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November 13, 1996, Vol 276, No. 18 >
ARTICLE | November 13, 1996

Cigarette Smoking, N-Acetyltransferase 2 Genetic Polymorphisms, and Breast Cancer Risk FREE

Christine B. Ambrosone, PhD; Jo L. Freudenheim, PhD; Saxon Graham, PhD; James R. Marshall, PhD; John E. Vena, PhD; John R. Brasure; Arthur M. Michalek, PhD; Rosemary Laughlin, PhD; Takuma Nemoto, MD; Kari A. Gillenwater; Anita M. Harrington; Peter G. Shields, MD
[+] Author Affiliations

This work was a collaborative effort by the Department of Social and Preventive Medicine, State University of New York at Buffalo, and the Laboratory of Human Carcinogenesis, National Cancer Institute. It is solely the responsibility of the authors and does not necessarily represent the views of the National Cancer Institute.

Reprints: Christine B. Ambrosone, PhD, National Center for Toxicological Research, Division of Molecular Epidemiology, 3900 NCTR Rd, Jefferson, AR 72079 (e-mail: cambrosone@nctr.fda.gov); or Peter G. Shields, MD, Bldg 37, Room 2C16, Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD 20892 (e-mail: peter—g—shields@nih.gov).


JAMA. 1996;276(18):1494-1501. doi:10.1001/jama.1996.03540180050032
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Published online
Article
References

Objective.  —To determine if N-acetyltransferase 2 (NAT2) polymorphisms result in decreased capacity to detoxify carcinogenic aromatic amines in cigarette smoke, thus making some women who smoke more susceptible to breast cancer.

Design.  —Case-control study with genetic analyses. DNA analyses were performed for 3 polymorphisms accounting for 90% to 95% of the slow acetylation phenotype among whites.

Setting and Participants.  —White women with incident primary breast cancer (n=304) and community controls (n=327).

Results.  —Neither smoking nor NAT2 status was independently associated with breast cancer risk. There were no clear patterns of increased risk associated with smoking by NAT2 status among premenopausal women. In postmenopausal women, NAT2 strongly modified the association of smoking with risk. For slow acetylators, current smoking and smoking in the distant past increased breast cancer risk in a dose-dependent manner (odds ratios [95% confidence intervals] for the highest quartile of cigarettes smoked 2 and 20 years previously, 4.4 [1.3-14.8] and 3.9 [1.4-10.8], respectively). Among rapid acetylators, smoking was not associated with increased breast cancer risk.

Conclusions.  —Our results suggest that smoking may be an important risk factor for breast cancer among postmenopausal women who are slow acetylators, demonstrate heterogeneity in response to carcinogenic exposures, and may explain previous inconsistent findings for cigarette smoking as a breast cancer risk factor.

