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Objection of the Truth in Labeling Campaign
submitted to the EPA in objection to granting processed free glutamic acid (MSG) an exemption from the requirement of a tolerance for residues of processed free glutamic acid (MSG)
August 20, 2001




August 16, 2001
 
 

Office of the Hearing Clerk (1900)
Environmental Protection Agency
1200 Pennsylvania Ave., NW.
Washington, DC 20460
 
 

SUBJECT

SUBJECT: L-Glutamic Acid and Gamma Aminobutyric Acid; Exemptions from the Requirement of a Tolerance; Final Rule.
Docket Control Number OPP-301136
 
 

OBJECTION

OBJECTION: The Truth in Labeling Campaign objects to granting the chemical referred to as "L-glutamic acid" an exemption from the requirement of a tolerance for residues of "L-glutamic acid" on all food commodities when applied/used in accordance with good agricultural practices. Granting such an exemption would free the U.S. Environmental Protection Agency (EPA) from setting a maximum permissible level for residues of the chemical they refer to as "L-glutamic acid," thereby allowing unrestricted amounts of processed free glutamic acid (MSG) residue, coming from any EPA regulated product, to remain in and on any and all food crops, that come under the EPA's jurisdiction.

The Truth in Labeling Campaign is dedicated to full disclosure and truthful labeling, particularly for processed free glutamic acid (MSG) found in foods regularly consumed by Americans in their every day diets.

As such, the Truth in Labeling Campaign is opposed to hiding any information about the components, contents, ingredients, or constituents of food; but is particularly concerned and opposed to using and hiding toxins, carcinogens, and substances that cause allergic and/or sensitivity reactions.

As such, the Truth in Labeling Campaign is opposed to treating food with AuxiGro WP (AuxiGro), a substance which, according to documents provided by Auxein Corporation (6a), contains, at minimum,

1) Allergenic material in the form of hydrolyzed casein (milk) protein;

2) Neurotoxic and endocrine disrupting material in the form of processed free glutamic acid (referred to by the EPA as "L-glutamic acid") which, in addition to its neurotoxic and endocrine disrupting properties, causes sensitivity reactions; and

3) Carcinogens.

Trace quantities of milk can cause anaphylaxis in a milk-allergic child.(134)

If the option were available, the Truth in Labeling Campaign would file an objection to the registration of AuxiGro: an objection that would include objections to the neurotoxic and endocrine disrupting material contained in AuxiGro, as well as objections to inclusion of material that causes allergic and sensitivity reactions, and objections to material that is carcinogenic.  But, it would appear, that formally objecting to the registration of AuxiGro is not now, and has never been an option, since, to the best of our knowledge, notice of  registration of AuxiGro was never published in the Federal Register.

At this time, however, the Truth in Labeling Campaign does have the opportunity to formally object to the EPA's granting an exemption from the requirement of a tolerance for residues of processed free glutamic acid (referred to by the EPA as "L-glutamic acid"), a neurotoxic, endocrine disrupting chemical that causes sensitivity reactions in at least 25 per cent of the American population.  SPECIFICALLY, The Truth in Labeling Campaign objects to granting the chemical referred to as "L-glutamic acid" an exemption from the requirement of a tolerance for residues of "L-glutamic acid" on all food commodities when applied/used in accordance with good agricultural practices. SPECIFICALLY,  The Truth in Labeling Campaign objects to allowing unrestricted amounts of processed free glutamic acid (MSG) residue to be present in and on food crops.

THE TRUTH IN LABELING CAMPAIGN is an Illinois not for profit corporation dedicated to full disclosure and truthful labeling, particularly for processed free glutamic acid (MSG) found in foods regularly consumed by Americans in their every day diets.

Friends of the Truth in Labeling Campaign reported having typical MSG reactions following ingestion of what they thought was unadulterated, unprocessed, produce (specifically, potatoes, head lettuce, and broccoli) before they, or anyone at the Truth in Labeling Campaign, knew that processed free glutamic acid (MSG) was being used in agricultural products applied to food crops.

The Truth in Labeling Campaign is filing this objection on behalf of themselves and friends of the Truth in Labeling Campaign:

1) Who have suffered debilitating and/or life-threatening reactions following ingestion of produce treated with agricultural products that contained processed free glutamic acid (MSG);

2) Who suffer debilitating and/or life-threatening reactions following ingestion of amounts of processed free glutamic acid (MSG) that exceed their tolerance levels;

3) Who have been told by their physicians to avoid ingestion of processed free glutamic acid (MSG);

4) Who, as physicians, recognize that ingestion of even minute amounts of processed free glutamic acid (MSG) can cause debilitating and life-threatening reactions in some people;

5) Who choose not to ingest processed free glutamic acid (MSG) in any form or in any amount;

6) Who object to having a known endocrine disruptor and neurotoxic amino acid deposited in and on food crops that they or their loved ones might unwittingly ingest -- no matter how small the amount of that neurotoxic amino acid; and/or

7) Who believe that they have the right to know what is in their food.

MATERIAL REVIEWED FOR THE PURPOSE OF FILING THIS OBJECTION

We have based this Objection on information contained in the:

August 8, 1997 Auxein Corporation; Application to Register a Pesticide Product: Notice;

October 29, 1997 Notice of Filing a Pesticide Petition to Establish an exemption from the requirement of a tolerance for residues of the biochemical glutamic acid;

January 7, 1998 Final Rule: Glutamic Acid; Pesticide Tolerance Exemption;

December 6, 2000 Notice: Notice of Filing Pesticide Petitions to Establish Tolerances for Certain Pesticide Chemicals in or on Food;

June 21, 2001 Final Rule: L-Glutamic Acid and Gamma Aminobutyric Acid; Exemptions from  the Requirement of a Tolerance;

Registration Eligibility Decision (RED) Document: Gamma Aminobutyric Acid (GABA) and L-Glutamic Acid (PC Codes 30802 and 374350);

List of the contents of Docket PF-978 (December 6, 2000 Notice: Notice of Filing Pesticide Petitions to Establish Tolerances for Certain Pesticide Chemicals in or on Food);

Limited  material from Docket PF-978 that was not denied to us;

Communications from Janet L. Andersen, Ph.D., Director, Biopesticides and Pollution Prevention Division, and Edward Allen, former Regulatory Action Leader, Biopesticides and Pollution Prevention Division;

Limited material submitted by Auxein Corporation to the California Department of Pesticide Regulation that was not denied to us;

Published glutamate-industry sponsored studies which are flawed to the point of being fraudulent; and

An article titled "The Toxicity/Safety of Processed Free Glutamic Acid (MSG): A Study in Suppression of Information," published in a peer reviewed journal.

In addition, we have reviewed:
The scientific literature, including studies of the toxic effects of glutamic acid (in its free form), its role as an endocrine disruptor, its role in human adverse reactions such as asthma, migraine headache, heart irregularities, fibromyalgia, and seizures, and its role in the "glutamate cascade."

FDA documents pertaining to the toxic potential of processed free glutamic acid including:

A 1992 report, "Safety of amino acids used as dietary supplements," done by the Federation of American Societies for Experimental Biology (FASEB) for the FDA;

The complete report (approximately 377 pages) titled "Analysis of Adverse Reactions to Monosodium Glutamate (MSG)," done by FASEB for the FDA and published July, 1995; and

Reports from the FDA Adverse Reactions Monitoring System.

OBSTACLES TO THE FILING OF THIS OBJECTION MOUNTED BY DR. CAROL FRAZER, PRODUCT MANAGER, BIOPESTICIDES AND POLLUTION PREVENTION DIVISION, OFFICE OF PESTICIDE PROGRAMS, EPA

In setting out to file this objection, we requested to see lists of contents of all of the Dockets mentioned above.  We were told by the people at Dockets that the only Docket that contained material was Docket PF-978, and a list of the contents of that Docket was immediately faxed to us.

At the same time, we were told that the other Dockets had never been opened -- that the product manager had never sent material to Docket OPP-300598 (January 7, 1998 Final Rule: Glutamic Acid; Pesticide Tolerance Exemption) or Docket OPP-30438 (August 8, 1997 Auxein Corporation; Application to Register a Pesticide Product: Notice), and that all of the material that should be available through the Dockets could only be accessed by contacting Dr. Carol Frazer, Product Manager, Biopesticides and Pollution Prevention Division, Office of Pesticide Programs, EPA.

This writer first contacted Dr. Frazer on June 27, 2001 asking for information, including a list of the material that should have been placed in the 1997-1998 Dockets OPP-30438 and OPP-300598, but was, instead, in Dr. Frazer's office.  Dr. Frazer sent me on one wild goose chase after another, and effectively kept me from finding out what material she had that should have been in Dockets OPP-30438 and OPP-300598; and, thus, prevented me from requesting material that might have been of value in submitting this Objection:

Suggesting that I file an FOI request for whatever I wanted (which would certainly not have been filled until well after the Objection period had passed);

Saying that she would look to see what relevant files she could find;

Saying that she had found some things, but that she would have to find out if she could send them to me (when, at the time, I had only asked for a list of the material she had that should have been sent to the 1998 Docket);

Saying that she was going to find all of the material (the material that she had told me she had found the week before) and send it to the Docket, where they would read it all and determine what material they could send me (when a list of the material that should have been sent to the 1998 Docket was all I was asking for);

Saying that she had a copy of the Auxein Corporation transmittal letter which contained a list of Auxein Corporation's submissions; and that she would see if she could send it to me.  There would be more things in the Docket, she told me, but that would be a start;

Saying that she could not send the transmittal letter to me.  Responding, when I asked "who said so," that someone in her office said she could not send it to me.  Responding, when I asked for the name of that person, that she would have to ask that person if she could give me a name;

Saying that some higher authority had told her to go ahead and send me a copy of the transmittal letter (which she did); while ignoring my request for a list of what should have been in the 1998 Docket;

Saying that she was working on getting the material ready to send to Dockets where they would read it all and determine what material they could send me (while all I had asked her for was a list of the material she had that should have been sent to the 1998 Docket).

For seven weeks, Dr. Frazer made excuses for not placing files in the 1998 Docket where the information might have been available to me if I had flown to Washington to review it; and made excuses for not sending me a list of the material relevant to the "L-glutamic acid" exemptions from the requirements of a tolerance that she had in her office.  When challenged, Dr. Frazer told me that it was on orders from someone in her department that she was not making material available to me.  As of August 15, 2001, I had received no list of the material that Dr. Frazer had said she would place in the 1998 Docket.  On August 15, 2001, just before this Objection was mailed to the Hearing Officer, I contacted Dockets and was informed that no material had been placed in either Docket OPP-300598 or Docket OPP-30438.
 
 

 GROUNDS

 SECTION I: OVERVIEW

In the following, we identify those areas that give us grounds for objecting to granting the chemical referred to as "L-glutamic acid" an exemption from the requirement of a tolerance for residues of  "L-glutamic acid" on all food commodities when applied/used in accordance with good agricultural practices, thereby allowing unrestricted amounts of processed free glutamic acid (MSG) residue to remain in and on any and all food crops that come under the EPA's jurisdiction.

There are three separate and distinct issues:

FIRST.  The subject of the exemption being challenged here is processed free glutamic acid (MSG), referred to by the EPA as "L-glutamic acid."  But the data supporting the exemption from the requirement of a tolerance for residues of the "L-glutamic acid" are, in part, data that pertain to the safety of the product AuxiGro, not data that pertain to the safety of the "L-glutamic acid" in and of itself.

The June 21, 2001 Final Rule, as written, grants an exemption from the requirement of a tolerance for residues of  "L-glutamic acid" on all food commodities when applied/used in accordance with good agricultural practices – with no restriction against applying the "L-glutamic acid" as a sole ingredient, or if not as a sole ingredient, then regardless of the product that the "L-glutamic acid" is contained in.

However, data submitted in support of the June 21, 2001 exemptions, the EPA's Registration Eligibility Decision: Gamma Aminobutyric Acid (GABA) and L-Glutamic Acid; PC Codes 30702 and 374350 (RED), and the Final Rules, make repeated references to the product called AuxiGro, a product manufactured by Emerald BioAgriculture (formerly known as Auxein Corporation), the corporation that filed the petitions for the exemptions from the requirements of a tolerance.

If Emerald BioAgriculture had made an effective case for the safety of their "L-glutamic acid," (which they have not), it would have been an effective case for the safety of their "L-glutamic acid" when used in AuxiGro, only.

SECOND.  In granting "L-Glutamic Acid and Gamma Aminobutyric Acid; Exemptions from the Requirement of a Tolerance" – which should properly have been called "L-Glutamic Acid and Gamma Aminobutyric Acid when used together in AuxiGro WP; Exemptions from the Requirement of a Tolerance"-- the EPA has violated Section 408(c)(2)(A)(i), Section 408(c)(2)(ii), Section 408(c)(2)(B), and Section 408(b)(2)(D) of the Federal Food, Drug, and Cosmetic Act (FFDCA).

Neither "L-Glutamic Acid and Gamma Aminobutyric Acid; Exemptions from the Requirement of a Tolerance; Final Rule" (Federal Register June 21, 2001) nor "Glutamic Acid; Pesticide Tolerance Exemption; Final Rule" (Federal Register January 7, 1998), which preceded it, met the criteria established by law for granting exemptions from the restriction of a tolerance.

To be specific:

Section 408(c)(2)(A)(i) of  the FFDCA allows EPA to establish an exemption from the requirement of a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the exemption is "safe.'' Section 408(c)(2)(ii) defines "safe'' to mean that "there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information." This includes exposure through drinking water and in residential settings, but does not include occupational exposure.

We find, however, that there is no reasonable certainty that no harm will result from aggregate exposure to the "L-glutamic acid" that is the subject of this Final Rule.  The data on which the EPA based its determination that there is a reasonable certainty that no harm will result from aggregate exposure to the "L-glutamic acid" were not valid, not complete, and not reliable.

Section 408(c)(2)(B) of the FFDCA requires EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to "ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue...''

We find, however, that the EPA did not give special consideration to exposure of infants and children to the "L-glutamic acid," and to ensuring that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the "L-glutamic acid.

Section 408(b)(2)(D) of the FFDCA requires that in establishing, modifying, leaving in effect, or revoking a tolerance or exemption for a pesticide chemical residue, the Administrator [of the EPA] shall consider, among other relevant factors–

(i) the validity, completeness, and reliability of the available data from studies of the pesticide chemical and pesticide chemical residue;
(ii) the nature of any toxic effect shown to be caused by the pesticide chemical or pesticide chemical residue in such studies;
(iii) available information concerning the relationship of the results of such studies to human risk;
(iv) available information concerning the dietary consumption patterns of consumers (and major identifiable subgroups of consumers);
(v) available information concerning the cumulative effects of such residues and other substances that have a common mechanism of toxicity;
(vi) available information concerning the aggregate exposure levels of consumers (and major identifiable subgroups of consumers) to the pesticide chemical residue and to other related substances, including dietary exposure under the tolerance and all other tolerances in effect for the pesticide chemical residue, and exposure from other non-occupational sources;
(vii) available information concerning the variability of the sensitivities of major identifiable subgroups of consumers;
(viii) such information as the Administrator may require on whether the pesticide chemical may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen or other endocrine effects; and
(ix) safety factors which in the opinion of experts qualified by scientific training and experience to evaluate the safety of food additives are generally recognized as appropriate for the use of animal experimentation data.
We find, however, that by and large, no such consideration was given.  Instead:
(i) The Administrator [of the EPA] obviously did not consider the validity, completeness, and reliability of the data submitted in support of the "L-glutamic acid" exemptions, because the data submitted in support of the "L-glutamic acid" exemptions were neither valid, complete nor reliable;

(ii) Data on the toxic effects of the "L-glutamic acid," which are chronicled in the published peer reviewed literature, were not included in the data submitted in support of the "L-glutamic acid" exemptions. They were not mentioned by the EPA in either the RED or any Final Rule, and, therefore, were obviously not considered as required;

(iii) Articles published in peer reviewed journals that discussed the relationship of the neurotoxic and endocrine disrupting properties of the "L-glutamic acid" to human risk were not included in the data submitted in support of the "L-glutamic acid" exemptions. They were not mentioned by the EPA in either the RED or any Final Rule, and, therefore, were obviously not considered as required;

(iv) Some available information concerning the dietary consumption patterns of consumers (and major identifiable subgroups of consumers) was discussed and, therefore, may have been considered;

(v) Data on the cumulative effects of the "L-glutamic acid" and other substances, such as aspartic acid and aspartame products (made with aspartic acid), that have a common mechanism of toxicity, were not included with the data submitted in support of the "L-glutamic acid" exemptions. They were not mentioned by the EPA in either the RED or any Final Rule, and, therefore, were obviously not considered as required;

(vi) Data on the aggregate exposure levels of consumers (and major identifiable subgroups of consumers) to the "L-glutamic acid" and to other related substances were not included in the data submitted in support of the "L-glutamic acid" exemptions.  They were not discussed by the EPA in either the RED or any Final Rule, and, therefore, were obviously not considered as required;

(vii) No attempt to assess the variability of the sensitivities of major identifiable subgroups of consumers was included with the data submitted in support of the "L-glutamic acid" exemptions. No assessment of the variability of the sensitivities of major identifiable subgroups of consumers was mentioned by the EPA in either the RED or any Final Rule, and, therefore, was obviously not considered as required;

(viii) The "L-glutamic acid" which is the subject of this exemption is an endocrine disruptor. The scientific literature is clear on that point. (See Sections II and IV that follow.) However, in the text of the January 7, 1998 Final Rule, the EPA dismissed the endocrine disrupting properties of the "L-glutamic acid" saying,

"The Agency has no information to suggest that glutamic acid will adversely affect the immune or endocrine systems. The Agency is not requiring information on the endocrine effects of this biochemical pesticide at this time."
The Administrator did not require information on the pesticide chemical's endocrine effects.

