Review of harmful gastrointestinal effects of carrageenan in animal experiments. (Research Review).
In this article I review the association between exposure to carrageenan car·ra·geen·an or car·ra·geen·in
Any of a group of closely related colloids derived from several red algae, widely used as a thickening, stabilizing, emulsifying, or suspending agent in pharmaceuticals. and the occurrence of colonic ulcerations Ulcerations
Breaks in skin or mucous membranes that are often accompanied by loss of tissue on the surface.
Mentioned in: Hypersplenism and gastrointestinal neoplasms in animal models. Although the International Agency for Research on Cancer The International Agency for Research on Cancer (IARC, or CIRC in its French acronym) is an intergovernmental agency forming part of the World Health Organisation of the United Nations.
Its main offices are in Lyon, France. in 1982 identified sufficient evidence for the carcinogenicity carcinogenicity /car·ci·no·ge·nic·i·ty/ (kahr?si-no-je-nis´i-te) the ability or tendency to produce cancer.
the ability or tendency to produce cancer. of degraded carrageenan in animals to regard it as posing a carcinogenic carcinogenic
having a capacity for carcinogenesis. risk to humans, carrageenan is still used widely as a thickener thick·en
tr. & intr.v. thick·ened, thick·en·ing, thick·ens
1. To make or become thick or thicker: Thicken the sauce with cornstarch. The crowd thickened near the doorway.
2. , stabilizer stabilizer: see airplane. , and texturizer in a variety of processed foods prevalent in the Western diet. I reviewed experimental data pertaining per·tain
intr.v. per·tained, per·tain·ing, per·tains
1. To have reference; relate: evidence that pertains to the accident.
2. to carrageenan's effects with particular attention to the occurrence of ulcerations and neoplasms in association with exposure to carrageenan. In addition, I reviewed from established sources mechanisms for production of degraded carrageenan from undegraded or native carrageenan and data with regard to carrageenan intake. Review of these data demonstrated that exposure to undegraded as well as to degraded carrageenan was associated with the occurrence of intestinal ulcerations and neoplasms. This association may be attributed to contamination of undegraded carrageenan by components of low molecular weight, spontaneous metabolism of undegraded carrageenan by acid hydrolysis hydrolysis (hīdrŏl`ĭsĭs), chemical reaction of a compound with water, usually resulting in the formation of one or more new compounds. under conditions of normal digestion, or the interactions with intestinal bacteria. Although in 1972, the U.S. Food and Drug Administration considered restricting dietary carrageenan to an average molecular weight > 100,000, this resolution did not prevail, and no subsequent regulation has restricted use. Because of the acknowledged carcinogenic properties of degraded in animal models and the cancer-promoting effects of undegraded in experimental models, the widespread use of carrageenan in the Western diet should be reconsidered. Key words: carcinogenesis car·ci·no·gen·e·sis
The production of cancer.
production of cancer.
viruses and some parasites are capable of initiating neoplasia. , carrageenan, carrageenase, diet, furcelleran (furcellaran), hydrolysis, inflammatory bowel disease inflammatory bowel disease
n. Abbr. IBD
Any of several incurable and debilitating diseases of the gastrointestinal tract characterized by inflammation and obstruction of parts of the intestine. , nutrition, poligeenan, promoter, sulfated polysaccharide polysaccharide: see carbohydrate.
Any of a large class of long-chain sugars composed of monosaccharides. Because the chains may be unbranched or branched and the monosaccharides may be of one, two, or occasionally more kinds, . Environ Health Perspect 109:983-994 (2001). [Online 24 September 2001] http://ehpnet1.niehs.gov/docs/2001/109p983-994tobacman/abstract.html
During the latter half of the twentieth century, inflammatory bowel disease and gastrointestinal malignancy malignancy: see cancer. have been major causes of morbidity and mortality Morbidity and Mortality can refer to:
Malignant tumour of the large intestine (colon) or rectum. Risk factors include age (after age 50), family history of colorectal cancer, chronic inflammatory bowel diseases, benign polyps, physical inactivity, and a diet high in fat. remains the second leading cause of cancer mortality in the United States. The Western diet has been considered a possible source of inflammatory bowel disease and colorectal malignancy, and intensive efforts have been undertaken to study the impact of specific constituents of the Western diet, such as fiber and fat (1-3).
One food additive Noun 1. food additive - an additive to food intended to improve its flavor or appearance or shelf-life
additive - something added to enhance food or gasoline or paint or medicine , carrageenan, has been associated with induction and promotion of intestinal neoplasms and ulcerations in numerous animal experiments; however, carrageenan remains a widely used food additive. In 1982, the International Agency for Research on Cancer (IARC) (4) designated degraded carrageenan as Group 2B, noting sufficient evidence for the carcinogenicity of degraded carrageenan in animal models to infer that "in the absence of adequate data on humans, it is reasonable, for practical purposes, to regard chemicals for which there is sufficient evidence of carcinogenicity in animals as if they presented a carcinogenic risk to humans" (p. 90). The National Research Council has noted this designation for degraded carrageenan in their 1996 monograph (5). Recognizing the impact of carrageenan in animal models, several European and British investigators have advised against the continued use of carrageenan in food (6-11). Several reports have called attention to the problems associated with carrageenan consumption (6-11).
