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WORLD HEALTH ORGANIZATION
   INTERNATIONAL AGENCY FOR RESEARCH ON CANCER




IARC Monographs on the Evaluation of
   Carcinogenic Risks to Humans




               VOLUME 100
  A Review of Human Carcinogens

            Part D: Radiation




                  LYON, FRANCE
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
WORLD HEALTH ORGANIZATION
    INTERNATIONAL AGENCY FOR RESEARCH ON CANCER




IARC Monographs on the Evaluation of
    Carcinogenic Risks to Humans

                    Volume 100

   A Review of Human Carcinogens

                Part D: Radiation




 This publication represents the views and expert opinions
             of an IARC Working Group on the
        Evaluation of Carcinogenic Risks to Humans,
                     which met in Lyon,

                      2–9 June 2009
IARC MONOGRAPHS
      In 1969, the International Agency for Research on Cancer (IARC) initiated a programme on the evaluation of the carcinogenic
risk of chemicals to humans involving the production of critically evaluated monographs on individual chemicals. The programme
was subsequently expanded to include evaluations of carcinogenic risks associated with exposures to complex mixtures, lifestyle
factors and biological and physical agents, as well as those in specific occupations. The objective of the programme is to elaborate
and publish in the form of monographs critical reviews of data on carcinogenicity for agents to which humans are known to be
exposed and on specific exposure situa­ ions; to evaluate these data in terms of human risk with the help of international working
                                         t
groups of experts in chemical carcinogenesis and related fields; and to indicate where additional research efforts are needed. The
lists of IARC evaluations are regularly updated and are available on the Internet at http://monographs.iarc.fr/.
      This programme has been supported since 1982 by Cooperative Agreement U01 CA33193 with the United States National
Cancer Institute, Department of Health and Human Services. Additional support has been provided since 1986 by the Health,
Safety and Hygiene at Work Unit of the European Commission Directorate-General for Employment, Social Affairs and Equal
Opportunities, and since 1992 by the United States National Institute of Environmental Health Sciences, Department of Health
and Human Services. The contents of this volume are solely the responsibility of the Working Group and do not necessarily
represent the official views of the U.S. National Cancer Institute, the U.S. National Institute of Environmental Health Sciences,
the U.S. Department of Health and Human Services, or the European Commission Directorate-General for Employment, Social
Affairs and Equal Opportunities.
      This volume was made possible, in part, through Cooperative Agreement CR 834012 with the United States Environmental
Protection Agency, Office of Research and Development. The contents of this volume do not necessarily reflect the views or
policies of the U.S. Environmental Protection Agency.
                                 Published by the International Agency for Research on Cancer,
                                    150 cours Albert Thomas, 69372 Lyon Cedex 08, France
                                      ©
                                       International Agency for Research on Cancer, 2012
            Distributed by WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland
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         Publications of the World Health Organization enjoy copyright protection in accordance with the provisions
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in part or in full. Requests for permission to reproduce or translate IARC publications – whether for sale or for noncommercial
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     The designations employed and the presentation of the material in this publication do not imply the expression of any
opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country,
territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
     The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or
recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and
omissions excepted, the names of proprietary products are distinguished by initial capital letters.
     The IARC Monographs Working Group alone is responsible for the views expressed in this publication.

IARC Library Cataloguing in Publication Data
      A review of human carcinogens. Part D: Radiation / IARC Working Group on the Evaluation of Carcinogenic
      Risks to Humans (2009: Lyon, France)
      (IARC monographs on the evaluation of carcinogenic risks to humans ; v. 100D)
      1. Carcinogens 2. Neoplasms – etiology 3. Radiation – adverse effects
      I. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans
      II. Series


      ISBN 978 92 832 1321 5							                                                                (NLM Classification: W1)
      ISSN 1017-1606



                                                     PRINTED IN FRANCE
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
CONTENTS
NOTE TO THE READER .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 1

List of Participants .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 3

PREAMBLE. .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 7
   A.	 GENERAL PRINCIPLES AND PROCEDURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
       1.	Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
       2.	 Objective and scope. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
       3.	 Selection of agents for review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
       4.	 Data for the Monographs .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 9
       5.	 Meeting participants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
       6.	 Working procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
   B.	 SCIENTIFIC REVIEW AND EVALUATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
       1.	 Exposure data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
       2.	 Studies of cancer in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
       3.	 Studies of cancer in experimental animals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
       4.	 Mechanistic and other relevant data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
       5.	Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
       6.	 Evaluation and rationale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
   References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

General Remarks. .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 31

SOLAR AND UV RADIATION. .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 35
   1.	 Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
       1.1	 Nomenclature and units. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
       1.2	 Methods for measuring UVR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
       1.3	 Sources and exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
   2.	 Cancer in Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
       2.1	 Natural sunlight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
       2.2	 Artificial UV radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
       2.3	 UVA, UVB, and UVC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
       2.4	Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
   3.	 Cancer in Experimental Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
       3.1 Non-melanoma skin cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
       3.2	Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

                                                                                                                                                                                                                                                                                                                   v
IARC MONOGRAPHS - 100D


             3.3	Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
         4.	 Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
             4.1	 Transmission and absorption in biological tissues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
             4.2	 Genetic and related effects: consequences of UVR exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
             4.3	 Genetic susceptibility: host factors modulating the response to UV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
             4.4	 Other effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
             4.5	Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
         5.	Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
         References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

X- AND γ-RADIATION.  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 103
    1.	 Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
        1.1	 Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
        1.2	 Interactions with matter. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
        1.3	Exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
    2.	 Cancer in Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
        2.1	 Detonation of atomic bombs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
        2.2	 Fallout from nuclear weapons testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
        2.3	 Medical exposures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
        2.4	 Occupational studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
        2.5	 Environmental studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
        2.6	Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
    3.	 Cancer in Experimental Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
        3.1	 Previous evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
        3.2	 Studies published since the previous IARC Monograph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
        3.3	 Studies in adult animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
        3.4	 Prenatal exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
        3.5	 Neonatal exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
        3.6	 Parental exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
        3.7	Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
    4.	 Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
        4.1	 Radionuclides: determining the distribution of dose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
        4.2	 Mechanisms of carcinogenesis induced by all ionizing radiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
        4.3	 Mechanism of carcinogenesis of neutrons: an example of ionizing radiation. . . . . . . . . . . . . . . . . .207
        4.4 Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
    5.	Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
    References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

NEUTRON RADIATION.  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 231
  1.	 Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
  2.	 Cancer in Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
  3.	 Cancer in Experimenal Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
      3.1	Previous IARC Monograph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
      3.2	 Carcinogenicity in adult animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
      3.3	 Prenatal exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
      3.4	Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237


vi
Contents


         4.	 Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
         5.	Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
         References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

INTERNALIZED α-PARTICLE EMITTING RADIONUCLIDES .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 241
   1.	 Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
   2.	 Cancer in Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
       2.1	Radon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
       2.2	 α-Particle emitters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
   3.	 Cancer in Experimental Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
       3.1	Previous IARC Monograph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
       3.2	 Studies published since the previous IARC Monograph .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 265
       3.3	 Other studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
       3.4	Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
   4.	 Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
   5.	Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
   References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275

INTERNALIZED β-PARTICLE EMITTING RADIONUCLIDES .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 285
   1.	 Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
   2.	 Cancer in Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
       2.1	 Pure β-particle emitters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
       2.2	 Mixed β-particle emitters–radioiodines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
       2.3	Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
   3.	 Cancer in Experimental Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
       3.1	 Previous evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
       3.2	 Pure β-particle-emitting radionuclides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
       3.3	 Mixed β-particle emitting radionuclides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
       3.4	Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
   4.	 Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
   5.	Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
   References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

List of Abbreviations.  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 305

CUMULATIVE CROSS INDEX TO IARC MONOGRAPHS .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 309

List of IARC Monographs .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 343




                                                                                                                                                                                                                                                                    vii
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
NOTE TO THE READER

    The term ‘carcinogenic risk’ in the IARC Monographs series is taken to mean that an agent is
capable of causing cancer. The Monographs evaluate cancer hazards, despite the historical presence
of the word ‘risks’ in the title.
    Inclusion of an agent in the Monographs does not imply that it is a carcinogen, only that the
published data have been examined. Equally, the fact that an agent has not yet been evaluated in a
Monograph does not mean that it is not carcinogenic. Similarly, identification of cancer sites with
sufficient evidence or limited evidence in humans should not be viewed as precluding the possibility
that an agent may cause cancer at other sites.
    The evaluations of carcinogenic risk are made by international working groups of independent
scientists and are qualitative in nature. No recommendation is given for regulation or legislation.
    Anyone who is aware of published data that may alter the evaluation of the carcinogenic risk
of an agent to humans is encouraged to make this information available to the Section of IARC
Monographs, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon
Cedex 08, France, in order that the agent may be considered for re-evaluation by a future Working
Group.
    Although every effort is made to prepare the monographs as accurately as possible, mistakes may
occur. Readers are requested to communicate any errors to the Section of IARC Monographs, so that
corrections can be reported in future volumes.




                                                                                                  1
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
List of Participants

Members1


Bruce Armstrong                                               David J. Brenner (unable to attend)
    School of Public Health                                        Center for Radiological Research
    University of Sydney                                           Columbia University
    NSW 2006                                                       New York, NY 10043
    Australia                                                      USA



Keith Baverstock                                              Elisabeth Cardis
Faculty of Natural and Environmental 		                            Center for Research in Environmental 		
	Sciences                                                     	       Epidemiology (CREAL)
University of Eastern Finland                                      E-08003 Barcelona
FI-70211 Kuopio                                                    Spain
Finland




1
  Working Group Members and Invited Specialists serve in their individual capacities as scientists and not as representa-
tives of their government or any organization with which they are affiliated. Affiliations are provided for identification
purposes only. Invited specialists are marked by an asterisk.
Each participant was asked to disclose pertinent research, employment, and financial interests. Current financial
interests and research and employment interests during the past 3 years or anticipated in the future are identified here.
Minor pertinent interests are not listed and include stock valued at no more than US$10 000 overall, grants that provide
no more than 5% of the research budget of the expert’s organization and that do not support the expert’s research or
position, and consulting or speaking on matters not before a court or government agency that does not exceed 2% of
total professional time or compensation. All grants that support the expert’s research or position and all consulting or
speaking on behalf of an interested party on matters before a court or government agency are listed as significant perti-
nent interests.


                                                                                                                        3
IARC MONOGRAPHS – 100D




Adele Green2                                                   David Hoel4
    Cancer & Population Studies Group                              College of Medicine
    Queensland Institute of Medical Research                       Medical University of South Carolina
    Queensland 4029                                                Charleston, SC 29401
    Australia                                                      USA


Raymond A. Guilmette
                                                               Daniel Krewski
    Lovelace Respiratory Research Institute
    Albuquerque, NM 87108-5127                                     McLaughlin Centre for Population
    USA                                                             Health Risk Assessment
                                                                   University of Ottawa
                                                                   Ottawa, Ontario K1N 6N5
Janet Hall3                                                        Canada

    Institut Curie Research Center
    INSERM Unit 612
    University Centre                                          Mark P. Little5
    91405 Orsay                                                    Division of Epidemiology, Public Health
    France                                                          and Primary Care
                                                                   Imperial College Faculty of Medicine
                                                                   London W2 1PG
Mark A. Hill                                                       United Kingdom
Gray Institute for Radiation Oncology & 		
	Biology
University of Oxford
Oxford OX3 7DQ
United Kingdom


2
  Dr Green receives research funds (not exceeding 5% of total research support) from L’Oréal which makes products
intended to reduce the dose from solar radiation.
3
  Dr Hall’s research unit receives funds (not exceeding 5% of total research support) from Electricité de France, an elec-
tric power company.
4
  Dr Hoel is providing assistance to Exxon Corp in court cases involving personal injury claimed to be related to radia-
tion. He owns stock in Duke Energy Corp, an electric power company. His university salary is supported in part by
grants from the U.S. National Aeronautics and Space Administration (NASA) and the U.S. Department of Energy.
5
  Dr Little wrote software for the British Nuclear Group to calculate risks for workers in the nuclear industry. This
represented less than 5% of his annual total professional compensation for 2006 and 2007, when the activity ceased. He
also advised the International Epidemiology Institute (USA) and Westlakes Research Institute (UK) on epidemiological
matters. This represented less than 5% of total professional income, and work ceased in 2007 for both contracts.
New address: Radiation Epidemiology Branch, National Cancer Institute, Rockville MD, USA


4
Participants




Michael Marshall (retired)6                                   David B. Richardson10
    UK Atomic Energy Authority                                    School of Public Health
    Blewbury, Didcot                                              University of North Carolina at Chapel Hill
    Oxon OX11 9NW                                                 Chapel Hill, NC 27599-7435
    United Kingdom                                                USA


Ronald E. J. Mitchel (retired)7                               Anthony E. Riddell11
    Atomic Energy of Canada Limited                               Westlakes Scientific Consulting Ltd
    Chalk River, Ontario K0J 1J0                                  University of Central Lancashire
    Canada                                                        Cumbria CA24 3JY
                                                                  United Kingdom

Colin R. Muirhead8
                                                              Laure Sabatier
    Centre for Radiation, Chemical and 		
	      Environmental Hazards                                      Radiobiology and Oncology Unit
    Health Protection Agency                                      French Alternative Energies and Atomic 		
    Chilton, Didcot                                           	       Energy Commission
    Oxon OX11 0RQ                                                 92265 Fontenay-aux-Roses
    United Kingdom                                                France


Nicholas D. Priest9                                           Mikhail E. Sokolnikov
    Radiation Biology and Health Physics                          Southern Urals Biophysics Institute
    Atomic Energy of Canada Limited                               Ozyorsk, 456780
    Chalk River, Ontario K0J 1P0                                  Russian Federation
    Canada
6
  Dr Marshall is retired from the United Kingdom Atomic Energy Authority (UKAEA).
7
  Dr Mitchel is retired from, and continues to consult for, Atomic Energy of Canada Ltd, a Crown corporation of Canada
whose mandate is to sustain and enhance nuclear technology, to manage nuclear wastes, and to maximize return on
investment in nuclear technology. The corporation also produces more than half of the world’s medical isotopes.
8
  Dr Muirhead manages a section at the Health Protection Agency that receives partial funding from the UK Ministry of
Defence to maintain an epidemiological database of nuclear test veterans.
New address: Institute of Health and Society, Newcastle University, UK.
9
  Dr Priest is a manager at Atomic Energy of Canada Ltd, a Crown corporation of Canada whose mandate is to sustain
and enhance nuclear technology, to manage nuclear wastes, and to maximize return on investment in nuclear technol-
ogy. The corporation also produces a significant fraction of the world’s medical isotopes.
10
   Dr Richardson provided written testimony on behalf of four persons seeking compensation for diseases claimed to be
related to X-rays. He reports receiving no compensation for this case.
11
   Dr Riddell is employed by Westlakes Scientific Consulting Ltd, a consulting firm specializing in the nuclear industry.

