Posted: 19 March 2007
From: Dr. Betty Martini,D.Hum., Bettym19@mindspring.com
Cc: "mitchell.cheeseman-fda.hhs.gov" email@example.com, David: ;, Jaffe Lyle D LJAFFE@OC.FDA.GOV, "Commissioner-fda.gov" Commissioner@fda.gov, "inforeply-cdc.gov" firstname.lastname@example.org, "AskDOJ-USDOJ.GOV" AskDOJ@USDOJ.GOV
Date: Sun, Mar 18, 2007 10:34 pm
Subject: Open Letter to Dr. Dick Adamson of American Beverage regarding protest of using aspartame in carbonated beverages
Dear Dr. Adamson:
Why did NSDA, file a protest against the approval of aspartame for soft drinks, then turn around and lobby for NutraSweet? NSDA's stunning protest is in the Congressional Record S 5507 - 5511, May 7, 1985 http://www.wnho.net/congressional_record1.pdf
Now you say that after this protest you interrogated the G. D. Searle Co., and the answers they gave assured you everything is fine. Please send me a copy of the questions and the answers which made you change your mind.
How do you repudiate the detailed and damning objections NSDA wrote against aspartame which fill 6 pages of the Congressional Record? For instance, NSDA said: "An important decomposition product of aspartame, aspartic acid, cannot be detected at all using TLC." Did Searle go back and use the right test, HPLC, high pressure liquid chromatography instead of TLC, thin layer chromatography? Did they not want their testing to detect aspartic acid because as an isolate its an excitotoxin (product that stimulates the neurons of the brain to death causing brain damage)? http://www.wnho.net/aspartame_brain_damage.htm
NSDA said: "The present record does not contain data which demonstrate that the use of APM in soft drinks will not result in the adulteration of the beverages under section 402 (a)(3)of the FDC Act. 21 U.S.C. 342 (a) (3), which provides that a food is adulterated if it contains, in whole or in part, "...a decomposed substance or if it is otherwise unfit for food." Since aspartame does decompose at 86 degrees or moderate temperature as stated how did they get around the fact that aspartame is adulterated and therefore against the law. It is also against the law to ship an adulterated product for sale which means it violates Interstate Commerce laws. The entire molecule breaks down to diketopiperazine, a brain tumor agent. Is there an answer for this too? And the many other questions NSDA posed in this protest?
If you don't answer this request we will announce there weren't any questions and answers, but NSDA lied, and approved aspartame because it's addictive and cheaper than sugar. That's the real truth, isn't it? The free methyl alcohol causes chronic methanol poisoning, affects the dopamine system of the brain and causes addiction. What do you expect when methanol is classified as a narcotic? (Louis, R. J. Sax's Dangerous Properties of Industrial Materials, Eighth Edition, New York: Van Nostrand Reingold (1992) pp. 2251 - 2252.)
Surprise me and answer this letter!
Dr. Betty Martini
Founder, Mission Possible World Health International
9270 River Club Parkway
Duluth, Georgia 30097
Aspartame Toxiocity Center: http://www.holisticmed.com/aspartame
Aspartame Documentary, Sweet Misery: A Poisoned World, http://www.amazon.com
Medical text on global plague: Aspartame Disease: An Ignored Epidemic, http://www.sunsentpress.com by H. J. Roberts, M.D.
Excitotoxins: The Taste That Kills by neurosurgeon Russell Blaylock, M.D., http://www.russellblaylockmd.com
The Truth About Aspartame: http://www.atavistik.com
********************* Lead-in to NSDA Protest *********************
Aspartame was never proven to be safe, nor effective as a diet aid.
Because it changes brain chemistry and breaks into a witches brew of toxins & tumor agent there was great concern by the National Soft Drink Association about putting this once-upon-a-time ulcer drug turned "food additive"... into beverages.
The NSDA was particularly concerned over how much a child could consume. An allowable daily dose was never set for humans to begin with... but for rats, because they tolerate more of the wood alcohol (methanol). In l983 aspartame was in a few hundred products, and yet, the NSDA and many others were concerned. The secret trade information read into the congressional record and the secret trade information (posted on dorway.com) was not for using aspartame as a universal sweetener. It noted that it converts into DKP (a brain tumor agent) and if they told the FDA this they would never get aspartame approved.
Donald Rumsfeld, CEO of the aspartame manufacture was able to get a new FDA commissioner appointed when Reagan was elected. This shill, Arthur Hayes, approved the toxin over the objection of his own scientists. Then NSDA turned around and lobbied for NutraSweet. What power these chemical and pharmaceutical producers possess!
As hundreds of complaints poured into the FDA the prophetic warnings of the NSDA came became reality. The CDC was asked to investigate, and released a damning report, which included memory loss, seizures, liver problems, mood alteration, cardiac arrest and death - for starters. But the coverup continued because a summary was added to this investigation that contradicted the report, and actually said aspartame reactions were "mild". By virtue of this short one-paragraph summary (to a 146 page report) the term "mild death" became a defacto part of CDC jargon.
Searle studies were so corrupt that the FDA had once asked the Department of Justice to prosecute the company for fraud. It was an open and shut case, and with no place to run the Searle attorneys pulled the classic stunt of hiring the Federal prosecuting attorneys, so the case expired with the statute of limitations. The Godfather hired the District Attorney!
Senator Metzenbaum introduced a bill that never got out of committee (in l985) because Monsanto lobbying power was too strong. On the program "60 Minutes" Dr. Ralph Walton declared that 83 of 90 independent tests showed aspartame to have significant problems (Dec 29, l996), but the usually aggressive 60 Minutes expose staff failed to name the problems, or to challenge the manufacturer.
The manufacturer and the FDA succeeded in smothering new independent studies and the FDA has refused to answer 26 questions on Dorway, even why the studies that showed aspartame triggers brain tumors were never replicated. In addition, the FDA has blessed aspartame as a universal sweetener. This betrayal of American consumers is the result of the parade of FDA officials who got fat jobs in the aspartame business.
