Evidence sufficient to demonstrate that
EPA 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 AuxiGro WP are unwarranted

Submitted to the California Department of Pesticide Regulation on June 15, 2001
_______________________________________

Introduction

On January 7, 1998, the US Environmental Protection Agency (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.

We have reviewed the "Registration Eligibility Decision (gamma aminobutyric acid [GABA] and L-glutamic acid)" and "Glutamic Acid; Pesticide Tolerance Exemption: Final rule," (henceforth referred to as the "Registration Eligibility Decision" and the "Final Rule," respectively) 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 three 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 Registration Eligibility Decision and the Final Rule.

Second, the applicant alleged, but failed to demonstrate, that there is reasonable certainty that no harm will follow the use of AuxiGro, GABA, or processed free glutamic acid when used as (or in) a plant growth enhancer on crops, lawn, turfgrasses, and ornamentals.

The applicant provided no information on the amount of processed free glutamic acid, GABA, and AuxiGro 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, GABA, and AuxiGro 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, GABA, and AuxiGro 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, GABA, and AuxiGro from residues on or in fruits, grains, and vegetables that might be consumed by individual adults and children consuming more than one AuxiGro treated food 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 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 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/orDid 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.

Third, 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.

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 Registration Eligibility Decision and Final Rule.

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 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, which is a component of 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.

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 Registration Eligibility Decision and Final Rule;

Flawed industry-sponsored studies submitted to the EPA; and

Studies conducted by the applicant which did not reflect the conditions under which AuxiGro would be used.

In brief, we will demonstrate that the Registration Eligibility Decision is deficient in the validity, completeness, and reliability of data from studies alleging to have demonstrated that AuxiGro, processed free glutamic acid, and GABA, are not toxic to the general population or to identifiable subgroups of consumers, including infants and children.

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. We will demonstrate that there is no reasonable certainty that no harm will follow the use of AuxiGro, GABA, and processed free glutamic acid. 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.

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

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

We found that the EPA's Registration Eligibility Decision and/or Final Rule misrepresented the chemical composition of the processed free glutamic acid 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 Registration Eligibility Decision and Final Rule, is manufactured/fabricated using the same methods used by Ajinomoto Co., Inc. and others to produce the processed free glutamic acid produced by Ajinomoto and others for use in the popular flavor enhancer called "monosodium glutamate;"

Failed to reveal the material fact that, regardless of the method of manufacture, processed free glutamic acid such as that used in AuxiGro 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),(2),(3),(4),(5) 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 contaminants  in addition to L-glutamic acid, is not ubiquitous in nature.(6)  In the Final Rule, the glutamic acid to be 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 Registration Eligibility Decision, 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 a paper titled "On the Subject of Manufactured vs. Natural Glutamic Acid" that can be found on the Internet at www.truthinlabeling.org/manufac.html.

II. History of use in food

We found that the EPA's Registration Eligibility Decision 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 both in the flavor enhancer called "monosodium glutamate" and 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.(7) Elsewhere, crude gluten or other starting materials were hydrolyzed by heating with hydrochloric acid.(8) 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.(7,8,9)

"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)(10) 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.(11)

In 1968, the first published report of an adverse reaction to "monosodium glutamate" appeared in The New England Journal of Medicine.(12) In 1969, the first evidence that processed free glutamic acid causes brain lesions and neuroendocrine disorders in laboratory animals was published in Science.(13) In 1969 and the early 1970s, the safety of using processed free glutamic acid (referred to as MSG) in baby food was questioned.(14),(15),(16) In the mid 1970s, epidemiological studies indicated that 25% or more of adults in the United States reacted adversely to "monosodium glutamate."(17),(18),(19),(20) 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.(21)

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.(22),(23),(24),(25) 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).(26)

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."(27)

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.(28)

It must be noted that in 1969, following the first published report of human adverse reactions to processed free glutamic acid, the International Glutamate Technical Committee (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. 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.(25) 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.(29) 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. 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(30) 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.(28)

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 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 such as that used in AuxiGro.