In the text of the June 21, 2001 Final Rule, which is the subject of this Objection, endocrine effects are not even mentioned.

Section 408(b)(2)(D) also requires that the EPA consider the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity.''

We find, however, that the cumulative effects of processed free glutamic acid and substances like aspartic acid (found in aspartame) that have a common mechanism of toxicity were not even discussed.

THIRD.  The processed free glutamic acid (referred to in the 1998 Final Rule as "L-glutamic acid") that was granted an exemption from the requirement of a tolerance, is a neurotoxic endocrine disruptor that causes brain lesions; causes endocrine disorders which manifest themselves in such things as growth abnormalities, gross obesity, and various reproductive disorders; causes learning, behavior, and memory deficits; causes adverse reactions such as asthma, tachycardia and other heart irregularities, nausea and vomiting, migraine headache, fibromyalgia, seizures and depression; and is associated with a number of pathological conditions such as addiction, stroke, epilepsy, brain trauma, neuropathic pain, schizophrenia, anxiety, depression, and degenerative disorders such as multiple sclerosis (MS), Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS).  It has been described by Choi as "a remarkably potent and rapidly acting neurotoxin.(5b)

There were no valid and reliable data submitted to the EPA that demonstrated that the processed free glutamic acid is not a neurotoxic endocrine disruptor; that it does not cause brain lesions; does not cause endocrine disorders; does not cause learning, behavior, and memory deficits; does not cause adverse reactions such as asthma, tachycardia and other heart irregularities, nausea and vomiting, migraine headache, fibromyalgia, seizures and depression; and is not associated with a number of pathological conditions such as addiction, stroke, epilepsy, brain trauma, neuropathic pain, schizophrenia, anxiety, depression, and degenerative disorders such as multiple sclerosis (MS), Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS).

The processed free glutamic acid that was granted an exemption from the requirement of a tolerance is a manufactured product, which can be produced in a number of distinctly different ways.  The method popularly used to manufacture the processed free glutamic acid used in "monosodium glutamate" is referred to as bacterial fermentation. In this method, bacteria are grown aerobically in a liquid nutrient medium. The bacteria, which have had the benefit of genetic engineering, have the ability to excrete glutamic acid they synthesize outside of their cell membrane into the liquid nutrient medium in which they are grown. The glutamic acid is then separated from the fermentation broth by filtration, concentration, acidification, and crystallization, and converted to its monosodium salt.(9-10)

It was shortly after production by bacterial fermentation began that adverse reactions following ingestion of "monosodium glutamate" were first reported.  It is interesting to note that D-glutamic acid (which could be considered a contaminant formed when L-glutamic acid is produced) is known to be present in the cell walls of bacteria.(2)  It is also interesting to note that fermented foods have been found to contain unusually high relative levels of free D-amino acids which have been attributed to the fermentation process.(2)  If D-glutamic acid as a contaminant in processed free glutamic acid (MSG) was the cause of human adverse reactions to MSG, that would explain, at least in part, why reactions to MSG were essentially reported only after Ajinomoto Co., Inc. began to produce "monosodium glutamate" by bacterial fermentation.

A second method of producing processed free glutamic acid is referred to as "acid hydrolysis."  In that method, a protein source is subjected to high heat and hydrochloric acid. The products of acid hydrolysis, which all contain processed free glutamic acid, are often referred to as "hydrolyzed proteins."  Acid hydrolysis of protein produces mono and dichloro propanols which are carcinogenic. Many European countries have restrictions on acid hydrolyzed products.

There are other methods used to produce processed free glutamic acid, as well.

The origin(s) of the processed free glutamic acid granted an exemption from the requirement of a tolerance were not discussed in either the RED or the Final Rules.

There were no data submitted to the EPA that established what amount of  processed free glutamic acid used will not cause brain lesions, disrupt the endocrine system, cause adverse reactions, or cause or exacerbate diverse disease conditions.  There were no data submitted that addressed the question of the amount of  the processed free glutamic acid residue that would remain in and on treated produce when brought to market; no data submitted that addressed the question of cumulative effects of processed free glutamic acid and "other substances that have a common mechanism of toxicity,'' and no data submitted that addressed the question of the least amount of processed free glutamic acid needed to cause adverse reactions in the subpopulation of people already sensitive to the substance, including infants, children, and the elderly, or the populations most at risk of becoming sensitive from ingestion of unregulated amounts of processed free glutamic acid, i.e., infants, children, and the elderly whose blood-brain barriers are not yet mature, or whose blood-brain barriers have been compromised by such things as drugs, seizures, stroke, trauma to the head, hypoglycemia, hypertension, extreme physical stress, high fever, and the normal process of aging.(125)  It is generally accepted that the young are particularly at risk from ingestion of MSG.

Moreover, there is a great deal of data in the published peer reviewed literature that demonstrates that processed free glutamic acid is a neurotoxic endocrine disruptor that causes brain lesions; causes endocrine disorders which manifest themselves in such things as growth abnormalities, gross obesity, and various reproductive disorders; causes learning, behavior, and memory deficits; causes adverse reactions such as asthma, tachycardia and other heart irregularities, nausea and vomiting, migraine headache, fibromyalgia, seizures, and depression; and is associated  with a number of pathological conditions such as addiction, stroke, epilepsy, brain trauma, neuropathic pain, schizophrenia, anxiety, depression, and degenerative disorders such as multiple sclerosis (MSG) Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS).  None of these data were included with the data submitted to the EPA in support of the exemptions.

To be more specific:

The data, abstracts, and discussions that Auxein Corporation (the applicant) submitted to the EPA in support of their application:
-- Were often irrelevant to the issue;
- Acute toxicity studies were carried out under conditions that did not replicate the real world conditions under which processed free glutamic acid would be applied to crops. Studies conducted by the applicant and evidently submitted by the applicant as evidence that there was essentially no acute mammalian toxicity caused by application of processed free glutamic acid did not reflect the conditions under which the processed free glutamic acid would be used. Those studies did not take into account the fact that mammals would not only be treated/sprayed with a product containing processed free glutamic acid several times a year, but would also live in environments wherein there would be residue from repeated treatment/spray in and on all animals, ground, water, and vegetation.

-Acute toxicity studies were studies of the safety of AuxiGro, not studies of the safety of the "L-glutamic acid" independent of the product it was being used in.

- Studies identified as studies of the metabolism of glutamic acid or L-glutamic acid were studies of metabolism of glutamic acid bound in protein when ingested. None were studies of metabolism of processed free glutamic acid.

-- Relied on methodology that was inadequate to the task of identifying brain lesions and neuroendocrine disorders in animals allegedly studied;

-- Had been refuted years ago by neuroscientists outside of the employ of Ajinomoto Company, Inc. (a world leader in the production of amino acids, and the world's largest producer of the food ingredient "monosodium glutamate"), its International Glutamate Technical Committee (IGTC), its Glutamate Association, and others in the glutamate industry;

-- Did not duplicate the real world conditions under which processed free glutamic acid would be used; and/or

-- Did not consider the total amount of processed free glutamic acid that would be ingested daily if products containing processed free glutamic acid were successfully marketed.

The little bit of data submitted to the EPA that the applicant might allege demonstrate that processed free glutamic acid is neither neurotoxic nor an endocrine disruptor were old data, full of methodological flaws, and long since refuted.

In addition, errors, inaccuracies, distortions, and literally false statements permeate the texts of the one and only RED and the two Final Rules relevant to the June 21, 2001 Final Rule.

The applicant failed to show the EPA the volumes of data published in peer reviewed journals that demonstrate that processed free glutamic acid places humans at risk. Omitted were:

-- Published studies of the endocrine disrupting effects of processed free glutamic acid;

-- Published studies relevant to the sensitivities of major identifiable subgroups, primarily infants and children, who have been shown to be most at risk from exposure to processed free glutamic acid;

--Published studies of deleterious effects on animals;

--Published studies of the neurotoxic effects of processed free glutamic acid.

Missing, also, were data relevant to a determination of the greatest amount of processed free glutamic acid that could be applied to crops without risk of causing or exacerbating either brain lesions; endocrine disorders; neurological disorders such as schizophrenia, depression, ALS, and Alzheimer's disease; diverse disease conditions associated with the glutamate cascade; and adverse reactions including asthma, migraine headache, heart irregularities, and seizures.  Absent were:
-- Data on the amount of processed free glutamic acid that would be ingested daily and yearly by individual adults and children ingesting fruit, grains, nuts, seeds, and vegetables treated with products containing processed free glutamic acid;

-- Data describing the least amount of processed free glutamic acid needed to cause brain lesions, and/or to cause or exacerbate neuroendocrine disorders; memory, behavior and learning disorders; debilitating and life threatening adverse reactions such as asthma, migraine headache, diarrhea and vomiting, depression, seizures, elevated blood pressure, tachycardia, and atrial fibrillation; or the various disease conditions associated with what the National Institutes of Health refers to as the "glutamate cascade."

-- Data on the amount of processed free glutamic acid that would remain as residue on or in each of the fruits, grains, and vegetables brought to market after the first harvest.

--  Data on the difference in uptake of processed free glutamic acid in leaves (such as lettuce and chard), in fruits (such as grapes and tomatoes), in stems (such as celery), in roots or tubers (such as potatoes and carrots), in nuts and seeds, and in the edible portion of grains.

-- Data on the amount of processed free glutamic acid that would remain as residue on or in each of the fruits, grains, and vegetables brought to market after subsequent harvests.

-- Data on the total amount of processed free glutamic acid from residues on or in fruits, grains, and vegetables that might be consumed by individual adults and children consuming more than one food treated with processed free glutamic acid during the course of a day.

-- Data describing the amount of processed free glutamic acid that will get into ground water and into drinking water.

-- Case studies and data from peer reviewed published literature that address the least amount of processed free glutamic acid needed to produce adverse reactions in persons - either adults, infants, or children -- acutely sensitive to processed free glutamic acid.

-- Credible data on the effects that feeding processed free glutamic acid to infants (either human or other) over a period of years would have on the production of brain lesions and neuroendocrine disorders.

--Testimony of physicians, researchers, and health care professionals who are concerned about the use of processed free glutamic acid in food.

Human studies conducted by the glutamate industry which alleged to have demonstrated that ingestion of processed free glutamic acid does not place consumers at risk were conspicuously absent.

Those double-blind human studies have been severely criticized because what glutamate-industry researchers called "placebos" contained enough processed free glutamic acid (MSG) and/or aspartic acid (in aspartame) to cause MSG-type reactions in some MSG-sensitive people. Thus, when subjects suffered reactions to the bogus "placebos," they were really suffering adverse reactions to processed free glutamic acid (MSG) and its structural analog, aspartic acid.  The test material (which contained processed free glutamic acid in the flavor enhancer "monosodium glutamate") also caused adverse reaction. Thus, those industry-sponsored studies, themselves, demonstrated that the neurotoxic amino acids in free form (free glutamic acid and free aspartic acid) cause adverse reactions.
 
 

GROUNDS

SECTION II: DETAIL

In the following, we will demonstrate that neither "L-Glutamic Acid and Gamma Aminobutyric Acid; Exemptions from the Requirement of a Tolerance; Final Rule" (Federal Register June 21, 2001) nor "Glutamic Acid; Pesticide Tolerance Exemption; Final Rule" (Federal Register January 7,1998), which preceded it, met the criteria established by law for granting exemptions from the restriction of a tolerance.

Introduction

On January 7, 1998, the EPA established exemptions for the requirement of a tolerance for residues of the biochemicals "glutamic acid" and "gamma aminobutyric acid (GABA)" in or on all food commodities when applied as a plant growth and crop yield enhancer in accordance with good agricultural practices. On that date, or shortly thereafter, the EPA granted the unconditional registration of AuxiGro WP (EPA File Symbol 70810-R) containing the two new active ingredients "GABA" and "Glutamic Acid" (PC Codes 30802 and 374350, respectively) for use as a growth enhancer for certain food crops and ornamentals. The exemptions and registration were granted to Auxein Corporation, Lansing, Michigan (now Emerald BioAgriculture).

On June 21, 2001, the EPA established exemptions from the requirement of a tolerance for residues of the chemicals they refer to as "L-glutamic acid" and "gamma aminobutyric acid" on all food commodities when applied/used for any reason in accordance with good agricultural practices. With this regulation in place, there are no limits to the amounts of "L-glutamic acid" and GABA that can be left as residues on food crops when brought to market.

We have reviewed the June 21, 2001 Final Rule (which is the subject of this Objection), the single existing RED, and the January 7, 1998 Final Rule which was referenced in the June 21, 2001 Final Rule, and have found the exemptions for the requirement of a tolerance for residues of "glutamic acid" and "GABA" in or on all food commodities, and the unconditional registration of "GABA," "glutamic acid" (sometimes referred to as "L-glutamic acid"), and AuxiGro WP (AuxiGro), to be unwarranted.

There are four separate and distinct sets of deficiencies, weaknesses, shortcomings, and problems associated with the exemptions and registration.

First, the data supplied to the EPA by the applicant are neither valid, complete, nor reliable.

A great deal of relevant information was omitted from Auxein's applications; and

Errors, inaccuracies, distortions, and literally false statements permeate the texts of both the RED and the Final Rules.

Second, material the applicant failed to show the EPA includes volumes of data published in peer reviewed journals that demonstrate that processed free glutamic acid places humans at risk.

Third, the subject of the exemptions granted by the June 21, 2001 Final Rule is processed free glutamic acid (MSG), referred to by the EPA as "L-glutamic acid."  But the data supporting the exemption from the requirement of a tolerance for residues of the "L-glutamic acid" are, in part, data that pertain to the safety of the product AuxiGro, not data that pertain to the safety of the "L-glutamic acid" in and of itself. For example, in Section IV: Aggregate Exposure, of the January 7, 1998 Final Rule (which is referenced in the June 21, 2001 Final Rule), the EPA concludes that "Considering the low dose of AuxiGro required to achieve the desired effect, the levels of glutamic acid found naturally in the diet from animal and vegetable proteins and the quantity consumed from processed foods, it can be concluded that incremental dietary exposure to glutamic acid resulting from AuxiGro applications is negligible." (Emphasis added.)  True or not (and it is not true that the incremental dietary exposure to processed free glutamic acid resulting from AuxiGro applications is negligible), if it were true that the amount of processed free glutamic acid in AuxiGro would not put consumers at risk, that would not be evidence that no amount of  processed free glutamic acid residue, from any product under the EPA's jurisdiction, would put consumers at risk.

Reference to AuxiGro is repeated throughout the RED, whose title "RED: GABA and L-Glutamic Acid," makes no reference to AuxiGro. According to the RED, acute mammalian toxicity studies were conducted using AuxiGro.  Thus, the risks of acute mammalian toxicity using the "L-glutamic acid" from any source other than AuxiGro have not been evaluate.

Fourth, Section 408 (c)(2)(A)(i) of the Federal Food, Drug, and Cosmetic Act allows EPA to establish an exemption from the requirement of a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the exemption is "safe;" and section 408 (c)(2)(A)(ii) defines "safe" to mean that there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures. In this case, the applicant alleged, but failed to demonstrate, that there is reasonable certainty that no harm will follow the use of processed free glutamic acid (referred to as "L-glutamic acid" by the applicant and as "MSG" by consumers) when applied/used for any reason falling under the jurisdiction of the EPA, and on any crop, in accordance with good agricultural practices:

The applicant provided no information on the amount of processed free glutamic that would remain as residue on or in each of the fruits, grains, and vegetables brought to market after the first harvest.

The applicant provided no information on the difference in uptake of processed free glutamic acid in leaves (such as lettuce and chard), in fruits (such as grapes and tomatoes), in stems (such as celery), in roots and tubers (such as potatoes and carrots), in nuts and seeds, and in the edible portion of grains.

The applicant provided no information on the amount of processed free glutamic acid that would remain as residue on or in each of the fruits, grains, and vegetables brought to market after subsequent harvests.

The applicant provided no information on the total amount of processed free glutamic acid from residues on or in fruits, grains, and vegetables that might be consumed by individual adults and children consuming more than one food treated with processed free glutamic acid during the course of a day.

The applicant provided neither case studies nor data from peer reviewed published literature that addressed the least amount of processed free glutamic acid needed to produce adverse reactions in persons -- either adults, infants, or children -- acutely sensitive to processed free glutamic acid.

The applicant provided no information on the amount of processed free glutamic acid that will get into ground water and into drinking water.

The applicant provided no credible data on the effects that feeding processed free glutamic acid to infants (either human or other) over a period of years would have on the production of brain lesions and neuroendocrine disorders.

