WORLD HEALTH ORGANIZATION   INTERNATIONAL AGENCY FOR RESEARCH ON CANCERIARC Monographs on the Evaluation of   Carcinogenic...
WORLD HEALTH ORGANIZATION    INTERNATIONAL AGENCY FOR RESEARCH ON CANCERIARC Monographs on the Evaluation of    Carcinogen...
IARC MONOGRAPHS      In 1969, the International Agency for Research on Cancer (IARC) initiated a programme on the evaluati...
CONTENTSNOTE TO THE READER .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . ...
IARC MONOGRAPHS - 100D             3.3	Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...
Contents         4.	 Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....
NOTE TO THE READER    The term ‘carcinogenic risk’ in the IARC Monographs series is taken to mean that an agent iscapable ...
List of ParticipantsMembers1Bruce Armstrong                                               David J. Brenner (unable to atte...
IARC MONOGRAPHS – 100DAdele Green2                                                   David Hoel4    Cancer & Population St...
ParticipantsMichael Marshall (retired)6                                   David B. Richardson10    UK Atomic Energy Author...
IARC MONOGRAPHS – 100DLadislav Tomasek                                                 Andrei Karotki     National Radiati...
PREAMBLEThe Preamble to the IARC Monographs describes the objective and scope of the programme,the scientific principles a...
IARC MONOGRAPHS – 100D    The criteria established in 1971 to evaluate       causation of, and susceptibility to, malignan...
Preambleon how specific mechanistic data can be used            exposure and (b) there is some evidence or sus-in an evalu...
IARC MONOGRAPHS – 100Dor irrelevant to the evaluation may be cited but      (a) The Working Groupnot summarized. If a grou...
Preamble(c) Representatives of national and                   whether there is a conflict that warrants some      internat...
IARC MONOGRAPHS – 100D    For most chemicals and some complex mix-          the entire volume is the joint product of thet...
Preamble     Exposure data                                     which the agent being evaluated is only one of     Studies ...
IARC MONOGRAPHS – 100Dwhich may give rise to different impurities, are       place. For biological agents, the epidemiolog...
Preambleparticular geographical areas or at particular         Bias is the effect of factors in study design ortimes), and...
IARC MONOGRAPHS – 100Dfrequency of disease among individuals at differ-          The advantages of combined analyses areen...
Preamblerelationships may be useful in making causal                of the agent being evaluated, data on this pheno-infer...
IARC MONOGRAPHS – 100Dcoherence of the overall database are consid-           3.	 Studies of cancer in experimentalered. D...
Preamble(e.g. too short a duration, too few animals, poor      (a)	 Qualitative aspectssurvival; see below) may be omitted...
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
IARC Monographs on the Evaluation of 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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Monografia de la INTERNATIONAL AGENCY FOR RESEARCH ON CANCER sobre el efecto de las radiaciones en la incidencia de cancer

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  1. 1. WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCERIARC Monographs on the Evaluation of Carcinogenic Risks to Humans VOLUME 100 A Review of Human Carcinogens Part D: Radiation LYON, FRANCE
  2. 2. WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCERIARC 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
  3. 3. IARC MONOGRAPHS In 1969, the International Agency for Research on Cancer (IARC) initiated a programme on the evaluation of the carcinogenicrisk of chemicals to humans involving the production of critically evaluated monographs on individual chemicals. The programmewas subsequently expanded to include evaluations of carcinogenic risks associated with exposures to complex mixtures, lifestylefactors and biological and physical agents, as well as those in specific occupations. The objective of the programme is to elaborateand publish in the form of monographs critical reviews of data on carcinogenicity for agents to which humans are known to beexposed and on specific exposure situa­ ions; to evaluate these data in terms of human risk with the help of international working tgroups of experts in chemical carcinogenesis and related fields; and to indicate where additional research efforts are needed. Thelists 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 NationalCancer 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 EqualOpportunities, and since 1992 by the United States National Institute of Environmental Health Sciences, Department of Healthand Human Services. The contents of this volume are solely the responsibility of the Working Group and do not necessarilyrepresent 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, SocialAffairs and Equal Opportunities. This volume was made possible, in part, through Cooperative Agreement CR 834012 with the United States EnvironmentalProtection Agency, Office of Research and Development. The contents of this volume do not necessarily reflect the views orpolicies 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 noncommercialdistribution – 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 anyopinion 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 orrecommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors andomissions 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
  4. 4. CONTENTSNOTE TO THE READER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1List of Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3PREAMBLE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29General Remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31SOLAR 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
  5. 5. 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90X- 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210NEUTRON 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237vi