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Field NA, Baptiste MS, Nasca PC, Metzger BB.  Cigarette smoking and breast cancer . Int J Epidemiol . 1992;;21:842-848.
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Hiatt RA, Klatsky AL, Armstrong MA.  Alcohol consumption and the risk of breast cancer in a prepaid health plan . Cancer Res . 1988;;48:2284-2287.
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Schatzkin A, Carter CL, Green SB, et al.  Is alcohol consumption related to breast cancer? results from the Framingham Heart Study . J Natl Cancer Inst . 1989;;81:31-35.
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Schecter MT, Miller AB, Howe GR, Baines CJ, Craib KJ, Wall C.  Cigarette smoking and breast cancer: case-control studies of prevalent and incident cancer in the Canadian National Breast Screening Study . Am J Epidemiol . 1989;;130:213-220.
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Vatten LJ, Kvinnsland S.  Cigarette smoking and risk of breast cancer: a prospective study of 24,329 Norwegian women . Eur J Cancer . 1990;:26:830-833.
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Morabia A, Bernstein M, Heritier S, Khatchatrian N.  Relation of breast cancer with passive and active exposure to tobacco smoke . Am J Epidemiol . 1996;;143:918-928.
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Stockwell HG, Lyman GH.  Cigarette smoking and the risk of female reproductive cancers . Am J Obstet Gynecol . 1987;;157:35-40.
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Chu SY, Stroup NE, Wingo PA, Lee NC, Peterson HB, Gwinn ML.  Cigarette smoking and the risk of breast cancer . Am J Epidemiol . 1990;;131:244-253.
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Brinton LA, Schairer C, Stanford JL, Hoover RN.  Cigarette smoking and breast cancer . Am J Epidemiol . 1986;;123:614-622.
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Meara J, McPherson K, Roberts M, Jones L, Vessey M.  Alcohol, cigarette smoking and breast cancer . Br J Cancer . 1989;;60:70-73.
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Brownson RC, Blackwell CW, Pearson DK, Reynolds RD, Richens JW Jr, Papermaster BW.  Risk of breast cancer in relation to cigarette smoking . Arch Intern Med . 1988;;148:140-144.
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Rohan TE, Baron JA.  Cigarette smoking and breast cancer . Am J Epidemiol . 1989;;129:36-42.
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Petrakis NL, Maack CA, Lee RE, Lyon M.  Mutagenic activity in nipple aspirates of human breast fluid . Cancer Res . 1980;;40:188-189.
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Perera FP, Estabrook A, Hewer A, et al.  Carcinogen-DNA adducts in human breast tissue . Cancer Epidemiol Biomarkers Prev . 1995;;4:233-238.
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Li D, Wang M, Dhingra K, Hittleman WM.  Aromatic DNA adducts in adjacent tissues of breast cancer patients: clues to breast cancer etiology . Cancer Res . 1996;;56:287-293.
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Swaminathan S, Frederickson SM, Hatcher JF.  Metabolic activation of N-hydroxy-4-acetylaminobiphenyl by cultured human breast epithelial cell line MCF 10A . Carcinogenesis . 1994;;15:611-617.
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Eldridge SR, Gould MN, Butterworth BE.  Genotoxicity of environmental agents in human mammary epithelial cells . Cancer Res . 1992;;52:5617-5621.
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Tonelli QJ, Custer RP, Sorof S.  Transformation of cultured mouse mammary glands by aromatic amines and amides and their derivatives . Cancer Res . 1979;;39:1784-1792.
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Shirai T, Fysh FM, Lee M-S, Vaught JB, King CM.  Relationship of metabolic activation of N-hydroxy-N-acylarylamines to biological response in the liver and mammary gland of the female CD rat . Cancer Res . 1981;;41:4346-4353.
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Kadlubar FR, Butler MA, Kaderlik KR.  Polymorphisms for aromatic amine metabolism in humans: relevance for human carcinogenesis . Environ Health Perspect . 1992;;98:69-74.
35 +
Minchin RF, Kadlubar FF, Ilett KF.  Role of acetylation in colorectal cancer . Mutat Res . 1993;;290:35-42.
36 +
Bell DA, Taylor JA, Butler MA, et al.  Genotype/phenotype discordance for human arylamine N-acetyltransferase (NAT2)reveals a new slow-acetylator allele common in African-Americans . Carcinogenesis . 1993;;14:1689-1692.