Following are the references cited in the Registration Eligibility Decision 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 Registration Eligibility Decision and/or Final Rule 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;(31),(32),(33),(34),(35),(36),(37),(38) studies that demonstrated that processed free glutamic acid, whether laboratory grade or found in "monosodium glutamate," cause retinal degeneration,(39),(40),(41),(42),(43),(44), (45),(46),(47),(48),(49) and brain lesions when given to immature animals after either subcutaneous (12, 48), (50),(51),(52), (53),(54),(55),(56),(57),(58),(59),(60),(61),(62),(63),(64),(65),(66),(67),(68),(69),(70),(71) or oral (56,62,63,65) ,(72),(73),(74),(75),(76) doses; studies detailing neuroendocrine disorders, (12,48,57,59,75),(77),(78),(79),(80),(81),(82),(83),(84),(85),(86),(87),(88),(89),(90),(91),(92),(93),(94) possible locomotor and learning deficits either immediately or in later life,(79,82,83),(95),(96),(97),(98),(99),(100),(101),(102),(103),(104) learning and memory, (105),(106),(107),(108) behavioral reactions including somnolence and seizures, (109),(110),(111),(112),(113),(114),(115),(116),(117),(118),(119) tail automutilation,(81,108) learned taste aversion,(120) 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;(16,17,18,19) and studies that demonstrated that free glutamic acid (including processed free glutamic acid) can cross the placenta during pregnancy,(118),(121),(122) 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.(123) (124),(125),(126) 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.

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.(127),(128),(129),(130),(131) 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.(132) 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 "gamma aminobutyric acid (GABA)" in or on all food commodities 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 AuxiGro will be gone prior to harvesting crops on which the AuxiGro 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 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 AuxiGro.

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.(19,133)  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.26 And 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, GABA, or AuxiGro 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.(134),(135),(136)  There is nothing in the literature that says that similarly 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 would have to be taken up by the plant, not simply left on the plant's surface.

While giving at least lip service to consideration of residues on crops, the applicant failed to consider the 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, GABA, and AuxiGro; and all food would potentially contain GABA, processed free glutamic acid, and AuxiGro 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.(137) 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 approximately 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."(138)

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.

Subjects in a single study of males who were not sensitive to processed free glutamic acid were inappropriately characterized as "humans administered levels up to 137 g daily for 14 to 41 days."

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 Rule 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 procedssed free glutamic acid was found to cause brain lesions, neuroendocrine disorders, and more, were not considered. (See Sections IV and XIII.)

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 Rule occurs naturally in the environment. That is not true. (See Section I.)

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

VII. 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 minute amounts of free glutamic acid associated with unadulterated/unprocessed/unfermented tomatoes or mushrooms, that free glutamic acid will not cause adverse reactions.(139) 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 time that 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 AuxiGro found in the Final Rule. 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 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." (Emphasis added.)

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.

VII. 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.25 It would appear that in their application to the EPA, the applicant did the same. In the Final Rule we are told that:

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 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.)

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 LD50 below 400 mg/kg,(140) 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 Registration Eligibility Decision and/or Final Rule.

-- In review of the EPA's Registration Eligibility Decision and/or Final Rule, 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 LD50 below 400 mg/kg.138 Although not mentioned in the text, 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 Registration Eligibility Decision. 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 which is, in part, the subject of the approvals being challenged) causes endocrine disturbances as infant animals exposed to the chemical approach puberty. In review of the EPA's Registration Eligibility Decision and/or Final Rule, 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 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."

-- In review of the EPA's Registration Eligibility Decision and/or Final Rule, 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 Registration Eligibility Decision 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 only one 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 Registration Eligibility Decision. 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 Registration Eligibility Decision contains citations to two studies by Olney et al., cited as follows:

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

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

which clearly demonstrate that processed free glutamic acid causes brain lesions, obesity, and other disturbances in mice; and brain damage in infant primates. Yet no mention of these data is made in the text of the Registration Eligibility Decision.

