Document JJX5LkmXjM4edJ4G89pd1ndMv

WORLD HEALTH ORGANIZATION ORGANISATION MONDIAL* DC LA SANT* CENTRE INTERNATIONAL OE RECHERCHE $UR LE CANCER \ international agency for research on cancer . *80, CMm AIMlMMlMl - mm LYOH C*d> ? - FRANCi - T*l.: C7R) 18(181 - T*I4flr.: UNICANCER-L'TOH - T*i*,, WCOIJ In <*o4y > '<*' > 1 C2/12 PnH* * la 11 July 1978 Dear Hr Barnard, Thank ycu tea: yaze letter of 23 June addressed to Dr Higginscn. I enclose herewith a photocopy of the Preamble to Volume 17 of the IAIC Monographs, Which will appear shortly. This preamble is the result of two Harking Group* that mat in Lycn in October 1977 and April 1978. This advisory document to the Director of the IASC will serve as a basis upen which each volume of the monographs will be prepared, and it may be modified by successive Hocking Groups in order to iiaprove its scientific starred. Yours sincerely, R. nentesano, m.u., en.D. Unit of Chemical Carcinogenesis Hr R.C. Barnard Cleary, Gottlieb, Steen *> Hamilton 1250 Connecticut Avenue, N.W. Washington, D.C. 20036 P5T ---------------- ac.d) . AP00047851 June 23, 1978 Dr* John Higginson Director International Agency tor Research on Cancer 150 Cours Albert Thomas 69003 Lyon France Dear Dr. Higginsont X represent the American Industrial Health Council, an organization made up of soma 100 companies which 13 par ticipating in the administrative proceeding regarding "The Proposed Regulation of the United states Occupational Safety and Health Administration for the Identification, Classifies tion and Regulation of Toxic Substances Posing a Potential Occupational Carcinogenic Risk to Humans." On April 4, 1970, Dr. L. Tometis filed a statement regarding the proposed regulations, at the request of the U.S. occupational Safety and Health Administration. Attached to Dr. Tcraatis* statement was a preprint of an article fron Cancer Research for April 1978 by Dr. Tcnatis and others entitled "Evaluation of the Carcinogenicity of Chemicals: A Review of the Monograph Program of the International Agency for Research on Cancer." The preprint describes the formation of a working group in October 1977 "to update and revise the criteria on ' which the carcinogenicity to humans and/or experimental animals is assessed and on which evaluation of the possible carcinogenic risk they may represent for humans is made?" The preprint summarises the report of that group stating that their conclusions would appear in the introduction to IARC Monograph Volume 17 (described-ias-in press). AP00047852 ( Dr. John nigginson -2- ( June 23, 1978 Dr. David Rail, Director of the National Institute of Environmental Health Sciences also testified as tp the conclusions reached as a result of the deliberations of the group. At the hearing, which began May 16, 1973, Dr. Saffiotti and Dr. Schneiderman of the National Cancer Institute testified that t new group had been formed to review the criteria which had been previously recommended and had recoimended modifications. Subsequently, Dr. Greisemer of the National Cancer Institute described some of the changes made as a result of the delibera tions of the second group. (Dr. Griesemer said he did not have the text of the changes.) There is great interest in the conclusions reached by the IARC on this Important subject, and those conclusions are particularly relevant to the hearings on the proposed regulation* As the record presently stands, the conclusions of the meeting in October 1977 are in the record but the changes are not. X am writing to request that you furnish to cte for submission to OSHA the text of the proposed changes in the intro duction to Honograph 17, which X understand is in press or about to go to press. Since the hearings will be over long before Volume 17 is published, this is the only way in which an accurate and correct copy of the IASC conclusions can be incorporated in the record and the present confusion eliminated. X will appreciate your consideration of the request. Since the hearings will terminate next month, it would be very helpful if we can receive a pre-publication copy of that part of the introduction relating to the criteria upon which carcinogenicity is assessed as soon as convenient. Thank you very much. Very truly yours. . Robert C. Barnard AP00047853 BUC MJCG3APH P5CG3M-ME CN TEE EVAH3AXXCN OF THE OSCEJCGENiC RISK OF CEBttCALS TO HUMANS UHWMHTB BALWIHX'NP In 1971, the International Agency for Pasearch on Cancer (IARC) initiated a programm cn the evaluation of the carcinogenic risk of <^w*itea3e to htanans centred cn tile production of critically evaluated seregrsphs cn individual chemicals. Since 1972, the progranre has under- gone considerable e^ansicn, primarily with the scientific fnnaiwralicn and support of the US National Cancer' Institute. The criteria established in 1971 to- evaluate the carcinogenic risk of chemicals to htnans were adopted in essence by all the working groups whose deliberations resulted in the first Iff volumes of the IARC Mov.cgrcpk Series. In October 1977, a joint IMCyftHO cd hoa Nothin? Grov^ met to reevaluate thesa guiding criteria; this praanble reflects the results of their deli Vibrations1. C&JBCTIVE AND SCOPE The objective of the ncncgraph programme is to collect n available relevant experimental and epideniological data about groups of chemicals to v&ich hsmans are known to be exposed, to evaluate these data in of human risk with the help of international working groups of experts in chemical carcinogenesis and related fields, and to publish and dissemi nate the ccmdusicns of those working groups as a series of monographs. Ca critical evaluations of eroerluental data given in these mcno-- graphs are intended to assist national ar international authorities in fdswlating decisions concerning preventive measures. The WBD publications cn food additives2, drugs2, pesticides and contaminants'* and occupational carcinogens* are particularly infoanative. 