Extracted from red seaweed seaweed, name commonly used for the multicellular marine algae. Simpler forms, consisting of one cell (e.g., the diatom) or of a few cells, are not generally called seaweeds; these tiny plants help to make up plankton. , carrageenan has been used in food products for centuries and was patented as a food additive for use in the United States in the 1930s. It has been used widely as a food additive, contributing to the texture of a variety of processed foods. It has also been used as a laxative laxative, drug or other substance used to stimulate the action of the intestines in eliminating waste from the body. The term laxative usually refers to a mild-acting substance; substances of increasingly drastic action are known as cathartics, purgatives, , as treatment for peptic ulcer disease Peptic ulcer disease (PUD)
A stomach disorder marked by corrosion of the stomach lining due to the acid in the digestive juices.
Mentioned in: Indigestion
peptic ulcer disease See Duodenal ulcer, Gastric ulcer, GERD. , and as a component of pharmaceuticals, toothpaste, aerosol sprays, arm other products (12-15). In 1959, carrageenan was granted GRAS GRAS - A public domain graph-oriented database system for software engineering applications from RWTH Aachen. (Generally Regarded as Safe) status in the United States. GRAS substances are permitted to be incorporated into food products as long as good manufacturing processes are used and the substance is used only in sufficient quantity to achieve the desired effect (16,17).
In the United States, the status of carrageenan was reconsidered by the Food and Drug Administration, and an amendment to the Code of Federal Regulations The New Deal program of legislation enacted during the administration of President franklin roosevelt established a large number of new federal agencies, which generated a shapeless and confusing mass of new regulations. for the food additive carrageenan was proposed in 1972 (18). To diminish the public's exposure to degraded carrageenan, the amendment supported inclusion of an average molecular weight for carrageenan of 100,000 and a minimum viscosity of 5 centipoises (cps) under specified conditions. However, the actual regulation was not amended, although several publications indicated that it had been modified (7,8,19-23). In 1979, the proposal to include the average molecular weight requirement of 100,000 and the associated viscosity requirement in the Code of Federal Regulations was withdrawn. It was anticipated that a new rule-making proposal on carrageenan that would comprehensively address all food safety aspects of carrageenan and its salts would be published in about a year, but this has not been forthcoming (24,25). The proposal withdrawal referred to interim specifications for food-grade carrageenan using the Food Chemical Codex codex
Manuscript book, especially of Scripture, early literature, or ancient mythological or historical annals. The earliest type of manuscript in the form of a modern book (i.e. ; these include a viscosity stipulation An agreement between attorneys that concerns business before a court and is designed to simplify or shorten litigation and save costs.
During the course of a civil lawsuit, criminal proceeding, or any other type of litigation, the opposing attorneys may come to an agreement , but no average molecular weight requirement (26).
In the Food Chemicals Codex and supplements, carrageenan is described with attention to specific requirements for its identification and tests of its properties, including its sulfate sulfate, chemical compound containing the sulfate (SO4) radical. Sulfates are salts or esters of sulfuric acid, H2SO4, formed by replacing one or both of the hydrogens with a metal (e.g., sodium) or a radical (e.g., ammonium or ethyl). content, heavy metal content, solubility solubility
Degree to which a substance dissolves in a solvent to make a solution (usually expressed as grams of solute per litre of solvent). Solubility of one fluid (liquid or gas) in another may be complete (totally miscible; e.g. in water, content of acid-insoluble matter, and viscosity [a 1.5% solution is to have viscosity [is greater than or equal to] 5 cps at 75 [degrees] C] (26,27). Although the viscosity is stipulated, viscosity may not adequately protect food-grade carrageenan from contamination by the lower molecular weight degraded carrageenans that IARC has denoted as Group 2B. Because undegraded carrageenan may have molecular weight in the millions, the actual viscosities of commercial carrageenans range from about 5 to 800 cps when measured at 1.5% at 75 [degrees] C (14). Native carrageenan has molecular weights of 1.5 x [10.sup.6]-2 x [10.sup.7] (28); poligeenan or degraded carrageenan is described as having average molecular weight of 20,000-30,000 (4). The average molecular weight of poligeenan has been described elsewhere as 10,000-20,000, but extending up to 80,000 (29). Food-grade carrageenan has been described as having average molecular weight of 200,000-400,000 (29), and elsewhere as having molecular weight of 100,000-800,000 (19). Furcelleran (or furcellaran), a degraded carrageenan of molecular weight 20,000-80,000, has a sulfate content of 8-19% (12,17). No viscosity or minimum average molecular weight was designated for furcelleran in the 1972 or 1979 Federal Register documents (18,24). In the Food Chemical Codex (fourth edition), a 1.5% solution of furcelleran at 75 [degrees] C is described as having minimum viscosity of 5 cps (27).