                                                                                                                       5
IARC MONOGRAPHS – 100D




Ladislav Tomasek                                                 Andrei Karotki
     National Radiation Protection Institute                     Ausra Kesminiene
     140 00 Prague 4                                             Béatrice Lauby-Secretan (Rapporteur, 		
     Czech Republic                                         	        Cancer in Humans)
                                                                 Ferid Shannoun (WHO geneva)
                                                                 Kurt Straif (Rapporteur, Cancer in Humans)
                                                                 Isabelle Thierry-Chef
Robert L. Ullrich12
     UTMB Cancer Center
     University of Texas Medical Branch                     Post-meeting Scientific Assistance
     Galveston, TX 77555-1048
     USA                                                         Farhad Islami


                                                            Administrative Assistance
IARC Secretariat
                                                                 Sandrine Egraz
  Philippe Autier                                                Michel Javin
  Robert Baan (Co-Responsible Officer;                           Brigitte Kajo
  Rapporteur, Mechanistic and Other Relevant	                    Helene Lorenzen-Augros
	Data)                                                           Karine Racinoux
  Lamia Benbrahim-Tallaa (Rapporteur,		
	     Cancer in Experimental Animals)
  Véronique Bouvard (Rapporteur, 			                        Reproduction of Graphics
	     Mechanistic and Other Relevant Data)
  Rafael Carel (Visiting Scientist)                              Arthur Bouvard
  Vincent Cogliano (Head of Programme)
  Emilie van Deventer (WHO geneva)
  Jean-François Doré (Visiting Scientist)
  Fatiha El Ghissassi (Responsible
                                                            Production Team
  	 Officer; Rapporteur, Mechanistic and
  	    Other Relevant Data)                                      Elisabeth Elbers
  Crystal Freeman (Rapporteur, Cancer in		                       Anne-Sophie Hameau
	Humans)                                                         Sylvia Moutinho
  Laurent Galichet (Editor)                                      Dorothy Russell
  Yann Grosse (Rapporteur, Cancer in		
	     Experimental Animals)
  Neela Guha (Rapporteur, Cancer in Humans)

12
  Dr Ullrich provided assistance to Raytheon Co in a court case involving thyroid and kidney cancer claimed to be
related to X-rays.


6
PREAMBLE
The Preamble to the IARC Monographs describes the objective and scope of the programme,
the scientific principles and procedures used in developing a Monograph, the types of
evidence considered and the scientific criteria that guide the evaluations. The Preamble
should be consulted when reading a Monograph or list of evaluations.



A.	 GENERAL PRINCIPLES AND                          risk of chemicals to man, which became the ini-
    PROCEDURES                                      tial title of the series.
                                                        In the succeeding years, the scope of the pro-
                                                    gramme broadened as Monographs were devel-
1.	Background                                       oped for groups of related chemicals, complex
    Soon after IARC was established in 1965, it     mixtures, occupational exposures, physical and
received frequent requests for advice on the car-   biological agents and lifestyle factors. In 1988,
cinogenic risk of chemicals, including requests     the phrase ‘of chemicals’ was dropped from
for lists of known and suspected human carcino-     the title, which assumed its present form, IARC
gens. It was clear that it would not be a simple    Monographs on the Evaluation of Carcinogenic
task to summarize adequately the complexity of      Risks to Humans.
the information that was available, and IARC            Through the Monographs programme, IARC
began to consider means of obtaining interna-       seeks to identify the causes of human cancer. This
tional expert opinion on this topic. In 1970, the   is the first step in cancer prevention, which is
IARC Advisory Committee on Environmental            needed as much today as when IARC was estab-
Carcinogenesis recommended ‘...that a com-          lished. The global burden of cancer is high and
pendium on carcinogenic chemicals be pre-           continues to increase: the annual number of new
pared by experts. The biological activity and       cases was estimated at 10.1 million in 2000 and
evaluation of practical importance to public        is expected to reach 15 million by 2020 (Stewart
health should be referenced and documented.’        & Kleihues, 2003). With current trends in demo-
The IARC Governing Council adopted a resolu-        graphics and exposure, the cancer burden has
tion concerning the role of IARC in providing       been shifting from high-resource countries to
government authorities with expert, independ-       low- and medium-resource countries. As a result
ent, scientific opinion on environmental carcino-   of Monographs evaluations, national health agen-
genesis. As one means to that end, the Governing    cies have been able, on scientific grounds, to take
Council recommended that IARC should prepare        measures to reduce human exposure to carcino-
monographs on the evaluation of carcinogenic        gens in the workplace and in the environment.



                                                                                                     7
IARC MONOGRAPHS – 100D


    The criteria established in 1971 to evaluate       causation of, and susceptibility to, malignant
carcinogenic risks to humans were adopted by the       disease become more fully understood.
Working Groups whose deliberations resulted in              A cancer ‘hazard’ is an agent that is capable
the first 16 volumes of the Monographs series.         of causing cancer under some circumstances,
Those criteria were subsequently updated by fur-       while a cancer ‘risk’ is an estimate of the carci-
ther ad hoc Advisory Groups (IARC, 1977, 1978,         nogenic effects expected from exposure to a can-
1979, 1982, 1983, 1987, 1988, 1991; Vainio et al.,     cer hazard. The Monographs are an exercise in
1992; IARC, 2005, 2006).                               evaluating cancer hazards, despite the historical
    The Preamble is primarily a statement of sci-      presence of the word ‘risks’ in the title. The dis-
entific principles, rather than a specification of     tinction between hazard and risk is important,
working procedures. The procedures through             and the Monographs identify cancer hazards
which a Working Group implements these prin-           even when risks are very low at current exposure
ciples are not specified in detail. They usually       levels, because new uses or unforeseen exposures
involve operations that have been established          could engender risks that are significantly higher.
as being effective during previous Monograph                In the Monographs, an agent is termed ‘car-
meetings but remain, predominantly, the pre-           cinogenic’ if it is capable of increasing the inci-
rogative of each individual Working Group.             dence of malignant neoplasms, reducing their
                                                       latency, or increasing their severity or multiplic-
                                                       ity. The induction of benign neoplasms may in
2.	 Objective and scope                                some circumstances (see Part B, Section 3a) con-
    The objective of the programme is to pre-          tribute to the judgement that the agent is carci-
pare, with the help of international Working           nogenic. The terms ‘neoplasm’ and ‘tumour’ are
Groups of experts, and to publish in the form of       used interchangeably.
Monographs, critical reviews and evaluations of             The Preamble continues the previous usage
evidence on the carcinogenicity of a wide range        of the phrase ‘strength of evidence’ as a matter
of human exposures. The Monographs repre-              of historical continuity, although it should be
sent the first step in carcinogen risk assessment,     understood that Monographs evaluations con-
which involves examination of all relevant infor-      sider studies that support a finding of a cancer
mation to assess the strength of the available evi-    hazard as well as studies that do not.
dence that an agent could alter the age-specific            Some epidemiological and experimental
incidence of cancer in humans. The Monographs          studies indicate that different agents may act at
may also indicate where additional research            different stages in the carcinogenic process, and
efforts are needed, specifically when data imme-       several different mechanisms may be involved.
diately relevant to an evaluation are not available.   The aim of the Monographs has been, from their
    In this Preamble, the term ‘agent’ refers to       inception, to evaluate evidence of carcinogenic-
any entity or circumstance that is subject to          ity at any stage in the carcinogenesis process,
evaluation in a Monograph. As the scope of the         independently of the underlying mechanisms.
programme has broadened, categories of agents          Information on mechanisms may, however, be
now include specific chemicals, groups of related      used in making the overall evaluation (IARC,
chemicals, complex mixtures, occupational or           1991; Vainio et al., 1992; IARC, 2005, 2006; see
environmental exposures, cultural or behav-            also Part B, Sections 4 and 6). As mechanisms
ioural practices, biological organisms and physi-      of carcinogenesis are elucidated, IARC convenes
cal agents. This list of categories may expand as      international scientific conferences to determine
                                                       whether a broad-based consensus has emerged

8
Preamble


on how specific mechanistic data can be used            exposure and (b) there is some evidence or sus-
in an evaluation of human carcinogenicity. The          picion of carcinogenicity. Mixed exposures may
results of such conferences are reported in IARC        occur in occupational and environmental set-
Scientific Publications, which, as long as they still   tings and as a result of individual and cultural
reflect the current state of scientific knowledge,      habits (such as tobacco smoking and dietary
may guide subsequent Working Groups.                    practices). Chemical analogues and compounds
    Although the Monographs have emphasized             with biological or physical characteristics simi-
hazard identification, important issues may also        lar to those of suspected carcinogens may also
involve dose–response assessment. In many               be considered, even in the absence of data on a
cases, the same epidemiological and experimen-          possible carcinogenic effect in humans or experi-
tal studies used to evaluate a cancer hazard can        mental animals.
also be used to estimate a dose–response relation-          The scientific literature is surveyed for pub-
ship. A Monograph may undertake to estimate             lished data relevant to an assessment of carci-
dose–response relationships within the range            nogenicity. Ad hoc Advisory Groups convened
of the available epidemiological data, or it may        by IARC in 1984, 1989, 1991, 1993, 1998 and
compare the dose–response information from              2003 made recommendations as to which
experimental and epidemiological studies. In            agents should be evaluated in the Monographs
some cases, a subsequent publication may be pre-        series. Recent recommendations are avail-
pared by a separate Working Group with exper-           able on the Monographs programme web site
tise in quantitative dose–response assessment.          (http://monographs.iarc.fr). IARC may schedule
    The Monographs are used by national and             other agents for review as it becomes aware of
international authorities to make risk assess-          new scientific information or as national health
ments, formulate decisions concerning preventive        agencies identify an urgent public health need
measures, provide effective cancer control pro-         related to cancer.
grammes and decide among alternative options                As significant new data become available
for public health decisions. The evaluations of         on an agent for which a Monograph exists, a re-
IARC Working Groups are scientific, qualita-            evaluation may be made at a subsequent meeting,
tive judgements on the evidence for or against          and a new Monograph published. In some cases it
carcinogenicity provided by the available data.         may be appropriate to review only the data pub-
These evaluations represent only one part of the        lished since a prior evaluation. This can be useful
body of information on which public health deci-        for updating a database, reviewing new data to
sions may be based. Public health options vary          resolve a previously open question or identifying
from one situation to another and from country          new tumour sites associated with a carcinogenic
to country and relate to many factors, including        agent. Major changes in an evaluation (e.g. a new
different socioeconomic and national priorities.        classification in Group 1 or a determination that a
Therefore, no recommendation is given with              mechanism does not operate in humans, see Part
regard to regulation or legislation, which are          B, Section 6) are more appropriately addressed by
the responsibility of individual governments or         a full review.
other international organizations.
                                                        4.	 Data for the Monographs
3.	 Selection of agents for review
                                                           Each Monograph reviews all pertinent epi-
   Agents are selected for review on the basis of       demiological studies and cancer bioassays in
two main criteria: (a) there is evidence of human       experimental animals. Those judged inadequate