11 AP00047854 gjjtp* tbs progrzsrtns began in 1971, 17 volures have been published.4"12 in the IASC Monograph series, and 380 separate chsnicals have been evalu ated (see curaalative index to the monographs, p. 353). Each volume is printed in 4000 rypi** and distributed via the World Health Organization (WHO) publications service (see inside covers for a listing of EA3C publi cations and bade outside cover for distribution and sales services). The IARC Monographs are recognized as an authoritative source of infatuation an the rrrinng*T?Hty of envirorsnsntal chenieals. Eie first users' survey, irede in 1976, indicates that the monographs 'are consulted routinely by various agencies in 24 countries. SFT3VTTCN OF QgMKaXS FOR MCMCGRftPHS The chsnicals (natural and synthetic, mixtures and manufacturing processes) are selected far evaluation an. the basis of two main criteria: (1) there is evidence of hunan exposure, and (2) there is sane experimental evidence of carcinogenicity and/or there is sore evidence or suspicion of a risk to hianans. Inclusion of a chemical in a volume does net imply that the chemical is carcinogenic, only that the published data have been examined. The evaluations must be consulted to ascertain the conalueions of the Working Group. Equally, the fact that a chemical has not appeared in a monograph doee net mean that the chemical is not carcinogenic. Bjs scientific literature is monitored for published data relevant to the monograph programs. Additionally, the IABC Survey of Qiani-~ig Being Pasted for Carcinogenicity2*"*1 often indicates these chemicals that are to he'scheduled for future meetings. 2he major aims of the survey are to prevent imnecessary duplication of research, to increase mrniiTTtrraMnn amerry scientists, and to make a census of chemicals that .are being tested and of available research facilities. When n&*, relevant information becomes available concerning a chesdcal(s) which has already teen evaluated, or when new principles for 'evaluating carcinogenic risk receive acceptance, reevaluatiens may be made at subsequent meetings, and a nenographCs} may be revised and published. 12 AP00047855 WORKING FKX2EUFES Approximately one year in advance of a vrarking group resting, a list, of the substance* to be considered is prepared by ISBC in consultation with other experts. Subsequently, all relevant biological data are oollectttl by IMC? in this context, US Public Health Servioe Publication Ho. 149,ft**,s has been particularly valuable and has been used in conjunc tion with other recognized sources of information cn chemical carcino genesis. The major effort in the collection of data and the preparation of first drafts for the sections cn- chemical and. physical properties, on production, use and occurrence and av analysis is made by SRI International under a separate contract with the US National Omrsr Institute. Most of the data they provide cn production, use and occurrence concern the United States and Japan; SRI and IASC try to supplement this inforseticm with 'that frca other sources in Europe. Xnportant bibliographical sources for mutagenicity end teratogenicity data are the Envircnsntal Mutagen infor mational Center and tile Environmental Teratology Infbnation Center, both locate at'the Oak-Ridge National laboratory, USA. Six to nine nenths before the meeting, reprints of articles contain ing relevant biological data are sent to an expert (s) , or are used by the IARC staff, for the preparation of first drafts of the nanographs. Case drafts are edited by IAFC staff and are sent prior to the meeting to all participants of the Vtoeking Group for their ccrmants. The working Group then meets in Lycn far seven to eight days to discuss and finalize the texts of the monographs aid. to fiaxnulate the evaluations. After the inflating, the taster ccpy of eadi itorcgraph is verified by consulting the original literature, then edited and prepared for r^roduction. The nenographs appear in print within six nenths after adjournment of the Working Group meeting. OMR FOR EVALUATiaS With regard to Mologirail data, generally cnly reports that have been published or accepted for publication are reviewed by the Marking groups. The monographs do not cite an of the literature cn a particular chenical: AP00047856 cnly those data considered by the Working Group to be relevant to the evaluation of the carcinogenic risk, of the chemical to humans ^are Included. Anyone who is aware of data that have been published cr are in press which are relevant to the evaluations of the carcinogenic risk to humans of chemicals for whidi Barographs have appeared is urged to make then available to the Unit of Chemical Carcinogenesis, International Agency fear Research on Cancer, Lycn, France. TSS W0RUM3 SRCCP t During a meeting the tasks of. the Working Groves are generally fivefold: (1) to confirm that all relevant published