The data that Auxein did submit to the EPA, alleging that it demonstrated that there is reasonable certainty that no harm will follow the use of processed free glutamic acid:

Were irrelevant to the issue;

Used methodology inadequate to the task of identifying brain lesions and neuroendocrine disorders in animals allegedly studied;

Had been refuted years ago by neuroscientists outside of the employ of Ajinomoto Co., Inc., their agents, and others in the glutamate industry;

Did not duplicate the real-world conditions under which the processed free glutamic acid would be used; and/or

Did not consider the total amount of processed free glutamic acid that would be ingested daily if agricultural products containing processed free glutamic acid were successfully marketed.

In the following, we will demonstrate that:
1) A great deal of relevant information was omitted from Auxein Corporation's applications. Most obvious, but by no means all inclusive were omissions of:
Published studies of the endocrine disrupting effects of processed free glutamic acid; and

Published studies relevant to the sensitivities of major identifiable subgroups, primarily infants and children, who have been shown to be most at risk from exposure to processed free glutamic acid.

 2) Errors, inaccuracies, distortions, and literally false statements permeate the texts of both the RED and Final Rules.

3) Industry-sponsored studies cited in the application and described as acute, subchronic and chronic mammalian toxicity studies for "L-glutamic acid" reported in public literature contain serious methodological flaws.

4) Studies conducted by the applicant and submitted by the applicant as evidence that there was essentially no acute mammalian toxicity caused by application of AuxiGro (which contains processed free glutamic acid) did not reflect the conditions under which AuxiGro would be used. Those studies did not take into account the fact that mammals would not only be treated/sprayed with AuxiGro (containing processed free glutamic acid) several times a year, but would also live in environments wherein there would be residue from repeated treatment/spray in and on all animals, ground, water, and vegetation.

5) In studies conducted by the applicant and submitted by the applicant as evidence that there was essentially no acute mammalian toxicity caused by application of AuxiGro, reports of adverse reactions in test subjects were glossed over and dismissed.

6) Human studies conducted by the glutamate industry which alleged to have demonstrated that ingestion of processed free glutamic acid does not place consumers at risk were conspicuously absent. In those studies, subjects suffered adverse reactions to both the test material (which contained processed free glutamic acid in the flavor enhancer "monosodium glutamate"), and the placebos, (which contained processed free glutamic acid in various hydrolyzed protein products and/or contained its structural analog, aspartic acid, as a component of aspartame). Those industry-sponsored studies, in and of themselves, are evidence that the neurotoxic amino acids in free form (free glutamic acid and free aspartic acid) cause adverse reactions.

7) Studies identified as studies of the metabolism of "glutamic acid" or "L-glutamic acid" were studies of metabolism of glutamic acid bound in protein when ingested. None were studies of metabolism of processed free glutamic acid such as that used in AuxiGro.

8) Waivers were granted based on:

Errors, inaccuracies, distortions, and literally false statements that permeate the texts of the RED and Final Rules;

Flawed industry-sponsored studies submitted to the EPA; and

Studies conducted by the applicant which did not reflect the conditions under which processed free glutamic acid would be used.

In brief, we will demonstrate that the RED is deficient in the validity, completeness, and reliability of data from studies alleging to have demonstrated that processed free glutamic acid is not toxic to the general population or to identifiable subgroups of consumers, including infants and children.  And we will also document the fact that there is a substantial body of evidence in the scientific literature that demonstrates that ingestion of processed free glutamic acid, in any form, places humans at risk.  We have already pointed out that Emerald BioAgriculture's supporting data not only lack completeness, validity, and reliability; that they often addressed the issue of the safety of the "L-glutamic acid" used in AuxiGro, and failed to address the issue of the safety of the "L-glutamic acid" in general.

Background: The EPA's approval

In 1998, the EPA established exemptions for the requirement of a tolerance for residues of the biochemicals "glutamic acid" and GABA in or on all food commodities, when applied as a plant growth and crop yield enhancer in accordance with good agricultural practices; and granted the unconditional registration of AuxiGro containing the two new active ingredients, GABA and "glutamic acid," for use as a growth enhancer for certain food crops and ornamentals.

According to a memorandum dated January 9, 1998 signed on behalf of Janet Andersen, Ph.D., all data requirements for granting the unconditional registration of AuxiGro containing the two new active ingredients, GABA and "glutamic acid," had been fulfilled.

In that memorandum, AuxiGro was described as an end-use product, manufactured by an integrated process. "Glutamic acid" and GABA were described as non-essential amino acids found in plant and animal cells. The mode of action was described as non-toxic plant growth enhancers, which qualify as biochemicals.

According to the memorandum, the unconditional registration of AuxiGro was considered in light of the nine safety factors listed in the Food Quality Protection Act (FQPA) of 1996:

- validity, completeness, reliability of available data from studies;

- nature of toxic effect shown by studies;

- available information on relationship of study results to human risk;

- available information on dietary consumption (consumers and major identifiable subgroups);

- available information on cumulative effects of residues and other substances with common mechanism of toxicity;

- available information on aggregate exposure (dietary and other non-occupational sources including drinking water);

- available information on variability of sensitivities of major identifiable subgroups;

- information on endocrine disruption effects;

- appropriate safety factors;

and a determination of reasonable certainty of no harm was made by the EPA.

According to the memorandum, it was concluded that the Biopesticides and Pollution Prevention Division (7511W) (BPPD) had not identified any subchronic, chronic, immune, endocrine, or nondietary exposure issues that might affect infants and children or the general population.

In conclusion, the BPPD alleged that all data requirements for granting this registration under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 3(c)(5) had been fulfilled.

 Anatomy of a grossly deficient application:
Omissions, errors, inaccuracies, distortions, methodological flaws,
 and literally false statements

In the following, we have followed the outline (but not the numbering system) of the January 7, 1998 Final Rule, which contains more detail than the June 21, 2001 Final Rule.  By and large, the text of the June 21, 2001 Final Rule, which is the subject of this Objection, refers to PP 7F4842 and PP 7F4843 (material that is described, at least in part, in the January 7, 1998 Final Rule).  Therefore, unless otherwise noted, from this point forward, reference to the Final Rule (singular) will be reference to the January 7, 1998 Final Rule.

I. The ingredient called "L-glutamic acid" or "glutamic acid"

We found that the EPA's RED and Final Rules misrepresented the chemical composition of the processed free glutamic acid granted an exemption from the requirement of a tolerance, and used in AuxiGro. In particular, they:

Failed to reveal the material fact that the processed free glutamic acid which was, in part, the subject of the EPA's RED and Final Rules, is manufactured/fabricated using the same methods used by Ajinomoto Co., Inc. and others to produce the processed free glutamic acid produced by Ajinomoto, Company, Inc. and others for use in the flavor enhancer called "monosodium glutamate;" that the processed free glutamic acid is manufactured/fabricated using acid hydrolysis which produces mono and dichloro propanols which are carcinogenic; that the processed free glutamic acid is manufactured by whatever method the GABA in AuxiGro is manufactured; and/or that it is manufactured by other methods.

Failed to reveal the material fact that, regardless of the method of manufacture, processed free glutamic acid such as that used in AuxiGro, which is the subject of this Objection, contains contaminants not found in protein; not associated with the L-glutamic acid found in protein; and not associated with any minute amounts of free glutamic acid that might occur without benefit of acid hydrolysis, enzymolysis, autolysis, fermentation, or other processes involving human intervention.(1-5,5a) Table 1 illustrates this point;

Referred to processed free glutamic acid as being ubiquitous in nature, which it is not. Protein is ubiquitous in nature. L-glutamic acid is found in unadulterated protein and in higher organisms. L-glutamic acid which is bound in protein is ubiquitous in nature. But processed free glutamic acid, a chemical compound which contains D-glutamic acid, pyroglutamic acid, and a variety of other contaminants(5a)N in addition to L-glutamic acid, is not ubiquitous in nature. In the Final Rule, the "glutamic acid" used in AuxiGro is described as "a white, practically odorless, free flowing crystalline powder." This writer knows of no white, practically odorless, free flowing crystalline powder that is ubiquitous in nature.

On page 2 of the RED, the applicant noted that free glutamic acid serves as an important brain neurotransmitter, and that disruption of its metabolism is associated with epileptic brain activity. But the applicant failed to note that free glutamic acid also: functions as a neurotoxin, killing brain cells; causes retinal degeneration; causes endocrine disorders; and, as part of what is referred to as the glutamate cascade, is associated with a number of pathological conditions such as addiction, stroke, epilepsy, brain trauma, neuropathic pain, schizophrenia, anxiety, depression, and degenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS).

The subject is discussed more fully in the enclosed  paper titled "On the Subject of Manufactured vs. Natural Glutamic Acid."  It can also be found on the Internet at www.truthinlabeling.org/manufac.html.

We found, also, that the RED did not address the fact that total processed free glutamic acid in any application may come from a number of sources.  For example, we have gleaned from government documents that AuxiGro contains processed free glutamic acid in the active ingredient identified as "L-glutamic acid;" but also derives processed free glutamic acid from the inert ingredients and from GABA, a second named active ingredient.

II. History of use in food

We found that the EPA's RED and/or Final Rule falsely asserted that processed free glutamic acid has a long history of food uses. That is not true.

The flavor-enhancing potential of the processed free glutamic acid used in the flavor enhancer called "monosodium glutamate" and possibly used in AuxiGro, was discovered in Japan in 1908. Prior to that time, the Japanese had used seaweed as a favorite flavor enhancer, without understanding that glutamic acid was its flavor-enhancing component. The first "monosodium glutamate" was made by extracting glutamic acid from seaweed.

From 1910 until 1956, the process underlying production of glutamic acid and "monosodium glutamate" in Japan was one of extraction, a slow and costly method.(6)  Elsewhere, crude gluten or other starting materials were hydrolyzed by heating with hydrochloric acid.(7) In 1956, the Japanese succeeded in producing glutamic acid by means of fermentation; and after considerable research to identify suitable strains of microorganisms for starting the requisite cultures, large- scale production of glutamic acid and "monosodium glutamate" through fermentation began.(6-8)

"Monosodium glutamate" was brought to the United States in the years following World War II
at which time it was still manufactured through extraction. In 1956, Ajinomoto Co., Inc. developed and began to use a method of bacterial fermentation wherein bacteria (some, if not all of which are genetically modified)(9) are grown aerobically in a liquid nutrient medium. These bacteria have the ability to synthesize glutamic acid outside of their cell membranes and excrete it into the medium to accumulate there.(10)

In 1968, the first published report of an adverse reaction to "monosodium glutamate" appeared in The  New England Journal of Medicine.(11)  In 1969, the first evidence that processed free glutamic acid causes brain lesions and neuroendocrine disorders in laboratory animals was published in Science.(12)  In 1969 and the early 1970s, the safety of using processed free glutamic acid (referred to as MSG) in baby food was questioned.(13-15) In the mid 1970s, epidemiological studies indicated that 25% or more of adults in the United States reacted adversely to "monosodium glutamate."(16-19) The controversy over the use of processed free glutamic acid in baby food continued until 1978 when baby food manufacturers "voluntarily" stopped using any form of processed free glutamic acid.(20)

Today, there is growing recognition that the reactive component of "monosodium glutamate" is processed free glutamic acid; and that processed free glutamic acid causes adverse reactions regardless of the names of the ingredients that contain it or the uses to which it is put.(21-24) This growing awareness and concern comes in spite of the close cooperation the glutamate industry gets from the Food and Drug Administration (FDA), the EPA, and the United States Department of Agriculture (USDA).(25)

Today, reports of adverse reactions submitted to the FDA are on file in FDA Dockets including Docket # 96N-0244 and Docket # 92N-0391; the FDA's Adverse Reactions Monitoring System (ARMS) accepts reports of MSG-sensitivity; and a report from the Federation of American Societies for Experimental Biology (FASEB) reads, in part:

"The continuing controversy over the potential effects of glutamate on growth and development of neonatal animal models suggests that it is prudent to avoid the use of dietary supplements of L-glutamic acid by pregnant women, infants, and children. The existence of evidence of potential endocrine responses, i.e., elevated cortisol and prolactin, and differential responses between males and females, would also suggest a neuroendocrine link and that supplemental L-glutamic acid should be avoided by women of childbearing age and individuals with affective disorders."(26)
Today, virtually every headache clinic in the country acknowledges that processed free glutamic acid (popularly referred to as MSG) is one of the triggers of migraine headache; and there is government prohibition against producing or importing "monosodium glutamate" in Myanmar.(27)

It must be noted that in 1969, following the first published report of human adverse reactions to processed free glutamic acid, the IGTC was formed by the Ajinomoto Co., Inc. The IGTC sponsors, gathers, and disseminates research on the use and safety of monosodium glutamate, designs and implements research protocols, provides financial assistance to researchers, and promotes the sale of monosodium glutamate. Since 1990, if not before, the International Food Information Council (IFIC) has been employed by the Glutamate Association and/or the IGTC to encourage sales of "monosodium glutamate."  The IGTC has been generous in its support of physicians, researchers, universities, medical schools, newsletters, journal editors, media representatives, and publishers who, directly or indirectly, promote the fiction that processed free glutamic acid does not place humans at risk. The extent of the industry's contributions to individual politicians and/or political parties is unknown.

III. Metabolism

In the 1970s, Olney and others noted a positive relationship between brain lesion and plasma glutamate levels, with relatively elevated levels of plasma glutamate being associated with introduction of brain lesions. Using the relationship between brain lesions and plasma glutamate levels as justification, glutamate-industry public relations people went on to conclude, without justification, that relatively elevated plasma glutamate levels would have to be reached before humans would experience glutamate-induced adverse reactions such as skin rash, nausea and vomiting, or migraine headache. Glutamate industry public relations people alleged that if ingestion of processed free glutamic acid did not cause a precipitous rise in plasma glutamate levels, or if any rise in plasma glutamate was of short duration, adverse reactions could not possibly occur.

The logic, of course, is faulty. Ingestion of processed free glutamic acid causes brain lesions, neuroendocrine disorders, retinal degeneration, seizures, and behavior and learning disorders. The published peer reviewed literature is clear about that. The published peer reviewed literature also tells us that a sharp rise in plasma glutamate level is often associated with production of brain lesions. But there is nothing in the published peer reviewed literature that tells us that sharp rises in plasma glutamate levels are also associated with neuroendocrine disorders, retinal degeneration, or behavior and leaning disorders, events which would seem to happen as a consequence of suffering brain lesions. Neither is there anything in the published peer reviewed literature that tells us that sharp rises in plasma glutamate levels are associated with adverse reactions such as asthma, skin rash, seizures, tachycardia, atrial fibrillation, or migraine headache.

In 1993, Martinez et al.(28) measured glutamic and aspartic acid levels in plasma and cerebrospinal fluid (CSF) of patients with common and classic migraine during attacks, making comparisons with controls suffering from stress. Plasma levels of amino acids in migraine patients were lower than in controls. But the CSF concentrations of glutamic acid were higher in migraineurs than in controls. The authors concluded that "... results suggest an excess of neuroexcitatory amino acids in the [central nervous system] of migraine patients during attacks, possibly favoring a state of neuronal hyperexcitability." Martinez et al. found a relationship between glutamate levels and migraine headache, but it was glutamate levels found in the CSF of the central nervous system, not glutamate levels in the plasma, that were related to migraine headache.

Ingestion of processed free glutamic acid causes adverse reactions in susceptible individuals -- reactions identical to the adverse reactions known to occur as side effects of neurotropic drugs such as Valium. The fairly recent discovery of glutamate receptors in many locations outside of the central nervous system(29) suggests that the readily observable toxic effects of processed free glutamic acid, referred to as adverse reactions, are facilitated by glutamate receptors in the mouth, lungs, intestines, and muscle, for example; and that the fate of ingested processed free glutamic acid is not to come to rest in the plasma as elevated plasma glutamate and from there to be excreted by the liver. Rather, it would appear that the fate of ingested processed free glutamic acid is to move with dispatch to any glutamate receptors available to it; and to create an adverse or toxic reaction if any one of those peripheral glutamate receptors is weak, crippled, diseased, or otherwise unhealthy.

Defenders of the safety of processed free glutamic acid allege that processed free glutamic acid is metabolized rapidly and efficiently; and that the rapid and efficient metabolism of processed free glutamic acid proves that processed free glutamic acid can not cause adverse reactions. There are two problems with their argument.

First and foremost, if it is true that ingestion of processed free glutamic acid does not cause a precipitous rise in plasma glutamate levels, or that any rise in plasma glutamate is of short duration, that tells us nothing about the fate of the ingested processed free glutamic acid. The fact that there is little or no excess plasma glutamate does not tell us that ingested glutamate has been excreted or been put to good use. As noted above, Martinez et al. found a relationship between glutamate levels and migraine headache, but it was glutamate levels found in the CSF of the central nervous system, not glutamate levels in the plasma, that were related to migraine headache.

Second, defenders of the safety of processed free glutamic acid cite studies of metabolism of intact protein, wherein the glutamic acid freed from intact protein during digestion of protein was metabolized "quickly." Because the glutamic acid in intact protein is metabolized "quickly," they concluded that processed free glutamic acid is metabolized "quickly."

The logic, again, is faulty, and the conclusion is unwarranted. The glutamic acid bound in protein when ingested is freed from that protein over a period of time, and during the course of its metabolism competes for transport and uptake with all of the other amino acids freed from that protein. On the other hand, glutamic acid which is in free form when ingested does not have the same sort of competition for uptake and transport.