  6. 6. Contents 4. Other Relevant Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 5. Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237INTERNALIZED 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275INTERNALIZED 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298List of Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305CUMULATIVE CROSS INDEX TO IARC MONOGRAPHS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309List of IARC Monographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 vii
  7. 7. NOTE TO THE READER The term ‘carcinogenic risk’ in the IARC Monographs series is taken to mean that an agent iscapable of causing cancer. The Monographs evaluate cancer hazards, despite the historical presenceof the word ‘risks’ in the title. Inclusion of an agent in the Monographs does not imply that it is a carcinogen, only that thepublished data have been examined. Equally, the fact that an agent has not yet been evaluated in aMonograph does not mean that it is not carcinogenic. Similarly, identification of cancer sites withsufficient evidence or limited evidence in humans should not be viewed as precluding the possibilitythat an agent may cause cancer at other sites. The evaluations of carcinogenic risk are made by international working groups of independentscientists 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 riskof an agent to humans is encouraged to make this information available to the Section of IARCMonographs, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 LyonCedex 08, France, in order that the agent may be considered for re-evaluation by a future WorkingGroup. Although every effort is made to prepare the monographs as accurately as possible, mistakes mayoccur. Readers are requested to communicate any errors to the Section of IARC Monographs, so thatcorrections can be reported in future volumes. 1
  8. 8. List of ParticipantsMembers1Bruce 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 USAKeith Baverstock Elisabeth CardisFaculty of Natural and Environmental Center for Research in Environmental Sciences Epidemiology (CREAL)University of Eastern Finland E-08003 BarcelonaFI-70211 Kuopio SpainFinland1 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 identificationpurposes only. Invited specialists are marked by an asterisk.Each participant was asked to disclose pertinent research, employment, and financial interests. Current financialinterests 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 provideno more than 5% of the research budget of the expert’s organization and that do not support the expert’s research orposition, and consulting or speaking on matters not before a court or government agency that does not exceed 2% oftotal professional time or compensation. All grants that support the expert’s research or position and all consulting orspeaking on behalf of an interested party on matters before a court or government agency are listed as significant perti-nent interests. 3
  9. 9. IARC MONOGRAPHS – 100DAdele 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 USARaymond 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 6N5Janet 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 1PGMark A. Hill United KingdomGray Institute for Radiation Oncology & BiologyUniversity of OxfordOxford OX3 7DQUnited Kingdom2 Dr Green receives research funds (not exceeding 5% of total research support) from L’Oréal which makes productsintended 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 bygrants 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. Thisrepresented less than 5% of his annual total professional compensation for 2006 and 2007, when the activity ceased. Healso advised the International Epidemiology Institute (USA) and Westlakes Research Institute (UK) on epidemiologicalmatters. 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, USA4
  10. 10. ParticipantsMichael 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 USARonald 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 KingdomColin 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 FranceNicholas 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 Canada6 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 Canadawhose mandate is to sustain and enhance nuclear technology, to manage nuclear wastes, and to maximize return oninvestment 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 ofDefence 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 sustainand 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 berelated 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
  11. 11. IARC MONOGRAPHS – 100DLadislav 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-ChefRobert L. Ullrich12 UTMB Cancer Center University of Texas Medical Branch Post-meeting Scientific Assistance Galveston, TX 77555-1048 USA Farhad Islami Administrative AssistanceIARC 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 berelated to X-rays.6
  12. 12. PREAMBLEThe 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 ofevidence considered and the scientific criteria that guide the evaluations. The Preambleshould 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 andreceived 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 fromfor lists of known and suspected human carcino- the title, which assumed its present form, IARCgens. It was clear that it would not be a simple Monographs on the Evaluation of Carcinogenictask to summarize adequately the complexity of Risks to Humans.the information that was available, and IARC Through the Monographs programme, IARCbegan to consider means of obtaining interna- seeks to identify the causes of human cancer. Thistional expert opinion on this topic. In 1970, the is the first step in cancer prevention, which isIARC 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 andpendium on carcinogenic chemicals be pre- continues to increase: the annual number of newpared by experts. The biological activity and cases was estimated at 10.1 million in 2000 andevaluation of practical importance to public is expected to reach 15 million by 2020 (Stewarthealth 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 hastion concerning the role of IARC in providing been shifting from high-resource countries togovernment authorities with expert, independ- low- and medium-resource countries. As a resultent, 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 takeCouncil 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
