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hypothetically have led to the exclusion of carcinogens that properly belong in Region C from the CPDB and from studies based on the CPDB. For purposes of discussion, we refer to these hypothetically excluded carcinogens that properly belong in Region C as "supercarcinogens"—defined for this purpose as carcinogens whose TD50s lie below the 95% error bound on the regression line in Figure 1, i.e., less than about MTD/7. One hypothetical source of bias is that some of these agents were identified as potent carcinogens long ago and, being well known as such, were never tested in up-to-date bioassays and so did not have met the inclusion criteria of the CPDB. Another possible source of bias is that some of the agents, if tested at the MTD, yielded tumors in very short periods and were excluded from the CPDB because of early termination of the studies. Krewski's criteria for selecting chemicals from the CPDB for analysis could have introduced other, more subtle biases.

To investigate whether those hypothetical biases are important, the committee conducted a search for supercarcinogens that exist but have been excluded from the CPDB or from Krewski's analysis. The search was necessarily informal, because there is no systematic compilation of carcinogenic potencies other than the CPDB. The committee's approach was to compile a list of candidate chemicals with various criteria and then to review the data on them to explore whether they might fall into Region C, either according to the inclusion criteria and calculation procedures of the CPDB and of Krewski or according to modified criteria and procedures. The results of the search are reported in this appendix.

CRITERIA AND CANDIDATE CHEMICALS

The following criteria were used to identify candidate chemicals for this study:

  1. "Classical" carcinogens—identified before 1965 and not subjected to modern bioassays.

  2. Agents that induced tumors in less than 6-months and might never have been tested in a lifetime bioassay.

  3. Other agents that are generally recognized as "potent" carcinogens and might never have been formally tested for carcinogenicity.



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OCR for page 175
APPENDIX G 175 original typesetting files. Page breaks are true to the original; line lengths, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be About this PDF file: This new digital representation of the original work has been recomposed from XML files created from the original paper book, not from the retained, and some typographic errors may have been accidentally inserted. Please use the print version of this publication as the authoritative version for attribution. hypothetically have led to the exclusion of carcinogens that properly belong in Region C from the CPDB and from studies based on the CPDB. For purposes of discussion, we refer to these hypothetically excluded carcinogens that properly belong in Region C as "supercarcinogens"—defined for this purpose as carcinogens whose TD50s lie below the 95% error bound on the regression line in Figure 1, i.e., less than about MTD/7. One hypothetical source of bias is that some of these agents were identified as potent carcinogens long ago and, being well known as such, were never tested in up-to-date bioassays and so did not have met the inclusion criteria of the CPDB. Another possible source of bias is that some of the agents, if tested at the MTD, yielded tumors in very short periods and were excluded from the CPDB because of early termination of the studies. Krewski's criteria for selecting chemicals from the CPDB for analysis could have introduced other, more subtle biases. To investigate whether those hypothetical biases are important, the committee conducted a search for supercarcinogens that exist but have been excluded from the CPDB or from Krewski's analysis. The search was necessarily informal, because there is no systematic compilation of carcinogenic potencies other than the CPDB. The committee's approach was to compile a list of candidate chemicals with various criteria and then to review the data on them to explore whether they might fall into Region C, either according to the inclusion criteria and calculation procedures of the CPDB and of Krewski or according to modified criteria and procedures. The results of the search are reported in this appendix. CRITERIA AND CANDIDATE CHEMICALS The following criteria were used to identify candidate chemicals for this study: A. "Classical" carcinogens—identified before 1965 and not subjected to modern bioassays. B. Agents that induced tumors in less than 6-months and might never have been tested in a lifetime bioassay. C. Other agents that are generally recognized as "potent" carcinogens and might never have been formally tested for carcinogenicity.

OCR for page 175
APPENDIX G 176 original typesetting files. Page breaks are true to the original; line lengths, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be About this PDF file: This new digital representation of the original work has been recomposed from XML files created from the original paper book, not from the retained, and some typographic errors may have been accidentally inserted. Please use the print version of this publication as the authoritative version for attribution. D. Agents that have been tested over an unusually wide range of doses and are believed to be effective at doses below the MTD by a factor of at least 100. E. Other agents nominated by committee members. On the basis of those criteria, the committee selected 18 candidate agents for study (Table G-1). TABLE G-1 Chemicals and Other Agents Considered in this Study Criteria for Inclusion in the Studya Agent 2-Acetylaminofluorene D Acrylonitrile E Benzidine B (parent compound of benzidine dyes) Benzo[a]pyrene A 1,3-Butadiene D Carbon tetrachloride C C.I. Direct Black 38 B C.I. Direct Blue 6 B C.I. Direct Brown 95 B Dibenz[a,h]anthracene A Dimethyl sulfate C Ethylene dibromide B Ethylene oxide E Ethylnitrosourea C Methyl bromide B MOCA E Plutonium A,B,C,D, (most potent member of class of radionuclides) Vinyl Chloride D aSee text.