In addition to the fact that studies of metabolism of processed free glutamic acid are very likely irrelevant to identification or an understanding of adverse reactions caused by processed free glutamic acid, it must be pointed out that the few studies submitted to the EPA as studies of the metabolism of glutamic acid or L-glutamic acid that actually were studies of metabolism, were studies of metabolism of glutamic acid bound in protein when ingested. None were studies of processed free glutamic acid, which is the subject of this Objection, such as that used in AuxiGro.

Following are the references cited in the RED as being studies of metabolism relevant to human risk assessment:

MRID 44296201 Meldrum, B. (1982) Pharmacology of GABA. Clinical Neuropharmacology 5(3):293-316.

MRID 44296202 McGilver, R., Goldstein, G. (1979) Amines. P 616-618. In: Biochemistry, A Functional Approach, 2nd ed. Philadelphia: Saunders.

MRID 44296203 Meister, A. (1979) Biochemistry of glutamate: Glutamine and glutathione. P 69-84 In: Glutamic Acid: Advances in Biochemistry and Physiology Filer, L.J. Jr., et al. Ed. New York: Raven Press.

MRID 44296204Munro, H.(1979) Factors in the regulation of glutamate metabolism. P 55- 68 In: Glutamic Acid: Advances in Biochemistry and Physiology Filer, L.J. Jr., et al. Ed. New York: Raven Press.

MRID 44296205 Fonnum, F. Hassel, B. (1995) Glutamate synthesis, metabolism, and uptake. P 19-34 In: CNS Neurotransmitter and Neruomodulators: Glutamate Stone, T., Ed. New York: CRC Press.

MRID 44296206 Tower, D. (1960) The administration of gamma-aminobutyric acid to man: Systemic effects and anticonfulsant action. P 562-578. In: Inhibition in the Central Nervous System and gamma-Aminobutyric Acid. New York: Pergamon Press.

MRID 44296402 Meister (same as MRID 44296203 above)

MRID 44296403 Munro, H.(same as MRID 44296204 above)

MRID 44296404 Fonnum (same as MRID 44296205 above)

MRID 44296405 Meldrum, B. (same as MRID 44296201 above)

MRID 44296415 Heywood, R, Worden, A. (1979) Glutamate toxicity in laboratory animals. P 203-215. In: Glutamic Acid: Advances in Biochemistry and Physiology Filer, L.J. Jr., et al. Ed. New York: Raven Press.

MRID 44296419 Stegink, L. Pitkin, R., Reynolds, A. et al. (1974) Placental transfer of glutamate and its metabolites in the primate. Am J. Obstet. Genecol., 122:70-78.

IV. Omission of data from the literature on toxic and endocrine disrupting properties of processed free glutamic acid and its ability to cause adverse reactions in humans

This writer found the EPA's RED and Final Rules to have ignored and omitted references to data from the published literature that describe the toxic and endocrine disrupting properties of all forms of free glutamic acid, including processed free glutamic acid, and its ability to cause adverse reactions in humans.

The first published report of human adverse reactions to processed free glutamic acid appeared in The New England Journal of Medicine in 1968.(11) That report was followed by published confirmations of adverse reactions;(30-37) studies that demonstrated that processed free glutamic acid, whether laboratory grade or found in "monosodium glutamate," cause retinal degeneration,(38-48) and brain lesions when given to immature animals after either subcutaneous (12,48-70) or oral (56,62,63,65,71-75,75a) doses; studies detailing neuroendocrine disorders, (12,48,57,59,75-93) possible locomotor and learning deficits either immediately or in later life,(79,82,83,94-103) learning and memory deficits,(104-107) behavioral reactions including somnolence and seizures,(108-118) tail automutilation,(81,108) learned taste aversion,(119) and conspicuous emotional change.(81)  In addition, there were epidemiologic studies completed in the 1970's demonstrating that at least 25% of the population react to processed free glutamic acid, the substance popularly referred to as MSG;(16-19) and studies that demonstrated that free glutamic acid (including processed free glutamic acid) can cross the placenta during pregnancy,(118,120-121, 121a) can cross the blood brain barrier in an unregulated manner during development, and can pass through the five circumventricular organs, which are "leaky" at best at any stage of life.(122-125) Moreover, the blood brain barrier is easily damaged by fever, stroke, trauma to the head, seizures, ingestion of processed free glutamic acid, and the normal process of aging.(112,125) It is generally accepted that the young are particularly at risk from ingestion of MSG.

Studies submitted with this Objection include:

Re: brain lesions following oral doses of processed free glutamic acid
**56. Olney, J.W. Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. J Neuropathol Exp Neurol 30: 75-90, 1971.

**62. Burde, R.M., Schainker, B., and Kayes, J. Acute effect of oral and subcutaneous administration of monosodium glutamate on the arcuate nucleus of the hypothalamus in mice and rats. Nature (Lond) 233: 58-60, 1971.

**63. Olney, J.W. Sharpe, L.G., Feigin, R.D. Glutamate-induced brain damage in infant primates. J Neuropathol Exp Neurol 31: 464-488, 1972.

**65. Burde, R.M., Schainker, B., and Kayes, J. Monosodium glutamate: necrosis of hypothalamic neurons in infant rats and mice following either oral or subcutaneous administration. J Neuropat hol Exp Neurol 31: 181, 1972.

**70. Olney, J.W., Rhee, V. and DeGubareff, T. Neurotoxic effects of glutamate on mouse area postrema. Brain Research 120: 151-157, 1977.

**71. Olney, J.W., Ho, O.L. Brain damage in infant mice following oral intake of glutamate, aspartate or cystine. Nature (Lond) 227: 609-611, 1970.

**72. Lemkey-Johnston, N., and Reynolds, W.A. Incidence and extent of brain lesions in mice following ingestion of monosodium glutamate (MSG). Anat Rec 172: 354, 1972.

**73. Takasaki, Y. Protective effect of mono- and disaccharides on glutamate-induced brain damage in mice. Toxicol Lett 4: 205-210, 1979.

**74. Takasaki, Y. Protective effect of arginine, leucine, and preinjection of insulin on glutamate neurotoxicity in mice. Toxicol Lett 5: 39-44, 1980.

**75. Lemkey-Johnston, N., and Reynolds, W.A. Nature and extent of brain lesions in mice related to ingestion of monosodium glutamate: a light and electron microscope study. J Neuropath Exp Neurol 33: 74-97, 1974.

**75a. Olney, J.W.Labruyere, J., and DeGubareff, T.  Brain damage in mice from voluntary ingestion of glutamate and aspartate. Neurobehavioral Toxicology 2:125-129, 1980.

Re: processed free glutamic acid causing neuroendocrine disorders

**12. Olney, J.W. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164: 719-721, 1969.

**57. Lamperti, A., and Blaha, G. The effects of neonatally-administered monosodium glutamate on the reproductive system of adult hamsters. Biol Reprod 14: 362-369, 1976.

**59. Holzwarth-McBride, M.A., Hurst, E.M., and Knigge, K.M. Monosodium glutamate induced lesions of the arcuate nucleus. I. Endocrine deficiency and ultrastructure of the median eminence. Anat Rec 186: 185-196, 1976.

**75. Lemkey-Johnston, N., and Reynolds, W.A. Nature and extent of brain lesions in mice related to ingestion of monosodium glutamate: a light and electron microscope study. J Neuropath Exp Neurol 33: 74-97, 1974.

**77. Redding, T.W., Schally, A.V., Arimura, A., and Wakabayashi, I. Effect of monosodium glutamate on some endocrine functions. Neuroendocrinology 8: 245-255, 1971.

**80. Nagasawa, H., Yanai R., and Kikuyama, S. Irreversible inhibition of pituitary prolactin and growth hormone secretion and of mammary gland development in mice by monosodium glutamate administered neonatally. Acta Endocrinol 75: 249-259, 1974.

**81. Nemeroff, C.B., Grant, L.D., Bissette, G., Ervin, G.N., Harrell, L.E., and Prange, A.J., Jr. Growth, endocrinological and behavioral deficits after monosodium L-glutamate in the neonatal rat: Possible involvement of arcuate dopamine neuron damage. Psychoneuroendocrinology 2: 179-196, 1977.

**82. Nemeroff, C.B., Konkol, R.J., Bissette, G., Youngblood, W., Martin, J.B., Brazeau, P., Rone, M.S., Prange, A.J. Jr., Breese, G.R. and Kizer, J.S. Analysis of the disruption in hypothalamic- pituitary regulation in rats treated neonatally with monosodium glutamate (MSG): Evidence for the involvement of tuberoinfundibular cholinergic and dopaminergic systems in neuroendocrine regulation. Endocrinology 101: 613-622, 1977.

**83. Pizzi, W.J., Barnhart, J.E., and Fanslow, D.J. Monosodium glutamate administration to the newborn reduces reproductive ability in female and male mice. Science 196: 452-454, 1977.

**88. Pizzi, W.J., and Barnhart, J.E. Effects of monosodium glutamate on somatic development, obesity and activity in the mouse. Pharmacol Biochem Behav 5: 551-557, 1976.

**89. Nikoletseas, M.M. Obesity in exercising, hypophagic rats treated with monosodium glutamate. Physiol Behav 19: 767-773, 1977.

**90. Redding, T.W., and Schally, A.V. Effect of monosodium glutamate on the endocrine axis in rats. Fed Proc Fed Am Soc Exp Biol 29: 378A (abstract #755), 1970.

**91. Holzwarth, M.A., and Hurst, E.M. Manifestations of monosodium glutamate (MSG) induced lesions of the arcuate nucleus of the mouse. Anat Rec 178: 378, 1974.

Re: processed free glutamic acid causing possible locomotor and learning deficits either immediately or in later life

**82. Nemeroff, C.B., Konkol, R.J., Bissette, G., Youngblood, W., Martin, J.B., Brazeau, P., Rone, M.S., Prange, A.J. Jr., Breese, G.R. and Kizer, J.S. Analysis of the disruption in hypothalamic- pituitary regulation in rats treated neonatally with monosodium glutamate (MSG): Evidence for the involvement of tuberoinfundibular cholinergic and dopaminergic systems in neuroendocrine regulation. Endocrinology 101: 613-622, 1977.

**83. Pizzi, W.J., Barnhart, J.E., and Fanslow, D.J. Monosodium glutamate administration to the newborn reduces reproductive ability in female and male mice. Science 196: 452-454, 1977.

**94. Pradhan, S.N., Lynch, J.F., Jr. Behavioral changes in adult rats treated with monosodium glutamate in the neonatal state. Arch Int Pharmacodyn Ther 197: 301-304, 1972.

**96. Vorhees, C.V., Butcher, R.E., Brunner, R.L., and Sobotka, T.J. A developmental test batter for neurobehavioral toxicity in rats: a preliminary analysis using monosodium glutamate, calcium carrageenan, and hydroxyurea. Toxicol Appl Pharm 50: 267-282, 1979.

**97. Vogel, J.R., and Nathan, B.A. Learned taste aversions induced by high doses of monosodium L-glutamate. Pharmacol Biochem Behav 3: 935-937, 1975.

**99. Berry, H.K., Butcher, R.E., Elliot, L.A., and Brunner, R.L. The effect of monosodium glutamate on the early biochemical and behavioral development of the rat. Devl Psychobiol 7: 165-173, 1974.

**101. Kubo, T, Kohira, R., Okano, T., and Ishikawa, K. Neonatal glutamate can destroy the hippocampal CA1 structure and impair discrimination learning in rats. Brain Research. 616: 311-314, 1993.

**102. Ali, MM, Bawari, M, Misra, UK, Babu, GN.Locomotor and learning deficits in adult rats exposed to monosodium-L-glutamate during early life. Neuroscience Letters 284(1-2):57-60, 2000.

**103. Wong, P.T.-H., Neo, L.H., Teo, W.L., Feng,H., Xue, Y.D., Loke, W.H. Deficits in water escape performance and alterations in hippocampal cholinergic mechanisms associated with neonatal monosodium glutamate treatment in mice. Pharmacology Biochemistry and Behavior 57:383-388, 1997.

Re: processed free glutamic acid causing learning and memory deficits

**104. Summers, M,J., Crowe, S.F., Ng, K.T. Modification of a weak learning experience by
memory retrieval in the day-old chick. Behavioral Neuroscience 114(4):713-9, 2000.

**105. Park, CH; Choi, SH; Piao, Y; Kim, S; Lee, YJ; Kim, HS; Jeong, SJ; Rah, JC;
Seo, JH; Lee, JH; Chang, K; Jung, YJ; Suh, YH.Glutamate and aspartate impair
memory retention and damage hypothalamic neurons in adult mice. Toxicology Letters 115(2):117-25, 2000.

**106. Xia, S, Liu, L, Feng, C, Guo, A. Drug disruption of short-term memory in
Drosophila melanogaster. Pharmacology, Biochemistry and Behavior 58(3):727-35, 1997.

**107. Summers, MJ, Crowe, SF, Ng, KT. Administration of glutamate following a
reminder induces transient memory loss in day-old chicks. Brain Research. Cognitive Brain Research 3(1):1-8, 1995.

Re: processed free glutamic acid crossing the placenta during pregnancy

**118. Frieder, B, and Grimm, VE. Prenatal monosodium glutamate (MSG) treatment given through the mother's diet causes behavioral deficits in rat offspring. Intern J Neurosci. 23:117-126,1984.

**120. Gao, J, Wu, J, Zhao, XN, Zhang, WN, Zhang, YY, Zhang, ZX. [Transplacental neurotoxic effects of monosodium glutamate on structures and functions of specific brain areas of filial mice.] Sheng Li Hsueh Pao Acta Physiologica Sinica. 46:44-51,1994.

**121. Yu, T, Zhao, Y, Shi, W, Ma, R, Yu, L. Effects of maternal oral administration of monosodium glutamate at a late stage of pregnancy on developing mouse fetal brain. Brain Research 747(2):195-206, 1997.

Re: processed free glutamic acid crossing the blood brain barrier in an unregulated manner during development; if the blood brain barrier is damaged by fever, stroke, trauma to the head, seizures, ingestion of processed free glutamic acid, or the normal process of aging; and passing through the five circumventricular organs, which are "leaky" at best at any stage of life.

**112. Nemeroff, C.B., and Crisley, F.D. Monosodium L-glutamate induced convulsions: temporary alteration in blood-brain barrier permeability to plasma proteins. Environ Physiol Biochem 5: 389-395, 1975.

**122. Skultaetyovaa, I., Tokarev, D., Jezovaa, D. Stress-induced increase in blood-brain barrier permeability in control and monosodium glutamate-treated rats. Brain Research Bulletin 45(2):175-8, 1998.

**123. Price MT, Olney JW, Lowry OH, Buchsbaum S. Uptake of exogenous glutamate and aspartate by circumventricular organs but not other regions of brain. J. Neurochem. 36:1774-1780,1981.

**124. Broadwell RD, Sofroniew MV. Serum proteins bypass the blood-brain fluid barriers for extracellular entry to the central nervous system. Exp Neurol. 120:245-263,1993.

**125. Blaylock, RL. Excitotoxins: The Taste That Kills. Santa Fe, NM: Health Press; 1994.

The reader should note that most of the neuroendocrine studies cited here are from1980 or before. By 1980, the consensus that processed free glutamic acid causes brain lesions and neuroendocrine disorders was so clear that there was little need to repeat the phenomenon.(126-130) Therefore, from 1980 to the present time, studies of the effects of processed free glutamic acid on neuroendocrine function were undertaken primarily to answer questions having to do with function, histology, or histopathology of parts of the endocrine system. The following is an example taken from a 1995-2001 Medline search:
Miskowiak, B; Partyka, M. Neonatal treatment with monosodium glutamate (MSG):structure of the TSH-immunoreactive pituitary cells. Histology and Histopathology. 15(2):415-9, 2000.
Indeed, since the 1980s, processed free glutamic acid has been used as an ablative tool to selectively kill brain cells to facilitate study of, and develop drugs for, endocrine dysfunction, neurodegenerative disease, and other disorders involving the brain.(131) The following are examples taken from a 1995-2001 Medline search:
Ishikawa, K, Kubo, T, Shibanoki, S, Matsumoto, A, Hata, H, Asai, S. Hippocampal degeneration inducing impairment of learning in rats: model of dementia? Behavioural Brain Research 83(1-2):39-44, 1997.

Arletti, R, Benelli, A, Mazzaferro, M, Calza, L. The effect of oxytocin on feeding, drinking, and make copulatory behavior is not diminished by neonatal monosodium glutamate. Hormones & Behavior. 4:499-510, 1993.

Herrmann, G., Steunitz, H., Nitsch, C. Composition of ibotenic acid-induced calcifications in rat substantia nigra. Brain Research 786:(1-2)205-14, 1998.

V. Chemical residue in and on food crops

The exemptions for the requirement of a tolerance for residues of the biochemicals "glutamic acid" and "GABA" in or on all food commodities (1998), and on all food commodities (2001), were based, in part, on acceptance of the applicant's claim that any small amount of residue from the use of AuxiGro will wash off or will otherwise have dissipated prior to use of the food. But the applicant failed to tell the EPA the whole story. There are six issues.

First, there is no evidence that surface residue from processed free glutamic acid will be gone prior to harvesting crops on which processed free glutamic acid was used.