                                                                                                         9
IARC MONOGRAPHS – 100D


or irrelevant to the evaluation may be cited but      (a) The Working Group
not summarized. If a group of similar studies is
not reviewed, the reasons are indicated.                  The Working Group is responsible for the crit-
    Mechanistic and other relevant data are also      ical reviews and evaluations that are developed
reviewed. A Monograph does not necessarily            during the meeting. The tasks of Working Group
cite all the mechanistic literature concerning        Members are: (i) to ascertain that all appropriate
the agent being evaluated (see Part B, Section        data have been collected; (ii) to select the data rel-
4). Only those data considered by the Working         evant for the evaluation on the basis of scientific
Group to be relevant to making the evaluation         merit; (iii) to prepare accurate summaries of the
are included.                                         data to enable the reader to follow the reasoning
    With regard to epidemiological studies, can-      of the Working Group; (iv) to evaluate the results
cer bioassays, and mechanistic and other relevant     of epidemiological and experimental studies on
data, only reports that have been published or        cancer; (v) to evaluate data relevant to the under-
accepted for publication in the openly available      standing of mechanisms of carcinogenesis; and
scientific literature are reviewed. The same publi-   (vi) to make an overall evaluation of the carci-
cation requirement applies to studies originating     nogenicity of the exposure to humans. Working
from IARC, including meta-analyses or pooled          Group Members generally have published sig-
analyses commissioned by IARC in advance of a         nificant research related to the carcinogenicity of
meeting (see Part B, Section 2c). Data from gov-      the agents being reviewed, and IARC uses litera-
ernment agency reports that are publicly avail-       ture searches to identify most experts. Working
able are also considered. Exceptionally, doctoral     Group Members are selected on the basis of (a)
theses and other material that are in their final     knowledge and experience and (b) absence of real
form and publicly available may be reviewed.          or apparent conflicts of interests. Consideration
    Exposure data and other information on an         is also given to demographic diversity and bal-
agent under consideration are also reviewed. In       ance of scientific findings and views.
the sections on chemical and physical proper-
ties, on analysis, on production and use and on       (b) Invited Specialists
occurrence, published and unpublished sources             Invited Specialists are experts who also have
of information may be considered.                     critical knowledge and experience but have
    Inclusion of a study does not imply accept-       a real or apparent conflict of interests. These
ance of the adequacy of the study design or of        experts are invited when necessary to assist in
the analysis and interpretation of the results, and   the Working Group by contributing their unique
limitations are clearly outlined in square brack-     knowledge and experience during subgroup and
ets at the end of each study description (see Part    plenary discussions. They may also contribute
B). The reasons for not giving further considera-     text on non-influential issues in the section on
tion to an individual study also are indicated in     exposure, such as a general description of data
the square brackets.                                  on production and use (see Part B, Section 1).
                                                      Invited Specialists do not serve as meeting chair
5.	 Meeting participants                              or subgroup chair, draft text that pertains to the
                                                      description or interpretation of cancer data, or
    Five categories of participant can be present     participate in the evaluations.
at Monograph meetings.



10
Preamble


(c) Representatives of national and                   whether there is a conflict that warrants some
      international health agencies                   limitation on participation. The declarations are
                                                      updated and reviewed again at the opening of
    Representatives of national and interna-          the meeting. Interests related to the subject of
tional health agencies often attend meetings          the meeting are disclosed to the meeting par-
because their agencies sponsor the programme          ticipants and in the published volume (Cogliano
or are interested in the subject of a meeting.        et al., 2004).
Representatives do not serve as meeting chair or           The names and principal affiliations of par-
subgroup chair, draft any part of a Monograph,        ticipants are available on the Monographs pro-
or participate in the evaluations.                    gramme web site (http://monographs.iarc.fr)
                                                      approximately two months before each meeting.
(d) Observers with relevant scientific
                                                      It is not acceptable for Observers or third parties
     credentials                                      to contact other participants before a meeting or
    Observers with relevant scientific credentials    to lobby them at any time. Meeting participants
may be admitted to a meeting by IARC in limited       are asked to report all such contacts to IARC
numbers. Attention will be given to achieving a       (Cogliano et al., 2005).
balance of Observers from constituencies with              All participants are listed, with their princi-
differing perspectives. They are invited to observe   pal affiliations, at the beginning of each volume.
the meeting and should not attempt to influence       Each participant who is a Member of a Working
it. Observers do not serve as meeting chair or        Group serves as an individual scientist and not as
subgroup chair, draft any part of a Monograph,        a representative of any organization, government
or participate in the evaluations. At the meeting,    or industry.
the meeting chair and subgroup chairs may grant
Observers an opportunity to speak, generally          6.	 Working procedures
after they have observed a discussion. Observers
agree to respect the Guidelines for Observers             A separate Working Group is responsible for
at IARC Monographs meetings (available at             developing each volume of Monographs. A vol-
http://monographs.iarc.fr).                           ume contains one or more Monographs, which
                                                      can cover either a single agent or several related
(e) The IARC Secretariat                              agents. Approximately one year in advance of the
    The IARC Secretariat consists of scientists       meeting of a Working Group, the agents to be
who are designated by IARC and who have rel-          reviewed are announced on the Monographs pro-
evant expertise. They serve as rapporteurs and        gramme web site (http://monographs.iarc.fr) and
participate in all discussions. When requested by     participants are selected by IARC staff in consul-
the meeting chair or subgroup chair, they may         tation with other experts. Subsequently, relevant
also draft text or prepare tables and analyses.       biological and epidemiological data are collected
    Before an invitation is extended, each poten-     by IARC from recognized sources of information
tial participant, including the IARC Secretariat,     on carcinogenesis, including data storage and
completes the WHO Declaration of Interests to         retrieval systems such as PubMed. Meeting par-
report financial interests, employment and con-       ticipants who are asked to prepare preliminary
sulting, and individual and institutional research    working papers for specific sections are expected
support related to the subject of the meeting.        to supplement the IARC literature searches with
IARC assesses these interests to determine            their own searches.


                                                                                                       11
IARC MONOGRAPHS – 100D


    For most chemicals and some complex mix-          the entire volume is the joint product of the
tures, the major collection of data and the prep-     Working Group, and there are no individually
aration of working papers for the sections on         authored sections.
chemical and physical properties, on analysis, on         IARC Working Groups strive to achieve a
production and use, and on occurrence are car-        consensus evaluation. Consensus reflects broad
ried out under a separate contract funded by the      agreement among Working Group Members, but
US National Cancer Institute. Industrial associ-      not necessarily unanimity. The chair may elect
ations, labour unions and other knowledgeable         to poll Working Group Members to determine
organizations may be asked to provide input to        the diversity of scientific opinion on issues where
the sections on production and use, although          consensus is not readily apparent.
this involvement is not required as a general rule.       After the meeting, the master copy is verified
Information on production and trade is obtained       by consulting the original literature, edited and
from governmental, trade and market research          prepared for publication. The aim is to publish
publications and, in some cases, by direct con-       the volume within six months of the Working
tact with industries. Separate production data        Group meeting. A summary of the outcome is
on some agents may not be available for a vari-       available on the Monographs programme web
ety of reasons (e.g. not collected or made public     site soon after the meeting.
in all producing countries, production is small).
Information on uses may be obtained from pub-
lished sources but is often complemented by           B.	 SCIENTIFIC REVIEW AND
direct contact with manufacturers. Efforts are            EVALUATION
made to supplement this information with data
from other national and international sources.            The available studies are summarized by the
    Six months before the meeting, the mate-          Working Group, with particular regard to the
rial obtained is sent to meeting participants to      qualitative aspects discussed below. In general,
prepare preliminary working papers. The work-         numerical findings are indicated as they appear
ing papers are compiled by IARC staff and sent,       in the original report; units are converted when
before the meeting, to Working Group Members          necessary for easier comparison. The Working
and Invited Specialists for review.                   Group may conduct additional analyses of the
    The Working Group meets at IARC for seven         published data and use them in their assessment
to eight days to discuss and finalize the texts       of the evidence; the results of such supplemen-
and to formulate the evaluations. The objectives      tary analyses are given in square brackets. When
of the meeting are peer review and consensus.         an important aspect of a study that directly
During the first few days, four subgroups (cov-       impinges on its interpretation should be brought
ering exposure data, cancer in humans, cancer         to the attention of the reader, a Working Group
in experimental animals, and mechanistic and          comment is given in square brackets.
other relevant data) review the working papers,           The scope of the IARC Monographs pro-
develop a joint subgroup draft and write sum-         gramme has expanded beyond chemicals to
maries. Care is taken to ensure that each study       include complex mixtures, occupational expo-
summary is written or reviewed by someone             sures, physical and biological agents, lifestyle
not associated with the study being considered.       factors and other potentially carcinogenic expo-
During the last few days, the Working Group           sures. Over time, the structure of a Monograph
meets in plenary session to review the subgroup       has evolved to include the following sections:
drafts and develop the evaluations. As a result,

12
Preamble


     Exposure data                                     which the agent being evaluated is only one of
     Studies of cancer in humans                       the ingredients.
     Studies of cancer in experimental animals             For biological agents, taxonomy, struc-
     Mechanistic and other relevant data               ture and biology are described, and the degree
     Summary                                           of variability is indicated. Mode of replication,
     Evaluation and rationale                          life cycle, target cells, persistence, latency, host
    In addition, a section of General Remarks at       response and clinical disease other than cancer
the front of the volume discusses the reasons the      are also presented.
agents were scheduled for evaluation and some              For physical agents that are forms of radia-
key issues the Working Group encountered dur-          tion, energy and range of the radiation are
ing the meeting.                                       included. For foreign bodies, fibres and respir-
    This part of the Preamble discusses the types      able particles, size range and relative dimensions
of evidence considered and summarized in each          are indicated.
section of a Monograph, followed by the scientific         For agents such as mixtures, drugs or lifestyle
criteria that guide the evaluations.                   factors, a description of the agent, including its
                                                       composition, is given.
                                                           Whenever appropriate, other information,
1.	 Exposure data                                      such as historical perspectives or the description
    Each Monograph includes general informa-           of an industry or habit, may be included.
tion on the agent: this information may vary sub-
stantially between agents and must be adapted          (b)	 Analysis and detection
accordingly. Also included is information on
                                                           An overview of methods of analysis and
production and use (when appropriate), meth-
                                                       detection of the agent is presented, including
ods of analysis and detection, occurrence, and
                                                       their sensitivity, specificity and reproducibility.
sources and routes of human occupational and
                                                       Methods widely used for regulatory purposes
environmental exposures. Depending on the
                                                       are emphasized. Methods for monitoring human
agent, regulations and guidelines for use may be
                                                       exposure are also given. No critical evaluation
presented.
                                                       or recommendation of any method is meant or
                                                       implied.
(a)	 General information on the agent
    For chemical agents, sections on chemical          (c)	   Production and use
and physical data are included: the Chemical
                                                           The dates of first synthesis and of first com-
Abstracts Service Registry Number, the latest pri-
                                                       mercial production of a chemical, mixture or
mary name and the IUPAC systematic name are
                                                       other agent are provided when available; for
recorded; other synonyms are given, but the list
                                                       agents that do not occur naturally, this informa-
is not necessarily comprehensive. Information
                                                       tion may allow a reasonable estimate to be made
on chemical and physical properties that are rel-
                                                       of the date before which no human exposure to
evant to identification, occurrence and biologi-
                                                       the agent could have occurred. The dates of first
cal activity is included. A description of technical
                                                       reported occurrence of an exposure are also pro-
products of chemicals includes trade names, rel-
                                                       vided when available. In addition, methods of
evant specifications and available information
                                                       synthesis used in past and present commercial
on composition and impurities. Some of the
                                                       production and different methods of production,
trade names given may be those of mixtures in

                                                                                                        13
IARC MONOGRAPHS – 100D


which may give rise to different impurities, are       place. For biological agents, the epidemiology of
described.                                             infection is described.
    The countries where companies report pro-
duction of the agent, and the number of compa-         (e)	   Regulations and guidelines
nies in each country, are identified. Available data
on production, international trade and uses are            Statements concerning regulations and
obtained for representative regions. It should not,    guidelines (e.g. occupational exposure limits,
however, be inferred that those areas or nations       maximal levels permitted in foods and water,
are necessarily the sole or major sources or users     pesticide registrations) are included, but they
of the agent. Some identified uses may not be          may not reflect the most recent situation, since
current or major applications, and the coverage        such limits are continuously reviewed and modi-
is not necessarily comprehensive. In the case of       fied. The absence of information on regulatory
drugs, mention of their therapeutic uses does not      status for a country should not be taken to imply
necessarily represent current practice nor does it     that that country does not have regulations with
imply judgement as to their therapeutic efficacy.      regard to the exposure. For biological agents, leg-
                                                       islation and control, including vaccination and
                                                       therapy, are described.
(d)	 Occurrence and exposure
    Information on the occurrence of an agent in
the environment is obtained from data derived
                                                       2.	 Studies of cancer in humans
from the monitoring and surveillance of levels             This section includes all pertinent epidemio-
in occupational environments, air, water, soil,        logical studies (see Part A, Section 4). Studies of
plants, foods and animal and human tissues.            biomarkers are included when they are relevant
When available, data on the generation, per-           to an evaluation of carcinogenicity to humans.
sistence and bioaccumulation of the agent are
also included. Such data may be available from         (a)	 Types of study considered
national databases.
    Data that indicate the extent of past and pre-         Several types of epidemiological study con-
sent human exposure, the sources of exposure,          tribute to the assessment of carcinogenicity in
the people most likely to be exposed and the fac-      humans — cohort studies, case–control studies,
tors that contribute to the exposure are reported.     correlation (or ecological) studies and interven-
Information is presented on the range of human         tion studies. Rarely, results from randomized tri-
exposure, including occupational and environ-          als may be available. Case reports and case series
mental exposures. This includes relevant findings      of cancer in humans may also be reviewed.
from both developed and developing countries.              Cohort and case–control studies relate indi-
Some of these data are not distributed widely and      vidual exposures under study to the occurrence of
may be available from government reports and           cancer in individuals and provide an estimate of
other sources. In the case of mixtures, indus-         effect (such as relative risk) as the main measure
tries, occupations or processes, information is        of association. Intervention studies may provide
given about all agents known to be present. For        strong evidence for making causal inferences, as
processes, industries and occupations, a histori-      exemplified by cessation of smoking and the sub-
cal description is also given, noting variations in    sequent decrease in risk for lung cancer.
chemical composition, physical properties and              In correlation studies, the units of inves-
levels of occupational exposure with date and          tigation are usually whole populations (e.g. in


