Subcommittee has found it useful to state gener alized definitions of malignant and benign neoplasms, recognizing that in practice the diagnosis of a particular neoplasm is an operational one based on convention, experience, and experimental data. - A malignant neoplasm is composed of a population of cells displaying progressive growth and varying degrees of autonomy and cellular atypia. It displays, or it has the capacity for, invasion of normal tissues, metasCases, and causing death to the host. Benign neoplasms are a less autonomous population of cells, exhibit little or no cel lular atypia or invasion of normal tissues, and do not metastasize. In particular cases, however, benign neo plasms may endanger the life of the host by a variety of mechanisms, including hemorrhage, encroachment on * a vital organ, or unregulated hormone production. The . cytologic and histologic criteria utilized in determining whether a lesion is benign or malignant differ depend ing upon the tissue in which the neoplasm arises. Evalu ation of whether a specific lesion is benign or malignant should, therefore, follow standard criteria used by ex perimental oncologists and pathologists with the empha sis on correlation of the histopathologic pattern with the biologic behavior of the lesion or type of lesion-. In equivocal cases, the diagnosis of a specific lesion may require a panel of experts, recognizing that they may not always agree. .. - Depending upon the particular case, benign neo plasms may represent a stage in the evolution of a malignant neoplasm and in other cases they may be "end points" which do not readily undergo transition to malignant neoplasms. (For more detailed discussions on the definition of benign and malignant neoplasms and their relationship to each other, the reader is referred to references given in the Aopendix.l if ' Subcommittee Members: Dr. Philippe Shubik, Chairman; Dr. Wil liam O. Baker, Dr. Edward J. Burger, Jr., Dr. Irving M. London,and Dr. William E. Powers. Consultants: Dr. Arnold L. Brown. Dr. Hans L. Falk, Mr. Arthur McGee. Dr. Norton Nelson, Dr. Irving J. Setikoff, Dr. Michael B. Shimkin, Dr. 1. Bernard Weinstein, Dr. Gerald N. Wogan. Dr. Ernst Wynder, Dr. Roy Albert, Dr. Herbert Blumenthal, Dr. David B. Clayson, Mr. Jerome Cornfield, Dr. Peter N. Magee, Dr. Henry C. Pitot III. Dr. David Rail, and Dr. Takeshi Hirayama. *Address reprint reifuests to Office of Cancer Communications, Na tional Institutes of Health, Building St, Room I0A17, Bethesda, Md. 20014. ... _ ,See letter from Dr. Rauscher in "Appendix.4 ' .. VOL. 58, NO. 1, FEBRUARY 1977 461 I NATL CANCER INST T*r ALCOA000459 9 462 REPORT Of SUBCOMMITTEE ON ENVIRONMENTAL CARCINOGENESIS The general criteria listed in this document reflect the tionship provides addiuonal evidence of a posidve re judgment of this Subcommittee based on its assessment sult. of the current "state of the art." These general criteria The occurrence of benign neoplasms raises the strong should be reviewed on a continuing basis and revised as possibility that the agent in quesuon is also carcinogenic necessary in the light of new knowledge. (For more since compounds that induce benign neoplasms fre- detailed discussions of carcinogenicity and carcinogen quendy induce malignant neoplasms. In addition. be assessment, the reader is referred to specific references nign neoplasms may be an early stage in a multi-step on this subject in the Appendix.) carcinogenic process and they may progress to malig nant neoplasms; also, benign neoplasms may themselves B. CRITERIA IN HUMAN STUDIES , jeopardize the health and life of the host. For these .I - An agent--which may comprise a combination of chemicals--is carcinogenic in man if it increases the incidence of malignant neoplasms (or a combination of benign and malignant neoplasms) in humans to levels that are^ significantly higher than those in*a comparable group not exposed (or exposed at a lower dose) to the reasons, if a substance is found to induce benign neo plasms in experimental animals it should be considered a potential human health hazard which requires further evaluation. In experiments where the increased