PRINCIPLES OF TOXICOLOGY - Biology East Borneo

13.8 OCCUPATIONAL CARCINOGENS 301TABLE 13.10 The Poor Correlation in Organ Sites among Positive Rodent TestsSite of Cancer N Rats/Mice Percent N Mice/Rats PercentLiver 25/33 75 25/78 32Lung 2/7 29 2/18 11Hematopoietic system 3/14 21 3/11 27Kidney (tubular cells) 3/21 14 3/4 75Mammary gland 4/18 22 4/7 57Forestomach 8/14 57 8/15 53Thyroid gland 7/16 44 7/9 78Zymbal gland 2/12 17 2/2 100Urinary bladder 2/12 17 2/3 67Skin 3/11 27 3/3 100Clitoral/Preputial gland 0/7 — 0/3 —Circulatory system 2/4 50 2/10 20Adrenal medulla 0/4 — 0/4 —Total 61/173 35 61/167 37Source: Adapted from Haseman and Lockhart (1993).analysis but compares the data from a subsequent update of the original study as well, illustrating thatas the number of chemicals tested expands, the agreement in results across species does not seem tobe changing.From this analysis it is evident that when a chemical induces cancer in one of these two rodentspecies, it is also carcinogenic in the other species less than 50 percent of the time. This lack ofconcordance between these two phylogenetically similar species raises a concern voiced by manyscientists when such data are extrapolated to humans without also considering mechanistic andpharmacokinetic data from both species that might help explain why such large differences exist.A similar problem arises when the issue of identifying the correct target organ is considered. Arecent analysis of the predictivity of the target organ for a carcinogen when extrapolating across tworodent species found one could predict the correct target organ about only about 37 percent of the time(Table 13.10). So, it would appear that not only is the assumption that a positive response in animalscan be assumed to predict the human response, but the likelihood that the correct target has beenidentified would also seem to be of some question.13.8 OCCUPATIONAL CARCINOGENSAlthough the first occupational carcinogen was identified by Sir Percival Pott in 1775, it was not until1970 with the passage of the Occupational Safety and Health Act and establishment of the OccupationalSafety and Health Administration (OSHA) that the United States had enforcement authority grantedto an agency to regulate the use of substances that were considered carcinogenic in the workplace.Prior to 1970, the source that was widely considered the most authoritative was the AmericanConference of Governmental Industrial Hygienists (ACGIH) and industry relied on this organizationto regulate worker exposure to chemicals and agents. The other event occurring about this time thathas shaped our current view of occupational carcinogens was the emergence of the cancer bioassay.The development and continued use of this bioassay over the years has identified many hundreds ofindustrial chemicals as having carcinogenic activity, at least in high-dose animal tests, many of whichhad never before been suspected of human carcinogenic activity. As certain chemicals or groups ofchemicals became identified as carcinogens, this, in turn, brought to bear new pressures on industriesas lower exposure levels or alternative chemicals were sought to reduce the possible risks associated