DR. LANE MAKES HIS CASE FOR AFLATOXIN

December 19, 2006 2:07 pm by Gene Borio

Dr. Kerry Lane has been investigating the link between the cigarette ingredient aflatoxin and cancer for many years now. On December 4, 2006, he set forth his case in an accompanying brief to his request to file the brief as amicus curiae.

Dr. Lane’s brief is unlikely to be accepted. It’s certainly late(!), and aflatoxin has not been a part of the evidence presented at trial. Even during the trial, Judge Kessler refused to deal with the fire-safe cigarette issue when DOJ tried to call Dr. Michael Watkins to the stand in February, 2005. Judge Kessler ruled that Dr. Watkins’ testimony at this point was largely irrelevant–fire-safe science never having come up before–and overly time-consuming. She expressed no excitement whatsoever for getting into the “coal drop-off” issue. That would undoubtedly go at least double for the aflatoxin issue, 15 months after the end of the trial and 5 months after her final order and judgement.

However, Dr. Lane in his brief certainly does make his most clear and referenced argument yet for aflatoxin’s toxicity.

From:

Lane Brief for Aflatoxin review, December 4, 2006

This brief contains evidence that Defendants knew, or should have known, of one particular method of making a safer cigarette but suppressed this information. Indeed, but for documents uncovered in this and related litigation, the information would likely have remained suppressed.

This Brief shows that Defendants knew, or should have known, that aflatoxin, a potent carcinogen, was a contaminant of tobacco products; that aflatoxin was a substantial source of the harm caused by tobacco products; and, that methods of neutralizing aflatoxin would have made tobacco products safer. While other issues before this Court are now under appellate review, this Brief urges the Court to consider aflatoxin contamination. Otherwise this highly significant public health issue will escape judicial review. Defendants have, and will continue, to make unsafe tobacco products by failing to publicly recognize and neutralize aflatoxin contamination.

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Texts follow of:

Lane Brief for Aflatoxin review, December 4, 2006

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Lane Motion for Aflatoxin review, December 4, 2006

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UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA

UNITED STATES OF AMERICA,

Plaintiff,

v. PHILIP MORRIS USA INC., f/k/a PHILIP MORRIS INC., et al

Defendants

Civil Action No. 99-CV-2496 (GK)

MOTION FOR LEAVE TO FILE BRIEF AS AMICUS CURIAE

Comes Now, Dr. Kerry M. Lane, and seeks leave to file a Brief, attached, as Amicus Curiae in connection with the above referenced litigation.

Dr. Lane is a medical physician who, through research and study, has acquired substantial background information and knowledge with respect to the subject of aflatoxin and tobacco and its effect on tobacco as a carcinogen. Dr. Lane believes that information regarding aflatoxin and its carcinogenic effect on tobacco was known and suppressed by one or more Joint Defendants and further believes that this information is relevant to the Court’s consideration of the subject litigation and necessary for the Court to form a complete response to the Joint Defendants actions. Otherwise a serious public health issue will escape judicial review.

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The parties consent for this filing has been sought in accordance with Local Civil Rule 7(m). The Joint Defendants oppose this filing. The Plaintiff, in view of government policy, has no comment. A proposed order is also attached.

Respectfully Submitted,

/s/

Bradford E. Kile DC Bar No. 66811 Kile Goekjian Reed & McManus, PLLC 1200 New Hampshire Ave. NW Suite 570 Washington DC 20036

Attorney for Amicus Curiae Dr. Kerry Scott Lane

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Lane Brief for Aflatoxin review, December 4, 2006

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UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA

UNITED STATES OF AMERICA,

Plaintiff,

v.

PHILIP MORRIS USA INC.,

f/k/a PHILIP MORRIS INC., et al

Defendants

Civil Action No. 99-CV-2496 (GK)

BRIEF FOR AMICI CURIAE

December 4, 2006

Kerry Scott Lane M.D.

St. Mary’s Medical Center

901 45th Street

West Palm Beach FL 33407

(561) 844-6300

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TABLE OF CONTENTS

I. INTRODUCTION……… 1

II. BACKGROUND……… 2

A. Tobacco, Aflatoxin, Fungal Toxins, Ammonia, and Human Disease……… 2

B. Defendants’ Experts Remain Silent About Aflatoxin Danger……… 7

1. Publications of B.S. Appleton Ph.D.- Head Scientist at RJR……… 7

2. Testimony of B.S. Appleton Ph.D. in the Tobacco Trial……… 7

3. Retention of Dr. Wogan of MIT……… 8

4. Testimony of David E. Townsend……… 8

C. Analysis of Retrieved Tobacco Documents in the Context of Aflatoxin Contamination……… 10

D. Suppression of Knowledge of Harmful Health Effects and Emerging Diseases-AIDS……… 28

E. The toxicology of aflatoxins as a basis for public health decisions……… 29

F. Aflatoxins and Smoke Studies……… 30

G. Aflatoxin Remediation by Ammoniation……… 30

H. p53 Tumor Suppressor Gene Mutated by Aflatoxin and Industry Deception….31

III. CONCLUSION ……… 32

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TABLE OF AUTHORITIES

Statutes

Racketeer Influenced and Corrupt Organizations Act (“RICO”) 18 U.S.C. § 1961, et seq. ……… 1

Other Authorities

Alvord ET, Cardon SZ. The Inhibition of Formation of 3-4 Benzpyrene in Cigarette Smoke. Brit J Cancer. 1956; 10: 498-503 ………16

Appleton, B.S., and Campbell, T.C. (1983). Effect of high and low dietary protien on the dosing and post dosing periods of aflatoxin B1-induced hepatic preneoplastic lesion development in the rat. Cancer Res. 43, 2150-2154………7

Appleton, B.S., Goetchius, M.P., and Campbell, T.C. (1982). Linear dose response curve for the hepatic macromolecular binding of aflatoxin B1 in rats in very low exposures. Cancer Res. 42, 3569-3662………7

Austin K. Substances in tobacco alleged to be causes of cancer, respiratory and other diseases. In: RJ Reynolds Center for Tobacco Research memo. June 8, 1966; RJR Website Doc. No. 502429578:1………19

Autrup H, Essigman JM, Croy RG, Trump BF, Wogan GN, Harris CC. Metabolism of aflatoxin B and identification of the major aflatoxin B1-DNA adducts formed in culture…….1

bronchus and colon. Cancer Res. 1979; 39:694-698 ………14

Blackmore R. Aflatoxin: Food Toxin. In: Phillip Morris memo; May 24, 1965; PM Website Doc. No. 2021551782………11, 12

Burg WR, Shotwell OR, Saltzman BE. Measurements of airborne aflatoxins during the handling of contaminated corn. Ann Ind Hyg. 1981; 42:1-11………14

Chapman R. Method for detoxifying foodstuffs. USPO. 1992; 1/21:U.S. Patent 5,082,679….. 27

Cherpillod P, Amstad PA. Benzo(a)pyrene-induced mutagenesis of p53 hot-spot condons 248 and 249 in human hepatocytes. Molecular Carcinogenesis 1995;13:15-20………3

Cordesman A. Weapons of mass destruction in Iraq: a summary of biological, chemical, nuclear and delivery efforts and capabilities. In: Middle East Program at the Center for Strategic and International Studies; Nov. 14, 1996; Washington, D.C………23

Cullen JM, Newberne PM. Acute Hepatotoxicity of Aflatoxins. In: Eaton DL, Groopman JD, eds. The Toxicology of Aflatoxins. San Diego, Ca: Academic Press; 1994: 3-26 ………22

DeBardeleben F. The Structure and Synthesis of Aflatoxin B and G1. In: Phillip Morris Project Report. Dec. 9, 1966; PM Website Doc. No. 2021551728. ………20

Denning DW, Allen R, Wilkinson, AP, Morgan MRA. Transplacental transfer of aflatoxin in humans. Carcinogenesis. 1990; 11:1033-1035………27

Dickens F, Jones HEH, Waynforth HB. Oral, Subcutaneous and Intratracheal Administration of Carcinogenic Lactones and Related Substances: the Intratracheal Administration of Cigarette Tar in the Rat. Br J Cancer. 1966; 20:134-144. RJR Website Doc. No. 500291239. ………19

Donnelly P, Stewart R, Ali S, Conlan A, Reid K, Petsikas D, et al. Biotransformation of

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aflatoxin B1 in human lung. Carcinogenesis 1996; Vol.17 No.11:2487-2494. ………4

Dvorackova I, Stora C, Ayraud N. Evidence of Aflatoxin B1 in Two Cases of Lung Cancer in Man. J Can Res. 1981; 100:221-224 ………14

Dvorackova I. Aflatoxins and Human Health. Boca Raton, Fl: CRC Press; 1990:135-150 …… 14

Editorial. Tobacco’s outrageous, unethical tactics a threat to public health. In: Sun Sentinel Editorial; Fort Laud, Fl.; Feb. 10, 98. The Secret of Marlboro is Ammonia…. Ammonia does many good things………26

Flalles D. Food toxins of fungal origin: Methodology and regulatory aspects. Food Technology. 1966; 20:61-pages unknown. PM Website Doc. No. 1000340451. ………12

Garner RC, Dvorackova I, Tursi F. Immunoassay procedures to detect exposure to aflatoxin B1 and benzo(a)pyrene in animals and man at the DNA level. Int Arc Occup Environ Health. 1988; 60:145-150………15

Glantz S, Slade J, Bero L, Hanauer P, Barnes D. The Cigarette Papers. Univ. of Calif. Press. Online; Berkley, Ca. 1966; Doc. ID 1165.03 Brown and Williamson Collection. www.library.ucsf.edu/toba…

Glantz SA, Slade J, Bero L, Hanauer P, Barnes. The Cigarette Papers. Univ. of Calif. Press. 1996, p.215 ………19

Griffith R. Importance of benzpyrene versus other PAH’s in Project Janus. The Brown and Williamson Collection. Online; Univ. Calif., San Francisco. 1967; Doc. ID 1101.1. ………19