14
Preamble


particular geographical areas or at particular         Bias is the effect of factors in study design or
times), and cancer frequency is related to a sum-      execution that lead erroneously to a stronger or
mary measure of the exposure of the population         weaker association than in fact exists between an
to the agent under study. In correlation studies,      agent and disease. Confounding is a form of bias
individual exposure is not documented, which           that occurs when the relationship with disease is
renders this kind of study more prone to con-          made to appear stronger or weaker than it truly is
founding. In some circumstances, however, cor-         as a result of an association between the apparent
relation studies may be more informative than          causal factor and another factor that is associated
analytical study designs (see, for example, the        with either an increase or decrease in the inci-
Monograph on arsenic in drinking-water; IARC,          dence of the disease. The role of chance is related
2004).                                                 to biological variability and the influence of sam-
    In some instances, case reports and case series    ple size on the precision of estimates of effect.
have provided important information about the              In evaluating the extent to which these fac-
carcinogenicity of an agent. These types of study      tors have been minimized in an individual study,
generally arise from a suspicion, based on clinical    consideration is given to several aspects of design
experience, that the concurrence of two events —       and analysis as described in the report of the
that is, a particular exposure and occurrence of       study. For example, when suspicion of carcino-
a cancer — has happened rather more frequently         genicity arises largely from a single small study,
than would be expected by chance. Case reports         careful consideration is given when interpreting
and case series usually lack complete ascertain-       subsequent studies that included these data in an
ment of cases in any population, definition or         enlarged population. Most of these considera-
enumeration of the population at risk and esti-        tions apply equally to case–control, cohort and
mation of the expected number of cases in the          correlation studies. Lack of clarity of any of these
absence of exposure.                                   aspects in the reporting of a study can decrease
    The uncertainties that surround the inter-         its credibility and the weight given to it in the
pretation of case reports, case series and corre-      final evaluation of the exposure.
lation studies make them inadequate, except in             First, the study population, disease (or dis-
rare instances, to form the sole basis for inferring   eases) and exposure should have been well
a causal relationship. When taken together with        defined by the authors. Cases of disease in the
case–control and cohort studies, however, these        study population should have been identified in
types of study may add materially to the judge-        a way that was independent of the exposure of
ment that a causal relationship exists.                interest, and exposure should have been assessed
    Epidemiological studies of benign neo-             in a way that was not related to disease status.
plasms, presumed preneoplastic lesions and                 Second, the authors should have taken into
other end-points thought to be relevant to cancer      account — in the study design and analysis —
are also reviewed. They may, in some instances,        other variables that can influence the risk of dis-
strengthen inferences drawn from studies of            ease and may have been related to the exposure
cancer itself.                                         of interest. Potential confounding by such vari-
                                                       ables should have been dealt with either in the
(b)	 Quality of studies considered                     design of the study, such as by matching, or in
                                                       the analysis, by statistical adjustment. In cohort
    It is necessary to take into account the pos-      studies, comparisons with local rates of disease
sible roles of bias, confounding and chance in         may or may not be more appropriate than those
the interpretation of epidemiological studies.         with national rates. Internal comparisons of

                                                                                                        15
IARC MONOGRAPHS – 100D


frequency of disease among individuals at differ-          The advantages of combined analyses are
ent levels of exposure are also desirable in cohort    increased precision due to increased sample size
studies, since they minimize the potential for         and the opportunity to explore potential con-
confounding related to the difference in risk fac-     founders, interactions and modifying effects
tors between an external reference group and the       that may explain heterogeneity among studies in
study population.                                      more detail. A disadvantage of combined analy-
    Third, the authors should have reported the        ses is the possible lack of compatibility of data
basic data on which the conclusions are founded,       from various studies due to differences in sub-
even if sophisticated statistical analyses were        ject recruitment, procedures of data collection,
employed. At the very least, they should have          methods of measurement and effects of unmeas-
given the numbers of exposed and unexposed             ured co-variates that may differ among studies.
cases and controls in a case–control study and         Despite these limitations, well conducted com-
the numbers of cases observed and expected in          bined analyses may provide a firmer basis than
a cohort study. Further tabulations by time since      individual studies for drawing conclusions about
exposure began and other temporal factors are          the potential carcinogenicity of agents.
also important. In a cohort study, data on all             IARC may commission a meta-analysis or
cancer sites and all causes of death should have       pooled analysis that is pertinent to a particular
been given, to reveal the possibility of reporting     Monograph (see Part A, Section 4). Additionally,
bias. In a case–control study, the effects of inves-   as a means of gaining insight from the results of
tigated factors other than the exposure of interest    multiple individual studies, ad hoc calculations
should have been reported.                             that combine data from different studies may
    Finally, the statistical methods used to obtain    be conducted by the Working Group during
estimates of relative risk, absolute rates of can-     the course of a Monograph meeting. The results
cer, confidence intervals and significance tests,      of such original calculations, which would be
and to adjust for confounding should have been         specified in the text by presentation in square
clearly stated by the authors. These methods have      brackets, might involve updates of previously
been reviewed for case–control studies (Breslow        conducted analyses that incorporate the results
& Day, 1980) and for cohort studies (Breslow &         of more recent studies or de-novo analyses.
Day, 1987).                                            Irrespective of the source of data for the meta-
                                                       analyses and pooled analyses, it is important that
(c)	   Meta-analyses and pooled analyses               the same criteria for data quality be applied as
                                                       those that would be applied to individual studies
    Independent epidemiological studies of the         and to ensure also that sources of heterogeneity
same agent may lead to results that are difficult      between studies be taken into account.
to interpret. Combined analyses of data from
multiple studies are a means of resolving this
                                                       (d)	 Temporal effects
ambiguity, and well conducted analyses can be
considered. There are two types of combined                Detailed analyses of both relative and abso-
analysis. The first involves combining summary         lute risks in relation to temporal variables, such
statistics such as relative risks from individual      as age at first exposure, time since first exposure,
studies (meta-analysis) and the second involves a      duration of exposure, cumulative exposure, peak
pooled analysis of the raw data from the individ-      exposure (when appropriate) and time since
ual studies (pooled analysis) (Greenland, 1998).       cessation of exposure, are reviewed and sum-
                                                       marized when available. Analyses of temporal

16
Preamble


relationships may be useful in making causal                of the agent being evaluated, data on this pheno-
inferences. In addition, such analyses may sug-             type may be useful in making causal inferences.
gest whether a carcinogen acts early or late in the
process of carcinogenesis, although, at best, they          (f)	   Criteria for causality
allow only indirect inferences about mechanisms
of carcinogenesis.                                              After the quality of individual epidemiologi-
                                                            cal studies of cancer has been summarized and
                                                            assessed, a judgement is made concerning the
(e)	   Use of biomarkers in epidemiological
                                                            strength of evidence that the agent in question
       studies                                              is carcinogenic to humans. In making its judge-
    Biomarkers indicate molecular, cellular or              ment, the Working Group considers several crite-
other biological changes and are increasingly               ria for causality (Hill, 1965). A strong association
used in epidemiological studies for various pur-            (e.g. a large relative risk) is more likely to indicate
poses (IARC, 1991; Vainio et al., 1992; Toniolo             causality than a weak association, although it is
et al., 1997; Vineis et al., 1999; Buffler et al., 2004).   recognized that estimates of effect of small mag-
These may include evidence of exposure, of early            nitude do not imply lack of causality and may be
effects, of cellular, tissue or organism responses,         important if the disease or exposure is common.
of individual susceptibility or host responses,             Associations that are replicated in several studies
and inference of a mechanism (see Part B, Section           of the same design or that use different epidemi-
4b). This is a rapidly evolving field that encom-           ological approaches or under different circum-
passes developments in genomics, epigenomics                stances of exposure are more likely to represent
and other emerging technologies.                            a causal relationship than isolated observations
    Molecular epidemiological data that identify            from single studies. If there are inconsistent
associations between genetic polymorphisms                  results among investigations, possible reasons
and interindividual differences in susceptibility           are sought (such as differences in exposure), and
to the agent(s) being evaluated may contribute              results of studies that are judged to be of high
to the identification of carcinogenic hazards to            quality are given more weight than those of stud-
humans. If the polymorphism has been demon-                 ies that are judged to be methodologically less
strated experimentally to modify the functional             sound.
activity of the gene product in a manner that is                If the risk increases with the exposure, this is
consistent with increased susceptibility, these             considered to be a strong indication of causality,
data may be useful in making causal inferences.             although the absence of a graded response is not
Similarly, molecular epidemiological studies that           necessarily evidence against a causal relation-
measure cell functions, enzymes or metabolites              ship. The demonstration of a decline in risk after
that are thought to be the basis of susceptibil-            cessation of or reduction in exposure in indi-
ity may provide evidence that reinforces biologi-           viduals or in whole populations also supports a
cal plausibility. It should be noted, however, that         causal interpretation of the findings.
when data on genetic susceptibility originate                   Several scenarios may increase confidence in
from multiple comparisons that arise from sub-              a causal relationship. On the one hand, an agent
group analyses, this can generate false-positive            may be specific in causing tumours at one site or
results and inconsistencies across studies, and             of one morphological type. On the other, carci-
such data therefore require careful evaluation.             nogenicity may be evident through the causation
If the known phenotype of a genetic polymor-                of multiple tumour types. Temporality, precision
phism can explain the carcinogenic mechanism                of estimates of effect, biological plausibility and

                                                                                                                17
IARC MONOGRAPHS – 100D


coherence of the overall database are consid-           3.	 Studies of cancer in experimental
ered. Data on biomarkers may be employed in                 animals
an assessment of the biological plausibility of epi-
demiological observations.                                   All known human carcinogens that have been
     Although rarely available, results from rand-      studied adequately for carcinogenicity in experi-
omized trials that show different rates of cancer       mental animals have produced positive results
among exposed and unexposed individuals pro-            in one or more animal species (Wilbourn et al.,
vide particularly strong evidence for causality.        1986; Tomatis et al., 1989). For several agents
     When several epidemiological studies show          (e.g. aflatoxins, diethylstilbestrol, solar radiation,
little or no indication of an association between       vinyl chloride), carcinogenicity in experimen-
an exposure and cancer, a judgement may be made         tal animals was established or highly suspected
that, in the aggregate, they show evidence of lack      before epidemiological studies confirmed their
of carcinogenicity. Such a judgement requires           carcinogenicity in humans (Vainio et al., 1995).
first that the studies meet, to a sufficient degree,    Although this association cannot establish that
the standards of design and analysis described          all agents that cause cancer in experimental ani-
above. Specifically, the possibility that bias, con-    mals also cause cancer in humans, it is biologically
founding or misclassification of exposure or out-       plausible that agents for which there is sufficient
come could explain the observed results should          evidence of carcinogenicity in experimental ani-
be considered and excluded with reasonable cer-         mals (see Part B, Section 6b) also present a car-
tainty. In addition, all studies that are judged to     cinogenic hazard to humans. Accordingly, in
be methodologically sound should (a) be con-            the absence of additional scientific information,
sistent with an estimate of effect of unity for any     these agents are considered to pose a carcinogenic
observed level of exposure, (b) when considered         hazard to humans. Examples of additional scien-
together, provide a pooled estimate of relative         tific information are data that demonstrate that
risk that is at or near to unity, and (c) have a nar-   a given agent causes cancer in animals through
row confidence interval, due to sufficient popula-      a species-specific mechanism that does not oper-
tion size. Moreover, no individual study nor the        ate in humans or data that demonstrate that the
pooled results of all the studies should show any       mechanism in experimental animals also oper-
consistent tendency that the relative risk of can-      ates in humans (see Part B, Section 6).
cer increases with increasing level of exposure.             Consideration is given to all available long-
It is important to note that evidence of lack of        term studies of cancer in experimental animals
carcinogenicity obtained from several epidemio-         with the agent under review (see Part A, Section
logical studies can apply only to the type(s) of        4). In all experimental settings, the nature and
cancer studied, to the dose levels reported, and to     extent of impurities or contaminants present in
the intervals between first exposure and disease        the agent being evaluated are given when avail-
onset observed in these studies. Experience with        able. Animal species, strain (including genetic
human cancer indicates that the period from first       background where applicable), sex, numbers per
exposure to the development of clinical cancer is       group, age at start of treatment, route of expo-
sometimes longer than 20 years; latent periods          sure, dose levels, duration of exposure, survival
substantially shorter than 30 years cannot pro-         and information on tumours (incidence, latency,
vide evidence for lack of carcinogenicity.              severity or multiplicity of neoplasms or prene-
                                                        oplastic lesions) are reported. Those studies in
                                                        experimental animals that are judged to be irrel-
                                                        evant to the evaluation or judged to be inadequate