At a press conference in the 80's, world famous Dr. H. J. Roberts warned we would have a worldwide plague on our hands within 5 to 10 years. FDA released a brochure of aspartame propaganda that is pure propaganda. In 1996 FDA removed all restrictions on aspartame, ignored the fact that aspartame breakdown accelerates at temperatures over 86F. Complaints were so rampant they began referring consumers to the Aids Hotline. Then FDA revised their book keeping to eliminate hundreds of valid consumer complaints in l996, and stopped taking further ones so Dr. David Kessler could grant blanket approval to this addictive excitoneurotoxic carcinogenic drug that changes brain chemistry and interacts with other drugs. In l995 The FDA's report showed 92 documented reactions from 10,000 consumer complaints.
The NSDA "knew the gun was loaded" but became turncoat, lobbying for industry, with full knowledge of what would happen to the public. Independent studies continue because the lab rats have been replaced by over hundreds of millions of human consumers who ingest this poison in over 6000 products.
ASPARTAME is a chameleon-like toxin that gives you 92 ways to ruin your life, including death."
or badnews.txt lists most of those 92 FDA acknowledged symptoms
or offasprt.txt rebuts their "safety" info with references
or enclosur.txt the long sordid trail to approval
Most of the 92 symptoms, a diet coke report and many commented links
Pages S5507 through S5511 of the Congressional Record dated May 7, l985
****************** NSDA Protest (summary) ********************
May 7 1985 CONGRESSIONAL RECORD -- SENATE S 5507
headaches, mood alterations, and behavior changes."
The report language accompanying this bill directs the FDA to ensure that these tests are undertaken.
At mark up, I proposed an amendment which would require the manufacturers of diet soft drinks to include on their label how much aspartame (NutraSweet) each serving contains.
I believe consumers have a right to this information given the questions which have been raised about NutraSweet and the extraordinary increase in consumption levels of this product since its introduction in1981 (last year per capita consumption increased 66%).
The National Soft Drink Association has lobbied strongly against this proposal. However, this is the same association which, in 1983, prepared a draft legal document objecting to NutraSweet's being allowed on the market, citing serious and unresolved questions about the public health. Though that document was not filed, it indicates the organization had significant health concerns relating to the amount of aspartame consumed before this product was approved for soft drinks.
The following quotes are from a document entitled "Objections of the National Soft Drink Association to a Final Rule Permitting the Use of Aspartame in Carbonated Beverages and Carbonated Beverage Syrup Bases and a Request for a Hearing on the Objections." The document is dated August 8, 1983, and was prepared by Patton, Boggs and Blow and the General Counsel for the National Soft Drink Association:
"G. D. Searle and Company has not demonstrated to a reasonable certainty that the use of aspartame in soft drinks, without quantitative limitations, will not adversely affect human health as a result of the changes such use is likely to cause in brain chemistry and under certain reasonably anticipated conditions of use."
"For these reasons, Searle has not met its burden of demonstrating to a reasonable certainty that the unlimited use of aspartame, especially in combination with carbohydrates, will not adversely affecthuman health. The questions posed by Dr. Wurtman are significant because of the seriousness of the potential effects (e.g., changes in blood pressure) and because of aspartame's anticipated widespread use--use that includes consumption by potentially vulnerable sub-groups, such as children, pregnant women and hypertensives."
"Specifically, Searle has not met its burdens under section 409....to demonstrate that aspartame is safe and functional for use in soft drinks."
"Collectively, the extensive deficiencies in the stability studies conducted by Searle to demonstrate that aspartame and its degradation products are safe in soft drinks intended to be sold in the United States, render those studies inadequate and unreliable."
There have been hundreds of reports from consumers around the country suggesting a possible relationship between their consumption of NutraSweet and subsequent symptoms including headaches, aberrational behavior, slurred speech, etc.
During the Labor Committee hearing on saccharin, NutraSweet and cyclamate held on April 2, Dr. Richard Wurtman of M.I.T., testified as follows:
"The problem at present is that it is difficult if not impossible for the patient or his physician to know how much aspartame it contains....I believe it is essential that companies which include aspartame in their products be required to indicate on the labels (in readable print) how much of the sweetener is present in each can or serving. This simple change in labeling practice would, I believe, sharply reduce the number of consumers who believe without probable foundation that they have suffered aspartame-related side-effects.
Perhaps more importantly, it would also enable physicians to identify those patients who might really have had such responses, so that such people might then undergo controlled clinical testing."
Since 1981, the FDA has attached an ADI (acceptable maximum daily intake) to NutraSweet. That ADI is currently 50 milligrams per kilogram of body weight. While an adult weight in 154 pounds would not meet that limit before he consumed 5 liters of diet soft drink, a four-year-old weight in 25 pounds would hit that limit at three cans of diet soda.
Consumers have no way of knowing if they have reached the FDA limit without knowing how much is in the can. Ideally, we should have the ADI on the can as well, but it will take some time to figure out how that could be done effectively. In the meantime we should ensure that the quantity is on the label. We must start somewhere, and this is an important first step.
Many questions must be resolved concerning aspartame. The FDA should take an active role to ensure that tests are conducted to determine whether individuals, particularly children, are likely to experience side-effects from NutraSweet at current and projected consumption levels. The FDA should also run tests on how NutraSweet affects those who might be taking different types of medication.
Finally, given the serious questions which remain regarding the FDA approval process for NutraSweet, the FDA should ensure that certain key pivotal animal tests are repeated. Only when all of these questions are resolved can consumers be certain that they are receiving the full protection provided by our food and drug laws.
OBJECTIONS OF THE NATIONAL SOFT DRINK ASSOCIATION
TO A FINAL RULE PERMITTING THE USE OF ASPARTAME IN CARBONATED BEVERAGES AND CARBONATED BEVERAGE SYRUP BASES AND A REQUEST FOR A HEARING ON THE OBJECTIONS.
(Docket No. 82F-0305)
DRAFT: JULY 28, 1983
Objection One: Searle has not demonstrated to a reasonable certainty that aspartame and its degradation products are safe for use in soft drinks. Without quantitative limitations, under temperatureconditions likely to prevail in the United States.