data are included; (2) to ensure that the sumries of data enable the reader to follow the reasoning of the camittee; (3} to judge the significance of the experimental and epidaniolcgical results; (4) to select and surrnarire tiro data cn which to base an evaluation; and (5) to formulate an evaluation of the carcinogenic risk, of the chemical. Working Group, participants v&o contributed to the consideration and evaluation of chemicals within a particular voliroa are listed, with their addresses, at the beginning of each publication (see p. 3). Each serves as an individual scientist and not as a representative of any ear government. In addition, observers are often invited from national and international, agencies, organizations and industries. (SME5RL PFadTiaS FCB EVAXaKTOC THE CR5CPPGEKIC SlSt OF CE5MTCXLS Tiro widely accepted meaning of the term 'chemical carcinogenesis', and that used in these monographs, is the inductiro by chemicals of neoplasms that are not usually observed, the earl -ter indixticn. by chemicals of necplaate that are usually-observed^ and/or the iwAv-^lan by.-Ami of asre neoplasms than are usually found, although fundamentally different mechanism ray ba involved in -arose three phenomena. Etymologically, the term 'carcinogenesis1 means the induction of cancer, that is, of malignant neoplasms; however, the cuuruily aoospted meaning is the induction of various types of neoplasms or of a combination of malignant and benign tumours. 14 AP00047857 Within the monographs, the wjrds 1 tumour* and neoplasm' are used inter* changeably {in scientific literature the terms 'turoirigen', 'oncogen' and 'blastcsrogen' have all been used synonymously with 'carcdnogarx1, although occasionally 'turaourigai' has teen used specifically to denote the induction of benign tumours). The tern 'carcinogenic risk' in this IASC Monograph series is taken to iraan the probability that exposure to the chemical will lead to in humans. Experimental- Evidence Qualitative aspect* Both the interpretation and evaluation of a particular study as well as the overall assessment of the cardiogenic activity of a chemical irwclve several qualitatively important. considerations, including: (1) the e^erimental conditions under which the chemical was tested/ irduding route of administration and exposure/ species, strain, sex,, age, etc.; (2} the consistency with which the chemical has been shown to be carcinogenic/ e.g., in hw many species acd at which tumour sites (s) r (3) the spectrum of neoplastic response, from benign neoplasia to multiple malignant tumours (this consideration warrants special attention); (4) the stage of turcrur fanraticn in which a chemical may be involved: senile chemicals act as corplete carcinogens and have initiating and pronoting- activity, while others are prccoters only; and- 5} the feasible role of modifying agents. Maiy chemicals induce both benign and malignant tumours; few instan ces are recorded in which only benign neoplasms are induced by chaxdcals that have been studied extensively. Benign, tamours may represent a stage in the evolution of a malignant neoplasm or they nay be 'end-points' . which do not readily undergo transition to malignant reop3-asms. If a substance is found to induce only benign neoplasms in experimental animals, tiie chemical should be suspected of being a carcinogen and requires further investigation. 15 AP00047858 Hormonal carcinogenesis Hosxmal cardiMgenesis presents certain distinctive features: the chemicals involved occur both naturally and exogenously; in nest instances, lenj exposure is required; tumours occur in the target issue in association with a stinulatico of ncn-necplastic grewth, but in sans cases, houncnes prorate tile proliferation of turrour cells in a target organ, Sormcnes that, occur in successive arcunts, hccscne-miiretic agents and agents that rmtKf. hyperactivity or hrhalanre in the endocrine system jmy require eval uative methods ccnparabla with those used to identify chemical carcinogens; particular ^t**"*** most be laid cn quantitative aspects and duration of exposure. Sam dscdcal carcinogens have significant side effects on the endocrine system, which nay also result in horncnal carcinogenesis. Syn thetic hrggmea and anti-hoarenes can be _ expected to possess other pharaeoalogical and tmicnlogical actions in addition to those cn the endocrine system, and in this respect they oust be treated libs any other chemical with regard to intrinsic carcinogenic potential. Quantitative aapsats Dose-response studies are important in the evaluation of carcino genesis : the confidence with which a carcinogenic effect can be established is strengthened fcy the observation of an increasing incidence of neoplasms with increasing esqpceuee. Oha assesssnt of carcinogenicity in antoals is frequently crrnplicated by recognized differences anong the test aniirals (species, strain, sex, age), in route (s) of aSrdnistratim and in dose/duration of exposure; often, target organs at which a cancer occurs and its histological type may vary with these conditions. Nevertheless, indices cf carcinogenic potency in particular experimental systems (fcr instance, the dose-rate required under umtlnuous exposure to halve the probability of the animats remaining tuncurless11) have bean fomilated in the hope that, at least among categories cf fairly similar agents, sudi indices ray he c sene predictive