Second, the applicant failed to note that label directions for use of AuxiGro recommend that it be used with a surfactant -- a chemical that will encourage the AuxiGro (and the processed free glutamic acid in it) to stick to the plant.

Third, the applicant failed to note that there would be chemical residue in food crops, as well as on food crops treated with processed free glutamic acid.

Fourth, human adverse reactions to ingestion of as little as 1.5 g and .5 g of processed free glutamic acid have been reported in the literature. (19,132) The Truth in Labeling Campaign has received reports of adverse reactions to the minute amounts of processed free glutamic acid that would be contained in products such as vitamins, vitamin and mineral enrichments, gelatin capsules, and produce treated with fertilizers that contain processed free glutamic acid. A number of those reports are on file with the FDA and the EPA. The Federation of American Societies for Experimental Biology (FASEB) concluded in a 1992 report on the safety of amino acids in dietary supplements that there is insufficient evidence to determine safe concentrations of dietary supplements of L-glutamic acid in the diets of normal healthy humans. Furthermore, no study of the least amount of processed free glutamic acid needed to trigger reactions in MSG-sensitive people has ever been done. Thus, while there are data to suggest that as little as .5g of processed free glutamic acid will trigger an adverse reaction, and there are anecdotal reports that reactions are triggered by much lesser amounts, there are no data to even suggest what the least amount of processed free glutamic acid needed to cause an adverse reaction in an MSG-sensitive person might be.

Fifth, it is common knowledge that minute amounts of certain allergens will trigger adverse reactions, including anaphylaxis, in people who are acutely sensitive to those allergens.(133-135) Food and drug-related reactions mimicking allergic reactions without specific sensitization of the immune system are also well known.(135a) For some years, the FDA has been encouraging manufacturers to declare allergenic substances on food labels.(135b) There is nothing in the literature that says that minute amounts of neurotoxic amino acids such as glutamic acid, aspartic acid, and L-cysteine will not trigger adverse reactions, including anaphylaxis, in people who are acutely sensitive to those neurotoxins.

Sixth, the Truth in Labeling Campaign received reports of MSG-reactions experienced following ingestion of unprocessed head lettuce, broccoli, and russet potatoes -- reports received in 1998 before any of those people or anyone at the Truth in Labeling Campaign was aware that processed free glutamic acid was being applied to crops.

The applicant failed to note the material fact that if AuxiGro is to be effective as a plant growth enhancer, the chemicals in AuxiGro (including the processed free glutamic acid -- and all of its contaminants) would have to be taken up by the plant, not simply left on the plant's surface.

While at least mentioning residues on crops (all be it without providing data relevant to the subject), the applicant chose to ignore the potential for toxic effects of chemical residues of processed free glutamic acid, GABA, and the inert materials in AuxiGro, in food crops.

The applicant failed to note the material fact that if the applicant is successful in its petitions/applications, and is successful in subsequent petitions/applications to have AuxiGro approved for use on all food crops, all food crops would potentially be treated with processed free glutamic acid; and all food would potentially contain processed free glutamic acid residues -- both on the surface of the food and incorporated in it.

Germane to the issue of chemical residue in and on food crops is the question of the speed with which AuxiGro and its components will degrade in the environment. In the Final Rule, it was noted that waivers were accepted based on "lack of persistence in the environment;" but no evidence in support of the claim of lack of persistence in the environment was given.
VI. Toxicological profile

The primary strategy found in most, if not all, glutamate-industry-sponsored research is to look for evidence of toxicity in subjects least likely to be sensitive to processed free glutamic acid; to use test materials least likely to produce observable reactions; to use placebos laced with neurotoxic amino acids and/or other substances that will cause identical or similar reactions to those caused by processed free glutamic acid test material; to serve "drinks," or a "standard breakfast" laced with neurotoxins with both test material and "placebo" material; to set up protocols that will obscure evidence of toxicity; to allege that finding no evidence of toxicity constitutes proof that their product is "safe;" and to allege that adverse reactions to their reactive "placebos" constitute evidence that reactions to the test material are not reactions to processed free glutamic acid.

Strong, in a study entitled "Why do some dietary migraine patients claim they get headaches from placebos?" tested the hypothesis that it was the gelatin capsules used to conceal placebo material that caused headaches from placebos, and concluded that capsules may give headaches to dietary migraine patients that are similar to those from foods.(136)  This, Strong said, would explain some of the headaches of patients from placebos.

In a previous study, Strong had found that 18% of his subjects reported headaches from placebos which were all concealed in gelatin capsules. Glutamate-industry double-blind studies of the "safety" of processed free glutamic acid almost always use gelatin capsules. Of interest is the fact that a gelatin capsule is over 11% processed free glutamic acid (MSG).

Another hallmark of glutamate-industry-sponsored research is to extrapolate from a single industry-sponsored study (which may or may not be relevant to the issue at hand) and draw conclusions about the state of the world.

We have observed that under Toxicological Profile in the Final Rule:

It is claimed that "glutamate [was] administered to numerous species in long term dietary studies without adverse effects"
-- but we know those studies to be seriously flawed (see Section XIII-B). Moreover, in a 1976 article, Olney reported that glutamate-induced lesions have been demonstrated in the [central nervous system] of immature mice, rats, rabbits, guinea pigs, chicks, and rhesus monkeys. According to Olney, "The primary form of cellular pathology induced by glutamic acid following either oral or subcutaneous administration is acute neuronal necrosis."(137)
It is claimed that "humans have the capacity to rapidly metabolize ingested glutamate..."
-- but we know that only the fate of glutamate that is bound in protein when it is ingested has been studied. There is nothing in the literature that speaks to what happens to processed free glutamic acid following ingestion, i.e., to glutamic acid that has been freed from protein prior to ingestion.
The third paragraph of Section III: Toxicological Profile, from the 1998 Final Rule, illustrates the deceptive practices used by the defenders of the safety of processed free glutamic acid (MSG) in promoting their product as being "safe."  That paragraph reads, in part:
"Humans have the capacity to rapidly metabolize ingested glutamate (the expected exposure route) to keep plasma glutamate levels constant: no adverse effects on neurological or hepatic function were observed in humans administered levels up to 137 g daily for 14-41 days..."
What's deceptive?
1) We have already noted that there are no studies of metabolism of glutamic acid ingested as free glutamic acid, which is the subject of the 1998 Final Rule and the subject of this Objection.  Whether or not humans have the capacity to rapidly metabolize glutamic acid that is bound in protein when ingested is irrelevant to an understanding of the toxic potential of processed free glutamic acid (MSG).

2) We have already noted that Martinez et al.(28) found a relationship between glutamate levels and migraine headache; but that it was glutamate levels found in the CSF of the central nervous system, not glutamate levels in the plasma, that were elevated during migraine headache. Martinez et al. illustrated the fact that MSG-induced adverse reactions such as migraine headache can occur when plasma glutamate levels are constant.

3) The study in which "no adverse effects on neurological or hepatic function were observed in humans administered levels up to 137 g daily for 14-41 days..." was done by Bazzano et al. and published in Science in 1970.(137a)  They used a handful of subjects, none of whom was sensitive to processed free glutamic acid (MSG); fed them a diet that contained glutamic acid -- but we don't know if it was bound in protein or in free form; and when "looking for" reactions to processed free glutamic acid (MSG), ignored 95% of the common reactions. Relevant to the Bazzano et al. study:

The "humans" were hand picked, not randomly selected from some population.

The "humans" were 14 adult males who were not sensitive to processed free glutamic acid (MSG).

In the Science article, the reader is told that the humans were administered "a chemically defined diet."  Whether the "chemically defined diet" was a diet of protein (which, under no circumstances, would cause MSG- adverse reactions in subjects) or a diet of individual amino acids (which, if it included processed free glutamic acid, would cause reactions in MSG-sensitive people if it exceeded their tolerance levels) is not noted.

In the Final Rule, the reader is told that there were "no adverse effects on neurological or hepatic function," but "adverse effects," "neurological function," and "hepatic function" are not defined.

In the Science article, the reader is also told that no subjects developed the Chinese restaurant syndrome (i.e., tingling, tightness, and numbness all occurring at the same time from 20 minutes to 2 hours after ingestion of the "monosodium glutamate").

If subjects experienced migraine headaches, asthma, skin rashes, depression, seizures, hear irregularities, nausea and vomiting, or any of the other adverse reactions know to be caused by "monosodium glutamate" and other forms of processed free glutamic acid following ingestion of the "monosodium glutamate" test material, their reactions would not have been counted as reactions to the "monosodium glutamate."

It is claimed that the blood brain barrier protects the brain from large infusions of glutamate, and in some cases, that will be true. But the blood brain barrier is easily damaged by fever, stroke, trauma to the head, seizures, ingestion of processed free glutamic acid, and the normal process of aging. In the very young, the blood brain barrier is not fully formed, maturing as late as puberty. And in the area of the five circumventricular organs, the blood brain barrier is leaky at best at any stage of life. Much of endocrine function is controlled by the hypothalamus which lies in the area of the circumventricular organs. Damage to the hypothalamus in the form of brain lesions caused when young animals are exposed to processed free glutamic acid causes neuroendocrine disorders later in life. (See Section IV.)

It is claimed that the placental barrier protects the developing fetus. In fact, however, the literature (not mentioned by the applicant) demonstrates that free glutamic acid (including processed free glutamic acid) can cross the placenta during pregnancy. (See Section IV.)
It is claimed that the glutamic acid which is the subject of the Final Rules is ubiquitous in nature. That is not true. (See Section I.)

It is claimed that glutamic acid has a long history of food uses which it does not have. (See Section II.)

It is claimed that "glutamic acid" has a favorable toxicological profile in chronic toxicology studies. However, we know that the industry-sponsored studies considered by the EPA were seriously flawed; and studies done by independent scientists wherein processed free glutamic acid was found to cause brain lesions, neuroendocrine disorders, and more, were not considered. (See Sections IV and XIII.)   We also know that in the sixth edition of N. Irving Sax's Dangerous Properties of Industrial Materials "monosodium glutamate"and "L-glutamic acid" were given hazard ratings of HR 3 (most toxic), indicating an LD 50 below 400 mg/kg.(138)

It is claimed that "glutamic acid" will have inconsequential exposure. In fact, however, exposure according to a real world model was not evaluated. (See Section XIII-B)

It is claimed that the "glutamic acid" which is the subject of the Final Rules occurs naturally in the environment. The subject of the Final Rules is processed free glutamic acid.  Processed free glutamic acid does not occur naturally in the environment.  It is produced in chemical plants -- sometimes "food-chemical" plants.

It is claimed that the "glutamic acid" which is the subject of the Final Rules lacks persistence in the environment. In fact, however, no evidence to that effect was presented in support of the application.

It is claimed that the "glutamic acid" which is the subject of the Final Rules occurs naturally in plants. That is not true. (See Section I.)

VIIa. Aggregate exposure - dietary exposure

Over the years, glutamate-industry public relations people have alleged that compared to the amount of "naturally occurring" glutamic acid available in food, the amounts of glutamic acid in their "monosodium glutamate" or other products would be negligible, and that the addition of such relatively small amounts of glutamic acid to such relatively large amounts of glutamic acid already present, could not possibly cause adverse reactions.

This argument assumes that the glutamic acid in "monosodium glutamate" or other processed foods is chemically identical to the L-glutamic acid found in unadulterated/unprocessed/ unfermented food -- but we have already demonstrated that such is not the case. (See Section I.) Once one recognizes that there is processed free glutamic acid in "monosodium glutamate" and in AuxiGro, and that there is no processed free glutamic acid in unadulterated/ unprocessed/unfermented meat or produce that has not been treated with fertilizers, fungicides, pesticides, or plant growth enhancers, the glutamate industry argument becomes transparently false.

There are variations of this industry-inspired argument. Glutamate-industry public relations people claim that a variety of products (tomatoes, mushroom, and Parmesan cheese are among their favorites) contain substantial amounts of free glutamic acid; and that if people were truly sensitive to "monosodium glutamate" or other products that contain free glutamic acid, they could not eat tomatoes, mushrooms, or Parmesan cheese without having adverse reactions.

But here, again, glutamate-industry public relations people have failed to distinguish between free glutamic acid and processed free glutamic acid. If, indeed, there are any minute amounts of free glutamic acid associated with unadulterated/unprocessed/unfermented tomatoes or mushrooms, that free glutamic acid will not cause adverse reactions.N Only processed free glutamic acid causes adverse reactions in MSG-sensitive people who ingest amounts that exceed their tolerance levels.

Glutamate-industry public relations people have also failed to distinguish between produce that is truly unadulterated/unprocessed/unfermented (as tomatoes or mushrooms might be) and processed ingredients/products such as Parmesan cheese. The amount of processed free glutamic acid found in a given Parmesan cheese will vary depending on such things as the milk or cream used, the nature of the enzymes used to break down the protein in the milk or cream used, and the length of time the enzymes are working; but Parmesan cheese will always contain processed free glutamic acid, and will cause adverse reactions in MSG-sensitive people who ingest amounts that exceed their tolerance levels.

Another glutamate-industry-inspired argument centers around dietary exposure. This is one of the arguments for the safety of processed free glutamic acid found in the Final Rules. Here, again, glutamate-industry public relations people fail to make the distinction between dietary exposure to glutamic acid bound in protein and dietary exposure to processed free glutamic acid. For example, the 1998 Final Rule reads, in part, "Many items in the human daily diet contain appreciable quantities of free glutamic acid. For example, ripe tomatoes, mushrooms, peas, corn, potatoes, squash, cheese, eggs, poultry, and meat provide from 20 to 150 mg of glutamic acid per 100 gram serving."

Failing to distinguish between dietary exposure to glutamic acid bound in protein (which is ubiquitous in nature) and processed free glutamic acid (which is not ubiquitous in nature) is not the only flaw in the industry's argument. Possibly the greatest flaw lies in claiming that the amount of glutamic acid bound in protein is relevant to the issue of sensitivity to processed free glutamic acid. In truth, it really doesn't matter to an MSG-sensitive person if there is a lot of bound glutamic acid available because it won't cause an adverse reaction. Similarly flawed is the argument that the amount of processed free glutamic acid available in the market place is relevant to the issue of sensitivity to processed free glutamic acid. It really doesn't matter to an MSG-sensitive person if there is a lot of processed free glutamic acid available in the market place, if the MSG-sensitive person doesn't eat it. The fact that there is processed free glutamic acid readily available in the market place does not mean that an MSG-sensitive person -- or any other particular person, for that matter -- necessarily eats it.

VIIb. Aggregate exposure - non-dietary exposure

Historically, we have observed that when glutamate industry public relations people have no data to manipulate, they simply make assumptions and pass them along as truths. It would appear that in their application to the EPA, the applicant did the same. In the Final Rule, the EPA uses phrases like:

Exposure is "expected to be minimal;"

"...use is not likely to result in potential chronic exposure...;" and

Exposure "is also anticipated to be negligible..."

VIII. Cumulative effects

In the Final Rule, we are told that "glutamic acid has a very low toxicity to humans." As we have already demonstrated in Sections I, II, IV, V, and VI, that simply is not true. But it is on that false premise, and without knowing what least amount of processed free glutamic acid is needed to cause brain damage, retinal degeneration, endocrine disorders, and other adverse reactions and disease conditions caused by processed free glutamic acid, that the EPA claims that "...there is no reason to expect any cumulative effects from glutamic acid and other substances."

IX. Endocrine disruptors

In the 1998 Final Rule, we are told that "The Agency has no information to suggest that glutamic acid will adversely affect the immune or endocrine systems." This writer can not speak to what information the EPA does or does not have. However, it is well documented in the literature, and has already been demonstrated here, that glutamic acid is an endocrine disruptor. (See Sections II. and IV.)

In the June 21, 2001 Final Rule, which is the subject of this Objection, the effects of processed free glutamic acid on the endocrine system are not even mentioned.

X. Safety determination for U.S. population, infants and children

The EPA has concluded that there is reasonable certainty that no harm will result from aggregate exposure to the U.S. population, including infants and children, to residues of glutamic acid. The EPA arrived at this conclusion because, they allege, "the toxicity of glutamic acid to mammals is very low." As we have already demonstrated, that simply is not true. (Sections I., II., IV., V., and VI.)

Not withstanding the volume of literature that demonstrates that glutamic acid causes brain lesions and subsequent endocrine disorders (Section IV) and the fact that in the sixth edition of N. Irving Sax's Dangerous Properties of Industrial Materials "monosodium glutamate"and "L-glutamic acid" were given hazard ratings of HR 3 (most toxic), indicating an LD 50 below 400 mg/kg,(138) the EPA has concluded that "the Agency believes there is reliable data to support the conclusion that "glutamic acid" is practically non-toxic to mammals, including infants and children..."

XI. Miscellaneous omissions, errors, inaccuracies, distortions, methodological flaws, and literally false statements

In addition to omissions, errors, inaccuracies, distortions and literally false statements pertaining to a description of the chemical referred to as "glutamic acid" or "L-glutamic acid;" history of its use in food; the toxic and endocrine disrupting properties of processed free glutamic acid; and chemical residues; there are a whole spate of miscellaneous omissions, errors, inaccuracies, distortions, methodological flaws, and literally false statements contained in the EPA's RED and Final Rules.

