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R A Division of loews Theatres. Inc., Research Center, 420 English Street, P.O. Box 21668, Greensboro, North Carolina 27420 October 6, 1983 Dr. Carol J. Henry Microbiological Associates 5221 River Road Bethesda, Md. 20816 Dear Dr. Henry: We have the fpllowinQ cnmen Reports Cigarette Smoke (D13 and D After Inhalation in Mice and 1-2130.003 . . /~N N _(1 /X--- 11-11 a""¢ OCT 12 1983 n L,,wn4.D questions concerning the Draft Comparative Toxicity of Test with Reference Cigarette Smoke in Rats, respectively. On page 12, paragraph 5, lines 3-9: the statistical differ- ences mentioned here should be described as being higher than the controls to reflect values in Table 4. 2. Same page, paragraph 6, line 2: Tables should be plural. 3. In Tables 5B and 5C a degree of severity is not indicated for the condition of "shallow breathing" under Observations Immediately After Exposure, whereas in Tables 5E and 5F this condition is described as being severe. Please explain this discrepancy. 4. In Tables 5E and 5F a degree of severity is not indicated for the condition of "unable to walk" under Observations Immediately After Exposure and also for the condition of 5. "lying prone" in Table 5E in the same section. indicate a reason for this. Table 5G is missing from the report. Please 1-2130.004 1. On page 6, paragraph 1, line 4: "to" should be omitted. 2. In Table 5C a degree of severity is not indicated for the condition of "eye tearing" under Observations Immediately After Exposure, whereas in Table 5D this condition is described as being slight. Please explain this discrepancy.

We have also reviewed the Draft Report for 1-1729.006: Six Week Repeated Smoke Inhalation in Rats to Compare Histopathology and Short Term Endpoints Using Test (D6 and D10) and Reference Cigarettes,•and have these comments: 1. On page 13, under Blood Collections, line 6: affect is misspelled. ~ 2. On page 15, under Evaluation, paragraph 3, line 9: the text should read "statistics will be used." 3. Throughout the text and Tables, the expression "signifi- cantly different" is used when discussing statistical differences. In future reports, it would be helpful to indicate the direction of the difference, i.e., "signifi- cantly higher" or "significantly lower." 4. On page 18, paragraph 4, line 11: the text should read "no other differences between smoke exposed groups were observed for." 5. On pages 18-19, in the discussion of the mitotic count results: please add a sentence summarizing the conclusions drawn from the mitotic counts. This information should also be included in Section VIII., Conclusions. 6. On page 20, paragraph 2 and page 21, paragraph 4; total and differential white blood cell counts are discussed. Both the 3 and 6 week data show similar patterns, i.e., increased total while blood cells, neutrophils, and monocytes in smoke-exposed groups and increased lymphocytes in sham- exposed groups. The discussion of 3 week data on page 20 did not mention neutrophil, monocyte, or lymphocyte results. Should this have been included and/or compared with the 6 week data? 7. On pages 20 and 21, paragraphs 5 and 1, respectively: transformations cf bilirubin and creatinine data are dis- cussed. Please include these data (showing any significant differences) in the Tables. 8. On page 21, last paragraph, line 17: choriomeningitis is misspelled. 9. On page 21 at the bottom, various rodent viruses are listed. What types of organisms were not screened for which could be responsible for the increased number of leukocytes? 10. On page 22, paragraph 2, line 8: the text should read "and kidneys was." ' 11. On page 23, paragraph 1, line 7: changes is misspelled. 2

12. On page 23, last line: the hyphen following "smoke" should be deleted. 13._ In Table GT3, Animal No. 1207, under Day 14 weight: does this weight (146.8 g) represent the Day 10 weight after death? Please specify in a footnote. 14. In Table GT12 at the top: a super4cript "a" should be added to correspond to footnote "a" at the bottom. 15. In Table CCH4: why were these values "not reported"? Since the protocol called for these levels to be checked, the text should mention why the values were not available. 16. In the title of Table CCH17: Analysis is misspelled. 17. In Table CCH33: the title should read "For 6 Week." 18. In Tables CCH39, CCH44, CCH52, and CCH53, in the lower right corners: "Not Significant" apparently refers to both the Welch and Brown-Forsythe statistics. Please clarify this with footnotes. 19. In Appendix A, page 2, paragraph 2: what does the descrip- tion "Thymus appeared excessive" mean? Will the signifi- cance of this finding be described in the follow-up report referred to on page 23? 20. Same paragraph as #19 above, line 3: were is misspelled. If you have any questions, please feel free to call. Sincerely, ~ ~ -/ ~ ri':~tc{ "'' Connie J.'' Stbne, Ph.D., D.A.B.T. CJS/lp:2 3