The bibliography of the Registration Eligibility Decision contains a citation to summary toxicity data,   (141) 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 Registration Eligibility Decision. In the 1984 edition of Dangerous Properties of Industrial Materials, L-glutamic acid and L-sodium glutamate (which contain the same processed free glutamic acid used in AuxiGro) 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 Registration Eligibility Decision and/or Final Rule, we found that waivers granted to the applicant were, in large measure, unwarranted.

According to the 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 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 residue of processed free glutamic acid, GABA, and/or AuxiGro in and on food crops - in and on all food crops; or to evaluate the persistence of processed free glutamic acid, GABA, and AuxiGro 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 Registration Eligibility Decision, 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.

According to the Registration Eligibility Decision, 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 exemptions and registrations being challenged, has not been studied.

XIII. 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.

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 Registration Eligibility Decision 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 are to a single review of studies of metabolism and are actually irrelevant. According to 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 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:

Researchers studying epilepsy in humans study humans who suffer from epilepsy. But in the industry sponsored studies of the toxicity of processed free glutamic acid in the flavor enhancer "monosodium glutamate"submitted in supported of Auxein Corporation's petitions/applications, researchers did not use humans subjects who were sensitive to processed free glutamic acid.

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.(142) In 1990, yeast food invariably contained either protease (which creates processed free glutamic acid during manufacture) or L-cysteine which produces neurotoxic effects(143) 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. 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 certainly have been discussed.

Although not discussed in the Registration Eligibility Decision, 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);(144) 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 acid and GABA 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.(145)

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. 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."(130)

XIII. Methodological flaws - B

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 Registration Eligibility Decision, "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 of use 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 Registration Eligibility Decision 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 Conclusions

The EPA has alleged that data requirements for granting the unconditional registration of AuxiGro containing the two active ingredients GABA and Glutamic Acid, have been fulfilled.

However, analysis of the Registration Eligibility Decision and the Final Rule, which is the subject of this paper, including analysis of 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/applications were incomplete, often unreliable, and/or lacking in relevance/validity.

In this paper we 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 LD50 below 400 mg/kg;

Data on the amount of processed free glutamic acid, GABA, and AuxiGro that would be ingested daily and yearly by individual adults and children ingesting fruit, grains, nuts, seeds, 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; or 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 Registration Eligibility Decision and Final Rule. For example we have demonstrated that:

-- The applicant misrepresented the chemical composition of the processed free glutamic acid used in AuxiGro. Auxein 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 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, GABA, or AuxiGro 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 Registration Eligibility Decision and Final Rule;

Flawed industry-sponsored studies submitted to the EPA; and

Studies conducted by the applicant which did not reflect the conditions under which AuxiGro would be used.

-- We have demonstrated that toxicity studies presented to the EPA by Auxein in support of their application 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 AuxiGro, GABA, or 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 information on the amount of processed free glutamic acid, GABA, and AuxiGro 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, GABA, and AuxiGro 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 information on the amount of processed free glutamic acid, GABA, and AuxiGro 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 information on the total amount of processed free glutamic acid, GABA, and AuxiGro 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.

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 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 the Registration Eligibility Decision is deficient in the validity, completeness, and reliability of data allegedly demonstrating that AuxiGro, processed free glutamic acid, and GABA, are 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 Registration Eligibility Decision and Final Rule were defined by the EPA as that information supplied to the EPA by the applicant -- and no other.

According to the Final Rule, 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 Registration Eligibility Decision and Final Rule - 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 Registration Eligibility Decision and Final rule - including analysis of omitted material which speaks to the toxicity of processed free glutamic acid -- leaves no doubt that use of processed free glutamic acid in and/or on food crops and/or otherwise used in the environment, places humans at risk, with the greatest risk to infants and children.