18
Preamble


(e.g. too short a duration, too few animals, poor      (a)	 Qualitative aspects
survival; see below) may be omitted. Guidelines
for conducting long-term carcinogenicity exper-             An assessment of carcinogenicity involves
iments have been published (e.g. OECD, 2002).          several considerations of qualitative impor-
    Other studies considered may include: exper-       tance, including (i) the experimental conditions
iments in which the agent was administered in          under which the test was performed, including
the presence of factors that modify carcinogenic       route, schedule and duration of exposure, spe-
effects (e.g. initiation–promotion studies, co-        cies, strain (including genetic background where
carcinogenicity studies and studies in geneti-         applicable), sex, age and duration of follow-up;
cally modified animals); studies in which the          (ii) the consistency of the results, for example,
end-point was not cancer but a defined precan-         across species and target organ(s); (iii) the spec-
cerous lesion; experiments on the carcinogenic-        trum of neoplastic response, from preneoplastic
ity of known metabolites and derivatives; and          lesions and benign tumours to malignant neo-
studies of cancer in non-laboratory animals (e.g.      plasms; and (iv) the possible role of modifying
livestock and companion animals) exposed to            factors.
the agent.                                                  Considerations of importance in the inter-
    For studies of mixtures, consideration is          pretation and evaluation of a particular study
given to the possibility that changes in the phys-     include: (i) how clearly the agent was defined and,
icochemical properties of the individual sub-          in the case of mixtures, how adequately the sam-
stances may occur during collection, storage,          ple characterization was reported; (ii) whether
extraction, concentration and delivery. Another        the dose was monitored adequately, particu-
consideration is that chemical and toxicological       larly in inhalation experiments; (iii) whether the
interactions of components in a mixture may            doses, duration of treatment and route of expo-
alter dose–response relationships. The relevance       sure were appropriate; (iv) whether the survival
to human exposure of the test mixture adminis-         of treated animals was similar to that of con-
tered in the animal experiment is also assessed.       trols; (v) whether there were adequate numbers
This may involve consideration of the following        of animals per group; (vi) whether both male and
aspects of the mixture tested: (i) physical and        female animals were used; (vii) whether animals
chemical characteristics, (ii) identified constitu-    were allocated randomly to groups; (viii) whether
ents that may indicate the presence of a class of      the duration of observation was adequate; and
substances and (iii) the results of genetic toxicity   (ix) whether the data were reported and analysed
and related tests.                                     adequately.
    The relevance of results obtained with an               When benign tumours (a) occur together
agent that is analogous (e.g. similar in structure     with and originate from the same cell type as
or of a similar virus genus) to that being evalu-      malignant tumours in an organ or tissue in a
ated is also considered. Such results may provide      particular study and (b) appear to represent a
biological and mechanistic information that is         stage in the progression to malignancy, they are
relevant to the understanding of the process of        usually combined in the assessment of tumour
carcinogenesis in humans and may strengthen            incidence (Huff et al., 1989). The occurrence of
the biological plausibility that the agent being       lesions presumed to be preneoplastic may in cer-
evaluated is carcinogenic to humans (see Part B,       tain instances aid in assessing the biological plau-
Section 2f).                                           sibility of any neoplastic response observed. If an
                                                       agent induces only benign neoplasms that appear
                                                       to be end-points that do not readily undergo


                                                                                                        19
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans

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IARC Monographs on the Evaluation of Carcinogenic Risks to Humans