value in other systems, including fcusans. Gieaical cardncgens differ widely in the dose required to produce a dwn lvel cf tirscur irA^tion, although many- of dan share cotutcn 16 AP00047859 biological properties which include metabolism, to reactive (electrophilic17-**) intermediates capable of interacting with ENA. The reason for this variation in dose-respcxise is not understood bat may be are either to differences within a cecum metabolic process cr to the operation of qualitatively distinct mechanisms. Statistical analysis of animal studies Tumours which wculd have arisen had an animal lived longer may not be observed because of the death of the animal frees unrelated causes, ani proper allowance must be trade for this possibility. Various analytical techniques have been developed which use the assimpticn of independence of carpeting risks to allow for the effects of intercurrent mortality on the final numbers of tunoar-fcearing animals in particular treatment groups. Far externally visible tumours and far neoplasms that cause death, methods such as Kaplan-Maier (i.e., 'life-table', 'prcdir^-limLt' or 'actuarial') estimates5*, with associated significance tests*0'1'l, are recampnded. For internal neopl&sos which are discovered 'incidentally'1,0 at autopsy but ^lich did ret cause the death of the host, different estimates*2 and significance tests* * * *1 van be necessary for the unbiased study of the ranters of tumour-bearing animals. All of these DwtiEd*5*'*0'*2'''2 can be used to analyse the numbers of animals tearing particular tumour types, but they do not distinguish hetsreen animals wdth ene or many such tmms. In experiments which end at a particular fixed time with the sinailtanecus sacrifice of many animals, analysis of the total rasters of internal raoplasns per animal found at autepsy at the end of the experiment is straightforward. However, there are no adequate statistical methods for analysing the rasters of particular neoplasms that kill an animal host. There are prdhlana not only of differential survival bat of differential todedty, vhich my be manifested by unequal growth and weight gain In treated and control animals. These ccnplexities should also be considered in the interpretation of data, cr, better, in the e^erdmental design. 17 AP00047860 N Evidence of Cfercdjrocghlcity in'alaraiia ............................_T.1I"-- --------------- Evidence of carcinogenicity 1a hisisris can be derived fror\ three types of study, the first two of which usually provide cnly suggestive evidence: (1) reports concerning Individual cancer patients Cease reports), including a history of e^osure to the supposed carcinogenic agent; (2) descriptive epidemiological studies in which the incidence sf cancer in hixnan. popula tions is found to vary (spatially or tencorally) with exposure to the agent); and (3) analytical ^>idendo2ogical studies (e.g., case-control or cohort studies) in which Individual exposure to the agent is found to be associated with an increased risk of cancer. An analytical study that shows a positive association between an agent and a cancer ray be interpreted as implying causality to a greater or lesser extent, i the following criteria are net: (1) tttare is no identifiable positive bias (By 'positive bias' is nwrint the operation of factors in study design or execution which lead erroneously to a more strongly positive association between an agent and *** then in fact exists. Examples of positive bias include, in case-central studies, core nearly ccnpleta ascertainnent of exposure to the agent in cases than in controls and, in cctarfr studies, tore nearly carplet* detection of cancer in individuals exposed to the agent than in individuals not exposed). (2) The possibility of positive confounding has been considered ($y 'posi tive confounding' is reant a situation, in which the relationship between an agent and a disease is rendered more strongly positive than it truly is as a result of an association between that agent and another agent which either causes car prevents the disease. An exarrple of positive confounding is the association between coffee ccnsuugrtdon and lung cancer, which results Iran their joint association with cigarette sncJdjg), (3) The association is unliKely to be due to chance alone. (4) Qte asso ciation is strong. (5) Share is a dose-response relationship. In sane instances, a single epidemiological stuc^* may be strongly indicative of a cause-effect relationship, however, the most convincing evidence of causality axes when several independent studies done under different circustances result in 'positive' findings. 18._____ AP00047861 Analytical epidemiological studies that..shew no association between an agent and a cancer {'negative' studies) should be interpreted according to criteria analogous to those n<*<* above: (1) There is no identifiable negative bias. (2) T3*e possibility of negative confounding has keen considered. 