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A Division of Loews Theatres, Inc., Research Center, 420 English Street, P.O. Box 21688, Greensboro, North Carolina 27420 April 15, 1985 Dr. Carol J. Henry Microbiological Associates, Inc. 5221 River Road Bethesda, MD 20816 Dear Dr. Henry: We have the following comments and questions concerning MA Project No. 1-2473.026, "90-Day Subchronic Smoke Inhalation in Rats to Compare Respiratory Tract Histopathology, Cytology of Lavage Fluid, and Selected Biochemical Endpoints Using Test (D23 and D24) and Reference Cigarettes," Draft Final Report. 1. On page 2, last paragraph, line 8: the "Matulionis" reference should be "Matulionis and Traurig". 2. On page 8, last paragraph, line 1: "achieved" is misspelled. 3. On page 14, under Blood Collections, line 5: "affect" should replace "effect". 4. On page 16, paragraph 1, line 6: the text should read "pathologies of the respiratory tract". 5. On pages 16 and 17, the text lists various parameters which are statistically compared by the Studentized Range test and the Kruskal-Wallis or Mann-Whitney U-test. The text states that values compared using the Mann-Whitney U-test are median values. Is this correct? Are some of the values in the Clinical Chemistry and Hematology tables median values? For example, Tables CCH2 and CCH11 show values which are statistically different using the Mann-Whitney U-test, yet these values appear to be means, not medians. Also, in Tables GT2 and GT3, mean (rather than median) COHb levels are compared using the Mann-Whitney U-test, and the text discusses mean COHb values on page 19. 6. On page 17, column 2, line 6: "beta-Glucuronidase" is m O 7 misspelled. line 5: On page 20 the abbreviation for methemo lobin N cA O . , should be "MetHb". g N V 1A

2 8. On page 20, under Body Weights, paragraph 2, line 7: the text should specify "Male shelf-control rats". 9. On page 21, last paragraph, line 1: "ratios for individual male rats". the text should read 10. On page 22, second complete paragraph: A. Line 4 - the phrase "smoke-exposed" should be hyphenated (following "D24"). B. Line 9 - the text should specify "heart and liver weights for smoke-exposed female groups". C. Line 13 - the text should state that the groups "were significantly lower than for shelf controls". 11. On page 23, line 6: "smoke-exposed" should be hyphenated. 12. On page 23, under Food Consumption: A. Paragraph 1, line 4: the text should read "average of the two cages is presented". B. Paragraph 3, lines 1-2: the text should read "for female rats are presented". 13. On page 24, lines 3-4: the text should delete the comma following 13%, and add ",respectively," after "food". 14. On page 25, under Male Rats, paragraph 2, last line: the text should read "between the D24 cigarette". 15. On page 26, line 2: "Test cigarette-exposed" should be hyphenated. 16. On page 26, second complete paragraph, line 5: "leukocytes" should be singular. 17. On page 27, line 1: "percentage" is misspelled. 18. On page 27, second complete paragraph, line 9: one "the" should be omitted. 19. On pages 27-28, in the discussions of urine samples from male rats in the D23 group, D24 group, sham group, and shelf group: the text did not mention that moderate amounts of bacteria were observed. GA 20. On page 27, a space should be added between the last two ~ paragraphs. ~ O N L11 N

3 21. On page 30, first complete paragraph, lines 4-5: the text 22. does not discuss that no differences were observed among the groups in monocyte counts. On page 31, paragraph 1, line 9: a comma should follow „i.e.". 23. On page 31, paragraph 2, lines 9-10: the text should read "Little or no hemoglobin was detected in the samples from 24. the other animals". On page 33, under Cytology, paragraph 2: A. Lines 6-7 - shelf controls had more macrophages/lung than did the sham-exposed and the smoke-exposed animals. B. Last line - should this refer to Table LF2? 25. On page 34, first complete paragraph: A. Line 5 - the text should read "presented in LF9-LF13". B. Line 7 - "controls" should be singular. 26. On page 34, under Biochemistry: A. Paragraph 2, line 4 - the text should read "The AKP activity in the D23 group was significantly less than in the Reference group". B. Paragraph 3, line 2 - a comma should follow "Reference". C. Paragraph 3, line 7 - "phospholipid" should be plural. 27. On page 35, third complete paragraph, line 7: the text should read "Reference and shelf control groups". 28. On page 36, paragraph 2: A. Line 1 - "within" is misspelled. B. Line 3 - the text should read "while for male rats it (or the dose) was RSD1 at 6 puffs/exposure". 29. On page 38, line 8: the text should read "most parameters were within the normal range". 30. On page 38, first complete paragraph, line 7: "activity" is misspelled. ~ O 31. On page 38, second complete paragraph, line 8: the word N "possibly" should replace "possible." W O n7 N W

4 32. Table GT1, last line at the bottom: the date should be 1110/04/84". 33. In several tables, the ± symbol (next to standard deviation) was either omitted or mistyped. The following list describes where this correction should be made. A. Table GT11, under Kidneys, in the left-hand column. B. Table GT11, under Reference, row 2. C. Table GT13, under Liver, in the left-hand column. D. Table GT17, under Liver, in the left-hand column. E. Table GT18, at the bottom of the page. 34. On the page defining the "Abbreviations for Clinical Chemistry, Hematology, and Urinalysis," the term "BASO- Basophils" should be added. 35. In Tables CCH2 and CCH11, the units for AKP should be VVI U / 1 11. 36. In Tables CCH3 and CCH12, the units for HGB should agree with Tables CCH4 and CCH13, respectively. 37. At the bottom of Tables LF2, LF4, LF6, and LF8, footnote "b": "significantly" is misspelled. The following comments pertain to the Pathology Report in Appendix A. 1. On the Table of Contents page, line 3: "incidence" is misspelled. 2. On page 1, under RESULTS AND DISCUSSION: the text states that lesions attributable to smoke treatment were observed "possibly in the testes of male rats". The way this is worded is unclear, and it does not provide important details which are explained later. On page 3, paragraph 4 of the pathology report, the text explains that the testicular lesions may have been caused by the restraining device, and it states that the higher incidence of testicular lesions "was not attributed to systemic effects of the smoke". This should be stated more clearly in the RESULTS AND DISCUSSION section. 3. On page 2, under MICROSCOPIC FINDINGS, paragraph 2, line 5: 0 "undetermined" is misspelled. ~A O N CJl oA

5 4. On page 3, paragraph 1, line 2: the text should read "in 1 of 10, 2 of 10, and 0 of 9 males rats" (according to page 58). - If you have any questions, please feel free to call. Sincje-rely., o~I i~-''""¢---- 'Connie ~J. Stone, Ph.D., D.A.B.T. CJS/jw:l