Griffith R. Report to executive committee. The Brown and Williamson Collection. Online; Univ. Calif., San Francisco. 1965; Doc ID 1105.01………16

Harris CC. 1995 Deichmann lecture — p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology and cancer risk assessment. Toxicology Letters 1995; Vol.82/83:1………4

Hempfling W. Are mycotoxins present in cured tobaccos? In: Phillip Morris USA Confidential memo; March 31, 1994; PM Website Doc. No. 2024111027. ………12

Hendrickse RG, Maxwell SM. Heroin addicts, AIDS, and aflatoxins. Brit Med J. 1988; 296:1257………28

Herrold KM. Aflatoxin induced lesions in Syrian hamsters. Br J Cancer. 1969:23; 655-660. .. 22

Hesseltine CW, Shotwell OL, Kwolek WF, Lillehoj EB, Jackson WK, Bothast RJ. Aflatoxin occurrence in 1973 corn at harvest. II. Mycological studies. Mycologia. 1976; 68:341353 ……… 14

Hitchcock R, Willoughby, Cardon SZ, Alvord RT. Cigarette wrapper material and method for making same. USPO. 1958; U.S. Patent 2,859,753. ………17

Hockett RC. Elimination of Benzpyrene from Tobacco Smoke. In: Phillip Morris memo; May 14, 1956; PM Website Doc. No. 2000756765-67. ………17

Husgafvel-Pursiainen K, Benhamou S, Kannio A, Nyberg F, Mukeria A, Constantinescu V, et al. p53 mutations in lung cancer among non-smokers exposed to environmental tobacco smoke. Proc Amer Assoc Can Res 1998;39. ………5

Karja VJ, Syrjanen KJ, Kurvinen AK, Syrjanen SM. Expression and Mutations of p53 in Salivary Gland Tumors. J of Oral Path & Med. 1997; 26/5: 217-23. ………15

Lane K. Method and system for continuous assay and removal of harmful toxins during processing of tobacco products. 1997; U.S. Patents 6,058,940, 6,637,438, 6,786,221 and pending. ………7

Langer AM, Nolan RP, Bowes DR, Shirey SB. Inorganic Particles Found in Cigarette Tobacco, Cigarette Ash, and Cigarette Smoke. In: Wehner AP, Felton D. Biological

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interaction of inhaled mineral fibers and cigarette smoke. Proceedings of an International Symposium/Workshop. Columbus, OH: Battelle Press; 1989: 430………24

Lasky T, Silbergeld E. p53 mutations associated with breast, colorectal, liver, lung, and ovarian cancers. Env Health Persp 1996; Vol.104 No.12: 1324-1334………4, 10

Lofroth G, Zebuhr Y. Polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) in mainstream and sidestream cigarette smoke. Env Contam and Tox. 1992; 48:789-794… 24

Lola N. On the Health Conditions of female tobacco workers: an investigation of a modern factory. Italian Tobacco. 1959; 693:431-433. ………12

Ma X, Gibbons J, Babish J. Benzo(e)pyrene pretreatment of immature, female C57BL/6J mice results in increased bioactivation of aflatoxin B1 in vitro. Toxicology Letters. 1991; 59:51-58……… 15

McGlynn KA, Rosvold EA, et al. Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1. Proc Natl Acad Sci. 1995; 92:2384-2387………15

McMillian WW, Widstrom NW, Beaver RW, Wilson DM. Aflatoxin in Georgia: Factors associated with its formation in corn. In: Aflatoxin in Corn–New Perspectives; Iowa Agri and Home Eco Exper Sta; Iowa St Univ. 1991; 599:329-334………14

Michelson I. Method of making a cigarette of reduced biological damage capability. USPO. 1974;U.S Patent 3,782,393………25

Michelson I. Smoking composition of reduced toxicity and method of making same. USPO. 1970;U.S Patent 3,631,865………25

Mitchell GF, et.al. The Total Synthesis of Racemic Aflatoxin B1. Jour of Am Chem Soc. 85: 19, Oct.5, 1966, PM Website Doc. No.2021551735-37………20

Newberne PM, Butler WH. Acute and Chronic Effects of aflatoxin on the liver of domestic and laboratory animals. A review. Cancer Res. 1969; 29: 236-250 ………22

Norred W, Morrissey R. Effects of long-term feeding of ammoniated aflatoxin-contaminated corn to Fischer 344 rats. Tox and App Pharm. 1983; 70:96-104 ………25

O’Donohue C. Literature Survey: Aflatoxin. In: Phillip Morris Incorporated Research Center report; November 11, 1966; PM Website Doc. No. 1000340449. ………12

O’Neill IK. Relevance to Human Cancer of N-Nitroso compounds, tobacco smoke and mycotoxins. Lyon, France: International Agency for Research on Cancer; 1991. ………27

Park DL, Lee LS. New perspectives on the ammonia treatment for decontamination of aflatoxins. In: A Perspective on Aflatoxin in Field Crops and Animal Food Products in the US: A Symposium; National Technical Information Services, Springfield, VA. 1990; 127-137……… 25

Park J, Ren Q, et al. p53 mutations in oral tumors are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use. Proc Amer Assoc Cancer Res. 1998; 39 # 1250………15

Peedin G, Smith D, Yelverton F, Melton T, Boyette M. Flue cured tobacco. N Carolina Coop Ex Svc 1993;145-148. ………5, 13

Pier AC, McLoughlin ME. Mycotoxic suppression of immunity. In: Lacey J. ed. Trichothecenes and Other Mycotoxins; John Wiley & Sons, Chichester; 1985: Pages 507-519………28

Prochaska HJ, Yeh Y, Baron P, Polsky B. Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication. Proc Natl Acad Sci. USA. 1993; 90:3953-3957………28

Puisieux A, Lim S, Groopman J, Ozturk M. Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens. Cancer Res 1991;51:6185-6189.4, 14

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Rodgman A. Biological Studies on Tobacco Products: Role of Animal Experimentation in Cancer Research. In: Phillip Morris study; Oct. 1, 1959; PM Website Doc. No.2025018236, 2025018276, 2025018713, 2025018279, 2025018286 ………18

Roe FJC, Salamon MM, Cohen I, Surgon LG. Role of 3,4-benzopyrene in experimental tobacco carcinogenisis. In: Abstracts of Papers, VII International Cancer Congress, 1962; Great Britain, London; PM Website Doc. No. 1005087287………18

Roebuck BD, Liu YL, Rogers AE, Groopman JD, Kensler TW. Protection against aflatoxin B1induced hepatocarcinogenesis in F344 rats by 5-(2-pyrazinyl)-4-methyl-1, 2-dithiole-3thione (oltipraz), predictive role for short-term molecular dosimetry. Cancer Res. 1991; 5501-5506………28

Salmon WD, Newberne PM. Occurrence of hepatomas in rats fed diets containing peanut meal as a major source of protein. Cancer Res. 1963; 23:571-575………22

Stewart LL. Total particulate matter delivery and nicotine delivery of cigarettes…treated with Ammonia, (versus) Untreated Tobacco. In: Phillip Morris study; Dec. 23, 1958; PM Website Doc. No. 1001920430……… 17

Townsend R. In: Minnesota Medicaid trial transcripts. March 29-30, 1998. ………26 US Dept. Labor, OSHA. Indoor air quality: proposed rule. Federal Register. 1994; 59/65:15988………24

Walsh AA, Hsieh DPH, Whitehead WE, Rice RH. Aflatoxin toxicity in cultured epidermal cells: Stimulation by TCDD. Toxicologist. 1992; 12: 207 ………24

Weider R, Wogan GN, Shimkin MB. Pulmonary tumors in strain “A” mice given injections of aflatoxin B1. J Natl Cancer Inst. 1968; 40:1195-1197………22

Weissman G. Benzpyrene research. In: Phillip Morris Interoffice Correspondence; Sept. 16, 1959; PM Website Doc. No. 1001882395………18

Wild CP, Pionneau F, Montesano R, Muitiro CF, Chetsanga CJ. Aflatoxin detected in human breast milk by immunoassay. Int J Cancer. 1987; 40:328-333………27

Wild CP, Umbenhauer D, Chapot B, Montesano R. Monitoring of individual human exposure to aflatoxins (AF) and N-nitrosamines (NNO) by immunoassays. J Cell Biochem. 1986; 30:171-179………27

Wogan GN, Newberne PM. Dose-response characteristics of aflatoxin B1 carcinogenesis in the rat. Cancer Res. 1967; 27:2370-2376………22 Wogan, G.N. (1966). Chemical nature and biological effects of the aflatoxins. Bacteriol. Rev. 30, 460-470………8

Wogan, G.N. (1973). Aflatoxin carcinogenesis. Methods Cancer Res. 7, 303-344………8

Wogan, G.N., and Paglialunga, S. (1974). Carcinogenicity of synthetic aflatoxin M1 in rats. Food Cosmet. Toxicol. 12, 381-384………8

Wogan, G.N., Edwards, E.S., and Shank, R.C. (1967). Excretion and tissue distribution of radioactivity from aflatoxin B1-14-C in rats. Cancer Res. 27, 1729-1736. ………8

Wogan, G.N., Edwards, G.S., and Newberne, P.M. (1971). Structure-activity relationships in toxicity and carcinogenicity of aflatoxin and analogs. Cancer Res. 31, 1936-1942………8

Wood NB, Caldarelli DD, et al. Mutation of p53 in Squamous Cell Cancer of the Head and Neck: Relationship to Tumor Cell Proliferation. Laryngoscope. 1997; 107/6:827-33………15

Yao Y, Hoffer A, Chang C, Puga A. Dioxin activates HIV-1 gene expression by an oxidative stress pathway requiring a functional cytochrome P450 CYP1A1 enzyme. Env Health Persp. 1995; 366………28

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I. INTRODUCTION

After a nine month trial, this Court issued its Memorandum Opinion and Order (Op.) on August 17, 2006 finding Defendants liable for violations of the Racketeer Influenced and Corrupt Organizations Act (“RICO”). 18 U.S.C. § 1961, et seq. Among myriad unlawful activities, the Court found that Defendants had engaged in a deliberate, decades-long campaign to deceive the public concerning the adverse health effects of smoking, cigarette addictiveness and Defendants’ manipulation of cigarette contents to enhance addictiveness, the effects of secondhand smoke, and the true health effects of “light” cigarettes. Thus, the Court found that “each and every one of these Defendants repeatedly, consistently, vigorously – and falsely – denied the existence of any adverse health effects from smoking,” Op. at 330, and made similar findings on these other matters. In light of the Court’s findings that “Defendants have made false, deceptive, and misleading public statements about cigarettes and smoking from at least January 1954, when the Frank Statement was published up until the present,” id. at 1632, among other remedies the Court has ordered:

Defendants to make corrective statements about addiction (that both nicotine and cigarette smoking are addictive); the adverse health effects of smoking (all the diseases which smoking has been proven to cause); the adverse health effects of exposure to [environmental tobacco smoke] ETS (all the diseases which exposure to ETS has been proven to cause); their manipulation of physical and chemical design of cigarettes (that Defendants do manipulate design of cigarettes in order to enhance the delivery of nicotine); and light and low tar cigarettes (that they are no less hazardous than full-flavor cigarettes).