Respectfully submitted,
 
 

Adrienne Samuels, Ph.D.
1547 Santa Sabina Court
Solana Beach, CA 92075

858-481-9333
adieonly@aol.com
 
 

REFERENCES
 

1. Man, E.H. and Bada, J.L. Dietary D-Amino Acids. Ann. Rev. Nutr. 1987;7:209-25.

2. Rundlett, K.L. and Armstrong, D.W. Evaluation of free D-glutamate in processed foods. Chirality. 1994;6:277-282

3. Konno, R. et al. Origin of D-alanine present in urine of mutant mice lacking D-amino-acid oxidase activity. American Journal of Physiology, 1993, 265:G699-703.

4. Pommer, K. (Novo Nordisk BioChem Inc., Franklinton, NC) Cereal Foods World. October, 1995 Vol 40. No 10. Page 745.

5. Life Sciences Research Office of the Federation of American Societies for Experimental Biology. Analysis of adverse reactions to monosodium glutamate (MSG). July, 1995. Prepared for the Center for Food Safety and Applied Nutrition, Food and Drug Administration. Page 31.

6. Contaminants vary depending on the methods used to fabricate/manufacture processed free glutamic acid.

7. Van Nostrand's Scientific Encyclopedia, 6th Edition, (1983.) s.v. "Flavor enhancers and potentiators." pp 1211-1212.

8. Kirk-Othmer Encyclopedia of Chemical Technology, 3rd Edition, Volume 2. New York: Wiley, 1978. pp 410-421.

9. Kirk-Othmer Encyclopedia of Chemical Technology Fourth Edition (Wiley, 1992) pp 571-579.

10. U.S. Patent #5,573,945. Mutant and method for producing L-glutamic acid by fermentation. Ajinomoto Co., Inc. (Tokyo, JP). November 12, 1996.

11. Leung, A. and Foster, S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs , and Cosmetics. New York: Wiley, 1996. pp 373-375.

12. Kwok, R.H.M. The Chinese restaurant syndrome. Letter to the editor. N Engl J Med 278: 796, 1968.

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

14. Senate Select Committee on Nutrition and Health. September, 1969.

15. Baltimore Sun. Nader Says Agency Lied: Claims FDA Falsified Data on Baby-Food Safety. September 19, 1969. P A12.

16. Senate Select Committee on Nutrition and Human Needs. Part 4A. Food Additives. September 19, 1972.

17. Reif-Lehrer, L. A questionnaire study of the prevalence of Chinese restaurant syndrome. Federation Proceedings 36:1617-1623,1977.

18. Kenney, RA and Tidball, CS Human susceptibility to oral monosodium L-glutamate. Am J Clin Nutr. 25:140-146,1972.

19. Kerr, GR, Wu-Lee, M, El-Lozy, M, McGandy, R, and Stare, F. Food-symptomatology questionnaires: risks of demand-bias questions and population-biased surveys. In: Glutamic Acid: Advances in Biochemistry and Physiology Filer, LJ, et al., eds. New York: Raven Press, 1979.

20. Schaumburg, H.H., Byck, R, Gerstl, R, and Mashman, J.H. Monosodium L-glutamate: its pharmacology and role in the Chinese restaurant syndrome. Science 163:826-828,1969.

21. Olney, J.W. Prepared Statement for the Public Meeting (April 1993) Pertaining to Adverse Reactions to Monosodium Glutamate (MSG). FDA Docket #92N-0391, Item #TS7.

22. U.S. Public Health Service, FDA. Food Code Annex 5:HACCP Guidelines. Table 2, page HACCP 8. 1995.

23. Olney, J.W. Excitotoxic food additives-Relevance of animal studies to human safety. Neurobehavioral Toxicology and teratology. 6: 455-462, 1984.

24. Olney, J.W. Food additives, excitotoxic. In. G. Adelman, Ed. Encyclopedia of Neuroscience. Volume I., Pages 436-438. Boston: Birkhauser, 1987.