  13. 13. IARC MONOGRAPHS – 100D The criteria established in 1971 to evaluate causation of, and susceptibility to, malignantcarcinogenic 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 capablethe 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 in1992; 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 hazardswhich a Working Group implements these prin- even when risks are very low at current exposureciples are not specified in detail. They usually levels, because new uses or unforeseen exposuresinvolve 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 in2. 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’ areGroups of experts, and to publish in the form of used interchangeably.Monographs, critical reviews and evaluations of The Preamble continues the previous usageevidence on the carcinogenicity of a wide range of the phrase ‘strength of evidence’ as a matterof human exposures. The Monographs repre- of historical continuity, although it should besent 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 cancermation 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 experimentalincidence of cancer in humans. The Monographs studies indicate that different agents may act atmay also indicate where additional research different stages in the carcinogenic process, andefforts 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, benow 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; seeenvironmental exposures, cultural or behav- also Part B, Sections 4 and 6). As mechanismsioural practices, biological organisms and physi- of carcinogenesis are elucidated, IARC convenescal agents. This list of categories may expand as international scientific conferences to determine whether a broad-based consensus has emerged8
  14. 14. Preambleon 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 mayresults 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 culturalreflect the current state of scientific knowledge, habits (such as tobacco smoking and dietarymay 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 alsoinvolve dose–response assessment. In many be considered, even in the absence of data on acases, 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 convenedof the available epidemiological data, or it may by IARC in 1984, 1989, 1991, 1993, 1998 andcompare the dose–response information from 2003 made recommendations as to whichexperimental and epidemiological studies. In agents should be evaluated in the Monographssome 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 sitetise 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 ofinternational authorities to make risk assess- new scientific information or as national healthments, formulate decisions concerning preventive agencies identify an urgent public health needmeasures, provide effective cancer control pro- related to cancer.grammes and decide among alternative options As significant new data become availablefor 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 itcarcinogenicity 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 usefulbody of information on which public health deci- for updating a database, reviewing new data tosions may be based. Public health options vary resolve a previously open question or identifyingfrom one situation to another and from country new tumour sites associated with a carcinogenicto country and relate to many factors, including agent. Major changes in an evaluation (e.g. a newdifferent socioeconomic and national priorities. classification in Group 1 or a determination that aTherefore, no recommendation is given with mechanism does not operate in humans, see Partregard to regulation or legislation, which are B, Section 6) are more appropriately addressed bythe responsibility of individual governments or a full review.other international organizations. 4. Data for the Monographs3. 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 intwo main criteria: (a) there is evidence of human experimental animals. Those judged inadequate 9
  15. 15. IARC MONOGRAPHS – 100Dor irrelevant to the evaluation may be cited but (a) The Working Groupnot summarized. If a group of similar studies isnot 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 developedreviewed. A Monograph does not necessarily during the meeting. The tasks of Working Groupcite all the mechanistic literature concerning Members are: (i) to ascertain that all appropriatethe 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 scientificGroup to be relevant to making the evaluation merit; (iii) to prepare accurate summaries of theare included. data to enable the reader to follow the reasoning With regard to epidemiological studies, can- of the Working Group; (iv) to evaluate the resultscer bioassays, and mechanistic and other relevant of epidemiological and experimental studies ondata, 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; andscientific 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. Workingfrom 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 ofmeeting (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. Workingable 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 realform 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 Specialistsoccurrence, published and unpublished sources Invited Specialists are experts who also haveof 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. Theseance of the adequacy of the study design or of experts are invited when necessary to assist inthe analysis and interpretation of the results, and the Working Group by contributing their uniquelimitations are clearly outlined in square brack- knowledge and experience during subgroup andets at the end of each study description (see Part plenary discussions. They may also contributeB). The reasons for not giving further considera- text on non-influential issues in the section ontion to an individual study also are indicated in exposure, such as a general description of datathe square brackets. on production and use (see Part B, Section 1). Invited Specialists do not serve as meeting chair5. 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
