Appendix Am A Comparison of the National Cancer Institute s and the International Agency for Research on Cancer s Evaluation of Bioassay Results

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1 Appendixe..

2 Content Page Appendix A: A Comparion of the National Cancer ntitute and the nternational Agency for Reearch on Cancer Evaluation of Bioaay Reult Appendix B: Unreaonable Rik Appendix C: Abbreviation and Gloary

3 Appendix Am A Comparion of the National Cancer ntitute and the nternational Agency for Reearch on Cancer Evaluation of Bioaay Reult A working group aembled by the nternational Agency for Reearch on Cancer (ARC) reevaluated data about 354 chemical previouly evaluated and decribed in the firt 20 ARC monograph (185,186). The working group developed the following criteria for grading evidence about carcinogenicity. The firt three categorie are eentially the ame a thoe ued in earlier ARC compilation (344), and two new categorie were added: Sufficient evidence of carcinogenicity indicate that there i an increaed incidence of malignant tumour: (a) in multiple pecie or train; (b) in multiple experiment (preferably with different route of adminitration or uing different doe level); (c) to an unuual degree with regard to incidence, ite or type of tumour, or age at onet. Additional evidence may be provided by data concerning doe-repone effect, a well a information on mutagenicity or chemical tructure. imited evidence of carcinogenicity mean that the data ugget a carcinogenic effect but are limited becaue: (a) the tudie involve a ingle pecie, train, or experiment, or (b) the experiment are retricted by inadequate doage level, inadequate duration of expoure to the agent, inadequate period of follow-up, poor urvival, too few animal, or inadequate reporting, or (c) the neoplam produced often occur pontaneouly or are difficult to claify a malignant by hitological criteria alone (e.g., lung and liver tumour in mice). nadequate evidence indicate that becaue of major qualitative or quantitative limitation, the tudie cannot be interpreted a howing either the preence or abence of a carcinogenic effect. Negative evidence mean that within the limit of the tet ued, the chemical i not carcinogenic. The number of negative tudie i mall, ince in general, tudie that how no effect are le likely to be publihed than thoe uggeting carcinogenicity. No data indicate that data were not available to the working group (185). ARC (185) made the following tatement about the value of bioaay reult:... in the abence of adequate data in human it i reaonable, for practical purpoe, to regard chemical for which there i ufficient evidence of carcinogenicity (i. e., a caual aociation) in animal a if they preented a carcinogenic rik for human. The ue of the expreion for practical purpoe and a if they preented a carcinogenic rik indicate that at the preent time a correlation between carcinogenicity in animal and poible human rik cannot be made on a cientific bai, but rather only pragmatically, with the intent of helping regulatory agencie in making deciion related to the primary prevention of cancer. (Emphai in original. ) The larget ingle teting effort i the National Cancer ntitute (NC) Carcinogenei Teting Program (now a part of the National Toxicology Program (NTP)). Grieemer and Cueto (146) analyzed the reult of NC teting 190 chemical and placed each teted chemical into one of nine claification (ee table A-l). Ninety-eight of the 190 were judged to be carcinogenic (claification 1 through 5); 28 were equivocal (claification 6); and 64 were noncarcinogenic (claification 7 through 9). The NC reult had earlier been reviewed by a panel of governmental and nongovernmental expert and Grieemer and Cueto drew on that review in their compilation. A ignificant difference between the data analyzed by Grieemer and Cueto (hereafter referred to a the NC lit ) and by ARC i that all the NC experiment were carried out according to a tandard protocol (331). The ARC evaluation conider experiment carried out under a variety of protocol including thoe done by NC. Thirty-three chemical appearing on the ARC lit of 354 alo appear in the NC lit. n table 39, uch chemical are lited in the cla to which they were aigned by Grieemer and Cueto. For intance, the chemical chloroform appear in the NC cla 1, and it i alo preent on the ARC lit. Following each lited chemical i an S,, or 1, The letter indicate ARC claification of ufficient, limited, or inadequate evidence for carcinogenicity. n ome cae, additional data that became available between the compilation of the 1978 (185) and 1979 (344) ARC lit changed a chemical from or to S; thee change are reflected in the table. Comparion between the NC and ARC lit are not direct becaue different criteria were ued, but the following cheme may be ueful. NC] Evidence ARC claification claification Strongly poitive Sufficient evidence (S) Clae 1, 2 Poitive imited evidence () Clae 3, 4, 5 Not Poitive nadequate evidence () Clae 6, 7, 8, 9 Agreement i good about the trongly poitive chemical, Seven of the 12 NC cla 1 chemical were found to have ufficient evidence for carcinogenicity by ARC. Of the remaining five, ome are likely to be reevaluated by ARC. For intance, reerpine wa claified in the inadequate evidence group by ARC before the reult of the NC bioaay 211