inci dence of malignant neoplasms in the treated group is of questionable significance, a parallel increase in inci same agent. If all of the induced neoplasms are benign rather than malignant, then, for the reasons given else* where in this document, the agent must be considered a dence of benign tumors in the same tissue adds weight to the evidence for carcinogenicity of the test substance. Certain methods (listed below) are imnortanunimcrv possible carcinogen and it should, therefore, be very to potential carcinogenicity and cannot be ignored; how carefully evaluated as a health hazard. Types of evidence suggesting that an agent is carcino genic in humans include: neoplastic response directly ever, they may require addiuonal studies before extrapolafiorTto particular conditions of human usage can be rtiade. Examples of these methods are: . related to exposure (both duration and dose); incidence and mortality differences related to occupational expo sure; incidence and mortality differences between geo Bioassays employing aataada rf animals which develop high incidences of particular tumors in the untreated sate. Is some of these studies the particular characteristics of the ani graphic regions related to different exposures rather mals and the results obtained may require additional evalua than genetic differences and/or altered incidence in mi tion--in other instances, such well controlled test systems may grant populations; time trends in incidence or mortality. related to either the introduction or removal of a spe be quite satisfactory for the establishment of carcinogenicity of -an agent.' - cific agent from the environment; case-control studies; Bioassays in which, in^ddj^uusakescsMgent, animals are and the results of retrospective-prospective and pro . .iS treated with a known carcinogen, or some other foreign mate spective studies of the consequences of human expo rial which itself may he carcinogenic orc^jiiwgsMc. sure. Clinical case reports may also provide early warn ing of a potential carcinogen. Negative epidemiologic data may not establish the safety of suspected materials. J'UainainaBia iia.wMi,ilit um jWBibi aw jin. h. irm4 n t ungl^sigj^gjj^QdiiJjyjgjggriatecondiuons. in addiuon to the iSmnutraaon oftn^est compouScT^nauiere is reason to Negative data on a given agent obtained from extensive epidemiologic studies of sufficient duradon are useful believe that these unphysiotogic conditions may in themselves enhance tumor induction. , ..r - for indicating upper limits for the rate at which a spe cific type of exposure to that agent could affect the incidence and/or mortality ofspecific human cancers. Bioassays in which the test compound is given by unusual routes of administration (such as bladder implantation) and there is reason to believe that the tumors that occurred may not be due to a specific effect of the test compound. This does not mean, C. CRITERIA IN EXPERIMENTAL ANIMAL STUDIES ^ however, that substances should only be tested in animals by the same route of administration as pertains to human exposure.. The carcinogenicity ofa substance is established when the administradon to groups of animals in adequately designed and conducted experiments results in in creases in the incidence of one or mare types of malig nant neoplasms (or a combinauon of benign and malig nant neoplasms) in the treated groups as compared to control groups maintained under idenucal condiuons but not given the test compound. The increased inci 0Statistically significant positive results in the above types of bioassay do, however, raise the possibility that the test substance may be carcinogenic. " In the evaluation of carcinogenesis data it is important to consider the composition and identity of the chemical substances tested and their stability under conditions of storage and administration. dence of neoplasms in one or more of the experimental groups should be evaluated statistically for significance, D. SHORT-TERM OR IN VITRO TESTS FOR CARCINOGENS' and the only major experimental variable between the <A major practical limitation in the bioassay of poten control and the experimental group should be