  • 1. WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER IARC Monographs on the Evaluation of Carcinogenic Risks to Humans VOLUME 100 A Review of Human Carcinogens Part D: Radiation LYON, FRANCE
  • 3. WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Volume 100 A Review of Human Carcinogens Part D: Radiation This publication represents the views and expert opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, which met in Lyon, 2–9 June 2009
  • 4. IARC MONOGRAPHS In 1969, the International Agency for Research on Cancer (IARC) initiated a programme on the evaluation of the carcinogenic risk of chemicals to humans involving the production of critically evaluated monographs on individual chemicals. The programme was subsequently expanded to include evaluations of carcinogenic risks associated with exposures to complex mixtures, lifestyle factors and biological and physical agents, as well as those in specific occupations. The objective of the programme is to elaborate and publish in the form of monographs critical reviews of data on carcinogenicity for agents to which humans are known to be exposed and on specific exposure situa­ ions; to evaluate these data in terms of human risk with the help of international working t groups of experts in chemical carcinogenesis and related fields; and to indicate where additional research efforts are needed. The lists of IARC evaluations are regularly updated and are available on the Internet at http://monographs.iarc.fr/. This programme has been supported since 1982 by Cooperative Agreement U01 CA33193 with the United States National Cancer Institute, Department of Health and Human Services. Additional support has been provided since 1986 by the Health, Safety and Hygiene at Work Unit of the European Commission Directorate-General for Employment, Social Affairs and Equal Opportunities, and since 1992 by the United States National Institute of Environmental Health Sciences, Department of Health and Human Services. The contents of this volume are solely the responsibility of the Working Group and do not necessarily represent the official views of the U.S. National Cancer Institute, the U.S. National Institute of Environmental Health Sciences, the U.S. Department of Health and Human Services, or the European Commission Directorate-General for Employment, Social Affairs and Equal Opportunities. This volume was made possible, in part, through Cooperative Agreement CR 834012 with the United States Environmental Protection Agency, Office of Research and Development. The contents of this volume do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. Published by the International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France © International Agency for Research on Cancer, 2012 Distributed by WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The International Agency for Research on Cancer welcomes requests for permission to reproduce or translate its publications, in part or in full. Requests for permission to reproduce or translate IARC publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; email: permissions@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The IARC Monographs Working Group alone is responsible for the views expressed in this publication. IARC Library Cataloguing in Publication Data A review of human carcinogens. Part D: Radiation / IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2009: Lyon, France) (IARC monographs on the evaluation of carcinogenic risks to humans ; v. 100D) 1. Carcinogens 2. Neoplasms – etiology 3. Radiation – adverse effects I. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans II. Series ISBN 978 92 832 1321 5 (NLM Classification: W1) ISSN 1017-1606 PRINTED IN FRANCE
  • 7. CONTENTS NOTE TO THE READER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 List of Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 PREAMBLE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 A. GENERAL PRINCIPLES AND PROCEDURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1. Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2. Objective and scope. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 3. Selection of agents for review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4. Data for the Monographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5. Meeting participants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 6. Working procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 B. SCIENTIFIC REVIEW AND EVALUATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 1. Exposure data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 2. Studies of cancer in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3. Studies of cancer in experimental animals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 4. Mechanistic and other relevant data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 5. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 6. Evaluation and rationale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 General Remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 SOLAR AND UV RADIATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 1. Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 1.1 Nomenclature and units. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 1.2 Methods for measuring UVR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 1.3 Sources and exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 2. Cancer in Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 2.1 Natural sunlight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 2.2 Artificial UV radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 2.3 UVA, UVB, and UVC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 2.4 Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 3. Cancer in Experimental Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 3.1 Non-melanoma skin cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 3.2 Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 v
  • 8. IARC MONOGRAPHS - 100D 3.3 Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 4. Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 4.1 Transmission and absorption in biological tissues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 4.2 Genetic and related effects: consequences of UVR exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 4.3 Genetic susceptibility: host factors modulating the response to UV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 4.4 Other effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 4.5 Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 5. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 X- AND γ-RADIATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 1. Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 1.1 Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 1.2 Interactions with matter. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 1.3 Exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 2. Cancer in Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 2.1 Detonation of atomic bombs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 2.2 Fallout from nuclear weapons testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 2.3 Medical exposures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 2.4 Occupational studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 2.5 Environmental studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 2.6 Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 3. Cancer in Experimental Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 3.1 Previous evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 3.2 Studies published since the previous IARC Monograph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 3.3 Studies in adult animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 3.4 Prenatal exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 3.5 Neonatal exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 3.6 Parental exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 3.7 Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 4. Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 4.1 Radionuclides: determining the distribution of dose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 4.2 Mechanisms of carcinogenesis induced by all ionizing radiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 4.3 Mechanism of carcinogenesis of neutrons: an example of ionizing radiation. . . . . . . . . . . . . . . . . .207 4.4 Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 5. Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 NEUTRON RADIATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 1. Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 2. Cancer in Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 3. Cancer in Experimenal Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 3.1 Previous IARC Monograph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 3.2 Carcinogenicity in adult animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 3.3 Prenatal exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 3.4 Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 vi
  • 9. Contents 4. Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 5. Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 INTERNALIZED α-PARTICLE EMITTING RADIONUCLIDES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 1. Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 2. Cancer in Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 2.1 Radon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 2.2 α-Particle emitters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 3. Cancer in Experimental Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 3.1 Previous IARC Monograph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 3.2 Studies published since the previous IARC Monograph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 3.3 Other studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 3.4 Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 4. Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 5. Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 INTERNALIZED β-PARTICLE EMITTING RADIONUCLIDES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 1. Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 2. Cancer in Humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 2.1 Pure β-particle emitters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 2.2 Mixed β-particle emitters–radioiodines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 2.3 Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 3. Cancer in Experimental Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 3.1 Previous evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 3.2 Pure β-particle-emitting radionuclides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 3.3 Mixed β-particle emitting radionuclides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 3.4 Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 4. Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 5. Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 List of Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 CUMULATIVE CROSS INDEX TO IARC MONOGRAPHS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 List of IARC Monographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 vii
  • 11. NOTE TO THE READER The term ‘carcinogenic risk’ in the IARC Monographs series is taken to mean that an agent is capable of causing cancer. The Monographs evaluate cancer hazards, despite the historical presence of the word ‘risks’ in the title. Inclusion of an agent in the Monographs does not imply that it is a carcinogen, only that the published data have been examined. Equally, the fact that an agent has not yet been evaluated in a Monograph does not mean that it is not carcinogenic. Similarly, identification of cancer sites with sufficient evidence or limited evidence in humans should not be viewed as precluding the possibility that an agent may cause cancer at other sites. The evaluations of carcinogenic risk are made by international working groups of independent scientists and are qualitative in nature. No recommendation is given for regulation or legislation. Anyone who is aware of published data that may alter the evaluation of the carcinogenic risk of an agent to humans is encouraged to make this information available to the Section of IARC Monographs, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France, in order that the agent may be considered for re-evaluation by a future Working Group. Although every effort is made to prepare the monographs as accurately as possible, mistakes may occur. Readers are requested to communicate any errors to the Section of IARC Monographs, so that corrections can be reported in future volumes. 1
  • 13. List of Participants Members1 Bruce Armstrong David J. Brenner (unable to attend) School of Public Health Center for Radiological Research University of Sydney Columbia University NSW 2006 New York, NY 10043 Australia USA Keith Baverstock Elisabeth Cardis Faculty of Natural and Environmental Center for Research in Environmental Sciences Epidemiology (CREAL) University of Eastern Finland E-08003 Barcelona FI-70211 Kuopio Spain Finland 1 Working Group Members and Invited Specialists serve in their individual capacities as scientists and not as representa- tives of their government or any organization with which they are affiliated. Affiliations are provided for identification purposes only. Invited specialists are marked by an asterisk. Each participant was asked to disclose pertinent research, employment, and financial interests. Current financial interests and research and employment interests during the past 3 years or anticipated in the future are identified here. Minor pertinent interests are not listed and include stock valued at no more than US$10 000 overall, grants that provide no more than 5% of the research budget of the expert’s organization and that do not support the expert’s research or position, and consulting or speaking on matters not before a court or government agency that does not exceed 2% of total professional time or compensation. All grants that support the expert’s research or position and all consulting or speaking on behalf of an interested party on matters before a court or government agency are listed as significant perti- nent interests. 3
  • 14. IARC MONOGRAPHS – 100D Adele Green2 David Hoel4 Cancer & Population Studies Group College of Medicine Queensland Institute of Medical Research Medical University of South Carolina Queensland 4029 Charleston, SC 29401 Australia USA Raymond A. Guilmette Daniel Krewski Lovelace Respiratory Research Institute Albuquerque, NM 87108-5127 McLaughlin Centre for Population USA Health Risk Assessment University of Ottawa Ottawa, Ontario K1N 6N5 Janet Hall3 Canada Institut Curie Research Center INSERM Unit 612 University Centre Mark P. Little5 91405 Orsay Division of Epidemiology, Public Health France and Primary Care Imperial College Faculty of Medicine London W2 1PG Mark A. Hill United Kingdom Gray Institute for Radiation Oncology & Biology University of Oxford Oxford OX3 7DQ United Kingdom 2 Dr Green receives research funds (not exceeding 5% of total research support) from L’Oréal which makes products intended to reduce the dose from solar radiation. 3 Dr Hall’s research unit receives funds (not exceeding 5% of total research support) from Electricité de France, an elec- tric power company. 4 Dr Hoel is providing assistance to Exxon Corp in court cases involving personal injury claimed to be related to radia- tion. He owns stock in Duke Energy Corp, an electric power company. His university salary is supported in part by grants from the U.S. National Aeronautics and Space Administration (NASA) and the U.S. Department of Energy. 5 Dr Little wrote software for the British Nuclear Group to calculate risks for workers in the nuclear industry. This represented less than 5% of his annual total professional compensation for 2006 and 2007, when the activity ceased. He also advised the International Epidemiology Institute (USA) and Westlakes Research Institute (UK) on epidemiological matters. This represented less than 5% of total professional income, and work ceased in 2007 for both contracts. New address: Radiation Epidemiology Branch, National Cancer Institute, Rockville MD, USA 4
  • 15. Participants Michael Marshall (retired)6 David B. Richardson10 UK Atomic Energy Authority School of Public Health Blewbury, Didcot University of North Carolina at Chapel Hill Oxon OX11 9NW Chapel Hill, NC 27599-7435 United Kingdom USA Ronald E. J. Mitchel (retired)7 Anthony E. Riddell11 Atomic Energy of Canada Limited Westlakes Scientific Consulting Ltd Chalk River, Ontario K0J 1J0 University of Central Lancashire Canada Cumbria CA24 3JY United Kingdom Colin R. Muirhead8 Laure Sabatier Centre for Radiation, Chemical and Environmental Hazards Radiobiology and Oncology Unit Health Protection Agency French Alternative Energies and Atomic Chilton, Didcot Energy Commission Oxon OX11 0RQ 92265 Fontenay-aux-Roses United Kingdom France Nicholas D. Priest9 Mikhail E. Sokolnikov Radiation Biology and Health Physics Southern Urals Biophysics Institute Atomic Energy of Canada Limited Ozyorsk, 456780 Chalk River, Ontario K0J 1P0 Russian Federation Canada 6 Dr Marshall is retired from the United Kingdom Atomic Energy Authority (UKAEA). 7 Dr Mitchel is retired from, and continues to consult for, Atomic Energy of Canada Ltd, a Crown corporation of Canada whose mandate is to sustain and enhance nuclear technology, to manage nuclear wastes, and to maximize return on investment in nuclear technology. The corporation also produces more than half of the world’s medical isotopes. 8 Dr Muirhead manages a section at the Health Protection Agency that receives partial funding from the UK Ministry of Defence to maintain an epidemiological database of nuclear test veterans. New address: Institute of Health and Society, Newcastle University, UK. 9 Dr Priest is a manager at Atomic Energy of Canada Ltd, a Crown corporation of Canada whose mandate is to sustain and enhance nuclear technology, to manage nuclear wastes, and to maximize return on investment in nuclear technol- ogy. The corporation also produces a significant fraction of the world’s medical isotopes. 10 Dr Richardson provided written testimony on behalf of four persons seeking compensation for diseases claimed to be related to X-rays. He reports receiving no compensation for this case. 11 Dr Riddell is employed by Westlakes Scientific Consulting Ltd, a consulting firm specializing in the nuclear industry. 5
  • 16. IARC MONOGRAPHS – 100D Ladislav Tomasek Andrei Karotki National Radiation Protection Institute Ausra Kesminiene 140 00 Prague 4 Béatrice Lauby-Secretan (Rapporteur, Czech Republic Cancer in Humans) Ferid Shannoun (WHO geneva) Kurt Straif (Rapporteur, Cancer in Humans) Isabelle Thierry-Chef Robert L. Ullrich12 UTMB Cancer Center University of Texas Medical Branch Post-meeting Scientific Assistance Galveston, TX 77555-1048 USA Farhad Islami Administrative Assistance IARC Secretariat Sandrine Egraz Philippe Autier Michel Javin Robert Baan (Co-Responsible Officer; Brigitte Kajo Rapporteur, Mechanistic and Other Relevant Helene Lorenzen-Augros Data) Karine Racinoux Lamia Benbrahim-Tallaa (Rapporteur, Cancer in Experimental Animals) Véronique Bouvard (Rapporteur, Reproduction of Graphics Mechanistic and Other Relevant Data) Rafael Carel (Visiting Scientist) Arthur Bouvard Vincent Cogliano (Head of Programme) Emilie van Deventer (WHO geneva) Jean-François Doré (Visiting Scientist) Fatiha El Ghissassi (Responsible Production Team Officer; Rapporteur, Mechanistic and Other Relevant Data) Elisabeth Elbers Crystal Freeman (Rapporteur, Cancer in Anne-Sophie Hameau Humans) Sylvia Moutinho Laurent Galichet (Editor) Dorothy Russell Yann Grosse (Rapporteur, Cancer in Experimental Animals) Neela Guha (Rapporteur, Cancer in Humans) 12 Dr Ullrich provided assistance to Raytheon Co in a court case involving thyroid and kidney cancer claimed to be related to X-rays. 6
  • 17. PREAMBLE The Preamble to the IARC Monographs describes the objective and scope of the programme, the scientific principles and procedures used in developing a Monograph, the types of evidence considered and the scientific criteria that guide the evaluations. The Preamble should be consulted when reading a Monograph or list of evaluations. A. GENERAL PRINCIPLES AND risk of chemicals to man, which became the ini- PROCEDURES tial title of the series. In the succeeding years, the scope of the pro- gramme broadened as Monographs were devel- 1. Background oped for groups of related chemicals, complex Soon after IARC was established in 1965, it mixtures, occupational exposures, physical and received frequent requests for advice on the car- biological agents and lifestyle factors. In 1988, cinogenic risk of chemicals, including requests the phrase ‘of chemicals’ was dropped from for lists of known and suspected human carcino- the title, which assumed its present form, IARC gens. It was clear that it would not be a simple Monographs on the Evaluation of Carcinogenic task to summarize adequately the complexity of Risks to Humans. the information that was available, and IARC Through the Monographs programme, IARC began to consider means of obtaining interna- seeks to identify the causes of human cancer. This tional expert opinion on this topic. In 1970, the is the first step in cancer prevention, which is IARC Advisory Committee on Environmental needed as much today as when IARC was estab- Carcinogenesis recommended ‘...that a com- lished. The global burden of cancer is high and pendium on carcinogenic chemicals be pre- continues to increase: the annual number of new pared by experts. The biological activity and cases was estimated at 10.1 million in 2000 and evaluation of practical importance to public is expected to reach 15 million by 2020 (Stewart health should be referenced and documented.’ & Kleihues, 2003). With current trends in demo- The IARC Governing Council adopted a resolu- graphics and exposure, the cancer burden has tion concerning the role of IARC in providing been shifting from high-resource countries to government authorities with expert, independ- low- and medium-resource countries. As a result ent, scientific opinion on environmental carcino- of Monographs evaluations, national health agen- genesis. As one means to that end, the Governing cies have been able, on scientific grounds, to take Council recommended that IARC should prepare measures to reduce human exposure to carcino- monographs on the evaluation of carcinogenic gens in the workplace and in the environment. 7