Id. at 1636. The final judgment and remedial order have been stayed pending appeal. No. 065267 (D.C. Cir., Oct. 31, 2006).

While Defendants were producing the misinformation described above, Defendants legal counsel were advising against producing a “safer” cigarette, “as that would create

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substantial legal concerns.” Op. at 1413. This brief contains evidence that Defendants knew, or should have known, of one particular method of making a safer cigarette but suppressed this information. Indeed, but for documents uncovered in this and related litigation, the information would likely have remained suppressed.

This Brief shows that Defendants knew, or should have known, that aflatoxin, a potent carcinogen, was a contaminant of tobacco products; that aflatoxin was a substantial source of the harm caused by tobacco products; and, that methods of neutralizing aflatoxin would have made tobacco products safer. While other issues before this Court are now under appellate review, this Brief urges the Court to consider aflatoxin contamination. Otherwise this highly significant public health issue will escape judicial review. Defendants have, and will continue, to make unsafe tobacco products by failing to publicly recognize and neutralize aflatoxin contamination.

II. BACKGROUND

A. Tobacco, Aflatoxin, Fungal Toxins, Ammonia, And Human Disease

Aflatoxins are toxins produced by fungi that invade agricultural commodities under warm and wet storage conditions after harvesting. Aflatoxin was first identified in 1960 as one of the most potent carcinogens known, and has been recognized as a teratogen (agent causing malformation of embryos), mutagen, carcinogen, immunosuppressant, and potent inhibitor of protein synthesis. The US Food and Drug Administration (FDA) began regulating aflatoxin on agricultural commodities, such as peanuts, corn, and grains, in 1966. Federal and state laws prohibit interstate shipment of contaminated aflatoxin commodities exceeding 20 parts per billion (ppb) (0.5 ppb for milk).

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Aflatoxin causes mutations in the p53 tumor-suppressor gene as well as ras mutations, which are involved in the majority of human cancers. A link between aflatoxin and tobacco products is suggested by their similar effects on human subjects. Tobacco-related cancers, including those associated with environmental tobacco smoke (ETS), often show the same p53 mutations associated with aflatoxin exposure. Another link is the use of ammonia, used in neutralizing aflatoxin contamination and used by the tobacco industry. This is explained below.

The mycotoxin aflatoxin B1 (AFB1) is known to mutate the p53 tumor-suppressor gene and to cause ras mutations. Dietary exposure to AFB1 indicates it is a hepatotoxin and hepatocarcinogen, specifically causing p53 mutations at codon 249. Aflatoxin has the potential in primary and secondary smoke to be a potent carcinogen, mutating the p53 tumor suppressor gene that is often associated with smoking- and chewing tobacco-related cancers.

Aflatoxin has been shown to cause cancer in every animal model and cellular system studied, and to form adducts in the p53 tumor-suppressor gene that mutates in approximately half of all human cancers. Cherpillod and Amstad showed that AFB1 binds to the middle and third positions of p53 codon 248, inducing G-T transversions associated with lung cancer, and binds strongly to the third base pair of codon 249, generating a G-T transversion in a liver cancer mutational hotspot. Cherpillod P, Amstad PA. Benzo(a)pyrene-induced mutagenesis of p53 hot-spot condons 248 and 249 in human hepatocytes. Molecular Carcinogenesis 1995;13:15-20. Benzopyrene has been shown to bind to positions in codon 248, but has not been shown to target codon 249. These codons are adjacent, and carcinogenic targeting is presently not well-understood; it has been suggested that targeting is affected by the positions of different nucleotides in short sequence. Puisieux A, Lim S, Groopman J, Ozturk M.

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Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens. Cancer Res 1991; 51:6185-6189.

“G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung, breast, esophagus and liver,” states Dr. Curtis C. Harris of the National Cancer Institute (NCI). “G to T transversion is more common in lung cancers from smokers when compared to never smokers.” Harris CC. 1995 Deichmann lecture — p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology and cancer risk assessment. Toxicology Letters 1995; Vol.82/83:1. Donnelly and coworkers state, “In addition to being a potent hepatocarcinogen, aflatoxin B1 (AFB1) is a pulmonary carcinogen in experimental animals, and epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans.” Donnelly P, Stewart R, Ali S, Conlan A, Reid K, Petsikas D, et al. Biotransformation of aflatoxin B1 in human lung. Carcinogenesis 1996; Vol.17 No.11:24872494. In their study, lung tumor samples collected from 76 mice treated with doses of AFB1 showed 100% K-ras mutations.

Lasky and Silbergeld suggest, through study of p53 mutations, that environmental carcinogens are a cause of breast, esophageal, lung, ovarian, pancreatic, prostate, and skin cancers. They state, “In lung cancer p53 mutations have been found in 56% of tissue samples, and in colorectal, esophageal, ovarian, pancreatic, and skin cancers, prevalences of 44-50% have been reported.” Lasky T, Silbergeld E. p53 mutations associated with breast, colorectal, liver, lung, and ovarian cancers. Env Health Persp 1996; Vol.104 No.12: 1324-1334. They suggest G to T transversions in breast and lung cancers are caused similarly by exogenous mutagenic chemicals. Aflatoxin from primary smoke and ETS is the likely carcinogen, as these cancers are more often associated with tobacco use.

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More recently, p53 mutations have been found in ETS lung cancer patients. A study done by Husgafvel-Pursiainen and associates investigated the presence of mutations in the p53 gene in samples of lung cancer patients who had never smoked, but who had reported a detailed history of exposure to ETS. “Although based on a relatively small number of mutated lung cancer cases among non-smokers, our findings are consistent with a carcinogenic effect of ETS on the human lung,” the authors state. Husgafvel-Pursiainen K, Benhamou S, Kannio A, Nyberg F, Mukeria A, Constantinescu V, et al. p53 mutations in lung cancer among nonsmokers exposed to environmental tobacco smoke. Proc Amer Assoc Can Res 1998;39.

As mentioned above, the FDA regulates aflatoxin in food commodities. With respect to tobacco crops, however, neither the FDA or any other organization monitors aflatoxin levels. Ignorance with respect to the level of tobacco contamination by aflatoxin and lack of a clear FDA role in regulating the aflatoxin levels has contributed to the public health catastrophe.

The tobacco industry heavily imports cheaper tobacco from tropical countries such as Brazil and Zimbabwe, in which the level of aflatoxin contamination is also unknown. Presently, in North Carolina alone, the flue-cured tobacco stabilization board has 195 million pounds of tobacco stored for sale, where it may remain for years and become contaminated. Peedin G, Smith D, Yelverton F, Melton T, Boyette M. Flue cured tobacco. N Carolina Coop Ex Svc 1993; 145-148. Contamination of tobacco may occur during extended storage time as well as during the curing process, yet there is little agricultural literature on this subject.

Since the mid-1950s, the tobacco companies have been aware that ammonium-based compounds neutralize benzpyrene compounds. Upon the discovery of aflatoxin in 1960, and chemosynthesis by Phillip Morris in 1966, the tobacco industry was likely aware that ammonia

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neutralized aflatoxin as well. Aflatoxin is 200 times more carcinogenic than benzpyrene and decomposes at 269°C, well above the combustion temperature of an idling cigarette.

RJR documents indicate that as early as 1968, collaborating researchers at the Wisconsin Alumni Research Foundation found a 100% carryover of aflatoxin from combusted tobacco.1 The heat stability of aflatoxin may explain studies showing related compounds, polychlorinated dibenzofurans, in ETS at levels two to ten times higher than those in mainstream smoke, which is combusted at higher temperatures. Aflatoxins are chemically classified as dibenzofurofurans, which are highly oxygenated heterocyclic compounds, and as such easily would be amenable to deactivation by a catalyst such as palladium. Significantly, the Liggett Group developed a less hazardous cigarette in 1977 using a palladium catalyst that essentially reduced the biological activity of the smoke condensate to zero, but it was never marketed (see p. 26 below).

Aflatoxin is metabolized to the active carcinogen — the epoxide — by benzpyrene, a product of combustion. Use of smokeless tobacco products often leads to oral cancers in a few years, indicating that benzpyrene is not the responsible compound in these cases. Uncombusted aflatoxin may be a causal agent or promoter of the early onset of oral malignancies, as p53 mutations have been found in tumors in proximity to the oral cavity.