0) The possible effects, of TM_s^ f* cat- < on of exposure or cutoare have bean considered. In addition, it nust be recognized that in any study there are confidence limits around the estimate of association, or relative risk. In a stuay regarded as .'negative', the \$per confidence Ifait may indicate a relative risk substantially greater1 than unit?; In that case, the study cnly relative risks that ere above this tpper limit. usually Beans that & 'negative' study oust be large to be convincing. Confidence in & 'negative* result is increased when several independent studies carried out under different droonstances are in agreerent. \ Finally, a 'negative* study nay be emsidared to be relevant only to dose levels within or below the range of those observed, in the study and is pertinent only if sufficient time has since first human e^osure to the agent, toperlerce with huaan cancers of knewn etiology suggests that the period fron first exposure to a chemical carcinogen to development of eUn4T iy cbseEved cantata: is. usually measured in decades and nay be in e>peaa of 30 years. Experimental Data Belavant to the Evaluatico of Carcinogenic Risk to Banana Ms adequate <siteria are presently available to interpret experimental carcinogenicity data directly in terms of carcinogenic potential for humans. ifcmetheless, utilizing data collected frem appropriate tests in animals, positive extrapolations to possible tartan risk can reasonably be approxirated. infdHnation carp.ilerl frcgi the first 17 volumes of the Monographs * ,"s`! shows that of about 26 dwnticsls or sanufacturing processes now generally accepted to cause cancer in humans, all but pcssibly two (arsenic ai*3 benzene) of those vhiefa have been tested appropriately produce in at least one animal species. For several (aflatcxins, 4-aminobiphenyl, diethyLstilboestcol, melphalan, snstard gas and vinyl chloride), evidence 13 AP00047862 of; carcinogenicity in esqperimsntal animals preceded evidence obtained Sraa epldemiological studies or case reports. ' In general, the evidence that a chsnical produces turrcurs in exceriTT*nfeai animals is of two degrees: (1) sufficient evidence of carcinogenicity is indicated by the production of malignant tumours; and (2) limited evidence of carcinogenicity reflects the qualitative and/or quantitative liadfcaticns of the o^exisental results. Bter many of the chemicals evaluated In the first 17 volumes of the IARC Monograph* far vfaich there is sufficient evidence of cardregenicity in. animals, data relating to carcinogenicity for huoens are either insuf ficient or nccewdstant. In the absence of adequata data an humans, it is reasonable to regard for practical purposes such chemicals as if they were to fcnsoans. Sufficient evidence of carcinogenicity is provided by experL-rental studies that show an increased incidence of malignant tircurs: (a) in mltiple species or strains, and/or (b) in multiple experinants (routes and/or doses), and/or (c) to an unusual degree (with regard to incidence, site, type and/or precocity of onset). Additional evidence may- be provided by data concerning dose 'response, irutagenicity or sttustuxe. Si the present state of knowledge, it would be difficult to define a predictable relationship betoken the dose (mg/Jcg bw/day) of a particular 'tam'ral required to piuJure cancer in test ard the dose which vxjuld produce a similar incidence of cancer in. humans. Ihe available data suggest, however, that such a relationship say estist*', at least far certain classes c carcinogenic (Amicals. Cats that provide sufficient evidence of carcinogenicity in test animals may therefore be used in an apprccdmate quantitative evaluation of the human risk at sane given erasure level, provided that the nature of the chemical concerned and the physiological, phnrrrwcological and toxicological differences between tha test animals and haras are ta)<en into accent. Bwever, no acceptable methods are currently available far quantifying the possible errors In such a procedure, whether it is used to generalize between species or to extrapolate froa high to low dcses. The rethcdalcgy for such quantitative extrapolation to husens requires further development, _ ----------------------- ----------------------------------------- 20 AP00047863 Evidence for the carcinogenicity of sore diedcals in e^eriirental arHtiai nay be limited for two reasons. Firstly, experimental* data may be restricted to such a point that it is not possible to determine a caus&l relationship between jfjnanistratign of a chenical and the development of a particular lesicn. in the animals. Secondly, there are certain necplasrs, including lung tmioura and hepatams in mice, which have been considered of significance than necplaaos occurring at other sites for the purpose of evaluating the carcinogenic risk of chemicals to hvsrans. Such tumours occur spontaneously in high incidence in ttesc animals, and their malignancy is often difficult to establish. An evaluation of the significance of these tappues following ^ministration of a chemical is the responsibility of the particular Vfcddng Group preparing the individual monograph, and it has not been possible to aet down, rigid, guidelines; the relevance of these tarours must be detenmLned fcy considerations viiich include e^erimental design and canpleteness of Escorting. Same chemicals for which there is limited evidence of earHnr^enigity in animals have also been studied in humans with, in general, inconclusive results. While such chemicals may indeed be carcinogenic to humans, more experimental and epidaniglogical Investigation is required. Bence, 'sufficient evidence* cf carcinogenicity and 'limited evidence' of carcinogenicity do sot indicate categories cf chenicals: the interest definitions of those tears indicate varying degrees of esqserlment&l evidence, which may change if and