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Vineis P, Bartsch H, Caporaso N, et al.  Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens . Nature . 1994;;369:154-156.
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Lin HJ, Han CY, Lin BK, Hardy S.  Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, blacks, Hispanics, and whites: application to metabolic epidemiology . Am J Hum Genet . 1993;;52:827-834.
39 +
Hanssen HP, Agarwal HW, Goedde H, et al.  Association of N-acetyltransferase polymorphism and environmental factors with bladder carcinogenesis . Eur Urol . 1985;;11:263-266.
40 +
Cartwright RA.  Epidemiological studies on N-acetylation and C-center ring oxidation in neoplasia . In: Omenn GS, Gelboin HV, eds. Genetic Variability in Responses to Chemical Exposure . Cold Spring Harbor, NY: Cold Spring Harbor Press; 1984;:359-368.
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Ilett KF, David BM, Detchon P, Castleden WM, Kwa R.  Acetylator phenotype in colorectal carcinoma . Cancer Res . 1987;;47:1466-1469.
42 +
Lang NP, Chu DZJ, Hunter CF, Kendall DC, Flammang TJ, Kadlubar FF.  Role of aromatic amine N-acetyltransferase in human colorectal cancer . Arch Surg . 1986;;121:1259-1261.
43 +
Lang NP, Butler MA, Massengill J, et al.  Rapid metabolic phenotypes for acetyltransferase and cytochrome P4501A2 and putative exposure to foodborne heterocyclic amines increase the risk for colorectal cancer or polyps . Cancer Epidemiol Biomarkers Prevention . 1994;;3:675-682.
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Bulovskaya LN, Krupkin RG, Bochina TA, Shipkova AA, Pavlova MV.  Acetylator phenotype in patients with breast cancer . Oncology . 1978;;35:185-188.
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Evans DAP.  Acetylation . Prog Clin Biol Res . 1986;;214:209-242.
46 +
Sardas S, Cod I, Sardas OS.  Polymorphic N-acetylation capacity in breast cancer patients . Int J Cancer . 1990;;46:1138-1139.
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Philip PA, Rogers HJ, Millis RR, Rubens RD, Cartwright RA.  Acetylator status and its relationship to breast cancer and other diseases of the breast . Eur J Cancer Clin Oncol . 1987;;23:1701-1706.
48 +
Ladero JM, Fernandez MJ, Palmeiro R, et al.  Hepatic acetylator polymorphism in breast cancer patients . Oncology . 1987;;44:341-344.
49 +
Graham S, Hellmann R, Marshall J, et al.  Nutritional epidemiology of postmenopausal breast cancer in western New York . Am J Epidemiol . 1991;;134:552-566.
50 +
Vatsis KP, Weber WW, Bell DA, et al.  Nomenclature for N-acetyltransferases . Pharmacogenetics . 1995;;5:1-17.
51 +
Begg CB, Zhang ZF.  Statistical analysis of molecular epidemiology studies employing case-series . Cancer Epidemiol Biomarkers Prev . 1994;;3:173-175.
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Piergorsch WW, Weinberg CR, Taylor JA.  Nonhierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies . Stat Med . 1994;;13:153-162.
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Wang CY, Yamada H, Morton KC, Zukowski K, Lee M-S, King CM.  Induction of repair synthesis of DNA in mammary and urinary bladder epithelial cells by N-hydroxy derivatives of carcinogenic arylamines . Cancer Res . 1988;;48:4227-4232.
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King CM, Traub NR, Lortz ZM, Thissen MR.  Metabolic activation of arylhydroxamic acids by N-O-acyltransferase of rat mammary gland . Cancer Res . 1979;;39:3369-3372.
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Allaben WT, Weis CC, Fullerton NF, Beland FA.  Formation and persistence of DNA adducts from the carcinogen N-hydroxy-2-acetylaminofluorene in rat mammary gland in vivo . Carcinogenesis . 1983;;4:1067-1070.
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Sadrieh N, Davis CD, Snyderwine EG.  N-Acetyltransferase expression and metabolic activation of the food-derived heterocyclic amines in the human mammary gland . Cancer Res . 1996;;56:2683-2687.
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Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles and Practice of Oncology . 3rd ed. Philadelphia, Pa: JB Lippincott Co; 1989;.
2 +
Adami HO, Lund E, Bergstrom R, Meirik O.  Cigarette smoking, alcohol consumption and risk of breast cancer in young women . Br J Cancer . 1988;;58:832-837.
3 +
Ewartz M.  Smoking and breast cancer risk in Denmark . Cancer Causes Control . 1990;;1:31-37.
4 +
Field NA, Baptiste MS, Nasca PC, Metzger BB.  Cigarette smoking and breast cancer . Int J Epidemiol . 1992;;21:842-848.
5 +
London SJ, Colditz GA, Stampfer MJ, Willett WC, Rosner BA, Speizer FE.  Prospective study of smoking and the risk of breast cancer . J Natl Cancer Inst . 1989;;81:1625-1631.