The above described studies strongly suggest that the genetic mutations known to be associated with aflatoxin are the same mutations often associated with the use of tobacco products. Aflatoxin is more than likely a causal agent or promoter of tobacco-associated cancers. The advancing technology of molecular epidemiology will presumably confirm this

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1 Senkus M. Re: meeting with Mr. P. Derse, Director, Wisconsin Alumni Research Foundation (WARF), Madison, Wisconsin. In: R.J. Reynolds report. 1968; Bates No. 501868781:1

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theory in the near future, with significant repercussions for public health and the tobacco industry. From Medscape General Medicine, September 1999. Kerry Scott Lane M.D.

Technology to prevent, remediate, and terminally test for these toxins, developed by the author of this Brief, is currently available for a fraction of the cost of the morbidity and mortality it will prevent. Lane K. Method and system for continuous assay and removal of harmful toxins during processing of tobacco products, 1997; U.S. Patents 6,058,940, 6,637,438, 6,786,221 and pending. The author also believes tobacco can be made safer simply by FDA regulation of levels of mycotoxin and aflatoxin contamination. The FDA currently regulates all other susceptible agricultural commodities.

B. Defendants’ Experts Remain Silent About Aflatoxin Danger

Defendants’ experts Drs. Townsend and Appleton had knowledge of aflatoxin’s harmful effects. Dr. Townsend learned of this during his years of employ (see below). Dr. Appleton had extensive knowledge about aflatoxin, having multiple publications in the field. Both remained silent about aflatoxin. A leading expert in aflatoxin research, Dr. Wogan, had been retained by Defendants in the past but did not testify in this trial.

1. Publications of B.S. Appleton Ph.D.- Head Scientist at RJR

a. Appleton, B.S., and Campbell, T.C. (1983). Effect of high and low dietary protein on the dosing and post dosing periods of aflatoxin B1-induced hepatic preneoplastic lesion development in the rat. Cancer Res. 43, 2150-2154.

b. Appleton, B.S., Goetchius, M.P., and Campbell, T.C. (1982). Linear dose response curve for the hepatic macromolecular binding of aflatoxin B1 in rats in very low exposures. Cancer Res. 42, 3569-3662.

2. Testimony of B.S. Appleton Ph.D. in the Tobacco Trial

See www.altria.com, Department of Justice Trial, Live Witness Filings. 7

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3. Retention of Dr. Wogan of MIT

Another of Defendants’ experts, Dr. Wogan of MIT, was one of the individuals who first isolated aflatoxin in 1960 after an outbreak of “Turkey X” disease in England in which 100,000 turkey poults died from ingesting aflatoxin contaminated peanut meal. Dr. Wogan is recognized as the world’s foremost authority on aflatoxin and has authored textbooks and dozens of articles on the subject. While Dr. Wogan was not called to testify, the fact that he has been retained strongly suggests the industry is aware of the problem. Listed below are representative scholarly articles of Dr. Wogan’s work from the text “The Toxicology of Aflatoxins” edited by Groopman and Eaton.

a. Wogan, G.N., and Newberne, P.M. (1967). Dose-response characteristics of aflatoxin B1 carcinogenesis in rats. Cancer Res. 27, 2370-2376.

b. Wogan, G.N., Edwards, E.S., and Shank, R.C. (1967). Excretion and tissue distribution of radioactivity from aflatoxin B1-14-C in rats. Cancer Res. 27, 1729-1736.

c. Wogan, G.N., Edwards, G.S., and Newberne, P.M. (1971). Structure-activity relationships in toxicity and carcinogenicity of aflatoxin and analogs. Cancer Res. 31, 1936-1942.

d. Wogan, G.N. (1966). Chemical nature and biological effects of the aflatoxins. Bacteriol. Rev. 30, 460-470.

e. Wogan, G.N. (1973). Aflatoxin carcinogenesis. Methods Cancer Res. 7, 303344.

f. Wogan, G.N., and Paglialunga, S. (1974). Carcinogenicity of synthetic aflatoxin M1 in rats. Food Cosmet. Toxicol. 12, 381-384.

4. Testimony of David E. Townsend

Dr. Townsend spent 27 years with his employer and was obviously familiar with the evolution of scientific thought in the causality of tobacco related diseases. The associations with the individuals listed below which he cites in his deposition illustrate his certain knowledge of aflatoxin issues.

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. a. Retention Of Gerald Wogan Ph.D.-The individual who first identified Aflatoxin. Townsend deposition pg. 135, line 22.

b. Citation of Dr. Tso-Author of one of the early aflatoxin articles published in the journal Beitr.Tabakforschung in 1967 in German where it was not seen by the English speaking media. Townsend deposition pg. 12, line 11.

c. Citation of Ernest Wynder-. Wynder wrote many of the now revealed documents in the early 1960s when tobacco scientists where looking at tobacco disease causality. He wrote in 1963 Benzpyrene (Bzp) cannot be a cause of cancer from tobacco. By 1964 tobacco lawyers attempted to limit work linking aflatoxin to tobacco disease.

Townsend deposition pg.50, line 1.

d. Citation of Murray Senkus- Senkus authored many of these similar documents including the WARF study showing 100 % carryover of aflatoxin in combustion studies. (see below). Townsend deposition pg.120, line 23.

e. Citation of Thomas Osdene Ph.D., Former Director R&D, PM. Originator of many aflatoxin documents dating to 1966 when he ordered a literature survey on the subject. Days later he received a document with 163 citations. In the Minnesota Medicaid trial he took the Fifth Amendment 135 times. Townsend deposition pg 121, line 3

f. Citation of p53 tumor suppressor gene, K-ras, DNA adducts. P53 was discovered in the late 1980s by Lane at the University of Dundee in Scotland. It is called the “Guardian of the Genome” as it instructs cells that have turned cancerous to die. When it is mutated cancer cells run amok and spread. Aflatoxin is the most prolific chemical to mutate p53. Surely the tobacco scientists know this fact. Townsend deposition pg. 166, Chart.

g. Citation concerning ammonia and tobacco by Townsend. Ammonia is used to decontaminate feedstuffs that have been contaminated with aflatoxin. Ammonia was experimented with by the tobacco companies in 1967. In the early 1970s Philip Morris was using ammonia on Marlboro. Townsend deposition pg. 169, line 22.

h. Citation concerning use of ammonia for other than taste. Generally tobacco companies claim they use ammonia for taste and they vehemently deny they use it to speed nicotine to the brain. This is a contentious argument. What other use could they be using it for?

Townsend deposition pg. 170, line 10.

i. Citation concerning use of ammonia on Winston. Many premium tobacco products are ammoniated. Many are not. Which ones have aflatoxin and

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aflatoxin and mycotoxin producing spores on them?

Townsend deposition pg. 174, line 1.

j. Citation concerning use of ammonia- “we do not use ammonia for that purpose”, concerning free-base ammonia effect. Why do they use it and why did they not explicitly state the reason? Townsend deposition pg.176, line 13.

C. Analysis Of Retrieved Tobacco Documents In The Context Of Aflatoxin Contamination

Aflatoxin, Tobacco, and Ammonia: Cancer’s Missing Link? Tobacco use in the United States today is estimated to account for 450,000 premature deaths annually, and the worldwide toll is increasing ever rapidly as American style marketing takes hold overseas. Approximately half of all tobacco deaths are due to cancers of many types, the predominant being cancer of the lung. Tobacco use is also associated with an increased incidence of breast, colon, pancreas, bladder, mouth, larynx and esophageal cancer, among others. Lasky T, Silbergeld E. p53 mutations associated with breast, colorectal, liver, lung, and ovarian cancers. Env Health Persp, 1996; 104/12:1324-1334. It is generally accepted that prevention of tobacco use coupled with the production of a considerably safer tobacco product would be the single greatest public health measure of our time.

Yet, despite these laudable but difficult to achieve goals, a serious but preventable hazard associated with the use of tobacco has been overlooked. Moreover, the tobacco industrial complex has suppressed and denied the fact that their product is regularly contaminated by one of the most potent carcinogens known, aflatoxin.

The recent legal and legislative attempts to address the issue of tobacco use in this Country have been a step in the right direction but are far from satisfactory. However, one positive result with the advent of the information age and the Internet, is the rapid dissemination of knowledge and the heretofore-concealed tobacco company documents. When

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these documents are pieced together with respect to the role of aflatoxin contamination of tobacco products, the following picture emerges. The industry has known of the potential for their product to be contaminated by mycotoxins, indeed the likelihood that it was and still is, at least as far back as 1965. Blackmore R. Aflatoxin: Food Toxin, In: Phillip Morris memo; May 24, 1965; PM Website Doc. No. 2021551782. Yet tobacco industry lawyers and their outside legal counsel have kept this knowledge suppressed.

There is more evidence. An internal company document from a British American Tobacco R &D Conference of October 26, 1967 stated “concern is expressed over microbiological contamination in concern that the government will require tobacco manufacturers to have conformed to standards similar to those in the food industries.” (To Glantz’ knowledge this never happened.) Glantz S, Slade J, Bero L, Hanauer P, Barnes D. The Cigarette Papers, Univ. of Calif. Press, Online; Berkley, Ca. 1996; Doc. ID 1165.03 Brown and Williamson Collection. www.library.ucsf.edu/toba… cigpapers/.

Still more Phillip Morris documents show an internal memo from 1965 entitled “Aflatoxin: Food Toxin.” The memo goes on to state that aflatoxin, the food toxin produced by the Aspergillus flavus mold, still is of major concern to the Food and Drug officials of the United States and that Aspergillus flavus has not been reported present in moldy tobacco. However, according to the memo, it is possible that this species of Aspergillus could be found in tobacco since this organism has been found in more than one cultivated crop (peanuts or groundnuts, small grains, corn, etc.). An Italian report indicated that Aspergillus flavus spores were present in minor numbers in the air of a tobacco processing plant. The memo concludes: “We shall keep up with the literature on this subject and maintain a file on the mold hazards in

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U.S. food crops.” Blackmore R. Aflatoxin: Food Toxin. In: Phillip Morris memo; May 24, 1965; PM Website Doc. No. 2021551782.