I. SUMMARY OF BASIS FOR OBJECTION
Aspartame is inherently, markedly and uniquely unstable in aqueous media.
In a liquid, such as a soft drink, APM will degrade as a function of temperature and pH. Higher temperatures and more acidic liquids increase the rate of degradation. Higher temperatures may also affect the degradation products which are formed. Given the circumstance of APM's unusual instability, reliable and comprehensive analyses of APMs degradation in soft drinks--both as to the rate of degradation (and the subsequent loss of sweetness) and to the confirmed identification of themajor degradation products--is crucial to establish the safety of the use of APM. Without adequate identification of AMP's significant decomposition products, it is not possible to find, to a reasonablecertainty, that APM is safe. The data and information submitted by Searle in support of its petition to amend 21 C.F.R. 172.804 to permit APM use in soft drinks, however, do not demonstrate that APM is safe for use in soft drinks. These data are insufficient to establish safety because the petition lacks comprehensive, reliable and accurate analytical data on APM and the products "adversely affected:" by the issuance of the regulation authorizing the use of aspartame ("APM") in soft drinks. As the national trade association representing the soft drink industry in this country, NSDA's member soft drink manufacturers and soft drink franchisers are directly and immediately affected by the issuance of a regulation which authorizes the use of a new sweetener in its products. Approximately seventy-six percent of the nations 1600 soft drink manufacturers are active members of the Association. These members account for more than ninety percent of the soft drink production in this country. In addition, the vast majority of soft drink franchisers which manufacture the concentrates and syrups from which soft drinks are made are associate members of the Association.
II. SUMMARY OF BASIS FOR THE OBJECTIONS
OBJECTIONS OF THE NATIONAL SOFT DRINK ASSOCIATION TO THE ISSUANCE BY THE FOOD AND DRUG ADMINISTRATION OF A REGULATION (21 C. F. R. 172.804) TO AUTHORIZE THE USE OF ASPARTAME IN CARBONATED BEVERAGES AND CARBONATED BEVERAGE BASES.
In the Federal Register of July 8, 1983 (48 Fed. Reg. 31376), the Food and Drug Administration ("FDA") issued a regulation amending section 172.804 of its regulations, 21 C. F. R. 172.804 to authorize theuse of aspartame in carbonated beverages and carbonated beverage bases (collectively referred to as "soft drinks"). This action was taken in response to a food additive petition (FAP 2A3661) filed on October 15, 1982 by the Searle Research and Development Division of the G. D. Searle Co. ("Searle").
In these objections, NSDA demonstrates that there exist genuine and substantial issues of fact material to FDA's amendment of its regulations to permit aspartame use in soft drinks. Specifically, Searle has not met its burdens under section 409 of the Federal Food, Drug and Cosmetic Act, 21 U.S. C. 348 ("FDC Act") to demonstrate that aspartame is safe and functional for use in soft drinks NSDA thereforeobjects to the Commissioner's order amending 21 C. F. R. 172.804 and requests that a hearing as provided under section 499 (f) of the FDC Act, 21 U.S.C. 348 (f) be convened.
NSDA is a party that is, within the meaning of section 409(f)(l) of the FDC Act. 21 U.S. C. 348 (f)(l). methyl ester (PM) and beta-aspartame (beta-APM). (1) (Searle FAP at 13) Only in the cases of APM and DKP did Searle use high pressure liquid chromatography (HPLC). For the other four known principal breakdown products, Searle used thin-layerchromatography (TLC).
HPLC is a far superior analytical method relative to TLC (cites) and numerous SPLC methods exist for the detection and quantification of amino acids (cites. Searle's choice of TLC over HPLC adversely affectedthe quality and type of analytical data generated on APM and its decomposition products in soft drinks The unfortunate and inexplicable choice (2) of an inferior analytical technique, when superior andrecognized methods are available, has resulted in inadequate characterization of APM's decomposition products.
********************** Begin Notes area **********************
(1) The importance of comprehensive and reliable analyses of APMs decomposition products is demonstrated by the fact that based on the chemical structure of APM, one would not expect PM or beta-APM to be degradation products, indeed, initially Searle did not look for either one. Other unexpected decomposition products of unproven safety could of course, also be present when APM degrades.
********************** End Notes area **********************
May 7, 1985 CONGRESSIONAL RECORD -- SENATE S5508
HPLC is a practicable, well-accepted analytical method (3) which is commonly-employed by FDA. When the safety and suitability for use of a food additive such as APM with an acknowledged degradation problem (and anticipated high consumption) is under evaluation, HPLC is clearly the analytical method of choice.
TLC, on the other hand, produces good qualitative results, but is, at best, only semi-quantitative, since the quantification used is based on visual comparisons of spot sizes and intensities. (cite) Indeed, Searle itself has acknowledged the inadequacy of the analytical method that it chose when it described, in the petition, the quantity of degradation products identified using TLC as "estimates." (cite)
The inappropriateness of using TLC as a principal analytical method is compounded by the fact that the values of APM degradation products being measured are close to the limits of detection of the method (cite). (4) Thus, the values purportedly obtained by the TLC method cannot be considered to be very precise. Finally, an important decomposition product of APM, aspartic acid (AA) cannot be detected at all using TLC.
In short, for reasons which are not apparent, the petitioner chose to use a semi-quantitative analytical method to analyze for numerous major APM breakdown products close to the limits of detection, when thatmethod is not the best method available. The quality of the analytical data presented are, therefore, substantially inferior to those which could have reasonably been obtained.
(b) The Searle Analyses for APM Decomposition Products are Deficient. Aside from its choice of TLC over HPLC, the analyses conducted by the petitioner to identify and quantify the breakdown products of APM in soft drinks are plagued by numerous significant deficiencies which result in clear and unmistakable inadequacies in the detection and quantification of the major decomposition products of APM in soft drinks. In the face of these deficiencies, Searle has not reasonably identified substances formed in soft drinks because of the use of APM, as required under section 409 (c) (5) (A) of the FDC Act 21 U.S.C. 348 (c) (5) (A). The safety of this use of APM cannot be said to have been shown to a reasonable certainty in the face of these inadequacies.