the ab tial carcinogens is the large number of test animals and sence or presence of the single test agent. Such increases the long duration required to obtain results. A number may be regarded with greater confidence if positive results are observed in more than one group of animals or in different laboratories. The demonstration that the occurrence of neoplasms follows a dose-dependent rela of short-term or in vitro tests are cunrendy under devel opment and appear promising. These include assays for: the induction of DNA damage and repair; muta genesis in bacteria, yeast. Drosophila melanogaster, or in J NATL CANCER INST VOL. U, NO. 2, FEBRUARY 1977 ALCOAO 004600 RETORT or SUBCOMMITTEE ON ENVIRONMENTAL CARCINOCENESI3 465 mammalian somatic cell cultures; and neoplastic trans formation of mammalian cells in culture. Other assays rit have been employed include the dominant lethal test and studies ofchromosomal damage. The latter two suffer from the fact that they are frequently non specific and/or difficult to quandfy. Of the various short-term tests, the Ames Salmonella mutagenesis sys tem has been studied the most extensively. Tests based on other in vitro approaches are also being developed. The intelligent application and interpretation of the in vitru tests must also take into account species varia tions in factors related to the pharmacologic distribution and metabolism of the parent compound as well as possible species differences in macromolecular repair and host defense mechanisms. A number of approaches addressed to the metabolic aspects are now available, including `'host-mediated" mutagenesis assays; the assay of urine and other biologic fluids taken from animals or humans receiving the test compound; the addition of microsomal enzymes and co-factors to the assay system; and the inclusion of specific cells in the assay. At present, one of the short-term rests gin fr------ 1 y establish whether a compo"^ nn-i. nogCHhTm humans nr rvpgrimenraL.animaU. Positive, 1rUresmts bEniinrf -------T'crgr** mg of the agent in long^rm-animaf i oarticu-^ larly tf"t!Kfe"are other reasons for rr*trintr~ res of the agent. This Subcommittee is enthusiastic about the possible future use of in vitro tests as part of a screening system for potential carcinogens and believes that their further development and validation deserve high priority. must be individually evaluated, taking into considera tion such factors as adequacy of experimental design, statistical significance of the data, dose-response rela tions, duration of exposure, route of administration, metabolism {(including species variations), host suscepti bility, co-factors and other modifying factors, and the amount of the material to which humans will be ex posed. The criteria for extrapolation may vary depend ing on the agent in question. For example, demonstra tion that a compound only produces subcutaneous sar comas in rodents may be relevant to a drug that will be injected subcutaneously in humans, but such animal data may not necessarily be appropriate in assessing the risks associated with a substance that humans will only receive orally. Because of the limitations inherent in animal bioassays, a negative result obtained in a particu lar animal bioassay does not exclude the potential carci nogenicity of a compound in humans. The inappro priate experimental species may have been chosen; the number of animals tested may have been too small; or the duration of observation may have been too short. Alternatively, test conditions may have been inappro-. priate in terms of their predictive value for the response of humans. The extrapolation of experimental carcino genicity data to the human situation is strengthened by obtaining results in more than one species. Negative results obtained in one species do not, however, detract from the significance of clearly positive results obtained in another species. For more detailed discussions of the problems of ex trapolation and the estimation of safe limits, the reader 'M is referred to references listed in the Appendix, F. EVALUATION OF BENEFITS VERSUS RISK .y% E. EXTRAPOLATION FROM EXPERIMENTAL DATA AND EVAL