It is significant to note that the Italian study cited was performed in 1959 and many of the fungal species found were capable of aflatoxin production. Lola N. On the Health Conditions of female tobacco workers: an investigation of a modern factory. Italian Tobacco, 1959; 693:431-433.

Significantly, many of the early aflatoxin documents disseminated from Phillip Morris internal memoranda were either written by or to Dr. Thomas Osdene, their lead researcher for some thirty plus years. On November 8, 1966, Dr. Osdene ordered a literature survey on the subject of aflatoxin. Three days later he received a package containing 163 citations, most describing the potent genetically disruptive and toxic effects of aflatoxin from a variety of crops in a myriad of animal models. O’Donohue C. Literature Survey: Aflatoxin. In: Phillip Morris Incorporated Research Center report; November 11, 1966; PM Website Doc. No. 1000340449. The third citation from 1966 was entitled “Food toxins of Fungal Origin. Methodology and Regulatory Aspects”, by an author from the Food and Drug Administration in the journal Food Technology. Flalles D. Food toxins of fungal origin: Methodology and regulatory aspects. Food Technology, 1966; 20:61-pages unknown. PM Website Doc. No. 1000340451.

Incredibly, in the Minnesota Medicaid trial in 1997, Dr. Osdene took the Fifth Amendment 135 times, answering little more than his name and title. He would answer virtually no questions posed to him, in spite of urgings by the present CEO of Phillip Morris, Geoffrey Bible, to be candid.

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It is unknown what Mr. Bible knows of efforts to remediate aflatoxin contaminated commodities and the role of ammonia in this process. However, the newly released documents and other readily available sources hint at the answer. Conspicuous by its absence is any significant study on this subject over the last thirty years.

As stated previously, aflatoxins are produced by fungi that invade agricultural commodities under warm and wet storage conditions after harvesting such as is often found, for instance, in the southeastern United States. Many of the fungal species commonly found worldwide are capable of producing mycotoxins, with aflatoxin the best studied, currently cited in Medline in over 8000 articles since 1966. Aflatoxin was first identified in 1960, and by 1966 was regulated by the Food and Drug Administration on peanuts, corn, grains and the like. Currently, the States and Federal government ban interstate shipment of contaminated aflatoxin commodities if they exceed 20 parts per billion (ppb), and for milk if the level exceeds 0.5 ppb.

Recently in North Carolina alone the flue-cured tobacco stabilization board has 195 millions pounds of tobacco warehoused for ultimate sale when price, supply and demand are harmonized. In addition there are over 50,000 bulk curing barns in North Carolina, yet there is not a word in the tobacco agricultural literature about the potential for aflatoxin contamination of this stored commodity. When tobacco is cured in a barn it may remain there for years and the state of disrepair of many tobacco barns is a matter of concern. Peedin G, Smith D, Yelverton F, Melton T, Boyette M, et al. Flue Cured Tobacc,. N. Carolina Coop Ex Svc, N. Carolina St. Univ. 1993; 145-148.

In 1996 the corn crop in North Carolina was stricken particularly hard by aflatoxin contamination and the State Agricultural extension service urged corn farmers to take their contaminated corn to the regional tobacco auction houses so it could be tested for aflatoxin.

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McMillian WW, Widstrom NW, Beaver RW, and Wilson DM. Aflatoxin in Georgia: Factors associated with its formation in corn. In: Aflatoxin in Corn–New Perspectives; Iowa Agri and Home Eco Exper Sta; Iowa St Univ. 1991; 599:329-334. To the tobacco insiders, the corn contamination would have been an unmistakable warning of aflatoxin contamination in tobacco. Like they do on corn, Aspergillus flavus and other mycotoxin producing fungi can inhabit a microbiological niche on tobacco.

Aflatoxin has been found to be a potent pulmonary carcinogen in grain handlers and others exposed to contaminated dusts, and DNA-aflatoxin adducts have been found in these patient’s lung tissue. Dvorackova I, Stora C, Ayraud N. Evidence of Aflatoxin B1 in Two Cases of Lung Cancer in Man. J Can Res. 1981; 100:221-224; Burg WR, Shotwell OR, Saltzman BE. Measurements of airborne aflatoxins during the handling of contaminated corn, Ann Ind Hyg. 1981; 42:1-11; Dvorackova I. Aflatoxins and Human Health, Boca Raton, Fl: CRC Press; 1990:135-150; Hesseltine CW, Shotwell OL, Kwolek WF, Lillehoj EB, Jackson WK, Bothast RJ. Aflatoxin occurrence in 1973 corn at harves,. II. Mycological studies. Mycologia. 1976; 68:341-353; Autrup H, Essigman JM, Croy RG, Trump BF, Wogan GN, Harris CC. Metabolism of aflatoxin B1 and identification of the major aflatoxin B1-DNA adducts formed in cultured human bronchus and colon, Cancer Res. 1979; 39:694-698.

Additionally, work by Groopman et.al. in 1991 showed DNA-carcinogen adducts at codon 249 of the p53 tumor suppressor gene in 45% of lung cancers. Puisieux A, Lim S, Groopman J, Ozturk M. Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens, Cancer Res. 1991; 51:6185-6189; Garner RC, Dvorackova I, Tursi F. Immunoassay procedures to detect exposure to aflatoxin B1 and benzo(a)pyrene in animals and man at the DNA level. Int Arc Occup Environ Health. 1988;

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60:145-150. This same site is often mutated by aflatoxin in hepatomas, where liver cancer is believed to be caused often by aflatoxin. McGlynn KA, Rosvold EA, et al, Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1. Proc Natl Acad Sci. 1995; 92:2384-2387.

There is no known safe dose of aflatoxin. Levels below one part per billion can cause cancer. Aflatoxin is more actively metabolized to the active carcinogen, the epoxide, by benzpyrene, the carcinogen heretofore suspected of being most likely responsible for cancer associated with tobacco use. Ma X, Gibbons J, Babish J. Benzo(e)pyrene pretreatment of immature, female C57BL/6J mice results in increased bioactivation of aflatoxin B1 in vitro, Toxicology Letters. 1991; 59:51-58. Yet aflatoxin is 200 times more carcinogenic than benzpyrene, a product of combustion.

Benzpyrene has been considered a principal carcinogen in tobacco. Uncovered Brown and Williamson documents suggest aflatoxin, not benzpyrene, as the causative agent. Is has been known that oral use of tobacco products often leads to cancers after only several years. It is difficult to implicate benzpyrene in this phenomenon. Uncombusted aflatoxin, however, may be the cause as mutations of p53 are often found in cancers of the oral cavity and throat. Park J, Ren Q, et al. p53 mutations in oral tumors are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use, Proc Amer Assoc Cancer Res. 1998; 39 # 1250; Wood NB, Caldarelli DD, et al. Mutation of p53 in Squamous Cell Cancer of the Head and Neck: Relationship to Tumor Cell Proliferation, Laryngoscope. 1997; 107/6:827-33; Karja VJ, Syrjanen KJ, Kurvinen AK, Syrjanen SM. Expression and Mutations of p53 in Salivary Gland Tumors. J of Oral Path & Med. 1997; 26/5: 217-23.

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Brown and Williamson data strongly support this hypothesis but these data were kept secret. Documents from August 1967 state, “These results would certainly indicate that reduction of benzpyrene does not necessarily result in a decrease in mouse skin activity, even though Wynder and others might like to think this is true. Actually, the data from the initial Harrowgate experiment would indicate that the benzpyrene fraction can account for, at most, one third of the activity of the total condensate…” Griffith R. Report to executive committee. The Brown and Williamson Collection Online; Univ. Calif., San Francisco. 1965; Doc ID 1105.01. Benzpyrene research relative to tobacco began in earnest after it was reported by Alvord and Cardon in the British Journal of Cancer in 1955 that ammonium based compounds were able to neutralize the carcinogenic effects of benzpyrene in cigarette smoke condensates. Alvord ET, Cardon SZ. The Inhibition of Formation of 3-4 Benzpyrene in Cigarette Smoke, Brit J Cancer. 1956; 10: 498-503. On May 14, 1956, R.C. Hockett of Phillip Morris (PM) wrote “[H]e has received a letter from Sir Robert Sinclair in which he inquires whether active efforts are under way in this country to remove 3-4 benzpyrene from tobacco. He writes: “(he) does not believe there is any 3- 4benzpyrene in tobacco … except from soot… etc.… Another conceivable possibility…is some trace of benzpyrene might reach tobacco leaves during…fluecuring. The benzpyrene reported by the British and a few Americans is claimed to be present in the condensed smoke. It is presumed to be formed during smoking by the action of heat on some of the constituents on tobacco under conditions where the oxygen supply is not sufficient to burn these constituents completely to carbon dioxide gas and water. . . .Sir Robert speaks of neutralization of benzpyrene. So far as chemists know, there is no method of neutralizing a compound of this class. It is already neutral chemically and there is no accepted knowledge in general as to how the biological activity of a chemical carcinogen can be neutralized (though

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there are some claims). The only practical course of action open to the technical man at present are removal of benzpyrene from smoke, its destruction, or the prevention of its formation in the first instance. … The development of better biological assay methods for carcinogens, which might be used for purposes outlined above, is one of the main objectives of the Scientific Advisory Board in its present program. It is regarded as a difficult task.… Other possibilities exist. For example benzpyrene may eventually be found to arise on heating chiefly from some specific compound present on tobacco.” Hockett RC. Elimination of Benzpyrene from Tobacco Smoke, In: Phillip Morris memo; May 14, 1956; PM Website Doc. No. 2000756765-67.