  16. 16. 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 oftional 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 (Coglianoor 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 participantsmay be admitted to a meeting by IARC in limited are asked to report all such contacts to IARCnumbers. 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 Workingit. Observers do not serve as meeting chair or Group serves as an individual scientist and not assubgroup chair, draft any part of a Monograph, a representative of any organization, governmentor participate in the evaluations. At the meeting, or industry.the meeting chair and subgroup chairs may grantObservers an opportunity to speak, generally 6. Working proceduresafter they have observed a discussion. Observersagree to respect the Guidelines for Observers A separate Working Group is responsible forat 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 bewho 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) andparticipate 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, relevantalso 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 informationtial participant, including the IARC Secretariat, on carcinogenesis, including data storage andcompletes 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 preliminarysulting, and individual and institutional research working papers for specific sections are expectedsupport related to the subject of the meeting. to supplement the IARC literature searches withIARC assesses these interests to determine their own searches. 11
  17. 17. IARC MONOGRAPHS – 100D For most chemicals and some complex mix- the entire volume is the joint product of thetures, the major collection of data and the prep- Working Group, and there are no individuallyaration of working papers for the sections on authored sections.chemical and physical properties, on analysis, on IARC Working Groups strive to achieve aproduction and use, and on occurrence are car- consensus evaluation. Consensus reflects broadried out under a separate contract funded by the agreement among Working Group Members, butUS National Cancer Institute. Industrial associ- not necessarily unanimity. The chair may electations, labour unions and other knowledgeable to poll Working Group Members to determineorganizations may be asked to provide input to the diversity of scientific opinion on issues wherethe 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 verifiedInformation on production and trade is obtained by consulting the original literature, edited andfrom governmental, trade and market research prepared for publication. The aim is to publishpublications and, in some cases, by direct con- the volume within six months of the Workingtact with industries. Separate production data Group meeting. A summary of the outcome ison some agents may not be available for a vari- available on the Monographs programme webety 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 ANDdirect contact with manufacturers. Efforts are EVALUATIONmade to supplement this information with datafrom 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 therial 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 appearing papers are compiled by IARC staff and sent, in the original report; units are converted whenbefore the meeting, to Working Group Members necessary for easier comparison. The Workingand 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 assessmentto 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. Whenof the meeting are peer review and consensus. an important aspect of a study that directlyDuring the first few days, four subgroups (cov- impinges on its interpretation should be broughtering exposure data, cancer in humans, cancer to the attention of the reader, a Working Groupin 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 tomaries. 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, lifestylenot 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 Monographmeets in plenary session to review the subgroup has evolved to include the following sections:drafts and develop the evaluations. As a result,12
  18. 18. 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 cancerthe 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 areing the meeting. included. For foreign bodies, fibres and respir- This part of the Preamble discusses the types able particles, size range and relative dimensionsof evidence considered and summarized in each are indicated.section of a Monograph, followed by the scientific For agents such as mixtures, drugs or lifestylecriteria 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 detectionaccordingly. Also included is information on An overview of methods of analysis andproduction and use (when appropriate), meth- detection of the agent is presented, includingods of analysis and detection, occurrence, and their sensitivity, specificity and reproducibility.sources and routes of human occupational and Methods widely used for regulatory purposesenvironmental exposures. Depending on the are emphasized. Methods for monitoring humanagent, regulations and guidelines for use may be exposure are also given. No critical evaluationpresented. or recommendation of any method is meant or implied.(a) General information on the agent For chemical agents, sections on chemical (c) Production and useand 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 ormary name and the IUPAC systematic name are other agent are provided when available; forrecorded; 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 madeon chemical and physical properties that are rel- of the date before which no human exposure toevant to identification, occurrence and biologi- the agent could have occurred. The dates of firstcal 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 ofevant specifications and available information synthesis used in past and present commercialon composition and impurities. Some of the production and different methods of production,trade names given may be those of mixtures in 13
