IARC MONOGRAPHS ON THE EVALUATION OF THE CARCINOGENIC RI SK OF CHEMI CALS TO MAN: CERTAIN POLYCYCLIC AROMATIC HYDROCARBONS AND HETEROCYCLIC COMPOUNDS Volume 3 This publication is the outcome of the meeting of the IARC Working Group on the Evalua tion of the Carcinogenic Risk of Chemicals to Man, Lyon, 5-11 December 1972 IARC WORKING GROUP ON THE EVALUATION OF THE CARCINOGENIC RISK OF CHEMICALS TO MAN: CERTAIN POLYCYCLIC AROMATIC HYDROCARBONS AND HETEROCYCLIC COMPOUNDS Lyon, 5-11 December 1972 Members Professor E. Boyland, 42, Bramerton Street, London SW3, UK Professor W. Dontenwill, Forschungsinstitut der Zigaretten Industrie, Gazellenkamp 38, Hamburg, Federal Republic of Germany (Vice,.Chairman) Dr H. L. Falk, National Ins ti tutes of Envi ronmen tal Heal th Sciences, Research Triangle Park, P .0. Box 12233, N.C. 27709, USA (Chairman) Dr B. G. Gor i, As soc i a teS cie nt if i c Di r e c t 0 r for Pro gram, Etiology, National CanceT Institute, National Institutes of Health, Bethesda, Maryland 200l4, USA Dr M.D. Kipling, Medical Adviser, Department of Employment, Somerset House, 37, Temple Street, Birmingham 2, UK Dr R.W. Miller, Chief, Epidemiology Branch, A52l Landow Building, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 200l4, USA Dr B. Terracini, Istituto di Anatomia e Istologie Patologica, Universi tà di Torino, via Santena 7, 10126 Torino, Ita1y Representative of the National Cancer Insti tute Dr J. Cooper, Director, Informa tion and Resources Segment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014, USA i .3 Invited guests Dr P. S. El ias, Principal Medical Officer, Department of Heal th and Social Securi ty, Alexander Fleming House, Elephant and Castle, London SEl, UK Dr H.P. Harke, Forschungsinstitut der Zigaretten Industrie, Gazellenkamp 38, Hamburg, Federal Republic of Germany Secretariat Dr C. Agthe, Uni t of Chemical Carcinogenes is (Secretary) Dr N. Breslow, Unit of Epidemiology and Biostatistics Dr P. Bogovski, Unit of Environmental Carcinogens Dr A.J. Cohen, lARC Consultant Dr J. Higginson, Director Dr R. Kratel, Occupational Heal th Uni t, WHO Mrs l. Peterschmitt, Unit of Chemical Carcinogenesis Dr L. Tomatis, Unit of Chemical Carcinogenesis Dr A.J. Tuyns, Unit of Epidemiology and Biostatistics Mr E.A. Walker, Unit of Environmental Carcinogens 4 CONTENTS Page BACKGROUND AND PURPOSE OF THE lARC PROGRAMME ON THE EVALUATION OF THE CARCINOGENIC RISK OF CHEMICALS TO MAN .................................................... 7 SCOPE OF THE MONOGRAPHS ............... ... ...... ...... .... 7 MECHANISM FOR PRODUCING THE MONOGRAPHS ................... 8 Priori ty for the preparation of monographs .......... 9 Data on which the evaluation was based .............. 9 The Working Group ......... ....... ....... ........ .... lO GENERAL REMARKS ON THE E V AL UA T I. 0 N ........................ lO Terminology . e. lO Response to carc ino gens ............................. 10 Qualitative aspects ................................. II Qu an t i ta t ive as p e c t s ................................ 1 1 Extrapolation from animals to man ................... l2 Evidence of carcinogenicity to humans ............... 12 Mixtures and groups of carcinogens .................. l3 EXPLANATORY NOTES ON THE MONOGRAPHS ...................... l4 GENERAL REMARKS ON THE SUBSTANCES CONS IDERED ............. l7 HISTORlCAL REVIEW OF CANCER IN WORKERS EXPOSED TO POLYCYCLIC AROMATIC HYDROCARBONS AND HETEROCYCLIC COMPOUNDS AND THEIR ROLE IN OTHER ENVIRONMENTAL SITU AT ION S ............................................. 22 S 0 0 t and car bon b lac k ............................... 2 2 Coal-tar and pitch .................................. 25 5 Contents (cont'd) Page Mineral oils ...................................... 30 The role of polycyclic aromatic hydrocarbons and heterocycl ic compounds in non-occupa t ional exp 0 5 ur e ........................................ 34 THE MONOGRAPHS Polycycl ic aroma tic hydrocarbons: Ben z ( a) an t h r a c en e ............................... 4 5 Benzo (b) fluoranthene ............................ 69 Benzo(j)fluoranthene ............................ 82 Benzo(a)pyrene .................................. 91 Benzo(e)pyrene .................................. l37 Ch r y 5 en e ........................................ 1 59 Dibenz (a, h) anthracene ........................... 178 Dibenzo(h,rst)pentaphene ........................ 197 Dib en z 0 ( a , e) p y r en e .............................. 2"01 Dibenzo(a,h)pyrene .............................. 207 Dibenzo(a,i)pyrene .............................. 215 Dibenzo(a,l)pyrene .............................. 224 Indeno(1,2,3-cd)pyrene .......................... 229 Heterocycl ic compounds: Benz(c)acridine ................................. 