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    In genetically predisposed individuals, exposure to gluten present in wheat, barley or rye, or the plant storage proteins of these grains, leads to the development of a permanent hypersensitivity reaction called the celiac disease (CD). CD is an immune-mediated enteropathy of the small intestine.

    The report is divided in two parts :

    • the hazard assessment part describes the morphological and clinical adverse effects that are reflective of CD. A number of estimates of gluten consumption from food products are also determined and presented.
    • the risk characterization part determines the tolerable daily intake (TDI) levels of gluten for the genetically predisposed individuals for each type of adverse morphological and clinical effects in gluten sensitive individuals.

    In addition, the uncertainty issues associated with the data available are addressed.

    What is Gluten?

      A significant discrepancy is found in the use and thus “definition” of the term gluten. For the most part, gluten is a component of wheat, rye and barley that consists of a complex mixture of heterogeneous plant storage proteins commonly referred to as the prolamin and glutelin category proteins.

      Although all cereal grains contain prolamin and glutelin proteins, technically, gluten is found only in wheat grain even if rye and barley also contain major plant storage proteins that are thought to trigger enteropathic reactions.

      These proteins differ in their amino acid sequences among different grains, and not all have been shown to provoke an abnormal immune response that affects the intestinal lining of individuals who are genetically susceptible to celiac disease.

      For single ingredient of foods made from wheat, rye, barley but alo triticale, and oats, the simple presence of "proteins" in that food may be used as an indicator that gluten-like proteins are present.

      Several studies have reported that most celiac patients tolerated moderate amounts (e.g., 50-70 grams daily) of oats as a grain alternative, but in the U.S., most commercially available oat products are believed to contain some gluten proteins from wheat, rye, or barley due to cross-contact with these grains during growth, harvest, transport, storage, or processing. The cereal grains assumed to be safe for people with celiac disease include amaranth, buckwheat, corn, Indian ricegrass, Job's tears, millet, quinoa, ragi, rice, sorghum, teff (or tef), and wild rice.

      What is the Celiac Disease (CD)?

        In people who have the genetic predisposition, Celiac Disease is a permanent hypersensitivity reaction triggered by ingestion of gluten. It is a serious illness that is associated with significant overt and covert toxicological effects. It also has a secondary connection to a number of other disorders and diseases.

        More specifically, a significant part of the genetic predisposition is associated with a specific class of genes , the human leukocyte antigen (HLA) class II genes located in the major histocompatibility complex (MHC) of chromosome 6. Other non-HLA genes may also have a determining influence on susceptibility to CD which include environmental factors (e.g., breast-feeding can lower the risk, infections can increase it), abnormalities in the immune system (e.g., selective IgA deficiency), and certain genetic based syndromes.


        In sensitive individuals, the reactions to gluten (or related protein subfractions) occur after acute, subacute, subchronic and long-term or chronic exposure durations to these substances with differences in reaction timeframes. Celiac disease affects only a small proportion of the population which is estimated at 1% in the U.S.

        It is thus important to underline that only individuals who are genetically sensitive to gluten ingestion will develop a Celiac Disease or its associated dematitis (DH, or dermatitis herpetiformis). Exposure to dietary gluten in a healthy individual who is not genetically predisposed, causes no detrimental health effects.

        What are the adverse effects of Celiac Disease resulting from an intolerance to gluten?

          To people predisposed to CD, gluten can be an acute, subchronic and/or chronic toxin. The critical effect is immune-mediated and consists of a progressive spectrum of adverse changes in the small intestine mucosa resulting in an enteropathy. The most significant abnormalities are usually found in the proximal small intestine (e.g., duodenum) mucosal and typically involves abnormal morphology such as inflammatory cell infiltrate, influx of lymphocytes and ultimately progress sequentially until the endstage of deterioration of the small intestine mucosa. The disorder can progress distally (e.g., to the jejunum), and even involve the entire small intestine in some individuals. This disease is often misdiagnosed to be another gastrointestinal malabsorptive disorder (e.g., irritable bowel syndrome), due to similarities in their symptoms.

          The enteropathy found in CD is tied, at least in part, to an array of clinical signs and symptoms (e.g. diarrhea, constipation, abdominal pain, nausea and/or vomiting), and also with other sequelae (e.g., anemia, nutritional deficiencies, growth disturbances, weight loss and osteopenia or osteoporosis) that are associated with enteropathy-induced malabsorption.

          Other signs and symptoms that have been reported in those afflicted by CD are, among many others, fatigue, irritability, malaise, anorexia, mouth ulcers, headaches, mood changes, depression, pain and various neurological responses. Also CD and exposure to gluten is associated to an increased risk of development of secondary disorders and diseases that include a number of autoimmune conditions, bone diseases and malignancies.

          A tremendous variability in the timing and of adverse clinical and/or morphological effects of effects exist between sensitive individuals. In addition, age differences are suggested to play a role in the nature of the adverse reaction to gluten ingestion.

          Of the total affected population, it is considered that individuals with clinical manifestations represent a small portion and that a larger number of individuals have "silent" celiac disease, which is characterized by intestinal mucosal abnormalities in the absence of symptoms or nutritional deficiencies. Some individuals that are asymptomatic lead to a delayed diagnosis of many years (often >10 years) prior to receiving a correct diagnoses of their illness.

          What are the criteria used to identify a Celiac Disease (CD) ?