A United States Patent was issued in 1958 entitled “Cigarette Wrapper Material and Method of Making Same” which described this technology of ammoniation to neutralize benzpyrene. Hitchcock R, Willoughby, Cardon SZ, Alvord ET. Cigarette wrapper material and method for making same. USPO, 1958; U.S. Patent 2,859,753. Research projects were undertaken by the individual tobacco companies and the Tobacco Institute to remediate this perceived benzpyrene problem. A December 23, 1958 Phillip Morris memo assessed the “Total Particulate Matter Delivery and Nicotine Delivery of Cigarettes…treated with Ammonia, (versus) Untreated Tobacco.” Stewart LL. Total particulate matter delivery and nicotine delivery of cigarettes…treated with Ammonia, (versus) Untreated Tobacco. In: Phillip Morris study; Dec. 23, 1958; PM Website Doc. No. 1001920430.

On Sept. 16, 1959, a document with the letterhead Phillip Morris Interoffice Correspondence on “Benzpyrene Research” states “Further to this, I discussed the problem …and I am in agreement with him that this is an important future area of work. It is basic in nature and is liable to plague us for years to come because of its fundamental aspect. Unless there is work about this which we are not aware, which lessens the likelihood of this becoming

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a major factor; I would think it most sound for the company to have a long-range research project in this area.” Weissman G. Benzpyrene research, In: Phillip Morris Interoffice Correspondence; Sept. 16, 1959; PM Website Doc. No. 1001882395.

On October 1, 1959, a memo was sent from Rodgman to Holtman which stated: “no specific carcinogen has previously been shown in such smoke… Benzpyrene…(is) only feebly (carcinogenic).” Wynder and Wright, by testing various fractions of tar, estimated that there can be no more than one part per million of 3,4-benzpyrene in the total condensate. They state, “We feel that as yet unestablished carcinogens or co-carcinogens are in tobacco tar, since the concentration in which benzpyrene seems to be in cigarette tar is insufficient to account for the observed carcinogenic activity to mouse epidermis.” Rodgman A. Biological Studies on Tobacco Products: Role of Animal Experimentation in Cancer Research. In: Phillip Morris study; Oct. 1, 1959; PM Website Doc. No.2025018236, 2025018276, 2025018713, 2025018279, 2025018286. Furthermore, subsequent researchers were not convinced benzpyrene was a significant contributor to the biological activity associated with tobacco use.

In 1962 Roe et.al, wrote in Abstracts of Papers, VII International Cancer Congress, 1962, Role of 3,4-Benzopyrene in Experimental Tobacco Carcinogenisis, “benzpyrene is a very weak carcinogen and may be, at most, responsible for a small fraction of the cancers associated with cigarette use.” Roe FJC, Salamon MM, Cohen I, Surgon LG. Role of 3,4-benzopyrene in experimental tobacco carcinogenisis, In: Abstracts of Papers, VII International Cancer Congress, 1962; Great Britain, London; PM Website Doc. No. 1005087287. Another document revealed “Most of the biological activity seems to be associated with the fraction containing the polynuclear hydrocarbons” which would include aflatoxin and benzpyrene but not the nitrosamine fraction. Griffith R. Importance of

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benzpyrene versus other PAH’s in Project Janus. The Brown and Williamson Collection, Online; Univ. Calif., San Francisco. 1967; Doc. ID 1101.1.

If these studies were credible one would have to conclude a polycyclic aromatic compound other than benzpyrene was responsible for the majority of biological activity of these cigarette condensate samples. Aflatoxin is the likely culprit. A subsequent study to prove this point by reducing or neutralizing benzpyrene was never performed because “if the experiment showed no protection, but benzo(a)pyrene levels were, in fact, lower, this result would suggest that other carcinogens in the smoke were responsible for the cigarettes’ carcinogenicity.” Glantz SA, Slade J, Bero L, Hanauer P, Barnes. The Cigarette Papers, Univ. of Calif. Press. 1996, p.215. The tobacco industry did not want this carcinogen publicly identified. In March of 1966 a journal article stated, “Aflatoxins by all routes tested (s.c., by mouth in drinking water, and intratrachealy) proved to be effective carcinogens. When aflatoxins were given intratrachealy, 3 of 6 rats developed squamous carcinoma of the trachea. Intratracheal benzpyrene did not lead to the formation of any tumors.” Dickens F, Jones HEH, Waynforth HB. Oral, Subcutaneous and Intratracheal Administration of Carcinogenic Lactones and Related Substances: the Intratracheal Administration of Cigarette Tar in the Rat. Br J Cancer, 1966; 20:134-144. RJR Website Doc. No. 500291239. This study was supported by the Tobacco Research Council and by The British Empire Cancer Campaign. On June 8, 1966, a memo was sent to the law firm representing the tobacco industry, Shook, Hardy, from K. Austin, where “aflatoxins” appeared at the top of the alphabetically arranged list. Austin K. Substances in tobacco alleged to be causes of cancer, respiratory and other diseases, In: RJ Reynolds Center for Tobacco Research memo. June 8, 1966; RJR Website Doc. No. 502429578:1.

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In 1968, a researcher for the Wisconsin Alumni Research Foundation met with RJ Reynolds and reported their work “has shown 100% carryover of aflatoxin from combusted tobacco.” Senkus, M. Meeting with Mr. P. Derse. RJ Reynolds, Feb. 27, 1968; RJR Website Doc. No. 501868781:1. Subsequent letters between RJR and their outside legal counsel, Shook Hardy, Ottman, Mitchell & Bacon reveal a significant level of concern with respect to this finding. Shinn WW. In: RJ Reynolds letter. July 20, 1968; RJR Website Doc. No. 501868751; Ramm HH. In: RJ Reynolds letter. July 25, 1968; RJR Website Doc. No. 501868750.

It is in this context that the revelations by documents posted on the Internet of Phillip Morris “Project 2500” and “Project 1801” can be understood. Project 2500 was produced by Phillip Morris in 1966. DeBardeleben F. The Structure and Synthesis of Aflatoxin B1 and G1, In: Phillip Morris Project Report. Dec. 9, 1966; PM Website Doc. No. 2021551728. Additionally, aflatoxin was synthesized at MIT in 1966, and was manufactured under contract to the Center for Tobacco Research (CTR) by Hoffman-Laroche in 1966. Mitchell GF, et.al. The Total Synthesis of Racemic Aflatoxin B1. Jour of Am Chem Soc, 85: 19, Oct.5, 1966, PM Website Doc. No. 2021551735-37.

Most likely, the tobacco industry required significant quantities of pure aflatoxin in order to learn a technique whereby it could be decontaminated from tobacco, much the same as the industry had done with benzpyrene some ten years previously. Once the chemists and toxicologists had an ample supply of this most deadly of carcinogens on hand, one of the first decontaminating agents they reached for was surely ammonia, as it had worked on benzpyrene. In 1967 a project was underway at Phillip Morris, which utilized ammonia to remove Tar Particulate Material (TPM), thought to contain most of the carcinogenic materials, including aflatoxin, from tobacco. A side effect of this process was removal of nicotine from the tobacco

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materials. Comes HA, Nichols DG, Liquid ammonia extracted bright tobacco. In: Phillip Morris report, Oct. 31, 1967; PM Website Doc. No. 1000704262. Thus, use of ammonia on tobacco was called a “denicotinization process” in what appears to have been a deliberate act of disinformation. In 1970, Phillip Morris Project 1801 demonstrated “that ammonia vapor saturated or impregnated tobacco was puffed successfully.” Deszyck EJ. Summary - Project 1801 activities. In: Phillip Morris memo, January 27, 1970; PM Website Doc. No. 2022232919. The tobacco industry would not call this an “aflatoxin-benzpyrene-neutralization process” as aflatoxin was at that time regulated by the FDA on corns, grains, and other commodities. The tobacco industry had no greater fear than regulation by the FDA, as is the case today some 39 years later. Indeed, even “Independent Counsel” Kenneth Starr represented the tobacco industry in 1995-1996 in an effort to prevent FDA jurisdiction over tobacco.

To the detriment of the public health, the FDA has never had explicit jurisdiction over tobacco and the mycotoxin and aflatoxin contamination of tobacco products, yet an estimated half of all deaths annually associated with tobacco use are attributable to cancer. R.J. Reynolds documents obtained from the Minnesota Medicaid trial stated the “greatest fear” of the company’s top lawyer throughout the 1950s and 1960s “was that RJR would do something that would enable the FDA to assert jurisdiction over cigarettes.” RJ Reynolds Fact Team, Minnesota Medicaid Trial. In: RJ Reynolds Research and Development Activities Fact Team Memorandum; Vol. III; 1985; RJR Website Doc. No. 515873867. “The company’s external scientific research program is controlled, not by its scientists or R&D department, but by its lawyers.” RJ Reynolds Fact Team. Minnesota Medicaid Trial, In: RJ Reynolds Research and Development Activities Fact Team Memorandum; Vol. III; 1985; RJR Website Doc. No. 515873880. “Much of this control was exerted, apparently, through an outside law firm which

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for years has exercised extraordinary influence over RJR research, even to the point of deciding which species of rodent would be used in one research project.” RJ Reynolds Fact Team. Minnesota Medicaid Trial,. In: RJ Reynolds Research and Development Activities Fact Team Memorandum; Vol. III; 1985; RJR Website Bates Nos. 515873880-515873884. The decision of which species of rodent to use in experimental tobacco toxicology studies becomes relevant when one reviews the study undertaken and funded by CTR which engaged the services of Microbiological Associates of Bethesda, Maryland. This study utilized 10,000 mice over a ten- year period beginning in 1974, and cost CTR over $10 million dollars. It was designed to test for tumors in lungs and organs of mice following inhalation of whole cigarette smoke. Yet it is likely the lawyers for CTR knew mice were relatively resistant to the effects of aflatoxins as research on these subjects was published as early as 1967. Wogan GN, Newberne PM. Dose- response characteristics of aflatoxin B1 carcinogenesis in the rat, Cancer Res. 1967; 27:23702376; Cullen JM, Newberne PM. Acute Hepatotoxicity of Aflatoxin, In: Eaton DL, Groopman JD, eds. The Toxicology of Aflatoxins, San Diego, Ca: Academic Press; 1994: 3-26; Weider R, Wogan GN, Shimkin MB. Pulmonary tumors in strain “A” mice given injections of aflatoxin B1, J Natl Cancer Inst. 1968; 40:1195-1197; Salmon WD, Newberne PM. Occurrence of hepatomas in rats fed diets containing peanut meal as a major source of protein, Cancer Res, 1963; 23:571-575; Newberne PM, Butler WH. Acute and Chronic Effects of aflatoxin on the liver of domestic and laboratory animals, A review. Cancer Res. 1969; 29: 236-250; Herrold KM. Aflatoxin induced lesions in Syrian hamsters. Br J Cancer, 1969:23; 655-660.