-- In review of the EPA's RED and Final Rules, we found that the applicant failed to cite the sixth edition of N. Irving Sax's Dangerous Properties of Industrial Materials wherein both "monosodium glutamate"and "L-glutamic acid" are given hazard ratings of HR 3 (most toxic), indicating an LD 50 below 400 mg/kg. Although not mentioned in the texts of the RED or Final Rules, the applicant makes reference to the US Department of Health and Human Services Registry of Toxic Effects of Chemical Substances in the bibliography of the RED. It is inconceivable, therefore, that the applicant (or whomever suggested that the applicant include, but not refer to that reference) was not aware of the hazard rating.

-- Among the omitted studies that demonstrate that processed free glutamic acid, whether laboratory grade or found in "monosodium glutamate," causes retinal degeneration, brain lesions, and neuroendocrine disorders (Section III), are studies that refute the industry-sponsored studies that the applicant submitted alleging that the submitted studies demonstrate that processed free glutamic acid does not place humans at risk

-- We have noted above (Section III), that the literature is clear in its consensus that free glutamic acid (including the processed free glutamic acid that is the subject of this Objection) causes endocrine disturbances as infant animals exposed to the chemical approach puberty. In review of the EPA's RED and Final Rules, however, we found that the applicant not only failed to acknowledge the fact that processed free glutamic acid is an endocrine disruptor, but that the EPA, in the 1998 Final Rule, had the audacity to state that "The Agency has no information to suggest that glutamic acid will adversely affect the immune or endocrine systems;" and in the 2001 Final Rule, which is the subject of this Objection, the EPA had the gall to ignore the subject of endocrine disruptors, entirely.

-- In review of the EPA's RED and Final Rules, we found that reports of adverse reactions in test subjects in studies of acute mammalian toxicity conducted by the applicant were glossed over and dismissed.

-- The RED is not a tightly written document. Along with the omissions, errors, inaccuracies, distortions, methodological flaws, and literally false statements are a number of "sloppinesses" that might cause the casual reader to think more positively about the safety of AuxiGro and its component amino acids than warranted. For example:

Table 3 is entitled "The Acute, subchronic and chronic mammalian toxicity studies for L-glutamic Acid and GABA reported in public literature." In that table, there are citations to seven human studies; but an analysis of the references listed preceding Table 3 revealed that no listed toxicity study cited included human subjects.

There are 11 citations given preceding Table 3 that purport to be citations to acute, subchronic and chronic mammalian toxicity for L-glutamic acid and GABA reported in public literature. Of those, only 8 are actually studies of acute, subchronic and chronic mammalian toxicity, and none are studies of acute, subchronic and chronic mammalian toxicity for GABA.

There is no discussion of acute, subchronic and chronic mammalian toxicity for "L- glutamic acid" and GABA in the text of the RED. There are citations to11 studies, and there are two tables presented; but although it states preceding Table 3 that the citations are to studies that are summarized in Tables 3 and 4, there is no information about how the citations and the tables are related -- if they are related.

The bibliography of the RED contains citations to two studies by Olney et al. which clearly demonstrate that processed free glutamic acid causes brain lesions, obesity, and other disturbances in mice; and brain damage in infant primates.  The citations in the bibliography are as follows:

44296414 -- Olney, J.W. (19??) Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. Science 164:719-721.(12)

44296417 -- Olney, J.W., Sharpe, L., Feigin, R. (19??) Glutamate-induced brain damage in infant primates. J. Neuropathol. Exp Neurol. 31:464-488.(63)

Yet no mention of these data is made in the text of the RED.

The bibliography of the RED contains a citation to summary toxicity data,(N3) yet no mention of these data or of toxicity data from Dangerous Properties of Industrial Materials or Hazardous Chemicals Desk Reference (wherein each of the chemicals identified in the Registry of Toxic Effects of Chemical Substances [RTECS] is listed, and a Hazard Rating is assigned) is made in the text of the RED. In the 1984 edition of Dangerous Properties of Industrial Materials, L-glutamic acid and L-sodium glutamate were given Hazard Ratings of HR 3, the rating for "high" (as opposed to "none," "low," or "medium") toxicity.

XII. Waivers

In review of the EPA's RED and Final Rules, we found that waivers granted to the applicant were, in large measure, unwarranted.

According to the 1998 Final Rule, waivers were granted for acute toxicity, genotoxicity, reproductive and developmental toxicity, subchronic toxicity, chronic toxicity, and acute toxicity to nontarget species based on glutamic acid's ubiquity in nature, long history of food uses, favorable toxicological profile in chronic toxicology studies, and inconsequential exposure resulting from label-directed use rates. We have already noted that the "glutamic acid" used in AuxiGro, processed free glutamic acid, is not ubiquitous in nature; does not have a long history of food uses; and does not have a favorable toxicological profile in chronic toxicology studies. Moreover, no attempt was made to quantify the exposure that would result from residues of processed free glutamic acid in and on all food crops; or to evaluate the persistence of processed free glutamic acid in the soil to which it would have been applied, and to quantify its effects.

Waivers were also granted for acute avian oral toxicity, nontarget plants, avian dietary, and nontarget insects. They were accepted based on:

(a) low acute toxicity in mammalian species,
(b) natural occurrence and lack of persistence in the environment, and
(c) natural occurrence in plants and ability to promote growth of numerous plant species.
We have already noted, however, that free glutamic acid, including processed free glutamic acid, causes retinal degeneration, brain lesions, and endocrine disorders in laboratory animals; is a manufactured product that does not occur naturally in the environment; and does not occur naturally in plants. Furthermore, the degree to which various forms of processed free glutamic acid and their components persist in the environment has not been evaluated.

According to the RED, metabolism studies were not required based on prevalence in nature and in food, no known effects for dietary exposure, GRAS status, and data available from the public literature. We have already noted, however, that processed free glutamic acid is not prevalent in nature; is not prevalent in unadulterated, unprocessed food; is known to cause adverse reactions in MSG-sensitive people; is known to cause brain lesions, behavior disorders, learning disorders, retinal degeneration, and neuroendocrine disorders such as obesity. As for its GRAS status, the flavor enhancer called "monosodium glutamate" was grandfathered, not tested for safety, when the GRAS list was first established in the 1950s.

But wait a minute.  According to the RED, metabolism studies were not required based on prevalence in nature and in food, no known effects for dietary exposure, GRAS status, and data available from the public literature pertaining to L-glutamic acid.  But isn't it the food ingredient "monosodium glutamate," rather than what the EPA refers to as "L-glutamic acid" that has GRAS status?  Actually, if I recall correctly, "monosodium glutamate" was grandfathered, not tested for safety, when the GRAS list was first established in the 1950s, so it doesn't technically have GRAS status.  But the defenders of the safety of processed free glutamic acid still talk about "monosodium glutamate" being GRAS.

But that's not the point.  This is the point:

The subject of the RED, the Final Rules, and this Objection, is referred to by the EPA as "L-glutamic acid."

The EPA maintains that the "L-glutamic acid" which is the subject of this Objection, is not the same as the glutamic acid found in "monosodium glutamate." (The EPA has acknowledged, elsewhere, that some people experience adverse reactions when they ingest the flavor enhancer called "monosodium glutamate."  Evidently, it wouldn't do to admit that the "L-glutamic acid" which is the subject of this Objection, might cause adverse reactions, too.)

Yet the EPA waives the requirement for metabolism studies of  "L-glutamic acid" because "monosodium glutamate" has GRAS status.

That's right. On the one hand, the EPA waives the requirement for metabolism studies of  "L-glutamic acid" because "monosodium glutamate" has GRAS status.  And on the other hand, the EPA  protests that the glutamic acid in the "L-glutamic acid" that has been granted an exemption from the requirement of a tolerance is not identical to the glutamic acid in "monosodium glutamate."

According to the RED, the Agency did not require information on the endocrine effects of glutamic acid. According to that document, "the BPPD has considered, among other relevant factors, available information concerning whether this biochemical compound may have an effect in humans similar to an effect produced by a naturally occurring estrogen or any other endocrine effects. The physiologic roles of L-Glutamic acid and GABA in humans are well established." We have already noted, however, that what the EPA called "available information" did not include information from the peer reviewed published literature about the endocrine disrupting roles of processed free glutamic acid; and that the published literature clearly indicates that processed free glutamic acid causes neuroendocrine disorders affecting growth, reproduction, and gross obesity.

We have also noted that while the physiological role of true L-glutamic acid in humans may be well established, the role of processed free glutamic acid, which is the chemical referred to as "glutamic acid" or "L-glutamic acid" in the exemption being challenged, has not been studied.

XIIIa. Methodological flaws - A

Historically, glutamate industry researchers, led by Andrew G. Ebert, Ph.D. of the IGTC and the Robert H. Kellen Company, have focused on research designed to demonstrate that processed free glutamic acid is "safe." Probably their most productive researchers have been L.D. Stegink, Lloyd J. Filer, and W. Ann Reynolds, who together did a number of studies designed to refute the findings of Olney and others of brain lesions and neuroendocrine disorders, and thus quell any concerns the public might have had about the toxic potential of their product, the flavor enhancer called "monosodium glutamate." It can be said of the Stegink/Reynolds/Filer group that they studied Olney's procedures carefully, having sent a representative to Olney's laboratory in the early 1970s where every courtesy was afforded her. It is particularly bothersome, therefore, that subsequent studies coming from the Stegink/Reynolds/Filer laboratory looked for evidence of brain lesions in areas of the brain that would not, according to Olney, have been affected; waited to examine the brain samples taken for 24 hours or more after insult after which time all evidence of lesions would have been obscured; and used inappropriate methods of fixation and staining.(20)

It is often difficult to determine just where the methodological flaws in any one industry- sponsored study lie, because very often adequate detail of methodology is not given. For example, beginning in 1978, if not before, industry-sponsored human double-blind studies of MSG safety (never toxicity) used aspartic acid (in aspartame) and/or processed free glutamic acid (in products other than monosodium glutamate) in placebos; but the contents of the placebos were not elucidated until the late1990s after being challenged by MSG-sensitive people in 1993.

Studies submitted in supported of Auxein Corporation's petitions/applications are not exceptions. Citations to eleven studies (listed below) were submitted to the EPA by Auxein Corporation as acute, subchronic and chronic mammalian toxicity studies for L-glutamic acid reported in the public literature. They were cited in section III (B)(1)(b) of the RED and, so the reader is told, are summarized in Tables 3 and 4 of that document.

The acute, subchronic and chronic mammalian toxicity studies for L-Glutamic Acid and GABA submitted to the EPA as having been reported in public literature are as follows:

MRID No. 44296204 Munro, H. (1979) Factors in the regulation of glutamate metabolism. P. 55-68 In: Glutamic Acid: Advances in Biochemistry and Physiology by L. Filer, Et al., ed. New York, NY: Raven Press.

MRID No. 44296403 Munro, H. (1979) Factors in the regulation of glutamate metabolism. P. 55-68 In: Glutamic Acid: Advances in Biochemistry and Physiology by L. Filer, Et al., ed. New York, NY: Raven Press.

MRID No. 44296406 Committee on Gras List Survey- Phase III (1976) Estimating distribution of daily intake of monosodium glutamate (MSG), Appendix E. P. 1-10 In: Estimating Distribution of Daily Intakes of Certain GRAS Substances. Washington DC: National Academy of Sciences

MRID No. 44296407 Ebert, A. (1970) Chronic toxicity and teratology studies of L- monosodium glutamate and related compounds. Toxicology and applied Pharmacology 17:274.

MRID No. 44296408 Owen, G., Cherry, C., Prentice, D., et al. (1978) The feeding of diets containing up to 4% monosodium glutamate to rats for 2 years. Toxicology Letters 1:221-226.

MRID No. 44296409 Owen, G., Cherry, C., Prentice, D., et al. (1978) The feeding of diets containing up to 10% monosodium glutamate to Beagle dogs for 2 years. Toxicology Letters 1:217-219.

MRID No. 44296410 Semprini, M., D'Amicis, A., Mariani, A. (1973) Effect of monosodium glutamate on fetus and newborn mouse. Nutr. Metab.

MRID No. 44296411 Semprini, M. Conti, L., Ciofi-Luzzatto, A., et al. (1974) Effect of oral administration of monosodium glutamate (MSG) on the hypothalamic arcuate region of rat and mouse: A histological assay. Biomedicine 21: 398-403.

MRID No. 44296412 Wen, C., Kenneth, C., Gershoff, S. (1973) Effects of dietary supplementation of MSG on infant monkeys, weanling rats and suckling mice. The American Journal of Clinical Nutrition 26: 803-813.

MRID No. 44296418 Newman, A., Heywood, R., Reynolds, A., et al. (1973) The administration of monosodium-L-glutamate to neonatal and pregnant rhesus monkeys. Toxicology 1:197-204.

MRID No. 44296419 Stegink, L., Pitkin, R., Reynolds, A, et al. (1974) Placental transfer of glutamate and its metabolites in the primate. Am J. Obstet. Genecol. 122:70-78.

Two of the 11 citations (MRID No. 44296204 and MRID No. 44296403) are to a single review of studies of metabolism and are actually irrelevant. According to, Munro, the author of that review, "The purpose of [the] review is to analyze the metabolism of glutamic acid in order to identify some of the mechanisms regulating its abundance in the free amino acid pools of the body."

A third citation (MRID No. 44296406) is to a survey entitled "Estimating distribution of daily intake of monosodium glutamate (MSG)." It is also irrelevant.

Each of the eight remaining studies contains serious methodological flaws. For example:

The industry-sponsored feeding studies accounted for the amount of food consumed by experimental and control groups, but did not account for the amount of processed free glutamic acid consumed as opposed to being left on the table. According to the methodology sections that covered the subject, processed free glutamic acid was added to each test animal's diet. Most studies outlined, in great detail, the amount of food given to test and control animals, the name (but not the components) of the basic diet (which might very well have contained processed free glutamic acid or some other neurotoxic amino acid like aspartic acid or l-cysteine), and the amount of processed free glutamic acid added to the diets of each animal or test group. One industry-sponsored study (not mentioned by the EPA, but submitted to the California Department of Pesticide Regulation) provided an unusual amount of detail, including detail of the exact nature of the basal diet provided wherein "yeast food" was listed as a component of the protein.(139)  In 1990, yeast food invariably contained either protease (which creates processed free glutamic acid during manufacture) or L-cysteine which produces neurotoxic effects(140) somewhat different from, but more extensive than, the effects of processed free glutamic acid. In that study, as well as in the industry-sponsored studies from the literature submitted by Auxein Corporation to the EPA, failure to find differences in growth or adverse reactions of control and experimental groups may very well have been due, in part, to the fact that control groups were receiving neurotoxic substances in their basal diets.

In the studies submitted by the applicant to the EPA, detail pertaining to the amount of food consumed was also given. But sorely lacking was any discussion of the amount of processed free glutamic acid consumed by animals in various test groups. The casual reader may assume that processed free glutamic acid would be ingested in proportion to the amount of basic diet ingested by test animals. But that is not true. Every animal owner knows that animals are quite adept at ferreting out and rejecting (not eating) pills or other goodies "hidden" in their food, and in avoiding food in which they have no interest. Thus, the processed free glutamic acid could have been left on the table by the test animals, causing there to be no difference in reactions expressed by test and control animals. This writer suspects that had this not been the case, both the form of the processed free glutamic acid added to each animals's diet and the consumption of processed free glutamic acid would have been discussed.

Although not discussed in the RED, there are other industry-sponsored studies wherein animals were treated once with processed free glutamic acid and sacrificed so the brains of those animals could be examined. In those studies, it was the practice of industry-sponsored researchers to look for lesions in areas of the brain that would not have been affected; look for lesions after lost neurons would have been replaced by glial cells (obscuring the fact that neurons had been killed);N and use inappropriate methods of fixation and staining.

It should be no surprise, therefore, that in studies of toxicity presented to the EPA by the applicant, where repeated doses of processed free glutamic acid were given daily to a variety of animals over an extended period of time, lesions, although they may have been present, would not have been observed. Why? Because every lesion produced more than 24 hours before the animal was sacrificed would have been filled in with glial cells and, in the 1970s, given the technology of the day, would not have been observable. Thus, if 10 brain cells were killed every day for 400 days, all evidence of lesions would have been obscured except for the lesion left when the 10 brain cells were killed less than 24 hours before the animal was sacrificed and the brain examined. While 4,000 brain cells would have been killed over the course of 400 days, the loss of the first 3,990 brain cells would not have been obvious. Only the last lesion of 10 cells would have been observable if there had been instruments in the 1970s strong enough to detect 10 missing brain cells, and if both the methods used for fixation and staining and the instruments used had been used appropriately.

All of the acute, subchronic and chronic mammalian toxicity studies for L-glutamic submitted to the EPA as having been reported in public literature were funded by the glutamate industry in the 1970s. By 1980, those studies done by glutamate-industry funded researchers in the 1970s that alleged to demonstrate that the food additive "monosodium glutamate" (and its reactive component, processed free glutamic acid) failed to cause brain lesions in laboratory animals had been refuted. Today, the neurotoxic effects of processed free glutamic acid are so clear cut that scientists use processed free glutamic acid as an ablative tool to selectively kill brain cells in order to study brain function and the effects of drugs on brain function.(141)

Glutamate-industry sponsored researchers never actually replicated of the work of Olney and others who had demonstrated that processed free glutamic acid causes brain lesions and subsequent neuroendocrine disorders in laboratory animals.(141a)  In a 1980 review of the literature, Nemeroff stated unequivocally that "...not one single [primate] study has truly replicated the methods utilized by Olney, making evaluation of the available data impossible."