241 Dibenz(a,h)acridine ............................. 247 Dibenz(a,j)acridine ............................. 254 7H-dibenzo(c,g)carbazole ........................ 260 CUMULATIVE INDEX TO MONOGRAPHS ......................... 269 6 BACKGROUND AND PURPOSE OF THE IARC PROGRAME ON THE EVALUATION OF THE CARCINOGENIC RISK OF CHEMICALS TO MAN ln the past few years the number and quanti ty of chemicals in the environment have increased. The possible adverse effect of these chemicals on human heal th 15 a matter of international concerne The International Agency for Research on Cancer (IARC) has consequently initiated a programme for the evaluation of the carcinogenic risk of chemicals to man, which was supported by a Resolution of the Governing Council at its Ninth Session concerning the role of the Agency in providing government autho- ri ties wi th expert, independent scientific opinion on environ- mental carcinogenes is. As one means to this end, the Governing Council recommended that the Agency should continue ta prepare monographs on the carcinogenic risk of individual chemicals to man. In view of the importance of this programme and in order to expedi te the production of monographs, the National Cancer Ins ti tute of the United States has provided IARC wi th addi tional funds for this purpose. The objective of this programme IS to achieve and publish a balanced evaluation of data through the deliberations of an international group of experts in chemical carcinogenesis and to put into perspective the present state of knowledge with the final aim of evaluating the data in terms of possible human risk, as well as to indicate the need for research efforts to close the gaps in our knowledge. SCOPE OF THE MONOGRAPHS In 1972 the first volume of these monographs was publ ishedl . 1 International Agency for Research on Cancer (1972) IARC on the Evaluation of Carcinogenic Risk of Chemicals to M~n, l, Lyon 7 These monographs summarize the evidence for the carcinogenicity of individual chemicals in a condensed uniform manner for easy comparison. The data were compiled, reviewed and evaluated by a working group of experts. No recommendations are given concerning preventive measures or legislation, since these matters depend on risk-benefi t evaluatiòn which seems best made by individual governments and/or international agencies such as WHO and ILO. The first volume covered a number of substances not belonging to a particular chemical group, and the second volumel contains monographs on some inorganic and organometall ic compounds. The present volume is devoted to a number of polycyclic aromatic hydrocarbons and heterocyclic compounds. As new data on chemicals for which monographs have already been written and new principles for evaluation become available, re-evalua tion will be made at future meetings and revised monographs will be published as necessary. Special meetings can be called to evaluate important compounds for which the data are controversial and for which there seems to be an urgent need for action by public health authorities. The monographs will be distributed to international and governmental agencies, will be available to industries and scientists deal ing with these chemicals, and will form the basis of advice from IARC on carcinogenesis from these subs tances. MECHANISM FOR PRODUCING THE MONOGRAPHS As a first step, a list of chemicals for possible consideration by the Working Group was established. IARC collected pertinent references regarding physico-chemical characteristics, use and occurrence, as well as biological data 1 International Agency for Research on Cancer (l973) IARC Monographs on the Evaluation of Carcinogenic Risk of Chemical s to Man, l, Some Inorganic and Organometallic Compounds (in press) 8 on these compounds. The ma terial was summarized by an expert consul tant or an lARC staff member, who prepared the first draft monograph, which in some cases was sent to another expert for comments. This draft was circulated to all members of the Working Group about two months before the meeting, at which further addi tions to and deletions from the da ta were agreed upon and a final vers ion of comments and evalua tion on each compound was adopted. Priority for the Preparation of Monographs Priority for consideration was given mainly to chemicals for which sorne adequa te experimental evidence of carcinogenici ty existed and/or for which there was evidence of human exposure. However, nei ther human exposure nor potential carcinogenici ty could be judged until all the relevant data had been collected and examined in detail. The inclusion of a particular compound in a monograph did not necessarily mean that the substance was considered to be carcinogenic. Equally,