  19. 19. IARC MONOGRAPHS – 100Dwhich may give rise to different impurities, are place. For biological agents, the epidemiology ofdescribed. infection is described. The countries where companies report pro-duction of the agent, and the number of compa- (e) Regulations and guidelinesnies in each country, are identified. Available dataon production, international trade and uses are Statements concerning regulations andobtained 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 theyof the agent. Some identified uses may not be may not reflect the most recent situation, sincecurrent 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 regulatorydrugs, mention of their therapeutic uses does not status for a country should not be taken to implynecessarily represent current practice nor does it that that country does not have regulations withimply 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 inthe environment is obtained from data derived 2. Studies of cancer in humansfrom 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 ofplants, foods and animal and human tissues. biomarkers are included when they are relevantWhen available, data on the generation, per- to an evaluation of carcinogenicity to humans.sistence and bioaccumulation of the agent arealso included. Such data may be available from (a) Types of study considerednational 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 inthe 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 seriesmental 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 ofmay be available from government reports and cancer in individuals and provide an estimate ofother sources. In the case of mixtures, indus- effect (such as relative risk) as the main measuretries, occupations or processes, information is of association. Intervention studies may providegiven about all agents known to be present. For strong evidence for making causal inferences, asprocesses, 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. in14
  20. 20. Preambleparticular geographical areas or at particular Bias is the effect of factors in study design ortimes), and cancer frequency is related to a sum- execution that lead erroneously to a stronger ormary measure of the exposure of the population weaker association than in fact exists between anto the agent under study. In correlation studies, agent and disease. Confounding is a form of biasindividual exposure is not documented, which that occurs when the relationship with disease isrenders this kind of study more prone to con- made to appear stronger or weaker than it truly isfounding. In some circumstances, however, cor- as a result of an association between the apparentrelation studies may be more informative than causal factor and another factor that is associatedanalytical 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 related2004). 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 designexperience, that the concurrence of two events — and analysis as described in the report of thethat 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 interpretingand case series usually lack complete ascertain- subsequent studies that included these data in anment 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 andmation of the expected number of cases in the correlation studies. Lack of clarity of any of theseabsence 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 thepretation 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 wella causal relationship. When taken together with defined by the authors. Cases of disease in thecase–control and cohort studies, however, these study population should have been identified intypes of study may add materially to the judge- a way that was independent of the exposure ofment 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 intoother 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 exposurecancer 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 diseasesible roles of bias, confounding and chance in may or may not be more appropriate than thosethe interpretation of epidemiological studies. with national rates. Internal comparisons of 15
  21. 21. IARC MONOGRAPHS – 100Dfrequency of disease among individuals at differ- The advantages of combined analyses areent levels of exposure are also desirable in cohort increased precision due to increased sample sizestudies, 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 effectstors between an external reference group and the that may explain heterogeneity among studies instudy population. more detail. A disadvantage of combined analy- Third, the authors should have reported the ses is the possible lack of compatibility of databasic 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 thana cohort study. Further tabulations by time since individual studies for drawing conclusions aboutexposure 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 orcancer sites and all causes of death should have pooled analysis that is pertinent to a particularbeen 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 oftigated factors other than the exposure of interest multiple individual studies, ad hoc calculationsshould have been reported. that combine data from different studies may Finally, the statistical methods used to obtain be conducted by the Working Group duringestimates of relative risk, absolute rates of can- the course of a Monograph meeting. The resultscer, confidence intervals and significance tests, of such original calculations, which would beand to adjust for confounding should have been specified in the text by presentation in squareclearly stated by the authors. These methods have brackets, might involve updates of previouslybeen 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 heterogeneitysame agent may lead to results that are difficult between studies be taken into account.to interpret. Combined analyses of data frommultiple studies are a means of resolving this (d) Temporal effectsambiguity, and well conducted analyses can beconsidered. 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, suchstatistics 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, peakpooled analysis of the raw data from the individ- exposure (when appropriate) and time sinceual studies (pooled analysis) (Greenland, 1998). cessation of exposure, are reviewed and sum- marized when available. Analyses of temporal16