4 212 Technologie for Determining Cancer Rik From the Environment Table A-1.National Cancer ntitute (NC Analyi of the Reult of Teting 190 Chemical a and the nternational Agency for Reearch on Cancer (ARC) Analyi of Chemical b c That Appear on the NC it NC Group A: Five categorie of reult howing increaed tumor incidence, ordered with mot convincing category being number 1. - Very trong evidence in 2 pecie. 317 chemical Chemical among the 31 that appear on the ARC it Chlorodecone (kepone) Chloroform ,4-diaminoaniole ,4-diaminotoluene Dibromochloropropane (DBCP) ,2-dichloroethane ,4-dioxane nitroacenaphthene Phenoxybenzamine hydrochloride Reerpine Selenium ulfide (ARC entry i elenium compound) Ortho-toluidine hydrochloride Evidence for carcinogenicity, ARC 1979 C 1978 b S d k < P e Very trong evidence in 1 pecie, ufficient evidence in 2d pecie. 9 chemical None of the 9 chemical appear on the ARC lit. Very trong evidence in 1 pecie, no evidence in 2d pecie. 35 chemical Chemical among the 35 that appear on the ARC lit 4-amino-2-nitrophenol Aniline hydrochloride (ARC entry i aniline) Azobenzene., Chlordane Chlorobenzilate Cinnamyl anthranilate Heptachlor aiocarpine Oetradiol mutard (ARC entry i etradiol mutard) Trichloroethylene Toxaphene chloro-ortho-toluidine hydrochloride (ARC entry i parachloro-ortho-toluidine hydrochloride) Sufficient evidence in 2 pecie. 4 chemical None of the 4 chemical appear on the ARC lit. Sufficient evidence in 1 pecie, no evidence in 2d pecie. 19 chemical Chemical among the 19 that appear on the ARC lit Aldrin Ethyl tellurac NC Group B: One category howing inufficient evidence to lead to a concluion about carcinogenic it y.

5 Appendix AA Comparion of NC and ARC Evaluation of Bioaay Reult 213 Table A-1.National Cancer ntitute (NC) Analyi of the Reult of Teting 190 Chemical n and the nternational Agency for Reearch on Cancer (ARC) Analyi of Chemical b c That Appear on the NC it (Continued) Equivocal evidence in 1 or 2 pecie. 28 chemical Evidence for carcinogenicity, ARC 1979 c 1978b Chemical among the 28 that appear on the ARC lit Phenacetin (teted by itelf by ARC; teted in combination with apirin and caffeine, APC, by NC) Styrene NC Group C: Three categorie howing no evidence of carcinogenicity. No evidence in limited experiment. 51 chemical Chemical among the 51 that appear on the ARC lit Dieldrin Endrin Ethionamide indane Methoxychlor No evidence in 1 pecie. 10 chemical 1 chemical among the 10 appear on the ARC lit Anthranilic acid No evidence in 2 pecie. 3 chemical None of the 3 chemical appear on the ARC lit. agrleemer #md Cueto, %omati, et al., 1978; Tomati, clarc, 1979; ARC, d ndicate ufficient evidence of carcinogen icity. ndicate limited evidence of carclnogenicity. indicate nadequate evidence of carcinogen icity. See text of that drug were available, and ortho-toluidine hydrochloride i being reevaluated by ARC. Both NC and ARC found that phenoxybenzamine hydrochloride i carcinogenic. Therefore the lit may only differ ignificantly over two chemical, and thoe difference, too, may diappear a more data become available. Agreement i not a good about chemical that are le poitive. NC clae 3, 4, and 5 roughly correpond to ARC group, but 5 of the 11 NC cla 3 compound common to both lit were put in the in adequate evidence category by ARC. Additionally, NC found no evidence for carcinogenicity for any chemical in clae 6 through 9, but ARC found limited evidence for carcinogenicity for five of the eight chemical that it reviewed in thoe clae. A wa mentioned, the data conidered by ARC and NC are not independent of each other; ARC conider NC reult in addition to all other. The difference in claification may reult from the different criteria ued by the two organization, a well a from ARC conidering other reult. Comparion of the 1978 and 1979 ARC liting how that the evidence for the carcinogenicity of ome chemical became more poitive. The progreion to more-ignificant-evidence clae ma y be important to the contention that repeated teting increae the chance that a chemical will be determined to be a carcinogen. Neither the ARC nor the NC lit include review of all chemical of interet. For intance, neither accharin nor odium nitrite appear on either lit, but

6 Technologie for Determining Cancer Rik From the Environment both compound have been much dicued by regulator and potentiall y regulated indutrie. The lat entence of the Grieemer and Cueto (146) paper draw attention to the importance attached to poitive reult. Thoe compound for which evidence for carcinogenicity wa not found... cannot necearily be conidered a noncarcinogen ince the tet were conducted under a limited et of circumtance. t i poible that evidence for carcinogenicity might be found if, for example, a different train of animal or a different route of expoure were ued. The quote illutrate the impoibilit y of proving a negative, and in a more immediate ene, it alo how that rule are not etablihed to allow claifying a chemical a afe. A workable approach to allow making a deciion that a chemical hould be regarded a afe rather than a a potential rik may be neceary to eparate important problem from minor and nonexitent one. n fact, Griemer and Cueto group C which include four grade of negative evidence how that concluion can be drawn that chemical were found not to be riky under condition of the tet.