XIIIb. Methodological flaws - B

It has been noted previously that some of the studies submitted by Emerald BioAgriculture in support of their petitions for an exemption from the requirement of a tolerance for the "L-glutamic acid," addressed only the issue of the safety of the "L-glutamic acid" used in AuxiGro, and failed to address the issue of the safety of the "L-glutamic acid" in general.  Those studies, like other studies submitted by Emerald BioAgriculture to the EPA, were seriously flawed.

In support of their application, Auxein Corporation did a number of acute exposure studies wherein subjects were treated once with AuxiGro and then observed for a number of hours or days. According to the RED, "No premature mortality or treatment-related toxic endpoints were identified from acute exposure to AuxiGro WP." It may well be true that no premature mortality or treatment-related toxic endpoints were identified from what Auxein referred to as acute exposure to AuxiGro; but any conclusion that exposure to AuxiGro under real-world conditions would not cause toxic reactions is unwarranted.

Why unwarranted? First, because in the test situation, animals' exposure to the potentially toxic substance, AuxiGro, was limited to a single application/treatment applied directly to each animal; and no attempt was made to mimic the real life situation wherein animals could be sprayed or otherwise come into initial contact with AuxiGro and then remain in the treated area where each animal would potentially have continuous exposure to AuxiGro-treated surfaces (with which the animals would come in contact) and would potentially ingest vegetation and drink water that had been treated with AuxiGro. Second, because in the test situation animals were treated only once with AuxiGro; while in real life, AuxiGro would be applied at least twice during the growing cycles of each crop. Third, because in a real life situation, the animals' test sites would not have been covered with surgical gauze secured with non-irritating tape so the animal could not ingest any of the toxic substance that had been applied to it; and the residual test article would not have been removed by gentle washing after 4 hours or 24 hours. Fourth, because there was no evaluation of brain damage given in the RED or the Final Rule.

Finally, despite the fact that protocols used would have minimized the toxic effects of AuxiGro, there were reports of toxic reactions:

Rats treated by inhalation (4 hours; 2.58 mg/L) developed piloerection, decreased activity, and a red crust around the nose within 6 hours that was resolved by day 4.

Rats treated orally with 5050 mg/kg had piloerection, discolored fur, and diarrhea that was resolved by day 5.

Rabbits treated dermally with 5050 mg/kg AuxiGro had slight erythema at the application site on the day of treatment and no other clinical toxicity.

In the primary dermal irritation study in rabbits, application of 0.5 g AuxiGro for 4 hours induced very slight erythema on one male and one female within an hour of treatment; it was resolved by 24 hours.

No dermal sensitization was observed in guinea pigs induced and challenged with 400 mg AuxiGro.

Eye irritation (corneal and conjunctival effects) occurred in rabbits eyes within 1 hour of instillation with 40.38 mg AuxiGro; these were resolved by 48 hours.

Would those evidences of toxicity have proliferated if the animals had lived in the AuxiGro- treated environment? This writer would guess they would; but we don't know. There are no data.

Would those evidences of toxicity have recurred in a more virulent form when AuxiGro was sprayed a second time? This writer would guess they would; but we don't know. There are no data.
 
 

SUMMARY AND CONCLUSION

The EPA has alleged that data requirements for granting the chemical referred to as "L-Glutamic Acid" an exemption from the requirement of a tolerance have been fulfilled. Furthermore, on June 21, 2001, the EPA issued a Final Rule granting "L-Glutamic Acid" an exemption from the requirement of a tolerance.

However, analysis of the Registration Eligibility Decision (RED), the June 21, 2001 Final Rule which is the subject of this Objection, the January 7, 1998 Final Rule referenced in the June 21, 2001 Final Rule, and omitted material which speaks to the toxicity of processed free glutamic acid (referred to by the EPA as "glutamic acid" or "L-glutamic acid"), has made it abundantly clear that data presented to the EPA in support of the Auxein Corporation petitions were incomplete, often unreliable, and/or lacking in relevance/validity.

In this paper, we have demonstrated that the data sent to the EPA by Auxein Corporation (or Emerald BioAgriculture) in support of granting the chemical referred to as "L-glutamic acid" an exemption from the requirement of a tolerance for residues of "L-glutamic acid" on all food commodities when applied/used in accordance with good agricultural practices, lack completeness, validity, and reliability.
In addition, we have demonstrated that those data often addressed the issue of the safety of the "L-glutamic acid" used in AuxiGro, and failed to address the issue of the safety of the "L-glutamic acid" in general.  Because much of the data submitted in support of granting the chemical referred to as "L-glutamic acid" an exemption from the requirement of a tolerance for residues of "L-glutamic acid" only addresses the subject of the safety of the "L-glutamic acid" used in AuxiGro, and no other, those data are irrelevant to the subject of the exemption granted.

Even though data addressing the safety of the "L-glutamic acid" used in AuxiGro are irrelevant, we can not ignore that they also lack completeness, validity, and reliability.  Therefore, in this paper we have discussed those data, along with other data, and have demonstrated that:

1) A great deal of relevant information was omitted from Auxein Corporation's applications. Most obvious, but by no means all inclusive were omissions of:

-- Material from the sixth edition of N. Irving Sax's Dangerous Properties of Industrial Materials wherein "monosodium glutamate"and "L-glutamic acid" were given hazard ratings of HR 3 (most toxic), indicating an LD 50 below 400 mg/kg;

– Data on the amount of processed free glutamic acid that could be ingested daily and yearly by individual adults, children, and animals ingesting fruit, grains, nuts, seeds, weeds, grasses, and vegetables treated with processed free glutamic acid from any and all sources regulated by the EPA;

-- Data on the amount of processed free glutamic acid that would be ingested daily and yearly by individual adults, children, and animals ingesting fruit, grains, nuts, seeds, weeds, grasses, and vegetables treated with AuxiGro;

-- Data describing the least amount of processed free glutamic acid needed to cause brain lesions, and/or to cause or exacerbate neuroendocrine disorders; memory, behavior and learning disorders; debilitating and life-threatening adverse reactions such as asthma, migraine headache, diarrhea and vomiting, depression, seizures, elevated blood pressure, tachycardia, and atrial fibrillation; and the various disease conditions associated with what the National Institutes of Health refers to as the "glutamate cascade."

-- Published studies detailing brain lesions, retinal degeneration, and behavior and learning disorders induced following treatment with processed free glutamic acid;

-- Published studies of the endocrine disrupting effects of processed free glutamic acid;

-- Published studies relevant to the sensitivities of major identifiable subgroups, primarily infants and children, who have been shown to be most at risk from exposure to processed free glutamic acid;

-- Published studies demonstrating that ingested processed free glutamic acid can cross both the blood-brain barrier and the placental barrier;

-- Human studies conducted by the glutamate industry which alleged to have demonstrated that ingestion of processed free glutamic acid does not place consumers at risk. In those studies, subjects suffered adverse reactions to both the test material (which contained processed free glutamic acid in the flavor enhancer "monosodium glutamate"), and the placebos, which contained processed free glutamic acid (in various hydrolyzed protein products) and/or contained glutamic acid's structural analog, aspartic acid (in aspartame).  Those industry-sponsored studies are, in and of themselves, evidence that the neurotoxic amino acids in free form (free glutamic acid and free aspartic acid) cause adverse reactions.

2) Errors, inaccuracies, distortions, and literally false statements permeate the texts of both the EPA's RED and Final Rules. For example we have demonstrated that:
-- The applicant misrepresented the chemical composition of the processed free glutamic acid that was used in AuxiGro that was granted an exemption from the requirement of a tolerance. Auxein Corporation based much of its argument for the safety of its product on the false assertion that the processed free glutamic acid used in AuxiGro (which invariably contains L-glutamic acid plus contaminants) is identical to the L-glutamic acid found in protein and in higher organisms (which is L-glutamic acid, only).

This is an important distinction because the exemption granted for the requirement of a tolerance for residues of "glutamic acid" is, in actuality, an exemption for processed free glutamic acid, not the glutamic acid that is bound with other amino acids in protein. Glutamic acid bound in protein does not cause brain lesions, neuroendocrine disorders, or human adverse reactions. Processed free glutamic acid does.

-- The applicant falsely asserted that the processed free glutamic acid used in AuxiGro has a long history of food uses. Seaweed, from which Ajinomoto Co., Inc. first extracted glutamic acid, has been used in food for thousands of year; but processed free glutamic acid was first extracted from seaweed in Japan in 1908. Ajinomoto's product called "monosodium glutamate" was brought to this country after World War II. The first published reports of adverse reactions and brain lesions following treatment with "monosodium glutamate" appeared in 1968 and 1969, respectively, after Ajinomoto changed its extraction process to a process of bacterial fermentation wherein glutamic acid was excreted through the cell walls of selected bacteria. Epidemiological studies conducted in the 1970s estimated that at least 25 per cent of the population in the United States suffered adverse reactions following ingestion of processed free glutamic acid at that time.

-- Auxein based much of its argument for the safety of its product on what they allege to be the fact that ingested processed free glutamic acid is metabolized quickly and efficiently. Glutamate industry public relations people equate fairly small and/or transient rises in plasma glutamate levels following ingestion of processed free glutamic acid with rapid metabolism of processed free glutamic acid, which they allege to have demonstrated. The defenders of the safety of processed free glutamic acid claim that since processed free glutamic acid clears the plasma quickly and efficiently, there can be no adverse reactions following ingestion of processed free glutamic acid.

The logic, of course, is faulty. We have demonstrated that there are published peer reviewed studies that demonstrate that there are glutamate receptors outside of the central nervous system; and that there are data that demonstrate that excess of neuroexcitatory amino acids such as glutamic acid found outside of the plasma, not in it, possibly favors a state of neuronal hyperexcitability leading to expression of adverse reactions. In addition, we have demonstrated that the studies submitted to the EPA by Auxein were studies of the metabolism of intact protein, not studies of the metabolism of glutamic acid freed from protein by a manufacturing process prior to ingestion. Thus the studies of metabolism submitted to the EPA by Auxein are irrelevant to an assessment of the safety/toxicity of processed free glutamic acid.

-- Auxein alleged that processed free glutamic acid could not cross either the blood-brain barrier or the placental barrier. We have demonstrated that both claims are blatantly untrue.

-- Auxein claimed that any small amount of "L-glutamic acid" residue from the use of AuxiGro will wash off or will otherwise have dissipated prior to use of the food. But the applicant, who presented no data at all on the subject, failed to substantiate that claim, and failed to acknowledge that if effective as a plant growth enhancer, AuxiGro would have to be taken up by the fruit, leaves, stems, tubers, and roots of each plant. No analysis of the uptake of processed free glutamic acid was made in Auxein's analysis of the safety of its product. In fact, the subject of uptake was not even mentioned.

-- We have demonstrated that the applicant further misrepresented the conditions that would accrue following treatment of vegetation with AuxiGro, ignoring the realities of repeated treatment of crop after crop, and the treatment of all produce to be used by animals and man, if Auxein were to be successful in marketing its product. If Auxein were to be successful in marketing its product, all produce would be treated with AuxiGro. No provision for that eventuality was made in Auxein's analysis of the safety of its product.

-- In discussing Toxicological Profile in the Final Rule, the applicant claimed that glutamate was administered to numerous species in long term dietary studies without adverse effects. We have demonstrated that the methodology of the long term studies was inappropriate to the real world conditions under which AuxiGro would be used; and that adverse effects were noted, but were trivialized and dismissed. The applicant also referred to plasma glutamate levels, and studies using subjects who were not sensitive to processed free glutamic acid; and cited protection of the blood-brain barrier and the placental barrier as evidence that their product is safe. We have demonstrated that data on metabolism presented by Auxein, and studies wherein subjects who are not sensitive to processed free glutamic acid are used, are irrelevant to a study of the safety/toxicity of processed free glutamic acid. We have demonstrated that neither the blood-brain barrier nor the placental barrier invariably protects the brain or placenta from invasion of glutamic acid. We have further demonstrated that waivers relevant to evidence of toxicity were granted to Auxein without justification.

-- We have demonstrated that Auxein's claim that incremental dietary exposure to processed free glutamic acid resulting from AuxiGro applications is negligible is unwarranted.

-- We have demonstrated that Auxein has presented no data to support its claim that incremental exposure from non-dietary sources to processed free glutamic acid resulting from AuxiGro applications is negligible.

-- We have demonstrated that Auxein has presented no data to support its claim that incremental dietary exposure to processed free glutamic acid resulting from AuxiGro applications is negligible.

-- We have demonstrated that alleging that "glutamic acid" has a very low toxicity to humans is unwarranted.

-- We have demonstrated that processed free glutamic acid is an endocrine disruptor.

-- We have demonstrated that there was no special consideration given to those subgroups most at risk from ingestion of processed free glutamic acid, namely infants, children, and people who are sensitive to processed free glutamic acid.

-- We have demonstrated that waivers granted by the EPA were unwarranted. Waivers were granted based on:

Errors, inaccuracies, distortions, and literally false statements that permeate the texts of the RED and Final Rules;

Flawed industry-sponsored studies submitted to the EPA; and

Studies conducted by the applicant which did not reflect the conditions under which processed free glutamic acid would be used

-- We have demonstrated that toxicity studies presented to the EPA by Auxein in support of their applications are replete with methodological flaws.
3) The applicant alleged, but failed to demonstrate, that there is reasonable certainty that no harm will follow the use of processed free glutamic acid when used as (or in) a plant growth enhancer on crops, lawn, turfgrasses, and ornamentals.

Quite to the contrary, however:

-- The applicant provided no data on the amount of processed free glutamic acid that would remain as residue on or in each of the fruits, grains, and vegetables brought to market after the first harvest.

-- The applicant provided no data on the difference in uptake of processed free glutamic acid in leaves (such as lettuce and chard), in fruits (such as grapes and tomatoes), in stems (such as celery), in roots or tubers (such as potatoes and carrots), in nuts and seeds, and in the edible portion of grains.

-- The applicant provided no data on the amount of processed free glutamic acid that would remain as residue on or in each of the fruits, grains, vegetables, and other produce brought to market after subsequent harvests.

-- The applicant provided no data on the total amount of processed free glutamic acid from residues on or in fruits, grains, and vegetables that might be consumed by individual adults and children during the course of a day.

-- The applicant provided neither case studies nor data from the peer reviewed published literature that spoke to the least amount of processed free glutamic acid needed to produce adverse reactions in persons acutely sensitive to processed free glutamic acid.

-- The applicant provided no credible data on the effects that feeding processed free glutamic acid to infants (either human or other) over a period of years would have on the production of brain lesions and neuroendocrine disorders.

– The applicant provided no data on the amount of processed free glutamic acid that will get into ground water and into drinking water.

4) The relationship of ingestion of processed free glutamic acid to human risk was obscured. The applicant made no mention of the reports of adverse reactions to processed free glutamic acid used in flavor enhancers (popularly referred to as MSG) on file at the FDA's Adverse Reactions Monitoring System. There was no mention of the reports of sensitivity to processed free glutamic acid submitted by consumers, physicians, and researchers to various Dockets at the FDA. There was no mention of published articles and both written and oral testimony from physicians and researchers not either directly or indirectly in the employ of Ajinomoto Co., Inc. or its International Glutamate Technical Committee, in whose considered opinions it was concluded that ingestion of processed free glutamic acid places humans, particularly infants and children, at risk. There was no mention of an FDA- sponsored study that concluded, in part, that:
"The continuing controversy over the potential effects of glutamate on growth and development of neonatal animal models suggests that it is prudent to avoid the use of dietary supplements of L-glutamic acid by pregnant women, infants, and children. The existence of evidence of potential endocrine responses, i.e., elevated cortisol and prolactin, and differential responses between males and females, would also suggest a neuroendocrine link and that supplemental L-glutamic acid should be avoided by women of childbearing age and individuals with affective disorders."
5) The data that Auxein Corporation did submit to the EPA, alleging that it demonstrated that there is reasonable certainty that no harm will follow the use of AuxiGro, GABA, and processed free glutamic acid:
-- Were irrelevant to the issue;

-- Used methodology inadequate to the task of identifying brain lesions and neuroendocrine disorders in animals allegedly studied;

-- Had been refuted years ago by neuroscientists outside of the employ of Ajinomoto Co., Inc. and others in the glutamate industry;

-- Did not duplicate the real-world conditions under which AuxiGro would be used; and/or

-- Did not consider the total amount of processed free glutamic acid, GABA, and AuxiGro that would be ingested daily if AuxiGro were to be successfully marketed.

6) There were reports of adverse reactions following ingestion of unprocessed head lettuce, broccoli, and russet potatoes before either the reporter or the group to which the reports were made were aware that processed free glutamic acid was being used (tested for use) as a plant growth enhancer and that the produce from those test fields was being sold in the open market.