  22. 22. Preamblerelationships 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 theprocess of carcinogenesis, although, at best, they (f) Criteria for causalityallow only indirect inferences about mechanismsof 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 associationused in epidemiological studies for various pur- (e.g. a large relative risk) is more likely to indicateposes (IARC, 1991; Vainio et al., 1992; Toniolo causality than a weak association, although it iset 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 beeffects, 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 studiesand 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 representand other emerging technologies. a causal relationship than isolated observations Molecular epidemiological data that identify from single studies. If there are inconsistentassociations between genetic polymorphisms results among investigations, possible reasonsand interindividual differences in susceptibility are sought (such as differences in exposure), andto the agent(s) being evaluated may contribute results of studies that are judged to be of highto 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 lessstrated experimentally to modify the functional sound.activity of the gene product in a manner that is If the risk increases with the exposure, this isconsistent 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 notSimilarly, molecular epidemiological studies that necessarily evidence against a causal relation-measure cell functions, enzymes or metabolites ship. The demonstration of a decline in risk afterthat 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 acal plausibility. It should be noted, however, that causal interpretation of the findings.when data on genetic susceptibility originate Several scenarios may increase confidence infrom multiple comparisons that arise from sub- a causal relationship. On the one hand, an agentgroup analyses, this can generate false-positive may be specific in causing tumours at one site orresults 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 causationIf the known phenotype of a genetic polymor- of multiple tumour types. Temporality, precisionphism can explain the carcinogenic mechanism of estimates of effect, biological plausibility and 17
  23. 23. IARC MONOGRAPHS – 100Dcoherence of the overall database are consid- 3. Studies of cancer in experimentalered. Data on biomarkers may be employed in animalsan 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 resultsamong 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 suspectedthat, in the aggregate, they show evidence of lack before epidemiological studies confirmed theirof 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 thatthe 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 biologicallyfounding or misclassification of exposure or out- plausible that agents for which there is sufficientcome 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, inbe 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 carcinogenicobserved 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 thatrisk that is at or near to unity, and (c) have a nar- a given agent causes cancer in animals throughrow 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 thepooled 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 animalscarcinogenicity obtained from several epidemio- with the agent under review (see Part A, Sectionlogical studies can apply only to the type(s) of 4). In all experimental settings, the nature andcancer studied, to the dose levels reported, and to extent of impurities or contaminants present inthe 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 genetichuman cancer indicates that the period from first background where applicable), sex, numbers perexposure 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, survivalsubstantially 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 inadequate18
  24. 24. Preamble(e.g. too short a duration, too few animals, poor (a) Qualitative aspectssurvival; see below) may be omitted. Guidelinesfor conducting long-term carcinogenicity exper- An assessment of carcinogenicity involvesiments have been published (e.g. OECD, 2002). several considerations of qualitative impor- Other studies considered may include: exper- tance, including (i) the experimental conditionsiments in which the agent was administered in under which the test was performed, includingthe 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 wherecarcinogenicity 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 preneoplasticity 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 modifyinglivestock 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 studygiven 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) whetherextraction, concentration and delivery. Another the dose was monitored adequately, particu-consideration is that chemical and toxicological larly in inhalation experiments; (iii) whether theinteractions 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 survivalto 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 numbersThis may involve consideration of the following of animals per group; (vi) whether both male andaspects of the mixture tested: (i) physical and female animals were used; (vii) whether animalschemical characteristics, (ii) identified constitu- were allocated randomly to groups; (viii) whetherents that may indicate the presence of a class of the duration of observation was adequate; andsubstances and (iii) the results of genetic toxicity (ix) whether the data were reported and analysedand related tests. adequately. The relevance of results obtained with an When benign tumours (a) occur togetheragent that is analogous (e.g. similar in structure with and originate from the same cell type asor of a similar virus genus) to that being evalu- malignant tumours in an organ or tissue in aated is also considered. Such results may provide particular study and (b) appear to represent abiological and mechanistic information that is stage in the progression to malignancy, they arerelevant to the understanding of the process of usually combined in the assessment of tumourcarcinogenesis in humans and may strengthen incidence (Huff et al., 1989). The occurrence ofthe 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

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