6 +
Rosenberg L, Schwingl PJ, Kaufman DW, et al.  Breast cancer and cigarette smoking . N Engl J Med . 1984;;310:92-94.
7 +
Baron JA, Byers T, Greenberg ER, Cummings KM, Swanson M.  Cigarette smoking in women with cancers of the breast and reproductive organs . J Natl Cancer Inst . 1986;;77:677-680.
8 +
Doll R, Gray R, Hafner B, Peto R.  Mortality in relation to smoking: 22 years' observations on female British doctors . BMJ . 1980;;280:967-971.
9 +
Hiatt RA, Klatsky AL, Armstrong MA.  Alcohol consumption and the risk of breast cancer in a prepaid health plan . Cancer Res . 1988;;48:2284-2287.
10 +
Schatzkin A, Carter CL, Green SB, et al.  Is alcohol consumption related to breast cancer? results from the Framingham Heart Study . J Natl Cancer Inst . 1989;;81:31-35.
11 +
Schecter MT, Miller AB, Howe GR, Baines CJ, Craib KJ, Wall C.  Cigarette smoking and breast cancer: case-control studies of prevalent and incident cancer in the Canadian National Breast Screening Study . Am J Epidemiol . 1989;;130:213-220.
12 +
Vatten LJ, Kvinnsland S.  Cigarette smoking and risk of breast cancer: a prospective study of 24,329 Norwegian women . Eur J Cancer . 1990;:26:830-833.
13 +
Morabia A, Bernstein M, Heritier S, Khatchatrian N.  Relation of breast cancer with passive and active exposure to tobacco smoke . Am J Epidemiol . 1996;;143:918-928.
14 +
Stockwell HG, Lyman GH.  Cigarette smoking and the risk of female reproductive cancers . Am J Obstet Gynecol . 1987;;157:35-40.
15 +
Chu SY, Stroup NE, Wingo PA, Lee NC, Peterson HB, Gwinn ML.  Cigarette smoking and the risk of breast cancer . Am J Epidemiol . 1990;;131:244-253.
16 +
Brinton LA, Schairer C, Stanford JL, Hoover RN.  Cigarette smoking and breast cancer . Am J Epidemiol . 1986;;123:614-622.
17 +
Meara J, McPherson K, Roberts M, Jones L, Vessey M.  Alcohol, cigarette smoking and breast cancer . Br J Cancer . 1989;;60:70-73.
18 +
Brownson RC, Blackwell CW, Pearson DK, Reynolds RD, Richens JW Jr, Papermaster BW.  Risk of breast cancer in relation to cigarette smoking . Arch Intern Med . 1988;;148:140-144.
19 +
Rohan TE, Baron JA.  Cigarette smoking and breast cancer . Am J Epidemiol . 1989;;129:36-42.
20 +
Palmer JR, Rosenberg L, Clarke E, et al.  Breast cancer and cigarette smoking: a hypothesis . Am J Epidemiol . 1991;;134:1-13.
21 +
Hiatt RA, Fireman BH.  Smoking, menopause, and breast cancer . J Natl Cancer Inst . 1986;;76:833-838.
22 +
Vessey M, Baron J, Doll R, McPherson K, Yeates D.  Oral contraceptives and breast cancer: final report of an epidemiological study . Br J Cancer . 1983;;47:455-462.
23 +
O'Connell DL, Hulka BS, Chambless LE, Wilkinson WE, Deubner DC.  Cigarette smoking, alcohol consumption, and breast cancer risk . J Natl Cancer Inst . 1987;;78:229-234.
24 +
Salber EJ, Trichopoulos D, MacMahon B.  Lactation and reproductive histories of breast cancer patients in Boston, 1965-1966 . J Natl Cancer Inst . 1969;;43:1013-1024.
25 +
Petrakis NL, Gruenke LD, Beelen TC, Castagnoli N Jr, Craig JC.  Nicotine in breast fluid of nonlactating women . Science . 1978;;199:303-304.
26 +
Petrakis NL, Maack CA, Lee RE, Lyon M.  Mutagenic activity in nipple aspirates of human breast fluid . Cancer Res . 1980;;40:188-189.
27 +
Perera FP, Estabrook A, Hewer A, et al.  Carcinogen-DNA adducts in human breast tissue . Cancer Epidemiol Biomarkers Prev . 1995;;4:233-238.
28 +
Li D, Wang M, Dhingra K, Hittleman WM.  Aromatic DNA adducts in adjacent tissues of breast cancer patients: clues to breast cancer etiology . Cancer Res . 1996;;56:287-293.
29 +
Swaminathan S, Frederickson SM, Hatcher JF.  Metabolic activation of N-hydroxy-4-acetylaminobiphenyl by cultured human breast epithelial cell line MCF 10A . Carcinogenesis . 1994;;15:611-617.
30 +
Eldridge SR, Gould MN, Butterworth BE.  Genotoxicity of environmental agents in human mammary epithelial cells . Cancer Res . 1992;;52:5617-5621.
31 +
Tonelli QJ, Custer RP, Sorof S.  Transformation of cultured mouse mammary glands by aromatic amines and amides and their derivatives . Cancer Res . 1979;;39:1784-1792.
32 +
Shirai T, Fysh FM, Lee M-S, Vaught JB, King CM.  Relationship of metabolic activation of N-hydroxy-N-acylarylamines to biological response in the liver and mammary gland of the female CD rat . Cancer Res . 1981;;41:4346-4353.
33 +
Allaben WT, Weeks CE, Weis CC, Burger GT, King CM,  Rat mammary gland carcinogenesis after local injection of N-hydroxy-N-acyl-2-aminofluorenes: relationship to metabolic activation . Carcinogenesis . 1982;;3:233-240.