There are at least six significant deficiencies in the HPLC analyses undertaken by Searle to identify and quantify APM and DKP in soft drinks:
(a) The standards for use of HPLC to detect APM and DKP were prepared in buffered aqueous solutions. A far better technique would have been to prepare the standards using beverage matrices. The use of beverage matrices would have reduced the danger of interfering compounds coeluting with the compounds of interest.
(b) Searle does not appear to have submitted to FDA to HPLC chromatograms of the blanks (unsweetened beverages); without these chromatograms, the results obtained in sweetened beverages cannot be evaluated.
(c) The chromatograms of the beverages which were submitted by Searle contain peaks which can cause difficulties with quantification. For example, the DKP in the root beer chromatograms is badly overlapped by another peak.
(d) No recovery data for DKP were presented and the precision of the DKP concentrations was only determined for standard solutions.
(e) The purity of the initial APM was not established, although it can contain at least five percent impurities, as calculated from the zero time values in Searle's studies.
(f) Searle analyzed only single bottles at any given time and temperature. This aspect of the study design fails to account for anticipated bottle-to-bottle variations. Single bottle analytical data cannot, under any circumstances, amount to a comprehensive and reliable characterization of the decomposition products of an additive with a well-known instability problem.
Likewise, the TLC analyses are deficient (these deficiencies are in addition to the inherent limitations of the TLC method):
(a) Standards for the TLC analyses were prepared in distilled water. As in the case of the HPLC analyses, the better technique would have been to prepare them in beverage matrices.
(b) Searle did not submit (and apparently did not attempt) any recovery or precision data for its TLC analyses.
(c) In the TLC analyses, only single aliquots of single bottles were analyzed at any given time and temperature, thus rendering the putative quantitative results inherently unreliable.
(d) Measurable levels of beta-APM and PM may have existed in the starting material, but were not quantified at the beginning of the analyses (presumably because they were unexpected decompositionproducts). Moreover, it is unclear from Searle's data how the spots on the TLC plates were identified. If, as appears to be the case, identification was based solely on the comparison of R values, theidentification can only be called tentative. Confirmation of the identifications by spectroscopic methods should have been undertaken.
The failure to confirm these identifications undermines many of the major assumptions made by Searle throughout its analytical studies.
Collectively, the extensive deficiencies in the stability studies conducted by Searle to demonstrate that APM and its degradation products are safe in soft drinks intended to be sold in the United States, renderthose studies inadequate and unreliable. It is not possible on the basis of these studies to conclude that the petitioner has demonstrated that, notwithstanding its inherent instability, APM is safe for use insoft drinks. The failure of proof by Searle is even more evident, as is shown in the following section of these objections, when one considers the extent to which the decomposition products of APM in soft drinks are not known or identified.
(c) APM Decomposes Extensively in Soft Drinks Under Moderate Conditions. But Searle's Data Fail to Identify Adequately the Decomposition Products.
Notwithstanding the multiple and serious deficiencies in the stability studies conducted on the APM in soft drinks, one conclusion does emerge: under moderate conditions, extensive decomposition of APMmay occur in soft drinks. Moreover, a substantial portion of the decomposition products are not known. APM cannot be considered to be shown to be safe for use in soft drinks when the results of its knowndecomposition phenomenon--marked breakdown in liquid beverages--are not well identified.
For example, in Searle studies, a cola beverage was kept at 10 degrees C (86 degrees F) for 40 weeks. (cite) In analyses conducted at that time, only fifty (50) percent (weight basis) of the original starting material was found. (5) Even if one accepts one of Searle's main assumptions about APM decomposition in soft drinks -- that is, that aspartic acid (AA) is formed in amounts equal to the PHE and PM (mole basis) (cite) -- the percent recovery to sixty-four (64) percent. (6) Thus, even when viewed most favorably, the analyses fail to account for over one-third of the original material.
This startling deficiency in the stability studies is further demonstrated by this table, also drawing from Searle data of beverages stored at 30 degrees C (86 degrees F), which illustrates the material balances obtained: (7)
The inability to account for as much as thirty-nine (39) percent of APM's decomposition products is significant. With such a high unknown factor, judgments about the safety of APM in soft drinks cannot be made confidently.
Possible explanations for, and speculation about, the material balance discrepancies abound: secondary reactions may be occurring (possibly with the flavor components in the beverages): additional, butunidentified decomposition products may exist, (as occurred in the case of PM and beta-APM): or the inaccuracy and inadequacies of the analytical methods may account for the gaps in the data. No explanation for the discrepancies in material balances--that is, for the high percentage of unknown material--can, however, be supported on the basis of the data submitted by Searle. The significance of the unknown decomposition products simply cannot be determined in the absence of complete, careful and reliable analyses--analyses which are not currently available because the petitioner failed to conduct or submit them. (8)
2. Searle Has Not Characterized The Decomposition Products of APM in Soft Drinks Under Temperature Conditions To Which the Beverages Are Likely To Be Exposed In the United States.
********************** Begin Notes area **********************
(2) The availability of HPLC to detect and quantify APM's decomposition products is demonstrated by, among other things, a paper presented by three representatives of Searle, (LeVon, Mazur and Ripper "Aspartame (APM) as a Sweetener in Carbonated Soft Drinks") (Appendix). In that paper, Searle stated that HPLC was currently used to detect APM. DKP and AP and PHE. Nevertheless, the petition does not contain HPLC generated data for AP or PHE.
(3) Section 171.1 (c) of the agency's regulations. 21 C.F.R. 171.1
(c), required that an analytical method for detection of a food additive and substances formed in or on food because of its use be practicable and one which "can be applied with consistent results by any property equipped and trained laboratory personnel." HPLC is clearly such a method.
(4) FN w examples.