25. Olney, J.W. Excitotoxins in Foods. NeuroToxicology 15(3): 535-544, 1994.

26. Samuels, A. The Toxicity/Safety of Processed Free Glutamic Acid (MSG): A Study in Suppression of Information. Accountability in Research 6(4): 259-310, 1999.

27. Safety of Amino Acids Used as Dietary Supplements. Prepared for Center for Food Safety and Applied Nutrition, Food and Drug Administration, Department of Health and Human Services. S.A. Anderson and D.J. Raiten, eds. p. 166. Bethesda, MD: Life Sciences Research Office of the Federation of American Societies for Experimental Biology, July 1992.

28. Reuters. Myanmar clamps down on smuggled Thai energy drinks. March 12, 2001.

29. Martinez, F. et al. Neuroexcitatory amino acid levels in plasma and cerebrospinal fluid during migraine attacks. Cephalalgia 13: 89-93, 1993.

30. Gill, S.S., Mueller, R.W., McGuire, P.F., Pulido, O.M. Potential target sites in peripheral tissues for excitatory neuro transmission and excitotoxicity. Toxicologic Pathology 28(2):277-284, 2000.

31. Schaumburg, H. Chinese-restaurant Syndrome. N Engl J Med 278: 1122, 1968.

32. McCaghren, T.J. Chinese-restaurant syndrome. N Engl J Med 278: 1123, 1968.

33. Menken, M. Chinese-restaurant syndrome. N Engl J Med 278: 1123, 1968.

34. Migden, W. Chinese-restaurant syndrome. N Engl J Med 278: 1123, 1968.

35. Rath, J. Chinese-restaurant syndrome. N Engl J Med 278: 1123, 1968.

36. Beron, E.L. Chinese-restaurant syndrome. N Engl J Med 278: 1123, 1968.

37. Kandall, S.R. Chinese-restaurant syndrome. N Engl J Med 278: 1123, 1968.

38. Gordon, M.E., Chinese-restaurant syndrome. N Engl J Med 278: 1123-1124, 1968.

39. Lucas, D.R. and Newhouse, J. P. The toxic effect of sodium-L-glutamate on the inner layers of the retina. AMA Arch Ophthalmol 58: 193-201, 1957.

40. Potts, A.M., Modrell, R.W., and Kingsbury, C. Permanent fractionation of the electroretinogram by sodium glutamate. Am J Ophthalmol 50: 900-907, 1960.

41. Freedman, J.K., and Potts, A.M. Repression of glutaminase I in the rat retina by administration of sodium L-glutamate. Invest Ophthalmol 1: 118-121, 1962.

42. Freedman, J.K., and Potts, A.M. Repression of glutaminase I in rat retina by administration of sodium L-glutamate. Invest Ophthal 2: 252, 1963.

43. Potts, A.M. Selective action of chemical agents on individual retinal layers. In: Biochemistry of the retina. Graymore, C.N., Ed. New York: Academic Press, 1965. pp 155-161.

44. Hamatsu, T. Experimental studies on the effect of sodium iodate and sodium L-glutamate on ERG and histological structure of retina in adult rabbits. Acta Soc Ophthalmol Jpn 68: 1621-1636, 1964. (Abstract)

45. Hansson, H.A. Ultrastructure studies on long-term effects of MSG on rat retina. Virchows Arch [Zellpathol] 6: 1, 1970.

46. Cohen, A.I. An electron microscopic study of the modification by monosodium glutamate of the retinas of normal and "rodless" mice. Am J Anat 120: 319-356, 1967.

47. Olney, J.W. Glutamate-induced retinal degeneration in neonatal mice. Electron-microscopy of the acutely evolving lesion. J Neuropathol Exp Neurol 28: 455-474, 1969.

48. Hansson, H.A. Scanning electron microscopic studies on the long term effects of sodium glutamate on the rat retina. Virchows Arch ABT B (Zellpathol) 4: 357-367, 1970.

49. Arees, E., Sandrew, B., and Mayer, J. MSG-induced optic pathway lesions in infant mice following subcutaneous injection. Fed Proc 30: 521, 1971.