  • 18. IARC MONOGRAPHS – 100D The criteria established in 1971 to evaluate causation of, and susceptibility to, malignant carcinogenic risks to humans were adopted by the disease become more fully understood. Working Groups whose deliberations resulted in A cancer ‘hazard’ is an agent that is capable the first 16 volumes of the Monographs series. of causing cancer under some circumstances, Those criteria were subsequently updated by fur- while a cancer ‘risk’ is an estimate of the carci- ther ad hoc Advisory Groups (IARC, 1977, 1978, nogenic effects expected from exposure to a can- 1979, 1982, 1983, 1987, 1988, 1991; Vainio et al., cer hazard. The Monographs are an exercise in 1992; IARC, 2005, 2006). evaluating cancer hazards, despite the historical The Preamble is primarily a statement of sci- presence of the word ‘risks’ in the title. The dis- entific principles, rather than a specification of tinction between hazard and risk is important, working procedures. The procedures through and the Monographs identify cancer hazards which a Working Group implements these prin- even when risks are very low at current exposure ciples are not specified in detail. They usually levels, because new uses or unforeseen exposures involve operations that have been established could engender risks that are significantly higher. as being effective during previous Monograph In the Monographs, an agent is termed ‘car- meetings but remain, predominantly, the pre- cinogenic’ if it is capable of increasing the inci- rogative of each individual Working Group. dence of malignant neoplasms, reducing their latency, or increasing their severity or multiplic- ity. The induction of benign neoplasms may in 2. Objective and scope some circumstances (see Part B, Section 3a) con- The objective of the programme is to pre- tribute to the judgement that the agent is carci- pare, with the help of international Working nogenic. The terms ‘neoplasm’ and ‘tumour’ are Groups of experts, and to publish in the form of used interchangeably. Monographs, critical reviews and evaluations of The Preamble continues the previous usage evidence on the carcinogenicity of a wide range of the phrase ‘strength of evidence’ as a matter of human exposures. The Monographs repre- of historical continuity, although it should be sent the first step in carcinogen risk assessment, understood that Monographs evaluations con- which involves examination of all relevant infor- sider studies that support a finding of a cancer mation to assess the strength of the available evi- hazard as well as studies that do not. dence that an agent could alter the age-specific Some epidemiological and experimental incidence of cancer in humans. The Monographs studies indicate that different agents may act at may also indicate where additional research different stages in the carcinogenic process, and efforts are needed, specifically when data imme- several different mechanisms may be involved. diately relevant to an evaluation are not available. The aim of the Monographs has been, from their In this Preamble, the term ‘agent’ refers to inception, to evaluate evidence of carcinogenic- any entity or circumstance that is subject to ity at any stage in the carcinogenesis process, evaluation in a Monograph. As the scope of the independently of the underlying mechanisms. programme has broadened, categories of agents Information on mechanisms may, however, be now include specific chemicals, groups of related used in making the overall evaluation (IARC, chemicals, complex mixtures, occupational or 1991; Vainio et al., 1992; IARC, 2005, 2006; see environmental exposures, cultural or behav- also Part B, Sections 4 and 6). As mechanisms ioural practices, biological organisms and physi- of carcinogenesis are elucidated, IARC convenes cal agents. This list of categories may expand as international scientific conferences to determine whether a broad-based consensus has emerged 8
  • 19. Preamble on how specific mechanistic data can be used exposure and (b) there is some evidence or sus- in an evaluation of human carcinogenicity. The picion of carcinogenicity. Mixed exposures may results of such conferences are reported in IARC occur in occupational and environmental set- Scientific Publications, which, as long as they still tings and as a result of individual and cultural reflect the current state of scientific knowledge, habits (such as tobacco smoking and dietary may guide subsequent Working Groups. practices). Chemical analogues and compounds Although the Monographs have emphasized with biological or physical characteristics simi- hazard identification, important issues may also lar to those of suspected carcinogens may also involve dose–response assessment. In many be considered, even in the absence of data on a cases, the same epidemiological and experimen- possible carcinogenic effect in humans or experi- tal studies used to evaluate a cancer hazard can mental animals. also be used to estimate a dose–response relation- The scientific literature is surveyed for pub- ship. A Monograph may undertake to estimate lished data relevant to an assessment of carci- dose–response relationships within the range nogenicity. Ad hoc Advisory Groups convened of the available epidemiological data, or it may by IARC in 1984, 1989, 1991, 1993, 1998 and compare the dose–response information from 2003 made recommendations as to which experimental and epidemiological studies. In agents should be evaluated in the Monographs some cases, a subsequent publication may be pre- series. Recent recommendations are avail- pared by a separate Working Group with exper- able on the Monographs programme web site tise in quantitative dose–response assessment. (http://monographs.iarc.fr). IARC may schedule The Monographs are used by national and other agents for review as it becomes aware of international authorities to make risk assess- new scientific information or as national health ments, formulate decisions concerning preventive agencies identify an urgent public health need measures, provide effective cancer control pro- related to cancer. grammes and decide among alternative options As significant new data become available for public health decisions. The evaluations of on an agent for which a Monograph exists, a re- IARC Working Groups are scientific, qualita- evaluation may be made at a subsequent meeting, tive judgements on the evidence for or against and a new Monograph published. In some cases it carcinogenicity provided by the available data. may be appropriate to review only the data pub- These evaluations represent only one part of the lished since a prior evaluation. This can be useful body of information on which public health deci- for updating a database, reviewing new data to sions may be based. Public health options vary resolve a previously open question or identifying from one situation to another and from country new tumour sites associated with a carcinogenic to country and relate to many factors, including agent. Major changes in an evaluation (e.g. a new different socioeconomic and national priorities. classification in Group 1 or a determination that a Therefore, no recommendation is given with mechanism does not operate in humans, see Part regard to regulation or legislation, which are B, Section 6) are more appropriately addressed by the responsibility of individual governments or a full review. other international organizations. 4. Data for the Monographs 3. Selection of agents for review Each Monograph reviews all pertinent epi- Agents are selected for review on the basis of demiological studies and cancer bioassays in two main criteria: (a) there is evidence of human experimental animals. Those judged inadequate 9
  • 20. IARC MONOGRAPHS – 100D or irrelevant to the evaluation may be cited but (a) The Working Group not summarized. If a group of similar studies is not reviewed, the reasons are indicated. The Working Group is responsible for the crit- Mechanistic and other relevant data are also ical reviews and evaluations that are developed reviewed. A Monograph does not necessarily during the meeting. The tasks of Working Group cite all the mechanistic literature concerning Members are: (i) to ascertain that all appropriate the agent being evaluated (see Part B, Section data have been collected; (ii) to select the data rel- 4). Only those data considered by the Working evant for the evaluation on the basis of scientific Group to be relevant to making the evaluation merit; (iii) to prepare accurate summaries of the are included. data to enable the reader to follow the reasoning With regard to epidemiological studies, can- of the Working Group; (iv) to evaluate the results cer bioassays, and mechanistic and other relevant of epidemiological and experimental studies on data, only reports that have been published or cancer; (v) to evaluate data relevant to the under- accepted for publication in the openly available standing of mechanisms of carcinogenesis; and scientific literature are reviewed. The same publi- (vi) to make an overall evaluation of the carci- cation requirement applies to studies originating nogenicity of the exposure to humans. Working from IARC, including meta-analyses or pooled Group Members generally have published sig- analyses commissioned by IARC in advance of a nificant research related to the carcinogenicity of meeting (see Part B, Section 2c). Data from gov- the agents being reviewed, and IARC uses litera- ernment agency reports that are publicly avail- ture searches to identify most experts. Working able are also considered. Exceptionally, doctoral Group Members are selected on the basis of (a) theses and other material that are in their final knowledge and experience and (b) absence of real form and publicly available may be reviewed. or apparent conflicts of interests. Consideration Exposure data and other information on an is also given to demographic diversity and bal- agent under consideration are also reviewed. In ance of scientific findings and views. the sections on chemical and physical proper- ties, on analysis, on production and use and on (b) Invited Specialists occurrence, published and unpublished sources Invited Specialists are experts who also have of information may be considered. critical knowledge and experience but have Inclusion of a study does not imply accept- a real or apparent conflict of interests. These ance of the adequacy of the study design or of experts are invited when necessary to assist in the analysis and interpretation of the results, and the Working Group by contributing their unique limitations are clearly outlined in square brack- knowledge and experience during subgroup and ets at the end of each study description (see Part plenary discussions. They may also contribute B). The reasons for not giving further considera- text on non-influential issues in the section on tion to an individual study also are indicated in exposure, such as a general description of data the square brackets. on production and use (see Part B, Section 1). Invited Specialists do not serve as meeting chair 5. Meeting participants or subgroup chair, draft text that pertains to the description or interpretation of cancer data, or Five categories of participant can be present participate in the evaluations. at Monograph meetings. 10
  • 21. Preamble (c) Representatives of national and whether there is a conflict that warrants some international health agencies limitation on participation. The declarations are updated and reviewed again at the opening of Representatives of national and interna- the meeting. Interests related to the subject of tional health agencies often attend meetings the meeting are disclosed to the meeting par- because their agencies sponsor the programme ticipants and in the published volume (Cogliano or are interested in the subject of a meeting. et al., 2004). Representatives do not serve as meeting chair or The names and principal affiliations of par- subgroup chair, draft any part of a Monograph, ticipants are available on the Monographs pro- or participate in the evaluations. gramme web site (http://monographs.iarc.fr) approximately two months before each meeting. (d) Observers with relevant scientific It is not acceptable for Observers or third parties credentials to contact other participants before a meeting or Observers with relevant scientific credentials to lobby them at any time. Meeting participants may be admitted to a meeting by IARC in limited are asked to report all such contacts to IARC numbers. Attention will be given to achieving a (Cogliano et al., 2005). balance of Observers from constituencies with All participants are listed, with their princi- differing perspectives. They are invited to observe pal affiliations, at the beginning of each volume. the meeting and should not attempt to influence Each participant who is a Member of a Working it. Observers do not serve as meeting chair or Group serves as an individual scientist and not as subgroup chair, draft any part of a Monograph, a representative of any organization, government or participate in the evaluations. At the meeting, or industry. the meeting chair and subgroup chairs may grant Observers an opportunity to speak, generally 6. Working procedures after they have observed a discussion. Observers agree to respect the Guidelines for Observers A separate Working Group is responsible for at IARC Monographs meetings (available at developing each volume of Monographs. A vol- http://monographs.iarc.fr). ume contains one or more Monographs, which can cover either a single agent or several related (e) The IARC Secretariat agents. Approximately one year in advance of the The IARC Secretariat consists of scientists meeting of a Working Group, the agents to be who are designated by IARC and who have rel- reviewed are announced on the Monographs pro- evant expertise. They serve as rapporteurs and gramme web site (http://monographs.iarc.fr) and participate in all discussions. When requested by participants are selected by IARC staff in consul- the meeting chair or subgroup chair, they may tation with other experts. Subsequently, relevant also draft text or prepare tables and analyses. biological and epidemiological data are collected Before an invitation is extended, each poten- by IARC from recognized sources of information tial participant, including the IARC Secretariat, on carcinogenesis, including data storage and completes the WHO Declaration of Interests to retrieval systems such as PubMed. Meeting par- report financial interests, employment and con- ticipants who are asked to prepare preliminary sulting, and individual and institutional research working papers for specific sections are expected support related to the subject of the meeting. to supplement the IARC literature searches with IARC assesses these interests to determine their own searches. 11
  • 22. IARC MONOGRAPHS – 100D For most chemicals and some complex mix- the entire volume is the joint product of the tures, the major collection of data and the prep- Working Group, and there are no individually aration of working papers for the sections on authored sections. chemical and physical properties, on analysis, on IARC Working Groups strive to achieve a production and use, and on occurrence are car- consensus evaluation. Consensus reflects broad ried out under a separate contract funded by the agreement among Working Group Members, but US National Cancer Institute. Industrial associ- not necessarily unanimity. The chair may elect ations, labour unions and other knowledgeable to poll Working Group Members to determine organizations may be asked to provide input to the diversity of scientific opinion on issues where the sections on production and use, although consensus is not readily apparent. this involvement is not required as a general rule. After the meeting, the master copy is verified Information on production and trade is obtained by consulting the original literature, edited and from governmental, trade and market research prepared for publication. The aim is to publish publications and, in some cases, by direct con- the volume within six months of the Working tact with industries. Separate production data Group meeting. A summary of the outcome is on some agents may not be available for a vari- available on the Monographs programme web ety of reasons (e.g. not collected or made public site soon after the meeting. in all producing countries, production is small). Information on uses may be obtained from pub- lished sources but is often complemented by B. SCIENTIFIC REVIEW AND direct contact with manufacturers. Efforts are EVALUATION made to supplement this information with data from other national and international sources. The available studies are summarized by the Six months before the meeting, the mate- Working Group, with particular regard to the rial obtained is sent to meeting participants to qualitative aspects discussed below. In general, prepare preliminary working papers. The work- numerical findings are indicated as they appear ing papers are compiled by IARC staff and sent, in the original report; units are converted when before the meeting, to Working Group Members necessary for easier comparison. The Working and Invited Specialists for review. Group may conduct additional analyses of the The Working Group meets at IARC for seven published data and use them in their assessment to eight days to discuss and finalize the texts of the evidence; the results of such supplemen- and to formulate the evaluations. The objectives tary analyses are given in square brackets. When of the meeting are peer review and consensus. an important aspect of a study that directly During the first few days, four subgroups (cov- impinges on its interpretation should be brought ering exposure data, cancer in humans, cancer to the attention of the reader, a Working Group in experimental animals, and mechanistic and comment is given in square brackets. other relevant data) review the working papers, The scope of the IARC Monographs pro- develop a joint subgroup draft and write sum- gramme has expanded beyond chemicals to maries. Care is taken to ensure that each study include complex mixtures, occupational expo- summary is written or reviewed by someone sures, physical and biological agents, lifestyle not associated with the study being considered. factors and other potentially carcinogenic expo- During the last few days, the Working Group sures. Over time, the structure of a Monograph meets in plenary session to review the subgroup has evolved to include the following sections: drafts and develop the evaluations. As a result, 12
  • 23. Preamble Exposure data which the agent being evaluated is only one of Studies of cancer in humans the ingredients. Studies of cancer in experimental animals For biological agents, taxonomy, struc- Mechanistic and other relevant data ture and biology are described, and the degree Summary of variability is indicated. Mode of replication, Evaluation and rationale life cycle, target cells, persistence, latency, host In addition, a section of General Remarks at response and clinical disease other than cancer the front of the volume discusses the reasons the are also presented. agents were scheduled for evaluation and some For physical agents that are forms of radia- key issues the Working Group encountered dur- tion, energy and range of the radiation are ing the meeting. included. For foreign bodies, fibres and respir- This part of the Preamble discusses the types able particles, size range and relative dimensions of evidence considered and summarized in each are indicated. section of a Monograph, followed by the scientific For agents such as mixtures, drugs or lifestyle criteria that guide the evaluations. factors, a description of the agent, including its composition, is given. Whenever appropriate, other information, 1. Exposure data such as historical perspectives or the description Each Monograph includes general informa- of an industry or habit, may be included. tion on the agent: this information may vary sub- stantially between agents and must be adapted (b) Analysis and detection accordingly. Also included is information on An overview of methods of analysis and production and use (when appropriate), meth- detection of the agent is presented, including ods of analysis and detection, occurrence, and their sensitivity, specificity and reproducibility. sources and routes of human occupational and Methods widely used for regulatory purposes environmental exposures. Depending on the are emphasized. Methods for monitoring human agent, regulations and guidelines for use may be exposure are also given. No critical evaluation presented. or recommendation of any method is meant or implied. (a) General information on the agent For chemical agents, sections on chemical (c) Production and use and physical data are included: the Chemical The dates of first synthesis and of first com- Abstracts Service Registry Number, the latest pri- mercial production of a chemical, mixture or mary name and the IUPAC systematic name are other agent are provided when available; for recorded; other synonyms are given, but the list agents that do not occur naturally, this informa- is not necessarily comprehensive. Information tion may allow a reasonable estimate to be made on chemical and physical properties that are rel- of the date before which no human exposure to evant to identification, occurrence and biologi- the agent could have occurred. The dates of first cal activity is included. A description of technical reported occurrence of an exposure are also pro- products of chemicals includes trade names, rel- vided when available. In addition, methods of evant specifications and available information synthesis used in past and present commercial on composition and impurities. Some of the production and different methods of production, trade names given may be those of mixtures in 13