These and other documents clearly indicate that the potential for aflatoxin contamination was known by the tobacco industry since 1965. In order to keep the FDA from exerting its jurisdiction over tobacco this knowledge of the possibility of contamination of

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tobacco by aflatoxin was suppressed both by neglect and by an active misinformation campaign. Indeed, even as of today, after the largest civil trial in history, aflatoxin is still not recognized as a carcinogen associated with tobacco use, in spite of knowledge of its potent carcinogenic properties. Cordesman, A. Weapons of mass destruction in Iraq: a summary of biological, chemical, nuclear and delivery efforts and capabilities. In: Middle East Program at the Center for Strategic and International Studies; Nov. 14, 1996; Washington, D.C (citing aflatoxin as a potential weapon of mass destruction manufactured and weaponized by Saddam Hussein).

As recently as 1994 internal Phillip Morris documents revealed a proposal for a project entitled “Are mycotoxins present in cured tobaccos?” Hempfling, W. March 31, 1994; Phillip Morris Website Doc. No. 2024111027, 2024111030. These documents place of origin are betrayed by the facsimile numbers on top of the document and the word Inbofan, the secret facility in Germany where Phillip Morris did most of their research which they wished to keep from the prying eyes of American trial lawyers. The proposal described a multi-million dollar effort to ascertain the level of aflatoxin and mycotoxin contamination of their product. Unfortunately, the results of this study are unavailable to health researchers at the present time, if indeed the project was ever undertaken. As with many of the tobacco industry’s deepest secrets, internecine competition, desire to secure market share and fear of catastrophic regulation have conspired to keep answers to many important questions from the public. Indeed, for many relevant subjects, researchers are not well versed enough in the ways of the industry to know which questions to ask.

Aflatoxins are relatively heat stable compounds, decomposing at 269 degrees centigrade, well above the combustion temperature of an idling cigarette. Langer AM, Nolan

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RP, Bowes DR, Shirey SB. Inorganic Particles Found in Cigarette Tobacco, Cigarette Ash, and Cigarette Smoke. In: Wehner AP, Felton D. Biological interaction of inhaled mineral fibers and cigarette smoke. Proceedings of an International Symposium/Workshop, Columbus, OH: Battelle Press; 1989: 430. Polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) have been found in sidestream or environmental smoke (ETS) at levels two to ten times that of mainstream smoke, which is combusted at higher temperatures. Lofroth G, Zebuhr Y. Polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) in mainstream and sidestream cigarette smoke. Env Contam and Tox, 1992; 48:789-794; US Dept. Labor, OSHA. Indoor air quality: proposed rule. Federal Register, 1994; 59/65:15988. These compounds have been shown to increase aflatoxin-DNA adducts in human epidermal cells twenty-fold, implicating dioxin in stimulation of the active metabolite of aflatoxin, the epoxide. Walsh AA, Hsieh DPH, Whitehead WE, Rice RH, Aflatoxin toxicity in cultured epidermal cells: Stimulation by TCDD. Toxicologist, 1992; 12: 207. Aflatoxins are chemically classified as dibenzofurofurans and are highly oxygenated heterocyclic compounds, and as such would be easily amenable to deactivation by a catalyst such as palladium. Liggett Corporation even had developed a safer cigarette in” Project XA” in 1977 which used a palladium catalyst which essentially reduced the biological activity of the smoke condensate to zero. This product was never developed because the companies with larger market share threatened retaliation as this might indicate the product in general was unsafe and might lead to unlimited litigation.

Generally, aflatoxin is decontaminated on foodstuffs by simple ammoniation, either in a liquid or gaseous form, or by contacting the product with a strong base or alkali. Park DL, Lee LS. New perspectives on the ammonia treatment for decontamination of aflatoxins, In: A Perspective on Aflatoxin in Field Crops and Animal Food Products in the US: A Symposium;

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National Technical Information Services, Springfield, VA. 1990; 127-137; Norred W, Morrissey R. Effects of long-term feeding of ammoniated aflatoxin-contaminated corn to Fischer 344 rats. Tox and App Pharm, 1983; 70:96-104. This technology dates to 1969 for foodstuffs as evidenced by U.S. Patent No.3, 429,709 assigned to the United States of America. Subsequent to this patents were granted in 1970 and 1974 for a technique whereby ammoniated cigarette paper was used to encircle the tobacco cylinder. Michelson I, Smoking composition of reduced toxicity and method of making same, USPO. 1970; U.S Patent 3,631,865; Michelson I, Method of making a cigarette of reduced biological damage capability, USPO. 1974; U.S Patent 3,782,393. This technology specifically claimed a 45% reduction in biological activity, a euphemism for cancer production ability, yet it is not apparent from the patent text if the cause of the biological activity was known to the inventor. Coincidentally, this 45% reduction in biological activity closely approximates the proportion of lung cancers which show the prototypical genetic change in p53 caused by aflatoxin.

Thus the technology to neutralize aflatoxin was generally known as of 1969 and indeed, the ammoniation of cigarette paper was patented as early as 1958. Clearly, ammoniation of tobacco products was initially performed in an effort to eliminate first benzpyrene, and subsequently aflatoxin, when it became apparent aflatoxin was the far more deadly of the two compounds. The tobacco industry apparently invented the aflatoxin-ammoniationneutralization process but did not patent this technology as patents require full disclosure of all relevant points. The industry dared not reveal their product was contaminated by the most potent carcinogen ever identified.

When these documents are viewed in a historical context in becomes strikingly clear the use of ammonia to enhance the nicotine delivery to the brain of the smoker was a secondary or

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tertiary goal after 1) detoxification of benzpyrene and aflatoxin, and 2) reduction of Tar Particulate Matter (TPM), which contained most of the carcinogens. A side effect of ammonia use resulted in “denicotinization.” Comes HA, Nichols DG, Liquid ammonia extracted bright tobacco. In: Phillip Morris report, Oct. 31, 1967; PM Website Doc. No. 1000704262. Consumer research had shown smoker satisfaction had been enhanced by a known ration of tar to nicotine. If tar was removed to eliminate some carcinogens, some proportion of nicotine needed to be removed also. This fact has important implications for future regulation of nicotine by the FDA. Neutralization of aflatoxin by ammonia results in loss of nicotine. The FDA should regulate the amount of nicotine that is added back in the reformulation process.

How widespread was ammonia use by the tobacco industry? Phillip Morris began using ammonia on tobacco in the late 1960s. A Brown and Williamson researcher stated “Ammonia does many good things, the secret to Marlboro is ammonia.” Editorial, Tobacco’s outrageous, unethical tactics a threat to public health, In: Sun Sentinel Editorial; Fort Laud, Fl.; Feb. 10, 98. By 1984, the tobacco industry was utilizing 5 million pounds of ammonia annually, and by 1989 usage had climbed to ten million pounds. Covington and Burling (Attorneys) to Phillip Morris Legal Dept. 4/17/86, Ammonia use. Phillip Morris Website Doc. No. 2056136056 pg. 2 of 11. In the Minnesota Medicaid trial when a lead researcher for RJ Reynolds was asked when RJR began using ammonia on tobacco products he acknowledged “from ‘74 to ‘79, the only brand that had any ammoniated reconstituted sheet was Camel Filter.” When asked what proportion of their product was ammoniated as of late, the researcher responded, “In 1994… thirty nine per cent of our products we sold had ammoniated reconstituted tobacco.” Townsend R. In: Minnesota Medicaid trial transcripts. March 29-30, 1998. The prevailing sentiment among the lay media is that ammoniation was performed to increase the free base of

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the nicotine, thus allowing a quicker and more intense high from a given amount of nicotine. Nicotine was coincidentally the addictive component of their product. The fact that ammonia neutralized aflatoxin was the prime intent of its use, with the nicotine boost a fortuitous effect, that also had significant implications for these companies final product design. Chapman R. Method for detoxifying foodstuffs. USPO, 1992; 1/21:U.S. Patent 5,082,679.

Thus the tobacco industry can no longer credibly deny their product does not cause cancer, and that aflatoxin does not play a substantial or possibly majority role in tobacco induced carcinogenesis. Wild CP, Umbenhauer D, Chapot B, Montesano R. Monitoring of individual human exposure to aflatoxins (AF) and N-nitrosamines (NNO) by immunoassays. J Cell Biochem, 1986; 30:171-179; O’Neill IK. Relevance to Human Cancer of N-Nitroso compounds, tobacco smoke and mycotoxins. Lyon, France: International Agency for Research on Cancer; 1991. The secondhand smoke controversy should similarly end at once as the entire civilian population of the United States may be inhaling aflatoxin in unknown but potentially harmful quantities when exposed to this toxin in enclosed spaces.

The Defendant’s suppression of aflatoxin in tobacco has also left unanswered other questions of paramount importance to the future health of the hundreds of millions of smokers worldwide, their dependents and their unborn children. Wild CP, Pionneau F, Montesano R, Muitiro CF, Chetsanga CJ. Aflatoxin detected in human breast milk by immunoassay. Int J Cancer, 1987; 40:328-333 Denning DW, Allen R, Wilkinson, AP, Morgan MRA. Transplacental transfer of aflatoxin in humans, Carcinogenesis, 1990; 11:1033-1035. Of particular concern are those crippled by disease of immune deficiency as benzpyrene and aflatoxin have been shown to increase HIV titers 500% and 400% respectively in vitro, which is in agreement with conventional clinical wisdom. Yao Y, Hoffer A, Chang C, Puga A.