50. Olney, J.W. Ho, O.L., and Rhee, V. Cytotoxic effects of acidic and sulphur containing amino acids on the infant mouse central nervous system. Exp Brain Res 14: 61-76, 1971.

51. Olney, J.W., and Sharpe, L.G. Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science 166: 386-388, 1969.

52. Snapir, N., Robinzon, B., and Perek, M. Brain damage in the male domestic fowl treated with monosodium glutamate. Poult Sci 50: 1511-1514, 1971.

53. 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.

54. Arees, E.A., and Mayer, J. Monosodium glutamate-induced brain lesions: electron microscopic examination. Science 170: 549-550, 1970.

55. Arees, E.A., and Mayer, J. Monosodium glutamate-induced brain lesions in mice. Presented at the 47th Annual Meeting of American Association of Neuropathologists, Puerto Rico, June 25-27, 1971. J Neuropath Exp Neurol 31: 181, 1972. (Abstract)

56. Everly, J.L. Light microscopy examination of monosodium glutamate induced lesions in the brain of fetal and neonatal rats. Anat Rec 169: 312, 1971.

57. Olney, J.W. Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. J Neuropathol Exp Neurol 30: 75-90, 1971.

58. 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. Takasaki, Y. Studies on brain lesion by administration of monosodium L-glutamate to mice. I. Brain lesions in infant mice caused by administration of monosodium L-glutamate. Toxicology 9: 293-305, 1978.

60. 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.

61. Holzwarth-McBride, M.A., Sladek, J.R., and Knigge, K.M. Monosodium glutamate induced lesions of the arcuate nucleus. II Fluorescence histochemistry of catecholamines. Anat Rec 186: 197-205, 1976.

62. Paull, W.K., and Lechan, R. The median eminence of mice with a MSG induced arcuate lesion. Anat Rec 180: 436, 1974.

63. 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.

64. 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. Abraham, R., Doughtery, W., Goldberg, L., and Coulston, F. The response of the hypothalamus to high doses of monosodium glutamate in mice and monkeys: cytochemistry and ultrastructural study of lysosomal changes. Exp Mol Pathol 15: 43-60, 1971.

66. 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 Neuropathol Exp Neurol 31: 181, 1972.

67. Robinzon, B., Snapir, N., and Perek, M. Age dependent sensitivity to monosodium glutamate inducing brain damage in the chicken. Poult Sci 53: 1539-1942, 1974.

68. Tafelski, T.J. Effects of monosodium glutamate on the neuroendocrine axis of the hamster. Anat Rec 184: 543-544, 1976.

69. Coulston, F. In: Report of NAS,NRC, Food Protection Subcommittee on Monosodium Glutamate. July, 1970. pp 24-25.

70. Inouye, M. and Murakami, U. Brain lesions and obesity in mouse offspring caused by maternal administration of monosodium glutamate during pregnancy.Congenital Anomalies 14: 77-83, 1974.

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

72. 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.

73. 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.

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

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

76. 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. Matsuyama, S. Studies on experimental obesity in mice treated with MSG. Jap J Vet Sci 32: 206, 1970.

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

79. Knittle, J.L., Ginsberg-Fellner, F. Cellular and metabolic alterations in obese rats treated with monosodium glutamate during the neonatal period. Program and Abstracts of the American Pediatric Society Atlantic City, New Jersey, April 29, 1970, p6. or Bulletin Am Peds Soc Gen Mtg Program Abstracts p 6, April 1970.

80. Araujo, P.E., and Mayer J. Activity increase associated with obesity induced by monosodium glutamate in mice. Am J Physiol 225: 764-765, 1973.

81. 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.

82. 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.

83. 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.

84. 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.

85. Tafelski, T.J. and Lamperti, A.A. The effects of a single injection of monosodium glutamate on the reproductive neuroendocrine axis of the female hamster. Biol Reprod 17: 404-411, 1977.