(5) This figure is derived as follows from Searle data: 13 percent APM, 21 percent DKP, 3 percent AP, 8 percent PHE, and 5 percent PM.
(6) The increase comes from 10 percent AA and 4 percent methanol.
(7) A material balance accounts for the quality of the starting material, the quantity of identified decomposition products (or by-products, reaction products, etc.) and the quantity of unknown material.
Because of the inadequacies in the analyses documented in section --- above, the figures in this table may be inaccurate. Nevertheless, the discrepancies in the material balance raise the possibility ofsignificant unknown decomposition products.
(8) A tempting, but unsatisfactory, resolution of the material balance discrepancy is to assume that the safety of the decomposition products were determined in the chronic studies in laboratory animals which Searle conducted. This putative resolution does not hold, however, because these degradation products would not have undergone testing, since the APM in the feeding regimen was in freshly prepared doses.
********************** End Notes area **********************
May 7, 1985 CONGRESSIONAL RECORD -- SENATE S 5509
A suitable assessment of the stability of APM in soft drinks can be conducted. Such an assessment would necessarily involve the use of sample beverages in a variety of flavors and varying pH, and, most importantly, involve exposure of the beverages to temperature conditions which approximate those which are reasonably expected to occur in practice (or under conditions which permit reasonable projections to be made to actual conditions). (9) Unless the sample APM-sweetened beverages are exposed to realistic temperature conditions, the temperature-sensitive degradation characteristics of APM, and in particular its potentially significant decomposition products, cannot be known. The data submitted by Searle are not derived from appropriate test conditions. Judgment about the extent of APM instability and its degradation products in soft drinks under actual conditions of use cannot, therefore, be inferred from the limited laboratory data.
To assess APM's instability in soft drinks, Searle exposed bottles of ready-to-drink beverages in four flavors (cola, root beer, lemon-lime and orange) to consistent temperatures of 55, 40, 50, 20 and 5 degrees C. (10) According to Searle's petition, "(I)n each flavor a loss of APM occurred with the rate of degradation directly related to the storage temperature for the carbonated beverages. The rate of APM loss from beverages was pH dependent." Moreover, Searle noted that "as the temperature increases, the rate of degradation becomes more pronounced."
(11) Some of the effects on APM degradation in soft drinks are illustrated in a table in the Searle petition. (12) In that table, for example, after 20 weeks at 30 degrees C (86 degrees F), a beverage with a pH between 2.5 and 3.0 contained less than 40 percent of the original amount of APM. For beverages with similar pH, but kept at 40 degrees C (104 degrees F) for 20 weeks, less than ten percent of the original APM remained. Less pronounced degradation is seen at higher pH and/or at lower temperatures.
Although these stability tests shown signification degradation of APM at consistent temperatures over relatively short time periods, they shed virtually no light on the probably degradation rate and products for soft drinks exposed to a variety of temperatures--including temperatures higher than any used in Searle's studies--during storage, handing, sale and use, temperatures which are known to occur and to which soft drinks are known to be exposed. Without stability studies conducted under such conditions, APM cannot be said to be appropriately stable in soft drinks, nor can its degradation products be considered to be adequately identified (assuming that analytical techniques were used which would yield complete and reliable results) nor can it be considered to have been shown to be safe.
The range of temperature conditions to which soft drinks are exposed during the summer months in the southern United States (13) is illustrated by a study conducted by the Coca-Cola Company's Corporate Packaging Department in 1976 and submitted to the Consumer Product Safety Commission. (14) That study shows that during the summer months, soft drinks are often exposed to relatively high temperatures for certain time periods in the course of distribution from the bottling plant to the consumer. High temperatures do, of course, routinely occur in much of the United States, including the southern regions; conditions of storage and distribution for soft drinks can elevate these temperatures significantly.
In summary, the study assessed: (1) warehouse temperatures in Marietta, Georgia and Wichita Falls, Texas: (2) route truck temperatures in Wichita Falls; (3) full sun and outside ambient temperatures in Wichita Falls; (15) and (4) parked car temperatures in Atlanta, Georgia and Wichita Falls. Each of these test environments is known to occur in practice and the tests were performed under actual, as opposed to laboratory conditions.
Several significant conclusions can be drawn from this study. First, in those situations where the bottled beverage is heated only by conduction from the surrounding air (shaded location in a warehouse orin the automobile trunk parked indoors) the ratio of product temperature to the temperature of the surrounding air would be 0.92 to 0.94. In enclosed environments exposed to sunlight, however, ratios much greater than one would be expected. For example, a ratio of product temperature to air temperature of 1.45 was found for a test car parked in full sunlight. In other situations where sunlight was a direct heating factor (e.g., open air service station promotions or open bay delivery trucks) typical ratios were 1.10 to 1.15.
The effects of these ratios on product temperature are demonstrated by using summer temperatures for Phoenix, Arizona, where the average daily high in July is 40 degrees C (104 degrees F). During July in Phoenix, a soft drink in full sunlight could reach a temperature of 49 degrees C (120 degrees F) (104 degrees x 1.15). The same product in a car parked in full sunlight could reach 66 degrees C (151 degrees F) (104 degrees F x 1.45) (16); soft drinks in a warehouse with an ambient temperature of 110 degrees could reach temperatures of 38 degrees C (101 degrees F) to 39 degrees C (103 degrees F) (0.92-0.94 x 110 degrees F).
Overall, the study, considered together with representative historical temperature data (Appendix ___) show that soft drinks will frequently be exposed to temperatures of 32 degrees C (90 degrees F) to49 degrees C (120 degrees F). In some cases product temperatures as high as 66 degrees C (151 degrees F) (especially in the southwestern United States) can be reached.
The effects of these high product temperatures on APM degradation and the formation of degradation products, and the effects of temperature variation (for example, soft drinks displayed at a servicestation may reach temperatures of 49 degrees C (120 degrees F) for most of the afternoon, drop in temperature overnight, and heat up again during the following day) cannot be determined from the data submitted by Searle to the FDA.
What those data do suggest, however, is that significant APM degradation at high temperatures occurs within a short period of time.