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Dioxin activates HIV-1 gene expression by an oxidative stress pathway requiring a functional cytochrome P450 CYP1A1 enzyme. Env Health Persp, 1995; 366; Hendrickse RG, Maxwell SM. Heroin addicts, AIDS, and aflatoxins, Brit Med J. 1988; 296:1257. Immunosuppression by aflatoxin is prevented by the chemo-protective drug oltipraz, which also inhibits HIV replication. Pier AC, McLoughlin ME. Mycotoxic suppression of immunity, In: Lacey J. ed. Trichothecenes and Other Mycotoxins; John Wiley & Sons, Chichester; 1985: Pages 507-519; Prochaska HJ, Yeh Y, Baron P, Polsky B. Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication. Proc Natl Acad Sci, USA. 1993; 90:3953-3957; Roebuck BD, Liu YL, Rogers AE, Groopman JD, Kensler TW, Protection against aflatoxin B1-induced hepatocarcinogenesis in F344 rats by 5-(2-pyrazinyl)-4-methyl-1, 2-dithiole-3-thione (oltipraz), predictive role for short-term molecular dosimetry. Cancer Res. 1991; 5501-5506.

D. Suppression of Knowledge of Harmful Health Effects and Emerging Diseases- AIDS

Aspergillus species can produce the mycotoxin Gliotoxin, which instantly kills CD4 cells in vivo. Low CD4 cell counts are the hallmark of AIDS. Aspergillus spores are aerosolized from tobacco combustion.

Aspergillus fumigatus (AF) is a ubiquitous mold and is the most common cause of invasive aspergillosis, an important source of morbidity and mortality in immunocompromised hosts. Using cytokine flow cytometry, we assessed the magnitude of functional CD4+ and CD8+ T-cell responses following stimulation with Aspergillus antigens. Relative to those seen with cytomegalovirus (CMV) or superantigen stimulation, responses to Aspergillus antigens were near background levels. Subsequently, we confirmed that gliotoxin, the most abundant mycotoxin produced by AF, was able to suppress functional T-cell responses following CMV or staphylococcal enterotoxin B (SEB) stimulation. Additional studies demonstrated that crude

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AF filtrates and purified gliotoxin inhibited antigen-presenting cell function and induced the preferential death of monocytes, leading to a marked decrease in the monocyte-lymphocyte ratio. Analysis of caspase-3 activation confirmed that gliotoxin preferentially induced apoptosis of monocytes; similar effects were observed in CD83+ monocyte-derived dendritic cells. Importantly, the physiologic effects of gliotoxin in vitro were observed below concentrations recently observed in the serum of patients with invasive aspergillosis. These studies suggest that the production of gliotoxin by AF may constitute an important immunoevasive mechanism that is mediated by direct effects on antigen-presenting cells and both direct and indirect effects on T cells. Aspergillus fumigatus suppresses the human cellular immune response via gliotoxin- mediated apoptosis of monocytes. Blood. 2005; 105(6): 2258-65 (ISSN: 0006-4971) Stanzani M; Orciuolo E; Lewis R; Kontoyiannis DP; Martins SL; St John LS; Komanduri KV. Transplant Immunology Section, Department of Blood and Marrow Transplantation, MD Anderson Cancer Center, SCRB 3.3019, Unit 900, 7455 Fannin St, Houston, TX 77030, USA.

E. The toxicology of aflatoxins as a basis for public health decisions

Aflatoxins have been extensively studied with respect to their mechanisms of toxicity. An understanding of metabolism, DNA adduct induction, mutagenicity and carcinogenicity has been paralleled by the development of biomarkers of aflatoxin exposure and biological effects (e.g. mutations) applied to human populations. The improvements in exposure assessment and their application in prospective epidemiological studies and the demonstration of a specific mutation in the TP53 gene in hepatocellular carcinomas from areas of high aflatoxin exposure have contributed significantly to the classification of aflatoxins as human carcinogens. In addition to establishing the carcinogenicity of aflatoxins in humans, understanding molecular mechanisms of action has provided the scientific rationale for prevention strategies, including primary and chemoprevention approaches. Overall, integrated, multidisciplinary research on

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aflatoxins has provided the platform on which to base decisions regarding acceptable exposures and priorities for interventions to reduce human risk in a public health context. From C.P. Wild and P.C. Turner , Molecular Epidemiology Unit, Epidemiology and Health Services Research, Algernon Firth Building, School of Medicine, University of Leeds, Leeds LS2 9JT, UK

F. Aflatoxins and Smoke Studies

Methods were developed to study sidestream smoke produced from machine-smoked cigarettes. These methods show aflatoxin is carried by sidestream smoke in significant amounts. Journal of Chromatography A, 1083 (2005) 127–132 Determination of aflatoxin B1 in sidestream cigarette smoke by immunoaffinity column extraction coupled with liquid chromatography/mass spectrometry. From Leslie E. Edinboro, H. Thomas Karnes, Department of Pharmaceutics, Virginia Commonwealth University, School of Pharmacy, P.O. Box 980533, 410 N 12th Street, Richmond, VA 23298-0533, USA.

G. Aflatoxin Remediation by Ammoniation

The effectiveness of ammonia treatment in reducing the chronic toxicity of aflatoxin- contaminated corn was determined. Fischer 344 rats were fed semi-purified rations containing 20% w/w corn that was either free of aflatoxin or naturally contaminated with 880 micrograms/kg total aflatoxin and was either treated with ammonia gas or was not treated. Therefore the rats that were fed the aflatoxin-contaminated diet received 176 ppb total aflatoxins. Body weight and food consumption were recorded throughout the study; hematological measurements were made after 87 weeks of feeding; and after 91 weeks the rats were killed and histopathological abnormalities were noted. Signs of chronic toxicosis in rats fed aflatoxin-contaminated corn included increased mortality, decreased hematocrit and hemoglobin levels, elevated serum alkaline phosphatase activities, and a 100% incidence of

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liver neoplasia. These signs did not occur in rats in the other dietary treatment groups, including those fed ammoniated, aflatoxin-contaminated corn. The results provide further evidence that the atmospheric ammoniation process effectively reduces the toxicity of aflatoxin. From Effects of long-term feeding of ammoniated, aflatoxin-contaminated corn to Fischer 344 rats, Norred WP; Morrissey RE, Toxicol Appl Pharmacol; VOL 70, ISS 1, 1983, P96-104, TOXBIB/83/303131.

H. p53 Tumor Suppressor Gene Mutated by Aflatoxin and Industry Deception

Mutations in the p53 tumour suppressor gene lead to uncontrolled cell division and are found in over 50% of all human tumours, including 60% of lung cancers. Research published in 1996 by Denissenko and colleagues demonstrated patterned in-vitro mutagenic effects on p53 of benzo[a]pyrene, a carcinogen present in tobacco smoke. We investigated the tobacco industry’s response to p53 research linking smoking to cancer. We searched online tobacco document archives, including the Legacy Tobacco Documents Library and Tobacco Documents Online, and archives maintained by tobacco companies such as Philip Morris and R J Reynolds. Documents were also obtained from the British American Tobacco Company depository in Guildford, UK. Informal correspondence was carried out with scientists, lawyers, and tobacco control experts in the USA and Europe. This research indicated that executives and scientists at the highest levels of the tobacco industry anticipated and carefully monitored p53 research. The tobacco industry’s own scientists conducted research which appeared to cast doubt on the link between smoking and p53 mutations. Researchers and a journal editor with tobacco industry ties participated in the publication of this research in a peer-reviewed journal without clear disclosure of their tobacco industry links. Tobacco industry responses to research linking smoking to carcinogenic p53 mutations mirror prior industry efforts to challenge the

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science linking smoking and lung cancer. The extent of tobacco industry involvement in p53 research and the potential conflict of interest discussed here demonstrate the need for consistent standards for the disclosure and evaluation of such potential conflicts in biomedical research. The p53 tumour suppressor gene and the tobacco industry: research, debate, and conflict of interest, Asaf Bitton MD, Mark D Neuman MD, Joaquin Barnoya MD and Stanton A Glantz Prof PhD, Center for Tobacco Control Research and Education, University of California, San Francisco, CA 94143, USA, Corresponding to: Prof Stanton A. Glantz.

III. CONCLUSION Several independent lines of evidence indicate the tobacco industry has been aware of the contamination of tobacco by aflatoxin, of the resulting adverse health effects of this contamination and of methods of making tobacco safer by aflatoxin removal. The details of programs to minimize this problem are unknown. Most likely documents exist that detail the industry response, but remain hidden. As it now stands many adverse health effects, including immunosuppressive diseases and cancers, may be tied, not to the tobacco itself, but to the more easily treatable infectious fungal spores and their mycotoxins which are found on the tobacco. This court needs to address these issues at this time in order to formulate a complete response to the Defendants’ actions.

Respectfully Submitted,

/s/

Kerry Scott Lane M.D. St. Mary’s Medical Center 901 45th Street West Palm Beach FL 33407

(561) 844-6300

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Financial Disclosure-Potential Conflict of Interest: In the course of researching this topic, the author, Kerry Scott Lane M.D. obtained patents on technologies to help solve this problem. He holds United States Patents 6,058,940, 6,637,438, 6,786,221 and others are pending. These include worldwide patent rights. Additional patents directed towards AIDS and other diseases are pending.

Duty to Confer under Local Civil Rule 7(m). The author certifies that he has conferred with counsel for the parties to this proceeding. The Joint Defendants oppose the filing of this amicus brief. The Plaintiff, in view of government policy, has no comment.

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One Response to “DR. LANE MAKES HIS CASE FOR AFLATOXIN”

  1. Gene Borio Says:

    Dr. Kerry’s request was denied by Judge Kessler on Dec. 28, 2006 “for the following reasons: (1) Movant has failed top serve the other parties and (2) the Motion is untimely.”

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