  • 24. IARC MONOGRAPHS – 100D which may give rise to different impurities, are place. For biological agents, the epidemiology of described. infection is described. The countries where companies report pro- duction of the agent, and the number of compa- (e) Regulations and guidelines nies in each country, are identified. Available data on production, international trade and uses are Statements concerning regulations and obtained for representative regions. It should not, guidelines (e.g. occupational exposure limits, however, be inferred that those areas or nations maximal levels permitted in foods and water, are necessarily the sole or major sources or users pesticide registrations) are included, but they of the agent. Some identified uses may not be may not reflect the most recent situation, since current or major applications, and the coverage such limits are continuously reviewed and modi- is not necessarily comprehensive. In the case of fied. The absence of information on regulatory drugs, mention of their therapeutic uses does not status for a country should not be taken to imply necessarily represent current practice nor does it that that country does not have regulations with imply judgement as to their therapeutic efficacy. regard to the exposure. For biological agents, leg- islation and control, including vaccination and therapy, are described. (d) Occurrence and exposure Information on the occurrence of an agent in the environment is obtained from data derived 2. Studies of cancer in humans from the monitoring and surveillance of levels This section includes all pertinent epidemio- in occupational environments, air, water, soil, logical studies (see Part A, Section 4). Studies of plants, foods and animal and human tissues. biomarkers are included when they are relevant When available, data on the generation, per- to an evaluation of carcinogenicity to humans. sistence and bioaccumulation of the agent are also included. Such data may be available from (a) Types of study considered national databases. Data that indicate the extent of past and pre- Several types of epidemiological study con- sent human exposure, the sources of exposure, tribute to the assessment of carcinogenicity in the people most likely to be exposed and the fac- humans — cohort studies, case–control studies, tors that contribute to the exposure are reported. correlation (or ecological) studies and interven- Information is presented on the range of human tion studies. Rarely, results from randomized tri- exposure, including occupational and environ- als may be available. Case reports and case series mental exposures. This includes relevant findings of cancer in humans may also be reviewed. from both developed and developing countries. Cohort and case–control studies relate indi- Some of these data are not distributed widely and vidual exposures under study to the occurrence of may be available from government reports and cancer in individuals and provide an estimate of other sources. In the case of mixtures, indus- effect (such as relative risk) as the main measure tries, occupations or processes, information is of association. Intervention studies may provide given about all agents known to be present. For strong evidence for making causal inferences, as processes, industries and occupations, a histori- exemplified by cessation of smoking and the sub- cal description is also given, noting variations in sequent decrease in risk for lung cancer. chemical composition, physical properties and In correlation studies, the units of inves- levels of occupational exposure with date and tigation are usually whole populations (e.g. in 14
  • 25. Preamble particular geographical areas or at particular Bias is the effect of factors in study design or times), and cancer frequency is related to a sum- execution that lead erroneously to a stronger or mary measure of the exposure of the population weaker association than in fact exists between an to the agent under study. In correlation studies, agent and disease. Confounding is a form of bias individual exposure is not documented, which that occurs when the relationship with disease is renders this kind of study more prone to con- made to appear stronger or weaker than it truly is founding. In some circumstances, however, cor- as a result of an association between the apparent relation studies may be more informative than causal factor and another factor that is associated analytical study designs (see, for example, the with either an increase or decrease in the inci- Monograph on arsenic in drinking-water; IARC, dence of the disease. The role of chance is related 2004). to biological variability and the influence of sam- In some instances, case reports and case series ple size on the precision of estimates of effect. have provided important information about the In evaluating the extent to which these fac- carcinogenicity of an agent. These types of study tors have been minimized in an individual study, generally arise from a suspicion, based on clinical consideration is given to several aspects of design experience, that the concurrence of two events — and analysis as described in the report of the that is, a particular exposure and occurrence of study. For example, when suspicion of carcino- a cancer — has happened rather more frequently genicity arises largely from a single small study, than would be expected by chance. Case reports careful consideration is given when interpreting and case series usually lack complete ascertain- subsequent studies that included these data in an ment of cases in any population, definition or enlarged population. Most of these considera- enumeration of the population at risk and esti- tions apply equally to case–control, cohort and mation of the expected number of cases in the correlation studies. Lack of clarity of any of these absence of exposure. aspects in the reporting of a study can decrease The uncertainties that surround the inter- its credibility and the weight given to it in the pretation of case reports, case series and corre- final evaluation of the exposure. lation studies make them inadequate, except in First, the study population, disease (or dis- rare instances, to form the sole basis for inferring eases) and exposure should have been well a causal relationship. When taken together with defined by the authors. Cases of disease in the case–control and cohort studies, however, these study population should have been identified in types of study may add materially to the judge- a way that was independent of the exposure of ment that a causal relationship exists. interest, and exposure should have been assessed Epidemiological studies of benign neo- in a way that was not related to disease status. plasms, presumed preneoplastic lesions and Second, the authors should have taken into other end-points thought to be relevant to cancer account — in the study design and analysis — are also reviewed. They may, in some instances, other variables that can influence the risk of dis- strengthen inferences drawn from studies of ease and may have been related to the exposure cancer itself. of interest. Potential confounding by such vari- ables should have been dealt with either in the (b) Quality of studies considered design of the study, such as by matching, or in the analysis, by statistical adjustment. In cohort It is necessary to take into account the pos- studies, comparisons with local rates of disease sible roles of bias, confounding and chance in may or may not be more appropriate than those the interpretation of epidemiological studies. with national rates. Internal comparisons of 15
  • 26. IARC MONOGRAPHS – 100D frequency of disease among individuals at differ- The advantages of combined analyses are ent levels of exposure are also desirable in cohort increased precision due to increased sample size studies, since they minimize the potential for and the opportunity to explore potential con- confounding related to the difference in risk fac- founders, interactions and modifying effects tors between an external reference group and the that may explain heterogeneity among studies in study population. more detail. A disadvantage of combined analy- Third, the authors should have reported the ses is the possible lack of compatibility of data basic data on which the conclusions are founded, from various studies due to differences in sub- even if sophisticated statistical analyses were ject recruitment, procedures of data collection, employed. At the very least, they should have methods of measurement and effects of unmeas- given the numbers of exposed and unexposed ured co-variates that may differ among studies. cases and controls in a case–control study and Despite these limitations, well conducted com- the numbers of cases observed and expected in bined analyses may provide a firmer basis than a cohort study. Further tabulations by time since individual studies for drawing conclusions about exposure began and other temporal factors are the potential carcinogenicity of agents. also important. In a cohort study, data on all IARC may commission a meta-analysis or cancer sites and all causes of death should have pooled analysis that is pertinent to a particular been given, to reveal the possibility of reporting Monograph (see Part A, Section 4). Additionally, bias. In a case–control study, the effects of inves- as a means of gaining insight from the results of tigated factors other than the exposure of interest multiple individual studies, ad hoc calculations should have been reported. that combine data from different studies may Finally, the statistical methods used to obtain be conducted by the Working Group during estimates of relative risk, absolute rates of can- the course of a Monograph meeting. The results cer, confidence intervals and significance tests, of such original calculations, which would be and to adjust for confounding should have been specified in the text by presentation in square clearly stated by the authors. These methods have brackets, might involve updates of previously been reviewed for case–control studies (Breslow conducted analyses that incorporate the results & Day, 1980) and for cohort studies (Breslow & of more recent studies or de-novo analyses. Day, 1987). Irrespective of the source of data for the meta- analyses and pooled analyses, it is important that (c) Meta-analyses and pooled analyses the same criteria for data quality be applied as those that would be applied to individual studies Independent epidemiological studies of the and to ensure also that sources of heterogeneity same agent may lead to results that are difficult between studies be taken into account. to interpret. Combined analyses of data from multiple studies are a means of resolving this (d) Temporal effects ambiguity, and well conducted analyses can be considered. There are two types of combined Detailed analyses of both relative and abso- analysis. The first involves combining summary lute risks in relation to temporal variables, such statistics such as relative risks from individual as age at first exposure, time since first exposure, studies (meta-analysis) and the second involves a duration of exposure, cumulative exposure, peak pooled analysis of the raw data from the individ- exposure (when appropriate) and time since ual studies (pooled analysis) (Greenland, 1998). cessation of exposure, are reviewed and sum- marized when available. Analyses of temporal 16
  • 27. Preamble relationships may be useful in making causal of the agent being evaluated, data on this pheno- inferences. In addition, such analyses may sug- type may be useful in making causal inferences. gest whether a carcinogen acts early or late in the process of carcinogenesis, although, at best, they (f) Criteria for causality allow only indirect inferences about mechanisms of carcinogenesis. After the quality of individual epidemiologi- cal studies of cancer has been summarized and assessed, a judgement is made concerning the (e) Use of biomarkers in epidemiological strength of evidence that the agent in question studies is carcinogenic to humans. In making its judge- Biomarkers indicate molecular, cellular or ment, the Working Group considers several crite- other biological changes and are increasingly ria for causality (Hill, 1965). A strong association used in epidemiological studies for various pur- (e.g. a large relative risk) is more likely to indicate poses (IARC, 1991; Vainio et al., 1992; Toniolo causality than a weak association, although it is et al., 1997; Vineis et al., 1999; Buffler et al., 2004). recognized that estimates of effect of small mag- These may include evidence of exposure, of early nitude do not imply lack of causality and may be effects, of cellular, tissue or organism responses, important if the disease or exposure is common. of individual susceptibility or host responses, Associations that are replicated in several studies and inference of a mechanism (see Part B, Section of the same design or that use different epidemi- 4b). This is a rapidly evolving field that encom- ological approaches or under different circum- passes developments in genomics, epigenomics stances of exposure are more likely to represent and other emerging technologies. a causal relationship than isolated observations Molecular epidemiological data that identify from single studies. If there are inconsistent associations between genetic polymorphisms results among investigations, possible reasons and interindividual differences in susceptibility are sought (such as differences in exposure), and to the agent(s) being evaluated may contribute results of studies that are judged to be of high to the identification of carcinogenic hazards to quality are given more weight than those of stud- humans. If the polymorphism has been demon- ies that are judged to be methodologically less strated experimentally to modify the functional sound. activity of the gene product in a manner that is If the risk increases with the exposure, this is consistent with increased susceptibility, these considered to be a strong indication of causality, data may be useful in making causal inferences. although the absence of a graded response is not Similarly, molecular epidemiological studies that necessarily evidence against a causal relation- measure cell functions, enzymes or metabolites ship. The demonstration of a decline in risk after that are thought to be the basis of susceptibil- cessation of or reduction in exposure in indi- ity may provide evidence that reinforces biologi- viduals or in whole populations also supports a cal plausibility. It should be noted, however, that causal interpretation of the findings. when data on genetic susceptibility originate Several scenarios may increase confidence in from multiple comparisons that arise from sub- a causal relationship. On the one hand, an agent group analyses, this can generate false-positive may be specific in causing tumours at one site or results and inconsistencies across studies, and of one morphological type. On the other, carci- such data therefore require careful evaluation. nogenicity may be evident through the causation If the known phenotype of a genetic polymor- of multiple tumour types. Temporality, precision phism can explain the carcinogenic mechanism of estimates of effect, biological plausibility and 17
  • 28. IARC MONOGRAPHS – 100D coherence of the overall database are consid- 3. Studies of cancer in experimental ered. Data on biomarkers may be employed in animals an assessment of the biological plausibility of epi- demiological observations. All known human carcinogens that have been Although rarely available, results from rand- studied adequately for carcinogenicity in experi- omized trials that show different rates of cancer mental animals have produced positive results among exposed and unexposed individuals pro- in one or more animal species (Wilbourn et al., vide particularly strong evidence for causality. 1986; Tomatis et al., 1989). For several agents When several epidemiological studies show (e.g. aflatoxins, diethylstilbestrol, solar radiation, little or no indication of an association between vinyl chloride), carcinogenicity in experimen- an exposure and cancer, a judgement may be made tal animals was established or highly suspected that, in the aggregate, they show evidence of lack before epidemiological studies confirmed their of carcinogenicity. Such a judgement requires carcinogenicity in humans (Vainio et al., 1995). first that the studies meet, to a sufficient degree, Although this association cannot establish that the standards of design and analysis described all agents that cause cancer in experimental ani- above. Specifically, the possibility that bias, con- mals also cause cancer in humans, it is biologically founding or misclassification of exposure or out- plausible that agents for which there is sufficient come could explain the observed results should evidence of carcinogenicity in experimental ani- be considered and excluded with reasonable cer- mals (see Part B, Section 6b) also present a car- tainty. In addition, all studies that are judged to cinogenic hazard to humans. Accordingly, in be methodologically sound should (a) be con- the absence of additional scientific information, sistent with an estimate of effect of unity for any these agents are considered to pose a carcinogenic observed level of exposure, (b) when considered hazard to humans. Examples of additional scien- together, provide a pooled estimate of relative tific information are data that demonstrate that risk that is at or near to unity, and (c) have a nar- a given agent causes cancer in animals through row confidence interval, due to sufficient popula- a species-specific mechanism that does not oper- tion size. Moreover, no individual study nor the ate in humans or data that demonstrate that the pooled results of all the studies should show any mechanism in experimental animals also oper- consistent tendency that the relative risk of can- ates in humans (see Part B, Section 6). cer increases with increasing level of exposure. Consideration is given to all available long- It is important to note that evidence of lack of term studies of cancer in experimental animals carcinogenicity obtained from several epidemio- with the agent under review (see Part A, Section logical studies can apply only to the type(s) of 4). In all experimental settings, the nature and cancer studied, to the dose levels reported, and to extent of impurities or contaminants present in the intervals between first exposure and disease the agent being evaluated are given when avail- onset observed in these studies. Experience with able. Animal species, strain (including genetic human cancer indicates that the period from first background where applicable), sex, numbers per exposure to the development of clinical cancer is group, age at start of treatment, route of expo- sometimes longer than 20 years; latent periods sure, dose levels, duration of exposure, survival substantially shorter than 30 years cannot pro- and information on tumours (incidence, latency, vide evidence for lack of carcinogenicity. severity or multiplicity of neoplasms or prene- oplastic lesions) are reported. Those studies in experimental animals that are judged to be irrel- evant to the evaluation or judged to be inadequate 18
  • 29. Preamble (e.g. too short a duration, too few animals, poor (a) Qualitative aspects survival; see below) may be omitted. Guidelines for conducting long-term carcinogenicity exper- An assessment of carcinogenicity involves iments have been published (e.g. OECD, 2002). several considerations of qualitative impor- Other studies considered may include: exper- tance, including (i) the experimental conditions iments in which the agent was administered in under which the test was performed, including the presence of factors that modify carcinogenic route, schedule and duration of exposure, spe- effects (e.g. initiation–promotion studies, co- cies, strain (including genetic background where carcinogenicity studies and studies in geneti- applicable), sex, age and duration of follow-up; cally modified animals); studies in which the (ii) the consistency of the results, for example, end-point was not cancer but a defined precan- across species and target organ(s); (iii) the spec- cerous lesion; experiments on the carcinogenic- trum of neoplastic response, from preneoplastic ity of known metabolites and derivatives; and lesions and benign tumours to malignant neo- studies of cancer in non-laboratory animals (e.g. plasms; and (iv) the possible role of modifying livestock and companion animals) exposed to factors. the agent. Considerations of importance in the inter- For studies of mixtures, consideration is pretation and evaluation of a particular study given to the possibility that changes in the phys- include: (i) how clearly the agent was defined and, icochemical properties of the individual sub- in the case of mixtures, how adequately the sam- stances may occur during collection, storage, ple characterization was reported; (ii) whether extraction, concentration and delivery. Another the dose was monitored adequately, particu- consideration is that chemical and toxicological larly in inhalation experiments; (iii) whether the interactions of components in a mixture may doses, duration of treatment and route of expo- alter dose–response relationships. The relevance sure were appropriate; (iv) whether the survival to human exposure of the test mixture adminis- of treated animals was similar to that of con- tered in the animal experiment is also assessed. trols; (v) whether there were adequate numbers This may involve consideration of the following of animals per group; (vi) whether both male and aspects of the mixture tested: (i) physical and female animals were used; (vii) whether animals chemical characteristics, (ii) identified constitu- were allocated randomly to groups; (viii) whether ents that may indicate the presence of a class of the duration of observation was adequate; and substances and (iii) the results of genetic toxicity (ix) whether the data were reported and analysed and related tests. adequately. The relevance of results obtained with an When benign tumours (a) occur together agent that is analogous (e.g. similar in structure with and originate from the same cell type as or of a similar virus genus) to that being evalu- malignant tumours in an organ or tissue in a ated is also considered. Such results may provide particular study and (b) appear to represent a biological and mechanistic information that is stage in the progression to malignancy, they are relevant to the understanding of the process of usually combined in the assessment of tumour carcinogenesis in humans and may strengthen incidence (Huff et al., 1989). The occurrence of the biological plausibility that the agent being lesions presumed to be preneoplastic may in cer- evaluated is carcinogenic to humans (see Part B, tain instances aid in assessing the biological plau- Section 2f). sibility of any neoplastic response observed. If an agent induces only benign neoplasms that appear to be end-points that do not readily undergo 19