86. Takasaki, Y, Sekine, S., Matsuzawa, Y., Iwata, S., and Sasaoka, M. Effects of parenteral and oral administration of monosodium L-glutamate (MSG) on somatic growth in rats. Toxicol Lett 4: 327-343, 1979.

87. Matsuzawa, Y., Yonetani, S., Takasaki, Y., Iwata, S., and Sekine, S. Studies on reproductive endocrine function in rats treated with monosodium L-glutamate early in life. Toxicol Lett 4: 359-371, 1979.

88. Matsuyama, S., Oki,Y., and Yokoki, Y. Obesity induced by monosodium glutamate in mice. Natl Inst Anim Health Q (Tokyo) 13: 91-101, 1973.

89. 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.

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

91. 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.

92. 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.

93. Trentini, G.P., Botticelli, A., and Botticelli, C.S. Effect of monosodium glutamate on the endocrine glands and on the reproductive function of the rat. Fertil Steril 25: 478-483, 1974.

94. Lynch, J.F. Jr., Lewis, L.M., Hove, E.L., and Adkins, J.S. Division of Nutrition, FDA, Washington, D.C. 20204. Effect of monosodium L-glutamate on development and reproduction in rats. Fed Proc 29: 567Abs, 1970.

95. 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. Iwata, S., Ichimura, M., Matsuzawa, Y., Takasaki, Y., and Sasaoka, M. Behavioral studies in rats treated with monosodium L-glutamate during the early states of life. Toxicol Lett 4: 345-357, 1979.

97. 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.

98. 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., and Butcher, R.E. Biochemical and behavioral effects of administration of monosodium glutamate to the young rat. Soc Neurosci 3rd Ann Mtg. S.D. 5/8/1973.

100. 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. Weiss, L.R., Reilly, J.F., Williams, J., and Krop, S. Effects of prolonged monosodium glutamate and other high salt diets on arterial pressure and learning ability in rats. Toxicol Appl Pharmacol 19: 389, 1971.

102. 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.

103. 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.

104. 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.

105. 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.

106. 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.

107. 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.

108. 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.

109. Bhagavan, HN, Coursin, DB, and Stewart, CN. Monosodium glutamate induces convulsive disorders in rats. Nature (London) 232: 275-276, 1971.

110. Johnston, GAR. Convulsions induced in 10-day-old rats by intraperitoneal injection of monosodium glutamate and related excitant amino acids. Biochem Pharmacol 22: 137-140, 1973.

111. Mushahwar, I.K, and Koeppe, RE. The toxicity of monosodium glutamate in young rats. Biochem Biophys Acta 244: 318-321, 1971.

112. Nemeroff, C.B., and Crisley, F.D. Lack of protection by pyridoxine or hydrazine pretreatment against monosodium glutamate induced seizures. Pharmacol Biochem Behav 3: 927-929, 1975.

113. 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.

114. Wiechert, P. Gollinitz, G. Metabolic investigations of epileptic seizures: the activity of the glutamate decarboxylase prior to and during experimentally produced convulsions. J Neurochem 15: 1265-1270, 1968. (Abstract)

115. Wiechert, P., and Herbst, A. Provocation of cerebral seizures by derangement of the natural balance between glutamic acid and y-aminobutyric acid. J Neurochem 13: 59-64, 1966.

116. Wiechert, P., and Gollnitz, G. Metabolic investigations of epileptic seizures: investigations of glutamate metabolism in regions of the dog brain in preconvulsive states. J Neurochem 17: 137-147, 1970. (Abstract)

117. Stricker-Krongrad, A., Burlet, C., Beck, B. Behavioral deficits in monosodium glutamate rats: Specific changes in the structure of feeding behavior. Life Sciences. Elsevier Science, Inc. US 62 (23):2127-2132, 1998.

118. Goldman, M., Stowe, G. E. The modifying influence of aging on behavior in mice neonatally injected with monosodium glutamate. Psychopharmacology 86 (3):359-364,1985.