In brief, we have demonstrated that data submitted in support of the exemption which is the subject of this Objection often addressed the issue of the safety of the "L-glutamic acid" used in AuxiGro, and failed to address the issue of the safety of the "L-glutamic acid" in general.  We have also demonstrate that the RED is deficient in the validity, completeness, and reliability of data allegedly demonstrating that processed free glutamic acid is not toxic to the general population or to identifiable subgroups of consumers, including infants and children.

In granting exemptions and registrations, the EPA is required to consider the validity, completeness, and reliability of available data from studies. It would appear, however, that in this case "available data" was defined as those data supplied by the applicant to the EPA.

Indeed, it would appear that "the evidence," "scientific data," "relevant information," and "available information" referred to in the RED and Final Rules were defined by the EPA as that information supplied to the EPA by the applicant -- and no other.

According to the the FFDCA, the EPA may only establish an exemption for the requirement of a tolerance if EPA determines that the exemption is "safe;" and "safe" is defined to mean that "there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information." Moreover, the EPA is required to give special consideration to exposure of infants and children.

Clearly, the EPA has abrogated its responsibility. Analysis of the RED and Final Rules, including analysis of omitted material which speaks to the toxicity of processed free glutamic acid, leaves no doubt that processed free glutamic acid is both a neurotoxic amino acid and an endocrine disruptor; that processed free glutamic acid causes adverse reactions in at least 25% of the population; and that the least amount of processed free glutamic acid needed to cause a reaction in a person sensitive to the substance has never been determined. Analysis of the RED and Final Rules – including analysis of omitted material which speaks to the toxicity of processed free glutamic acid – leaves no doubt that residue of processed free glutamic acid in and on food crops places humans at risk, with the greatest risk to infants and children.

References follow.  Copies of selected (representative) studies referred to in this Objection are enclosed.

Respectfully submitted,
 

In this paper, we have demonstrated that the data sent to the EPA by Auxein Corporation (or Emerald BioAgriculture) in support of granting the chemical referred to as "L-glutamic acid" an exemption from the requirement of a tolerance for residues of "L-glutamic acid" on all food commodities when applied/used in accordance with good agricultural practices, lack completeness, validity, and reliability.
In addition, we have demonstrated that those data often addressed the issue of the safety of the "L-glutamic acid" used in AuxiGro, and failed to address the issue of the safety of the "L-glutamic acid" in general.  Because much of the data submitted in support of granting the chemical referred to as "L-glutamic acid" an exemption from the requirement of a tolerance for residues of "L-glutamic acid" only addresses the subject of the safety of the "L-glutamic acid" used in AuxiGro, and no other, those data are irrelevant to the subject of the exemption granted.

Even though data addressing the safety of the "L-glutamic acid" used in AuxiGro are irrelevant, we can not ignore that they also lack completeness, validity, and reliability.  Therefore, in this paper we have discussed those data, along with other data, and have demonstrated that:

1) A great deal of relevant information was omitted from Auxein Corporation's applications. Most obvious, but by no means all inclusive were omissions of:

-- Material from the sixth edition of N. Irving Sax's Dangerous Properties of Industrial Materials wherein "monosodium glutamate"and "L-glutamic acid" were given hazard ratings of HR 3 (most toxic), indicating an LD 50 below 400 mg/kg;

– Data on the amount of processed free glutamic acid that could be ingested daily and yearly by individual adults, children, and animals ingesting fruit, grains, nuts, seeds, weeds, grasses, and vegetables treated with processed free glutamic acid from any and all sources regulated by the EPA;

-- Data on the amount of processed free glutamic acid that would be ingested daily and yearly by individual adults, children, and animals ingesting fruit, grains, nuts, seeds, weeds, grasses, and vegetables treated with AuxiGro;

-- Data describing the least amount of processed free glutamic acid needed to cause brain lesions, and/or to cause or exacerbate neuroendocrine disorders; memory, behavior and learning disorders; debilitating and life-threatening adverse reactions such as asthma, migraine headache, diarrhea and vomiting, depression, seizures, elevated blood pressure, tachycardia, and atrial fibrillation; and the various disease conditions associated with what the National Institutes of Health refers to as the "glutamate cascade."

-- Published studies detailing brain lesions, retinal degeneration, and behavior and learning disorders induced following treatment with processed free glutamic acid;

-- Published studies of the endocrine disrupting effects of processed free glutamic acid;

-- Published studies relevant to the sensitivities of major identifiable subgroups, primarily infants and children, who have been shown to be most at risk from exposure to processed free glutamic acid;

-- Published studies demonstrating that ingested processed free glutamic acid can cross both the blood-brain barrier and the placental barrier;

-- Human studies conducted by the glutamate industry which alleged to have demonstrated that ingestion of processed free glutamic acid does not place consumers at risk. In those studies, subjects suffered adverse reactions to both the test material (which contained processed free glutamic acid in the flavor enhancer "monosodium glutamate"), and the placebos, which contained processed free glutamic acid (in various hydrolyzed protein products) and/or contained glutamic acid's structural analog, aspartic acid (in aspartame).  Those industry-sponsored studies are, in and of themselves, evidence that the neurotoxic amino acids in free form (free glutamic acid and free aspartic acid) cause adverse reactions.

2) Errors, inaccuracies, distortions, and literally false statements permeate the texts of both the EPA's RED and Final Rules. For example we have demonstrated that:
-- The applicant misrepresented the chemical composition of the processed free glutamic acid that was used in AuxiGro that was granted an exemption from the requirement of a tolerance. Auxein Corporation based much of its argument for the safety of its product on the false assertion that the processed free glutamic acid used in AuxiGro (which invariably contains L-glutamic acid plus contaminants) is identical to the L-glutamic acid found in protein and in higher organisms (which is L-glutamic acid, only).

This is an important distinction because the exemption granted for the requirement of a tolerance for residues of "glutamic acid" is, in actuality, an exemption for processed free glutamic acid, not the glutamic acid that is bound with other amino acids in protein. Glutamic acid bound in protein does not cause brain lesions, neuroendocrine disorders, or human adverse reactions. Processed free glutamic acid does.

-- The applicant falsely asserted that the processed free glutamic acid used in AuxiGro has a long history of food uses. Seaweed, from which Ajinomoto Co., Inc. first extracted glutamic acid, has been used in food for thousands of year; but processed free glutamic acid was first extracted from seaweed in Japan in 1908. Ajinomoto's product called "monosodium glutamate" was brought to this country after World War II. The first published reports of adverse reactions and brain lesions following treatment with "monosodium glutamate" appeared in 1968 and 1969, respectively, after Ajinomoto changed its extraction process to a process of bacterial fermentation wherein glutamic acid was excreted through the cell walls of selected bacteria. Epidemiological studies conducted in the 1970s estimated that at least 25 per cent of the population in the United States suffered adverse reactions following ingestion of processed free glutamic acid at that time.

-- Auxein based much of its argument for the safety of its product on what they allege to be the fact that ingested processed free glutamic acid is metabolized quickly and efficiently. Glutamate industry public relations people equate fairly small and/or transient rises in plasma glutamate levels following ingestion of processed free glutamic acid with rapid metabolism of processed free glutamic acid, which they allege to have demonstrated. The defenders of the safety of processed free glutamic acid claim that since processed free glutamic acid clears the plasma quickly and efficiently, there can be no adverse reactions following ingestion of processed free glutamic acid.

The logic, of course, is faulty. We have demonstrated that there are published peer reviewed studies that demonstrate that there are glutamate receptors outside of the central nervous system; and that there are data that demonstrate that excess of neuroexcitatory amino acids such as glutamic acid found outside of the plasma, not in it, possibly favors a state of neuronal hyperexcitability leading to expression of adverse reactions. In addition, we have demonstrated that the studies submitted to the EPA by Auxein were studies of the metabolism of intact protein, not studies of the metabolism of glutamic acid freed from protein by a manufacturing process prior to ingestion. Thus the studies of metabolism submitted to the EPA by Auxein are irrelevant to an assessment of the safety/toxicity of processed free glutamic acid.

-- Auxein alleged that processed free glutamic acid could not cross either the blood-brain barrier or the placental barrier. We have demonstrated that both claims are blatantly untrue.

-- Auxein claimed that any small amount of "L-glutamic acid" residue from the use of AuxiGro will wash off or will otherwise have dissipated prior to use of the food. But the applicant, who presented no data at all on the subject, failed to substantiate that claim, and failed to acknowledge that if effective as a plant growth enhancer, AuxiGro would have to be taken up by the fruit, leaves, stems, tubers, and roots of each plant. No analysis of the uptake of processed free glutamic acid was made in Auxein's analysis of the safety of its product. In fact, the subject of uptake was not even mentioned.

-- We have demonstrated that the applicant further misrepresented the conditions that would accrue following treatment of vegetation with AuxiGro, ignoring the realities of repeated treatment of crop after crop, and the treatment of all produce to be used by animals and man, if Auxein were to be successful in marketing its product. If Auxein were to be successful in marketing its product, all produce would be treated with AuxiGro. No provision for that eventuality was made in Auxein's analysis of the safety of its product.

-- In discussing Toxicological Profile in the Final Rule, the applicant claimed that glutamate was administered to numerous species in long term dietary studies without adverse effects. We have demonstrated that the methodology of the long term studies was inappropriate to the real world conditions under which AuxiGro would be used; and that adverse effects were noted, but were trivialized and dismissed. The applicant also referred to plasma glutamate levels, and studies using subjects who were not sensitive to processed free glutamic acid; and cited protection of the blood-brain barrier and the placental barrier as evidence that their product is safe. We have demonstrated that data on metabolism presented by Auxein, and studies wherein subjects who are not sensitive to processed free glutamic acid are used, are irrelevant to a study of the safety/toxicity of processed free glutamic acid. We have demonstrated that neither the blood-brain barrier nor the placental barrier invariably protects the brain or placenta from invasion of glutamic acid. We have further demonstrated that waivers relevant to evidence of toxicity were granted to Auxein without justification.

-- We have demonstrated that Auxein's claim that incremental dietary exposure to processed free glutamic acid resulting from AuxiGro applications is negligible is unwarranted.

-- We have demonstrated that Auxein has presented no data to support its claim that incremental exposure from non-dietary sources to processed free glutamic acid resulting from AuxiGro applications is negligible.

-- We have demonstrated that Auxein has presented no data to support its claim that incremental dietary exposure to processed free glutamic acid resulting from AuxiGro applications is negligible.

-- We have demonstrated that alleging that "glutamic acid" has a very low toxicity to humans is unwarranted.

-- We have demonstrated that processed free glutamic acid is an endocrine disruptor.

-- We have demonstrated that there was no special consideration given to those subgroups most at risk from ingestion of processed free glutamic acid, namely infants, children, and people who are sensitive to processed free glutamic acid.

-- We have demonstrated that waivers granted by the EPA were unwarranted. Waivers were granted based on:

Errors, inaccuracies, distortions, and literally false statements that permeate the texts of the RED and Final Rules;

Flawed industry-sponsored studies submitted to the EPA; and

Studies conducted by the applicant which did not reflect the conditions under which processed free glutamic acid would be used

-- We have demonstrated that toxicity studies presented to the EPA by Auxein in support of their applications are replete with methodological flaws.
3) The applicant alleged, but failed to demonstrate, that there is reasonable certainty that no harm will follow the use of processed free glutamic acid when used as (or in) a plant growth enhancer on crops, lawn, turfgrasses, and ornamentals.

Quite to the contrary, however:

-- The applicant provided no data on the amount of processed free glutamic acid that would remain as residue on or in each of the fruits, grains, and vegetables brought to market after the first harvest.

-- The applicant provided no data on the difference in uptake of processed free glutamic acid in leaves (such as lettuce and chard), in fruits (such as grapes and tomatoes), in stems (such as celery), in roots or tubers (such as potatoes and carrots), in nuts and seeds, and in the edible portion of grains.

-- The applicant provided no data on the amount of processed free glutamic acid that would remain as residue on or in each of the fruits, grains, vegetables, and other produce brought to market after subsequent harvests.

-- The applicant provided no data on the total amount of processed free glutamic acid from residues on or in fruits, grains, and vegetables that might be consumed by individual adults and children during the course of a day.

-- The applicant provided neither case studies nor data from the peer reviewed published literature that spoke to the least amount of processed free glutamic acid needed to produce adverse reactions in persons acutely sensitive to processed free glutamic acid.

-- The applicant provided no credible data on the effects that feeding processed free glutamic acid to infants (either human or other) over a period of years would have on the production of brain lesions and neuroendocrine disorders.

– The applicant provided no data on the amount of processed free glutamic acid that will get into ground water and into drinking water.

4) The relationship of ingestion of processed free glutamic acid to human risk was obscured. The applicant made no mention of the reports of adverse reactions to processed free glutamic acid used in flavor enhancers (popularly referred to as MSG) on file at the FDA's Adverse Reactions Monitoring System. There was no mention of the reports of sensitivity to processed free glutamic acid submitted by consumers, physicians, and researchers to various Dockets at the FDA. There was no mention of published articles and both written and oral testimony from physicians and researchers not either directly or indirectly in the employ of Ajinomoto Co., Inc. or its International Glutamate Technical Committee, in whose considered opinions it was concluded that ingestion of processed free glutamic acid places humans, particularly infants and children, at risk. There was no mention of an FDA- sponsored study that concluded, in part, that:
"The continuing controversy over the potential effects of glutamate on growth and development of neonatal animal models suggests that it is prudent to avoid the use of dietary supplements of L-glutamic acid by pregnant women, infants, and children. The existence of evidence of potential endocrine responses, i.e., elevated cortisol and prolactin, and differential responses between males and females, would also suggest a neuroendocrine link and that supplemental L-glutamic acid should be avoided by women of childbearing age and individuals with affective disorders."
5) The data that Auxein Corporation did submit to the EPA, alleging that it demonstrated that there is reasonable certainty that no harm will follow the use of AuxiGro, GABA, and processed free glutamic acid:
-- Were irrelevant to the issue;

-- Used methodology inadequate to the task of identifying brain lesions and neuroendocrine disorders in animals allegedly studied;

-- Had been refuted years ago by neuroscientists outside of the employ of Ajinomoto Co., Inc. and others in the glutamate industry;

-- Did not duplicate the real-world conditions under which AuxiGro would be used; and/or

-- Did not consider the total amount of processed free glutamic acid, GABA, and AuxiGro that would be ingested daily if AuxiGro were to be successfully marketed.

6) There were reports of adverse reactions following ingestion of unprocessed head lettuce, broccoli, and russet potatoes before either the reporter or the group to which the reports were made were aware that processed free glutamic acid was being used (tested for use) as a plant growth enhancer and that the produce from those test fields was being sold in the open market.

In brief, we have demonstrated that data submitted in support of the exemption which is the subject of this Objection often addressed the issue of the safety of the "L-glutamic acid" used in AuxiGro, and failed to address the issue of the safety of the "L-glutamic acid" in general.  We have also demonstrate that the RED is deficient in the validity, completeness, and reliability of data allegedly demonstrating that processed free glutamic acid is not toxic to the general population or to identifiable subgroups of consumers, including infants and children.

In granting exemptions and registrations, the EPA is required to consider the validity, completeness, and reliability of available data from studies. It would appear, however, that in this case "available data" was defined as those data supplied by the applicant to the EPA.

Indeed, it would appear that "the evidence," "scientific data," "relevant information," and "available information" referred to in the RED and Final Rules were defined by the EPA as that information supplied to the EPA by the applicant -- and no other.

According to the the FFDCA, the EPA may only establish an exemption for the requirement of a tolerance if EPA determines that the exemption is "safe;" and "safe" is defined to mean that "there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information." Moreover, the EPA is required to give special consideration to exposure of infants and children.

Clearly, the EPA has abrogated its responsibility. Analysis of the RED and Final Rules, including analysis of omitted material which speaks to the toxicity of processed free glutamic acid, leaves no doubt that processed free glutamic acid is both a neurotoxic amino acid and an endocrine disruptor; that processed free glutamic acid causes adverse reactions in at least 25% of the population; and that the least amount of processed free glutamic acid needed to cause a reaction in a person sensitive to the substance has never been determined. Analysis of the RED and Final Rules – including analysis of omitted material which speaks to the toxicity of processed free glutamic acid – leaves no doubt that residue of processed free glutamic acid in and on food crops places humans at risk, with the greatest risk to infants and children.
The Truth in Labeling Campaign
Adrienne Samuels, Ph.D.
Director
1547 Santa Sabina Court
Solana Beach, CA 92075

858-481-9333
msgfacts@aol.com
www.truthinlabeling.org

cc: EPA Docket # OPP-301136
     California Department of Pesticide Regulation

encl: "Registration Eligibility Decision" (RED)
         "On the Subject of Manufactured vs. Natural Glutamic Acid."
         Excitotoxins: The Taste That Kills
         Copies of selected (representative) studies referred to in this Objection.
 

REFERENCES: (** Copy enclosed with the EPA Objection)

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6a. June 10, 1997 EPA Data Evaluation Report; Case No. 061704; Submission No. S525722; MRID No. 44296801; Title of Report: Product Chemistry Data for AuxiGro WP, formula ID: Aux01F03. OPP # PF-978.
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52. Perez, V.J. and Olney, J.W. Accumulation of glutamic acid in the arcuate nucleus of the hypothalamus of the infant mouse following subcutaneous administration of monosodium glutamate. J Neurochem 19: 1777-1782, 1972.
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