when new data cn the chemicals become available. The main drawback to ary rigid of chanicals with regard to their carcinogenic capacity is the as yet incenplete knowledge of the mocfaaniau(s) of carcinogenesis. . - --' In recent years, several ahort-teaa tests for the detection of potext~ tial carcinogens have been developed.' When cnly inadequate esq^xijrental data are available, positive results in validated short-tem tests (see p. 25) are an indication that the compound is a potential carcinogen ard that it should be tested in animals far an assessment of its carcinogenicity. Negative results frem short-tem tests cannot be considered sufficient evidence to rule cut carcinogenicity. Vbether shart-tam tests will 21 AP00047864 eventually attain a stature similar to that of long-term tests in predict ing carcinogenicity in humans will depend an farther dencnstr&ticns of consistency with long-term experiments and with data from ftmans. EffiZANKEOTO' MOTES CK TOE M3CGRAPH CCNEEMTS Chemical and Physical Data {Section 1) The Chemical Abstracts Service Registry Number and the latest OjearLcal Abstracts primary Name. (9th Collective Index) are recorded.in section 1. Other syneryms and trade names are given, but this list is often not comprehensive. Farther, earn of the `bade names are those of mixtures in which the oaiyound being evaluated is only cca of the ingredients. The structural and molecular fnnwalae, molecular weight and. chemical and physical properties are given. The properties listed refer to tile pure substance, unless otherwise specified, and include, in particular, data that might be relevant to carcinogenicity (for cample, lipid solubility) *rv* those that acncem Identification. A separata description of the coxpositicn of technical products includes available infonmtian cn impurities and formulated products. Production, Use, Occurrence and. Analysis (Section 2) 3he purpose of section 2 is to provide indications of the extent of past and present human ejqjosure to this chemical. Synthesis Since cancer is a delayed toxic effect, the dates of first synthesis and of first cumercial production of the chemical are provided. In addition, methods of synthesis used in past and present ceornereial produc tion are described. Ibis infotmaticn allows a reasonable estimate to be made of the before which no human e^osure could have occurred. Preehnsticn Since Europe, Japan and the United States are reasonably representative industrialized areas of the world, asst data on production, foreign trade Bad uses are obtained from those countries. It shsuld not, however, be 22 AP00047865 inferred that those nations axe the sola dr even' the rrajor sources of users of any individual chsnical. Production and. foreign trade data are obtained fscm both governmental and trade publications by ehwical aoananista in the three geographical areas. In seas cases, separate production data cm organic nanu^ factured in the United States are not available because their publication could disclose confidential infcoaticn. 'In surii cases, an indication of the nrirfimtm quantity produced carv be obtained frera the number of carpwmw^ reporting cainercdal production. Each, errpany is required to repent cm individual chemicals if the sales value car the weight of the annual produc tion; of a chardcal exceeds a specified minim,im level. These levels vary for chemicals classified for different uses, e.g., iredicinals, plastics? however, the minimal annual sales value is between $1000 and $50,000 and the minimi annual weight of production is between 450 and 22,700 kg. Data, cm production in scree European countries are obtained ty means of 'yw* questionnaires sent to cecpanies thought to produce 'die compounds being evaluated* Infcaanatien fran the. consisted questionnaires is carpiled by country, and the resulting estimates of production are included in the individual neoographs. V6 . Information on uses is msaitt to serve as a guide only and is not ccnplete. It is usually obtained from published data but is often corplenentsd by direct contact with manufacturers of the daecdcal. In die case of drugs, mention of their therapeutic uses dees rot necessarily represent current practice nor does it inply judgment as to their-clinical efficacy. Statements concerning regulations ard standards (e.g., pesticide registration, mxzsuDi levels permitted in foods, occupational standards and allowable limits) in specific countries are mentioned as exanples only. They my not reflect the most recent situation, since such legislation is in a constant state of change; nor should it be taken to irply that other ccwnuriee do net have cim-Mar- regulations. 23 AP00047866 Occurrence............... ................................................ _L. " ' . r.' .V lnfeainatj.cn on the occurrence of a chemical in the environment is obtained froa published data, including that derived, feat the ncnitoring and surveillance of levels of the chaidcal in occupation eawiruraierits, air, water/ soil, foods and tissues of aninals awi humans, when available, data on the generation, persistence and faioacenmlatioi of a chemical are also included. Analysis She purpose of the section an analysis is to give the reader an indication, rather than a aorplete review, of methods dted in the literature. No attespt is made to evaluate critically or to reccnznend any of the methods. Biological Data Relevant to toe evaluaticn of Carcinogenic Risk to Humans jsection 3) In general, the data recorded in section 3 are sunmariged as given by the author; however, certain shortccnlnga of reporting, of statistical analysis or of experimental design are cannented upon by the Wadcing Group in square brackets. The nature and extent of inpurities/ccntamiiiajits in the chemicals being tested are given v&en available. Carcinogenicity and rotated studies in animate . file scnograpfas are tut intended to oover all reported studies. Some studies are purposely emitted (1) because they are inadequate, as judged firm previously described criteriav7~99 (e.g., too short a duration, too few aniflala, pear survival); (21 bsranse they cnly caifinn findings that have already been fully described; or (3) because they axe judged Irrele vant fear toe purpose of toe evaluation. In certain cases, however, such studies axe mentioned briefly, particularly when toe infaeration is consi dered to be a useful supplaient to other recocts or when, it- is the. only data available, Sheir incHwlcxi does not, bwwver, imply aoceptanoe of the adequacy of their experimental design and/or of toe analysis and interpretation of their results. Mention is teds of all routes of administration by which the ccrrpourri has been adequately tested and of all species In which r&levarrt tests have 24 AP00047867 been dan''*0. In nest cases, animal strains are given (general charac teristics of mouse strains have been reviewed51). Quantitative data are given to Indicate the order of magnitude of the effective carcinogenic doses. In general, the doses and schedules are indicated as they appear in the original paper? somtiacss units have been converted for easier comparison. Experiments cn the carcinogenicity of known metabolites, chemical precursors, analogues end derivatives, and experiments cn factors that modify the carcinogenic effect aza also reported. Other relevant biological data lethality data are given when available, and other data cn toxicity are included whan considered relevant. The metabolic data are restricted to studies that show- the metabolic fate of the chemical in animals and teen, "M cesparisena of data fran animals and humans are made when possible. Tn^CTTmatj^n is also given ax absorption, distribution, excretion and pla cental transfer. Embryotoxicity and teratogenicity Data on teratogenicity fran studies in experimental animals and obser vations in humans are also included. There appears to be no necessary relationship between teratogenicity51 and carcinogenicity, but chemicals often have both properties. Evidence of teratogenicity suggests transplacental, ^ansfee, viiich is a praraquisita for -transplacental, carcdro-- genesis. Mutagenicity and other short-term tests Data fran indirect tests ere also included, since meet of these tests have the advantage of taking less time and being- less expensive than mammalian carcinogenicity studies, they are generally loom as `short-term1 tests. They emprise assay procedures vMch rely cn the induction of biological and biochemical effects in in vivo and/or in vitro systems. The end-point of the majority of these tests is rot the producticn of tsc^ plasma in animals but changes at the molecular, cellular or zmltieellular level* these include the inducticn of ENA damage and repair, mutagenesis in taafftgy-i* and other organisms, transformation of mamnalian in culture, and otter systams. ................................................................... 25 AP00047868 * " 'ifc^-ahort-tesan tests proposed for use (15 in predicting' potential carcimgenicity in the hwine of carcinogenicity data in anirals, (2) as a crentrTtT*-ln in deciding vfcich chemicals should be tested ih animals, (3) in identifying active fractions of ccnplex mixtures containing carcino- ges, (4) for recognising active metabolites of town carcinogens in huran an3/r animal body fluids and (5) to help elucidate metiianisns of carcii- genesis. Alt&augfa the theory that cancer is induced as a result of san&tic nutaticn suggests that agents which damage QA in vivo say be carcinogens, the prwjcn relevance of short-tens tests to the mechanist by which <-*Tvr is induced is not known. Predictions of potential carcinogenicity are currently based cn correlations betvea responses in short-term tests and data from animal carcinogenicity and/or hucan epidemiological studies, mis approach is because the nmbsr of chemicals kncwn to be carcinogenic in humans is insufficient to provide a HwbIs for validation, and most validation studies involve chemicals that have been evaluated for carcinogenicity' only in animals, me select!cn of chgn(<^*lq is in turn limited, to those classes for vhich data oi carcinogenicity are available, me results of validation studies could be stoangly inflnencai by such selection of chemicals and by tte proportion of carcinogens in the series of dsmicals tested; tins should be kept in mind when evaluating the predictivity of a particular test, me usefulness of ary test is reflected by its ability to classify carcinogens n*i noncardnogens, using the animal data as a standard.; however, animal tests may not always a perfect standard, me attainable level of correlation between ^1'-* r~ tests and animal bdcassays is still under investigation. Since many chmicals require metabolism to an active fosa, test systems .that do not take tills into account may to &to certain potsitial carcinogens, me metabolic activation systans in short--tem tests (for example, the cell-free systems used in tests) are meant to slnulata the intact hurran. Each has its advantages and limitations; thus, mare confidence can be placed in the conclusions when negative or positive results far a chemical are ecuifinrad in several such test systans. Defi ciencies in metabolic cmpatence may to r^*Hon of chemicals, 26 AP00047869 which means that not all tests are suitable for assessing the potential carcinogenicity of all classes of ccrcouMs. pnsant state o tacwledge dees not permit the selection of a specific test(s) as the cost appropriate for identifying potential carcino genicity. Before the results of a particular test can be considered to'be fully acceptable for p.