            Clinical symptoms are currently viewed as the best indicators, or biomarkers, of the hypersensitivity response and of its severity.

            Different medical societies, associations and groups have promulgated varying criteria that are used to define CD and to establish the presence of this disease in patients. These criteria have several components to be met :

            • The first component is the performance of a small intestinal biopsy while individuals are consuming a gluten-containing diet, and the determination of the presence of abnormal mucosal morphology;
            • A second component is the assessment of the result of patient responses to a gluten free diet (GFD) The resolution of clinical symptoms in patients within weeks or months on a GFD provides additional support to the diagnosis of CD.
            • A formal « gluten challenge » test (a controlled exposure to gluten) is another component of the diagnostic criteria for CD required by some medical groups.
            • Some additional measures and tests such as the use of antibody tests have been suggested in support of the diagnosis.

            The responses exhibited by subjects in « gluten challenge » tests vary widely, they are different for each subject and differ between children and adults. Some subjects exhibit clinical signs and symptoms (e.g. diarrhea, constipation, abdominal pain, nausea, fatigue) and others do not. For some subjects, the only adverse reaction exhibited was morphological (e.g., small intestine mucosa), or possibly physiological (e.g., gastrointestinal absorption measures, immune response), in nature. Some subjects, have a combination of types of adverse reactions.

            What are the Tolerable Daily Intake doses for Gluten for subjects intolerant to gluten?

              The estimated tolerable daily intake (TDI) level from data of a critical study in individuals with CD for acute (single) gluten exposure to avoid acute morphological effect is 12.5 mg/day ; the TDI for subchronic (repeated) exposure to avoid effects is 0.4 mg gluten/day and for chronic exposure is 7.0 mg gluten/day. Possible reasons that the TDI is lower for subchronic exposure than for chronic exposure may be due to the fact that the former is based on data from adults, while the latter is based on data from children. These TDI values apply only to exposure to wheat gluten and were derived applying margins of safety to a No Adverse Effect Level (NOAEL) of exposure and an acute Low Adverse Effect Level (LOAEL) of exposure of 125 and 625 mg gluten/day, respectively.

              Because of the significant degree of individual variability in the sensitivity and responsiveness to gluten a wider margin of safety may be warranted to provide a higher level of protection for gluten-sensitive individuals, especially those who are the most sensitive.

              Regarding the presence of gluten in food, globally, a less than 1 mg gluten/kg food (or ppm) is the level that protects the most sensitive individuals and thus, also protects the greatest number of individuals with CD from experiencing any detrimental health effects from extended to long-term exposure to gluten.

              More specifically, the “Level of Concern” (or LOC = concentrations of gluten in food that corresponds to the TDIs) for gluten consumption in wheat gluten-free “replacement” food were estimated as 0.04 mg gluten/kg food for clinical symptoms and 1 mg/kg food for morphological symptoms.

              These values are estimates of the level of consumption of "gluten-free" foods which are based on an assumed comparable intake to similar foods that would normally contained wheat-based gluten for each "exposure type" duration.

              Extrapolation of quantitative data and estimates derived from wheat gluten studies to other grains is problematic, but it is assumed in this report that the toxic potency of wheat gluten is comparable to the gluten-like proteins in rye and barley.

              Are there other health effects of gluten intolerance?

                Another chronic condition associated with exposure to wheat gluten and related protein derivatives in rye and barley is Dermatitis Herpetiformis (DH). It is an autoimmune skin disease that results in clusters of an intensely pruritic skin rash characterized by papules and vesicles typically located in a symmetrical fashion on the extensor surface of the elbows and knees in addition to the lower back or buttocks, scalp of the back of the head and posterior neck.

                Other medical conditions or states that have also emerged as a part of the spectrum of clinical presentations associated with Celiac Disease are:

                • Autoimmune Diseases: a number of autoimmune diseases are more likely to occur in patients with CD than in the general population;
                • Bone Diseases: CD is often accompanied by secondary diseases that reflect the existence of abnormalities in bone metabolism;
                • Cancer that occurs more often in celiac disease patients than in others without the disease. Many of the cancers associated with CD are gastrointestinal malignancies such as enteropathy-associated T-cell lymphoma, small bowel adenocarcinoma, and esophageal and oropharyngeal squamous carcinoma;
                • Higher Mortality Rate reported for individuals with CD than for the general population, which has been attributed to both the associations between CD and autoimmune disease(s) and/or cancer.

                What is the effective treatment against the Celiac Disease (CD) induced by gluten in sensitive individuals?

                  The only effective treatment currently available for the sensitive subpopulation of individuals that develop CD and other associated conditions, is to avoid the trigger of the disease. This can be achieved by the “gluten-free diet” (or GFD) dietary regimen, which permanently eliminates the cereals of wheat, rye and barley and all their respective disease-inducing protein constituents, from the diet. Although the rate of recovery varies between individuals, this treatment is associated with decreases in clinical signs and symptoms, resolution of histopathological signs of the small intestine, and reports of improved quality of life in individuals with CD. The improvements seen in CD sufferers on a GFD relapse upon re-introduction of dietary gluten.

                  Meanwhile, it has been recognized that it is difficult, if not impossible, to maintain a diet that is completely devoid of gluten. Therefore, in the US, a food product can be labeled as "gluten-free" if it contains less than 20 ppm of gluten.

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