UATION OF HUMAN RISKS .... w.U-V The criteria listed above provide a guide to determin ing whether a compound is carcinogenic under a spe cific set of exposure conditions in a given species or subpopulation. Quantitative extrapolation from animal studies for the purposes of evaluating human risks en tails large uncertainties at the present time. Each case .. In those cases in which a compound has been proved to be carcinogenic remains the decision to what extent the possible risks to man are counterbalanced by the possible social, economic, or medical benefits of that substance. Scientists must play a major role in these decisions by providing and interpreting the available data. The final decision, however, must be made by society at large through informed governmental regula tory and legislative groups. .; . "Mri's APPENDIX Jfc URnority Statement by Dr. Burgee -*h* r* - Since I feel that this matter is so important I am obliged to submit a minority view which is that the following explicit language should be a part of the final report: The finding of histologically benign tumors--especially in experimental animals--presents a particular challenge. In the lint instance, the judgment of malignancy, resting on morphological cellular characteristics, is made through the exercise of sound judgment and experience. Secondly, the inference of progression from histologically benign tumors * . 10 malignant neoplasia is sometimes plagued with uncertainty. Transformations are known to occur--more often in *ome "E*1* systems and cell types than in others. Appropriate judgment should rest on detailed knowledge and ^ experience as to what these various probabilities are in each case. Finally, this picture is particularly complicated when 'r . uma" "Penence from the finding of histologically benign tumors in experimental animals. Confirma- - . *nr mve*tigauons should be sought in these cues wherever appropriate. . ./ - June 3. I97S Edward J. Burger. Jr., MJ>,, SeJ). * ,,7 .. VOL. 58, NO. I, FEBRUARY 1977 J NATL CANCER INST . JV i -.-..a '5--V ALCOAO 004601 1 46# gUOKTOr SUBCOMMITTEE ON ENVIRONMENTAL CARCINOGENESIS Letter from Or. Rauacher to the Subcommittee Chairmen ___ Dr. PhilippeShuhifc. Director. The Eppkf Institute for Research in Cancer . Universe?ofNebrask* - , Omaha. Nebraska 6810 -nr- September 19. 1975 Dear Phifc - r. ' --------- ; ^- As part ofmy responsibilides as Director ofthe National Cancer Program. I am frequently called upon to render advice on the general subject of cancer-producing substances. Those seeking such advice are well known to both of us; they include the Congress, other Federal agencies (both within and outside the Department of Health. Education, and Welfare), representa tives of industry, consumer advocates, the news media, and the general public. As you know, current program activities supported largely by the National Cancer Institute have and will condnue to produce data on the subject ofenvironmental carcinogenesis and on chemical carcinogenesis in particular. Thus it is now possible and certainly necessary to give greater priority and emphasis to efforts that better define, in functional terms, a chemical carcinogen, and to the development of general guidelines which can be used for interpreting carcinogenicity data. The pressures upon us and regulatory agencies are mounting due largely to program efforts ofthis Institute and therefore we must be certain that we are prepared to respond to the inevitable questions and to render responsible advice. To this end, 1 ask that you as chairman of the National Cancer Advisory Board Subcommittee on Environmental Carcinogenesis undertake, with your members and consultants and whatever additional consultants you find necessary, to determine whether the current state of the an will permit the development of definitive and interpretive guidelines, the latter to include such issues as dosage, risk-benefit, etc. *y- I am sure you appreciate the importance and significance ofthis undertaking and recognize as I do the urgency of the matter. - ....... Sincerely, . - Frank J. Rauscher, Jr.,PAJ>. Director, National Cancer Program r.