For example, in Searle's stability tests, an orange beverage held at 40degrees C (104 degrees F) average daily high for Phoenix during July) for eight weeks, contained only fifty (50) percent of the original amount of APM. A cola beverage held under the same conditions contained only forty (40) percent of the original APM amount. And beverages exposed to higher temperatures degrade even more rapidly. And, of course, because of the temperature elevation ratios, product temperatures could easily be much higher during actual conditions than the stable temperatures used in the Searle laboratory studies.
Thus, it is known that APM will degrade rapidly at high temperatures, including temperatures to which soft drinks are known to be exposed intermittently during the summer. What is not known, although the FDC Act requires the proponent of use to demonstrate it, is what effects of degradation occur by virtue of exposure to these temperatures.
More specifically, to demonstrate that APM is safe for use in soft drinks, the petitioner must reasonably identify what degradation products are formed under those conditions. Ultimately, of course, the safety of the major degradation products must be determined. Under the FDC Act, the data needed to make that determination--reliable and competent data--must be provided by the petitioner.
Objection Two: Searle has not demonstrated that APM use in soft drinks will not adulterate the beverages under Section 402 (a)(3) of the FDC Act.
SUMMARY OF BASIS FOR OBJECTION
As discussed above, it is well established that the petitioner for issuance of a regulation authorizing the use of a food additive bears the burden of proving, through reliable and competent data, each element of the criteria set forth in section 409 of the FDC Act, 21 U.S.C. 348. for issuance of a food additive regulation. The present record does not contain data which demonstrate that the use of APM in soft drinks will not result in the adulteration of the beverages under section 402 (a)(3) of the FDC Act. 21 U.S.C. 342 (a) (3), which provides that a food is adulterated if it contains, in whole or in part, "...a decomposed substance or if it is otherwise unfit for food." Indeed, the present record strongly suggests that the rapid degradation of APM in soft drinks and the consequent loss of sweetness may well result, under certain actual time and temperature conditions, in products which would be adulterated under section 402. Without data which demonstrate that APM-sweetened beverages will not be adulterated under section 402 (a)(3). Searle has not met its burden of proof under section 409 (c) (3) (B) of the FDC Act. 21 U.S.C. 348 (c) (3) (B).
FACTUAL BASIS FOR OBJECTION TWO
The marked and rapid decomposition of APM in soft drinks under temperatures known to prevail is apparent from data in the present record and discussed above in these objections. Those data show that it is reasonable to expect APM to decompose in soft drinks sufficiently rapidly under current handling and distribution procedures to adversely affect product quality and taste. (17)
S 5510 CONGRESSIONAL RECORD -- SENATE May 7, 1985
It is well-established under section 402 (a) (3), that a food which contains a decomposed substance (i.e., the decomposition products of APM which, Searle's data show, can readily exceed the quantity of APM itself in a short time)--especially where the decomposition has adversely affected product quality or made the product unpalatable--is adulterated and subject to seizure. FDA would consider beverages which had lost substantial sweetness because of APM decomposition and which were therefore not palatable, to be adulterated under section 402 (ax3). The record is devoid, however, of evidence which demonstrate that APM used to sweeten soft drinks will not, under reasonably anticipated conditions of use, in fact cause the products to be adulterated. Without such evidence Searle has not met the burden imposed under section 409 (c) (3)
(This objection will be expanded.)
Objection three: Searle has not demonstrated that APM is functional for use in soft drinks under temperature conditions likely to prevail in the United States.
SUMMARY OF BASIS FOR OBJECTION
In addition to data intended to assess the stability of APM in soft drinks, Searle's petition for use of APM in soft drinks contains data intended to show that APM is functional in the beverages, i.e., that it achieves and retains the intended technical effect (sweetening) under the conditions of use reasonably anticipated to occur. Searle has not demonstrated that APM is functional in soft drinks because its data show a significant loss of sweetness at temperatures to which soft drinks are known to be exposed and within the range of time periods between bottling and projected consumption. The functionality of an additive cannot be considered to have been demonstrated if significant loss of its intended technical effect because of temperature and pH dependent degradation may occur under reasonably anticipated conditions of handling, storage and use.
FACTUAL BASIS FOR OBJECTION THREE
To evaluate the functionality of APM, Searle conducted "sensory evaluation" tests which used consumer taste panels to assess "perceived sweetness" (cola, beverages only) and "overall liking" (or "acceptance") (all flavors) over time periods up to 52 weeks and at three temperatures: 5 degrees C (41 degrees F), 20 degrees C (66 degrees F) and 30 degrees C (86 degrees F) Beverages sweetened with APM only (5, 20 and 30 degrees C) and APM with saccharin (20 degrees C) were tested; beverages sweetened with sucrose (______ C) and saccharin (_______C) were used as references. The beverages were rated at different time periods by the panelists. (18)
Although no temperature used in Searle's sensory evaluation tests approached the actual product temperatures which soft drinks will reach (see section ____ above), significant loss of sweetening and overall liking occurred for beverages sweetened with APM only within extraordinarily short time periods. For example, APM-sweetened cola beverages stored at 30 degrees C 86 degrees F) received on overall liking score of less than 20 on a 0-100 scale after only 290 weeks (after 20 weeks the product was apparently unpalatable, since Searle did not present sensory evaluation data beyond this time). For an orange beverage, overall likeness after 20 weeks at 30 degrees C 86 degrees F) approached 5 (on a nine point hedonic scale), the "neither like nor dislike" or mean rating. Again, sensory evaluations were apparently not conducted beyond 20 weeks.
Searle's characterization of the results of the sensory evaluation tests avoid the clear implication of those tests: That APM has not been shown to retain sufficient sweetness at temperatures which are known to occur for APM-sweetened beverages to retain an acceptable "overall liking" rating. Instead, Searle emphasizes an interesting, but legally irrelevant finding: That APM sweetened beverages tested after holding at relatively low temperatures were preferred to beverages sweetened with alternative sweeteners. This characterization misses the statutory purpose for which the studies were undertaken, that is, to demonstrate that APM is a functional sweeteners in soft drinks.