34 +
Kadlubar FR, Butler MA, Kaderlik KR.  Polymorphisms for aromatic amine metabolism in humans: relevance for human carcinogenesis . Environ Health Perspect . 1992;;98:69-74.
35 +
Minchin RF, Kadlubar FF, Ilett KF.  Role of acetylation in colorectal cancer . Mutat Res . 1993;;290:35-42.
36 +
Bell DA, Taylor JA, Butler MA, et al.  Genotype/phenotype discordance for human arylamine N-acetyltransferase (NAT2)reveals a new slow-acetylator allele common in African-Americans . Carcinogenesis . 1993;;14:1689-1692.
37 +
Vineis P, Bartsch H, Caporaso N, et al.  Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens . Nature . 1994;;369:154-156.
38 +
Lin HJ, Han CY, Lin BK, Hardy S.  Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, blacks, Hispanics, and whites: application to metabolic epidemiology . Am J Hum Genet . 1993;;52:827-834.
39 +
Hanssen HP, Agarwal HW, Goedde H, et al.  Association of N-acetyltransferase polymorphism and environmental factors with bladder carcinogenesis . Eur Urol . 1985;;11:263-266.
40 +
Cartwright RA.  Epidemiological studies on N-acetylation and C-center ring oxidation in neoplasia . In: Omenn GS, Gelboin HV, eds. Genetic Variability in Responses to Chemical Exposure . Cold Spring Harbor, NY: Cold Spring Harbor Press; 1984;:359-368.
41 +
Ilett KF, David BM, Detchon P, Castleden WM, Kwa R.  Acetylator phenotype in colorectal carcinoma . Cancer Res . 1987;;47:1466-1469.
42 +
Lang NP, Chu DZJ, Hunter CF, Kendall DC, Flammang TJ, Kadlubar FF.  Role of aromatic amine N-acetyltransferase in human colorectal cancer . Arch Surg . 1986;;121:1259-1261.
43 +
Lang NP, Butler MA, Massengill J, et al.  Rapid metabolic phenotypes for acetyltransferase and cytochrome P4501A2 and putative exposure to foodborne heterocyclic amines increase the risk for colorectal cancer or polyps . Cancer Epidemiol Biomarkers Prevention . 1994;;3:675-682.
44 +
Bulovskaya LN, Krupkin RG, Bochina TA, Shipkova AA, Pavlova MV.  Acetylator phenotype in patients with breast cancer . Oncology . 1978;;35:185-188.
45 +
Evans DAP.  Acetylation . Prog Clin Biol Res . 1986;;214:209-242.
46 +
Sardas S, Cod I, Sardas OS.  Polymorphic N-acetylation capacity in breast cancer patients . Int J Cancer . 1990;;46:1138-1139.
47 +
Philip PA, Rogers HJ, Millis RR, Rubens RD, Cartwright RA.  Acetylator status and its relationship to breast cancer and other diseases of the breast . Eur J Cancer Clin Oncol . 1987;;23:1701-1706.
48 +
Ladero JM, Fernandez MJ, Palmeiro R, et al.  Hepatic acetylator polymorphism in breast cancer patients . Oncology . 1987;;44:341-344.
49 +
Graham S, Hellmann R, Marshall J, et al.  Nutritional epidemiology of postmenopausal breast cancer in western New York . Am J Epidemiol . 1991;;134:552-566.
50 +
Vatsis KP, Weber WW, Bell DA, et al.  Nomenclature for N-acetyltransferases . Pharmacogenetics . 1995;;5:1-17.
51 +
Begg CB, Zhang ZF.  Statistical analysis of molecular epidemiology studies employing case-series . Cancer Epidemiol Biomarkers Prev . 1994;;3:173-175.
52 +
Piergorsch WW, Weinberg CR, Taylor JA.  Nonhierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies . Stat Med . 1994;;13:153-162.
53 +
Wang CY, Yamada H, Morton KC, Zukowski K, Lee M-S, King CM.  Induction of repair synthesis of DNA in mammary and urinary bladder epithelial cells by N-hydroxy derivatives of carcinogenic arylamines . Cancer Res . 1988;;48:4227-4232.
54 +
King CM, Traub NR, Lortz ZM, Thissen MR.  Metabolic activation of arylhydroxamic acids by N-O-acyltransferase of rat mammary gland . Cancer Res . 1979;;39:3369-3372.
55 +
Allaben WT, Weis CC, Fullerton NF, Beland FA.  Formation and persistence of DNA adducts from the carcinogen N-hydroxy-2-acetylaminofluorene in rat mammary gland in vivo . Carcinogenesis . 1983;;4:1067-1070.
56 +
International Agency for Research on Cancer. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Part 1 . Lyon, France: International Agency for Research on Cancer; 1972;:74-79.
57 +
Sadrieh N, Davis CD, Snyderwine EG.  N-Acetyltransferase expression and metabolic activation of the food-derived heterocyclic amines in the human mammary gland . Cancer Res . 1996;;56:2683-2687.
58 +
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To understand the clinical management of acute heart failure syndromes.
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Compression-Only CPR: Pushing the Science Forward
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AAM 2010;304:1493-1495.
All you need to read in the other general journals
BMJ 2010;341:c5893-c1494.
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