- is _ -**' Vi?': Related References y-ij'-'^'iancer testing in the safety evaluation of food additives and pesticides. Toxicol. Appl. Pharmacol. 20, 419-438, 1971. Biology and Pathology ofNeoplasms (3) International Agency for Research on Cancer; IARC Monographs am the Evaluation afCarcmogmk Risk ofChemicals to Man. Lyon. (/) Berenblum. I. "The Nature of Tumor Growth** in General fsd- prance> World Health Organization. Volume 1, 1972, 184 p.; otogy, 4th Ed. ':-.-r: Volume 2, "Some Inorganic and Organometallic Com (2) Florey, C, ed. W. B. Saunders Co.. London. 1970, p. 661. pounds.** 1973. 181 p.; Volume 3, "Some Polycyclic Aromatic (J) Robbins, S. L-, Pathologic Barit tf Disease, W. B. Saunders. Hydrocarbons and Heterocyclic Compounds,** 1973, 271 p.; - Philadelphia. 1974, pp. 18-19. Volume 4. "Some Aromatic Amines, Hydrazine and Related (f) Foulds, L.. Neoplastic Development, Vol. 1, Academic Press. Lon- Substances. N-nitroso Compounds and Miscellaneous Alkyl - don and New York, 1969. * -. -,; .-'.'.iVT.y. . ating Agents," 1974,286 p.; Volume 5, "Some Organochlorine -- - ; Pesticides," 1974, 241 p.; Volume 6, "Sex Hormones." 1974, Chemistry, Metabolism and Mechanisms ofAction ofChemical Carcinogens *- - - -- - rs.-----.... . V 243 p.; Volume 7, "Some Anti-Thyroid and Related Substances. Nitrofurans and Industrial Chemicals," 1974,326 p.; Volume 8, "Some Aromatic Azo Dyes," 1975.357 p.; Volume (1) Heidelberger. C. "Chemical Carcinogenesis'* inAtonal Review tf ' 9, "Some Ariridines, N-, S-, e O-Mustards and Selenium," Biochemistry, 44, 79-121, 1975. - 1975, 268 p.; Volume 10, "Naturally Occurring Substances," (2) Ts'o. P. O. P. and DiPaolo. J. A., eds. Chemical Cnaupwa .1'. m press; and Volume 11. "Epoxides and Miscellaneous Indus- Parts A and B. Marcel Dekker. Inc., New York. 1974. : ~ trial Chemicals," in press. (4) Report of a WHO Scientific Group: Assessment of the cardno- Promotion and Modifying Factors)- genicicy and mutagenicity of chemicals. WHO Tech. Rep. - Ser.. 546. 1-19. 1974. . (/) BoutweO, R. K. The Function and Mechanism of Promoters of (5) Goldberg. L. ed. Carcinogenesis Testing of Chemicals, Proceed- Carcinogenesis, CRC Critical Reviews in Toxicology, pp. 419- < mgs Conference on Carcinogenesis Testing in the Develop 443.1974. C Y ment of New Drugs. CRC Press, Cleveland. Ohio. 1974 (2) Wynder. E. L. Nutrition and Cancer. Fed. Proc. 15, 1309-1315. 1976 (and references therein). .-.-s.- - ii -7-' ; '-T-'!.-. - ! . . Principles of Carcinogen Testing and Evaluation [ ?jl........ -.'.s>Y"*": (/) Food Protection Committee. Food and Nutrition Board: f*iu4 Irms in the Evaluation afCarcinogenic Hazardsfrom the Use ofFood Addition. Washington. D. C.. National Academy of Sciences-- National Research Council Publication No. 749, 1960, 44 po and Cancer Res., 21, 429-456, 1961. (2) Food and Drug Administration Advisory Committee on Proto cols for Safety Evaluation: Panel on carcinogenesis report on Short-Term and In Vitro Tests . . . . .V (1) Montesano, R-. Bartsch, H. Tomatis. L. and Davis, W. eds. . Screening Tests in Chemical Carcinogenesis. Inti. Agency for Re'' search on Cancer, IARC Scientific Publication No. 12, Lyon, France, 1978. (2) McCann, J., Choi. E., Yamasaki, E. and Ames, B. N. Detection r. of Carcinogens as Mutagens in the Salawiuda/Microsome Test: Assay of 300 Chemicals. Proc. Natl. Acad. Sd. U.S.A., 72. 5135-5139. 1975. J NATL CANCER INST/ VOL. 58, NO. 2, FEBRUARY 1977 ^CoAO 04602 RZPOBT or SUBCOMMITTEE OM ENVIRONMENTAL CAKCINOCENEStS 465 Eiimfio/tihon and Risk AssessmtjtM CO Hod. D. G-. Cayfar. D. W.. Ktrschuein. R. L.. SafHotti. U. and *irhnridn--nr H ft fninsrin* y IT11I1 if rrrnrfr'H- r-'rrrd Tmualy. J. ofToxicology * Environmental Health. / (1), 133151. 1973. (2) Mantel. N. and Schneidcrman. M. A. Estimating "Safe1* Levels. a Hazardous Undertaking. Cancer Res,,JJ, 1379-1386, 1975.. 9) Albeit, R. E. and Altshuler, B. Considerations Relating to the Formulation of Limits for Unavoidable Population Exposures to Environmental Carcinogens. In Radimuclidt Cartmogttusa. ed. J. E. Ballou, et al., pp. 233-253, 1973. AEC Symposium Series, CONF-72050. Springfield, Va., NTIS. -r v VOL. 58, NO* J, FEBRUARY 1977