Of particular importance is the fact that Searle's sensory evaluation tests do not explore the effects on either sweetness or overall likeness of APM-sweetened beverages exposed, either consistently or intermittently, to the higher temperatures which prevail in much of the United States. What is the effect on these two measures, for example, of product temperatures of 100 to 120 degrees F? Is the degradation greatly accelerated and the overall liking therefore diminished in even shorter time periods? Will APM-sweetened beverages stored in warehouses and carried on open route trucks or stored in warehouses and displayed in open air service station promotions in the southern states be acceptable when the consumer attempts to consume them several weeks later? Is APM a functional sweetener for soft drinks if APM-sweetened beverages in certain parts of the country would, during the summer months, have to be treated as if they were perishable commodities?19
(To be expanded with age distribution data.)
Objection No. Four: G. D. Searle and Company Has Not Demonstrated To A Reasonable Certainty That The Use of Aspartame In Soft Drinks. Without Quantitative Limitation. Will Not Adversely Affect Human Health As a Result Of The Changes Such Use Is Likely To Cause In Brain Chemistry And Function Under Certain Reasonably Anticipated Conditions of Use.
SUMMARY OF BASIS FOR OBJECTION
In its July 8 Federal Register notice, FDA acknowledged receiving a comment expressing concern about the effect on plasma and brain phenylalanine PHE) and tyrosine (TYR) levels when aspartame is fed in combination with a carbohydrate. 498 Fed. Reg. at 31379. The comment included data demonstrating that in both rats and humans the feeding of a carbohydrate with aspartame significantly enhances aspartame's positive effect on the ratio of PHE and TYR to other large neutral amino acids (LNAA) in the blood. The data submitted with the comment also demonstrate that brain PHE and TYR levels in the rat are significantly increased by the aspartame/carbohydrate combination.
The concern of the commentator, Dr. Richard J. Wurtman, Professor of Neuroendocrine Regulation at the Massachusetts Institute of Technology, was that, increased brain levels of PHE and TYR are likely to affect the synthesis of certain neurotransmitters--substances vital to the regulation of brain function--and that changes in the levels of neurotransmitters could in turn cause adverse physiological effects (by, for example, modifying the function of the autonomic nervous system) and/or behavioral effects.>
FDA response to Dr. Wurtman's comments by stating that it ".. believes that the comment's conclusion regarding potential phenylalanine induced changes in neurotransmitter function appear to be unwarranted extrapolations..." (48 Fed. Reg. at 31379; emphasis added) and by concluding that "...the data supplied with this comment do not provide support for its hypothesis that the ingestion of aspartame and carbohydrate will alter the brain levels of neurotransmitters and thereby produce behavioral modifications." 48 Fed. Reg. at 31380, FDA cites as support for its conclusion several studies submitted by Searle: FDA did not discuss, however, much of the data submitted by Dr. Wurtman (including those demonstrating significantly elevated brain levels of PHE and TYR), and it apparently overlooked the significance of aspartame's demonstrated blocking effect on glucose-induced elevation of brain serotonin levels.
In light of the allocation of the burden of proof and the nature of the safety standard in food additive proceedings (discussed above).
FDA's handling of Dr. Wurtman's concerns was unusual. The tone of the July 8 notice suggested that the burden was on Dr. Wurtman to demonstrate that aspartame is harmful and that, absent affirmativedemonstration of harm (which obviously is lacking at this point), aspartame must be approved. To the contrary, however the burden is on Searle to prove to a reasonable certainty that no harm to human health will result from aspartame. Thus, the question for FDA in evaluating Dr. Wurtman's concern is whether, in the minds of competent scientists, the questions posed by Dr. Wurtman, and his data are sufficiently significant from a safety standpoint that they should be more thoroughly addressed by Searle in order to provide the statutorily required "reasonable certainty" that no harm will result from aspartame's use.
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17) FDA acknowledges this distinct possibility when it states its "belief" that changes in these procedures will avoid the problem.
Section 409 cb3 B does not contemplate that a "belief" in unspecified, but fundamental changes in industry practice are adequate to assure that widespread use of a food additive will not adulterate the food.
18) Fn stating rating periods
19) In the preamble to the APM regulation, FDA dismissed summarily the concern about the functionality of APM in soft drinks at temperatures above 30 degrees C (86 degrees F): "The agency believes, however, that storage at these times and temperatures can be avoided by attention to handling and distribution." (48 Fed. Reg. at 31377). This summary resolution of the functionality issued is inconsistent with the FDC Act for two reasons. First, it is based on the agency's "belief" and not on any objective evidence. The Act requires the agency to resolve material issues based on facts, not on beliefs. Moreover, the facts--actual temperature conditions to which the beverages are exposed and actual beverage temperatures--suggest that degradation and consequent loss of sweetness and overall liking (and hence functionality) may occur within even shorter periods than the agency appeared to find acceptable.
Secondly, the purported resolution of the functionality issue by assuming that significant loss of sweetness "can be avoided by attention to handling and distribution" is an assumption unsupported by any evidence in the present record (none is cited by the agency). In all likelihood, the agency's "resolution" is entirely impracticable. To assume that fundamental changes in handling and distribution will occurto avoid an acknowledged functionality problem turns the FDC Act on its head.