-.-edicting potential carcinogenicity, rer*-in criteria should be met: (1) the test should have been validated with respect to known animal carcinogens and found to have a high capacity for discrimin ating between carcinogens and noncaxdrogens, and (2) when possible, a at-j-iwi MT-ai-iy related cardnogen(s) and nsmearcinogenCs) should have been tested simultaneously with the dienieal in question, aha results shruld have been reproduced in different laboratories, and a prediction of car cinogenicity should have been confined in additional test systems. Confidence in positive results is -try-re* w* if a- Trarfraniaw of action can be deduced ard if appropriate dose-nespensa data are available. For opticus usefulness, data an purity oust be given. Ofce shert-tesa tests in current use that have been, the most extensively validated are the Salmonella tgpfcwnuruon plate-incccporaticn. assay5*"57, the JC-linieed recessive lethal test in Drosophila melenogaster1*, unscheduled DMA synthesis55 and in vitro transformation57' *0. Each is ccopatible with current concepts of the possible mechanism (s) of carrirogenesis. An adequate assessment of the genetic activity of a chemical depends cn data ron a wide ranga of test systems. She nxmegraphs include, there fore, data not only frnn those already mentioned, bet also cn the induction of point nutations in other systems**"**, of structural*7 and numerical chrcncscoie aberrations, including dezrdnant lethal effects**, of mitotic reccmfainaticn in fungi*1 and of sister chranatid exchanges*5'7'. Use existence of a correlation between quantitative aspects of cutagenic and carcinogenic activity has been suggested1*'**"7'', hut it is not sufficiently well established to allcw general use. Further infcarnation about nutagenicit/ and other shart-tficn tests is given in references 71-T7. 27 AP00047870 Cat* itpart* &id epidemiological studims - ----------- ------------; Observations in humans are surrmarized in this section. > Sunrtary of Data. Aoparted and Evaluation, (section 4) Section 4 summarises the relevant data fxcnt anirrals and humans and gives the critical viesvs of the Storking Group an those data. Experimental data Data relevant to the evaluation of the carcinogenicity of a chenical in anioals are simitarArad in this section. Results from. validated muta genicity and other short-term tests are reported if the Kbrkr*j Group considered the data to he relevant. Dose-response data are given when available. An assessment of the carcinogenicity of the chemical in animals is made an. the basis of all of the available data. Ska aniaal species mentioned are these in which the carcinogenicity of the substance was clearly deecnstrated. 3&e route of administration used in experimental animals' that is similar to the possible human axpocure is given particular mention. Tutour sites are also indicated. If the substance has produced tuncurs after prenatal exposure or in single-dose experiments, this is indicated. Euman data Hatan exposure to the chemical is suroarized, and the significance of data on production, use and occurrence and other relevant biological data is discussed. Case reports and epidemiological studies that are considered to be pertinent to an assessment of human carcinogenicity are described. Adequate dcse-sespanse data are given when available. An assessment of the carcinogenicity of the ctedcal in humans is rede an the basis of all of die available evidence. Evaluation Hils section cmyrises the overall evaluation by the Working Group of the carcinogenic risk of -die chemical to humans. All of the data in the monograph, and particularly the samagized irfozratian an eayerisental and hunaa data, are considered in order to nake an evaluation. In addition, are made regarding areas in which further investigation is considered to be necessary. - - ... - --.........- ... 28 ..... AP00047871 References 1. PRC (1377) Technical Report 77/002, Preamble, Intamaticnal J^ency far Research on Career,~LycaT~ 2. KBQ (1961) Fifth Report of the Joint EA0/V420 Scert Comuttee on. Food Additives. Evaluation of carcinogenic hazard of food additives. Mid Hlth Ore, techn. Rep. Ser., No. 220, jp. 5, is, 19 3. KBO (1969) Report of a V3D Scientific Group. Principles for the testing and evaluation of drugs for carcinogenicity. Wld Hlth ..~j Qrg.'techn. Bap. Ser,, NO. 426, pp. 19, 21, 22 ' " 4. WX (1974) Report of a TOO Scientific Group. Assessment of the carcinogenicity and mitagenicity of chflRdcals. Wld- Hlth Qrg. .. tedm. Rep. Ser., No. 546 5. KSO (1964) Report of a WB3 Ej^erfc Ccrmittao.. 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