119. 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. 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.

121. 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.

122. 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.

123. 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.

124. 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.

125. 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.

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

127. Olney, J.W. and Price, M.T. Neuroendocrine interactions of excitatory and inhibitory amino acids. Brain Research Bulletin 5: Suppl 2, 361-368, 1980.

128. Olney, J.W. and Price M.T. Excitotoxic amino acids as neuroendocrine probes. In: Kainic Acid as a Tool in Neurobiology McGeer, E.G., et al. Eds. New York: Raven Press, 1978.

129. Olney, J.W. Excitotoxic amino acids: research applications and safety implications. In: Glutamic Acid: Advances in Biochemistry and Physiology Filer, L.J. Jr., et al. Ed. New York: Raven Press, 1979.

130. Olney, J.W. and Price, M.T. Neuroendocrine interactions of excitatory and inhibitory amino acids. Brain Research Bulletin 5: Suppl 2, 361-368, 1980.

131. Nemeroff, C.B. Monosodium glutamate-induced neurotoxicity: review of the literature and call for further research. In: Nutrition & Behavior Miller, S.A., Ed. Philadelphia: The Franklin Institute Press, 1981.

132. Olney, J.W. and Price M.T. Excitotoxic amino acids as neuroendocrine probes. In: Kainic Acid as a Tool in Neurobiology McGeer, E.G., et al. Eds. New York: Raven Press, 1978.

133. Allen, DH, Delohery, MB, Baker, G. Monosodium L-glutamate-induced asthma. J Allergy Clin Immunol. 80(4):530-537.

134. Winter, G. Food companies agree to make labels clearer, list trace amounts. San Diego Union-Tribune May 31, 2001. P A11.

135. Laoprasert, N, Wallen, ND, Jones, RT, Hefle, SL, Taylor, SL, Yunginger, JW. Anaphylaxis in a milk-allergic child following ingestion of lemon sorbet containing trace quantities of milk. Journal of Food Protection 61(11):1522-4,1998.

136. Hourihane, JO'B, Kilburn, SA, Nordlee, JA, Hefle, SL, Taylor, SL, Warner, JO. An evaluation of the sensitivity of subjects with peanut allergy to very low doses of peanut protein: a randomized, double-blind, placebo-controlled food challenge study. Journal of Allergy and Clinical Immunology 100(5):596-600, 1997.

137. Strong, F.C. Why do some dietary migraine patients claim they get headaches from placebos? Clinical and Experimental Allergy 30:739-743, 2000.

138. Olney, J.W. Brain damage and oral intake of certain amino acids. Advances in Experimental Medicine and Biology 69:497-506, 1976.

139. The minute amounts of free glutamic acid referred to by the applicant, which were cited in studies done years ago, may be artifacts of the analytical methods used at that time.

140. Sax, N.I. Dangerous Properties of Industrial Materials. Sixth Edition. New York: Van Nostrand, 1984.

141. 44296413 - US Department of Health and Human Services (1986) (Summary toxicity data). P 2522-2527 in NIOSH Registry of Toxic Effects of Chemical Substances (RTECS)-(1985-1986). v.3

142. Anantharaman, K. In utero and dietary administration of monosodium L-glutamate to mice: reproductive performance and development in a multigeneration study. In: Glutamic Acid: Advances in Biochemistry and Physiology New York: Raven, 1979, pp 231-253.(See page 236, Table 3.)

143. Janaky, R; Varga, V; Hermann, A; Saransaari, P; Oja, S.S. Mechanisms of L-cysteine neurotoxicity Neurochemical Research 25(9-10):1397-405, 2000.

144. In the 1970s, in order to identify brain damage, it was necessary to observe and compare the brains of treated and control animals within 24 hours following treatment. Within 24 hours after lesions in the brain are produced by treatment with processed free glutamic acid or any other neurotoxic substance, those lesions begin to fill in with glial cells which, in the 1970s, could not be distinguished from the neurons they replaced.

145. 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.