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May 7, 1985 CONGRESSIONAL RECORD -- SENATE S5511
We object to the approval of aspartame for unrestricted use in soft drinks (which could be as high as 550 mg/liter, or higher) on the ground that Searle has not made the required showing. This objection issupported by (1.e following points, which are discussed farther below and supported by the accompanying affidavits: (1) available evidence demonstrates that the consumption of aspartame/carbohydrate combinations by rats in amounts comparable to those likely to be encountered by humans under certain reasonable anticipated conditions of use elevates plasma ratios of PHE and TYR significantly and brain PHE and TYR levels by factors of 3.0 and 3.5, respectively; (2) available evidence from human studies demonstrates that consumption of aspartame/carbohydrate combinations in amounts likely to be to be encountered under certain reasonable anticipated conditions of use elevates human plasma levels of PHE significantly beyond the normal range: (3) there are sound scientific reasons to believe that human brain levels of PHE and TYR will respond to aspartame consumption in a manner similar to rats: (4) there are sound scientific reasons to believe that increased brain levels of PHE and TYR could affect the synthesis of neurotransmitters and in turn various physiological functions and/or behavior: for example. TYR is a known precursor of the catecholamine neurotransmitters, and tyrosine levels have been shown to affect several bodily functions controlled by the autonomic nervous system (including regulation of blood pressure): and (5) the demonstrated ability of aspartame to inhibit the glucose induced release of serotonin has the potential to affect important serotonin-mediated behaviors, such as satiety, food choice and sleep.
Despite the potential effects of aspartame/carbohydrate combinations, the present record is devoid of readily obtainable evidence that could resolve whether the effects are in fact likely to occur. As will be demonstrated the data cited by FDA in its July 8 notice are not sufficient to resolve the issue. It would be possible, however, to perform within approximately six months studies in rats that would resolve conclusively whether levels of aspartame and carbohydrates corresponding to those likely to be consumed by humans would affect the synthesis of neurotransmitters and in turn cause detectable physiological and behavioral effects. It also would be possible to perform additional short-term studies in humans to determine whether aspartame/carbohydrate combinations have observable effects on physiological parameters (such as blood pressure) or behavior.
For these reasons, Searle has not met its burden of demonstrating to a reasonable certainty that the unlimited use of aspartame, especially in combination with carbohydrates, will not adversely affect human health. The questions posed by Dr. Wurtman are significant because of the seriousness of the potential effects (e.g., changes in blood pressure) and because of aspartame's anticipated widespread use-- use that includes consumption by potentially vulnerable sub-groups, such as children, pregnant women, and hypertensives. Dr. Wurtman's concerns are shared by other distinguished scientists expert in this field (affidavits attached). It is Searle's legal burden to submit data sufficient to resolve the concerns.
FACTUAL INFORMATION SUPPORTING OBJECTION FOUR
1. FDA has underestimated the amount of aspartame that can be consumed through its use in soft drinks because the agency has focused on adult users assumed to average 60 kilograms in weight). FDA relied upon an intake value of 34 mg/kg/day in assessing the possible risks of aspartame, describing that level as the "...highest obtained from any estimate of potential consumption and exceeding) the 99th percentile consumption (25 mg/kg) for all age groups..." 48 Fed. Reg. at 31377.
For a 30 kg child, however, it would not be unusual for that level to be achieved or, in terms of the effect on plasma PHE levels, even exceeded.
For example, if a 30 kg child consumed on a warm day after exercise approximately two-thirds of a two-liter bottle of soft drink sweetened solely with aspartame, that child would be consuming approximately 700 mg. of aspartame, or approximately 23 mg/kg. This alone roughly equals what FDA considered the 99th percentile consumption level. If during the day this child consumed other aspartame sweetened products, the exposure level could quickly approximately FDA's so called "loading dose" of 34 mg./kg. 18 Fed Reg. at 31377. In addition, however, data derived from rats and humans demonstrate that concurrent consumption of a modest amount of carbohydrate (approximately 3 grams per kg. or, for a 30 kg child perhaps several cookies) approximately doubles the effect of the aspartame on the ratio of plasma PHE to other large neutral amino acids (LNAA) (Wurtman affidavit). Thus, in terms of effect on the PHE/ LNAA ratio in the blood, the above described concurrent consumption of aspartame and a carbohydrate is equivalent to an aspartame dose of as much as 50 to 60 mg./kg.
2. Aspartame has been tested in rats to determine the effect of aspartame and aspartame/carbohydrate combinations on the plasma ratios and brain levels of various amino acids (Wurtman affidavit). In rats fed 200 mg/kg aspartame, the plasma PHE/LNAA ratio increased to 0.185 from 0.110 in the controls, and the brain PHE level increased from 52 n-moles/g in the controls to 110 in the treated animals. When the same amount of aspartame was fed with 3 g/kg glucose, however, the plasma PHE/LNAA ratio increased sharply again to 0.240, while the brain PHE level increased to 143 n-moles/g. In addition, there was a 3.5 fold increase in brain TYR levels.
3. Aspartame and aspartame/carbohydrate combinations have also been tested in humans by Searle and Dr. Wurtman (cite to Searle petition and Wurtman affidavit). An aspartame dose of 34 mg/kg significantly elevated the plasma PHE/LNAA ratio, an effect that is almost doubled by the addition of 30 g of carbohydrate (equivalent to 4 or 5 cookies).
4. It is not possible to measure in vivo human brain levels of amino acids resulting from consumption of aspartame or subsequent effects on neurotransmitter synthesis. There are sound theoretical reasons, however, far considering the rat to be an appropriate model for assessing possible human effects (Wurtman affidavit). Moreover, there is empirical evidence to support the use of the rat as a model for evaluating possible effects of aspartame on human brain chemistry (Wurtman affidavit).
5. There is scientific evidence suggesting that increases in brain PHE and TYR levels of the order seen in the rat studies can effect synthesis of neurotransmitters, which themselves can effect important physiological functions and potentially behavior. (Wurtman affidavit should catalogue this evidence.) Readily available tests could determine whether aspartame has such neurotransmitter effects in rats or effects the rat's physiological functions or behavior. (Wurtman affidavit should describe tests.)
6. Aspartame has been demonstrated to inhibit the carbohydrate-induced-synthesis of the neurotransmitter serotonin (Wurtman affidavit) Serotonin blunts the sensation of craving carbohydrates and thus is part of the body's feedback system that helps limit consumption of carbohydrate to appropriate levels. Its inhibition by aspartame could lead to the anomalous result of a diet product causing increased consumption of carbohydrates.
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Also it should be noted that this was written in l983 and put in the Congressional Record in l985. After protesting the NSDA turned around and lobbied for NutraSweet.
End of protest