Today, carrageenan is still included among the food additives food additives, substances added to foods by manufacturers to prevent spoilage or to enhance appearance, taste, texture, or nutritive value. By quantity, the most common food additives are flavorings, which include spices, vinegar, synthetic flavors, and, in the designated GRAS in the Code of Federal Regulations. The stipulations for its use include the following: a) it is a sulfated polysaccharide, the dominant hexose hexose /hex·ose/ (hek´sos) a monosaccharide containing six carbon atoms in a molecule.
n. units of which are galactose and anhydrogalactose; b) range of sulfate content is 20-40% on a dry-weight basis; c) the food additive is used or intended for use in the amount necessary for an emulsifier emulsifier /emul·si·fi·er/ (e-mul´si-fi?er) an agent used to produce an emulsion.
An agent used to make an emulsion of a fixed oil. , stabilizer, or thickener in foods, except for those standardized foods that do not provide for such use; d) to assure safe use of the additive, the label and labeling of the additive shall bear the name of the additive, carrageenan. Also included are similar standards for carrageenan salts and for furcelleran and furcelleran salts (30). In 1999-2000, approved uses for carrageenan were extended to include additional incorporation into food and medicinal products, including both degraded and undegraded carrageenan in laxatives Laxatives Definition
Laxatives are products that promote bowel movements.
Laxatives are used to treat constipation—the passage of small amounts of hard, dry stools, usually fewer than three times a week. (31-33).
For use in experimental models, degraded carrageenan (poligeenan) is derived from carrageenan by acid hydrolysis, frequently by a method developed by Watt et al. (34). This method is expected to yield a degraded carrageenan of average molecular weight 20,000-30,000 (35). Experiments demonstrate that reaction conditions similar to those of normal digestion can lead to the formation of degraded carrageenan (9-11). In addition, experimental data have revealed the contamination of food-grade carrageenan by substantial amounts of degraded carrageenan (10). Also, some bacteria are known to hydrolyze hydrolyze
to performance hydrolysis. carrageenan and form low molecular weight derivatives (36-40).
The sections that follow and the accompanying tables summarize many experimental observations with regard to the intestinal effects of carrageenan. In addition, I review possible mechanisms for production of degraded carrageenan from undegraded carrageenan under physiologic conditions, as well as evidence that provides a basis for the mechanism of carrageenan's effects and for the reconsideration of the safety of carrageenan in the human diet.
Characteristics of Carrageenan
Three forms of carrageenan predominate, known as kappa Kappa
Used in regression analysis, Kappa represents the ratio of the dollar price change in the price of an option to a 1% change in the expected price volatility.
Remember, the price of the option increases simultaneously with the volatility. , iota, and lambda. All have similar D-galactose backbones (alternating [alpha]-1,3 to [beta]-1,4 linkages), but they differ in degree of sulfation, extent of branching, solubility, cation cation (kăt'ī`ən), atom or group of atoms carrying a positive charge. The charge results because there are more protons than electrons in the cation. binding, and ability to form gels under different conditions. [lambda]-Carrageenan is the least branched and the least gel forming; it is readily soluble at cold temperatures, in contrast to [kappa]- or [iota]-carrageenan. Table 1 presents some of the basic characteristics of [kappa], [iota], and [lambda] carrageenan (4,12-15,20-22,31-33,41-44)
In addition to food additive uses, carrageenan has been used in cosmetics, pesticides, and pharmaceuticals, as well as in toothpaste and room deodorizers. It has been used as a treatment of ulcers and as an emulsifier in mineral oil laxatives, liquid petrolatum petrolatum (pĕtrəlā`təm), colorless to yellowish-white hydrocarbon mixture obtained by fractional distillation of petroleum. , and cod liver oil cod liver oil
an oil pressed from the fresh liver of the cod and purified. It is one of the best-known natural sources of vitamin D, and a rich source of vitamin A. Because cod liver oil is more easily absorbed than other oils, it was formerly widely used as a nutrient and tonic, . However, its predominant role has been in food preparations, in which it is used across a wide variety of food groups because of its ability to substitute for fat and its ability to combine easily with milk proteins to increase solubility and improve texture. Hence, it is used in low-calorie formulations of dietetic dietetic /di·e·tet·ic/ (di?ah-tet´ik) pertaining to diet or proper food.
1. Of or relating to diet.
2. beverages, infant formula Infant formula is an artificial substitute for human breast milk. Formulas are designed for infant consumption, and are usually based on either cow milk or soy milk. Use of infant formula has been decreasing in industrial countries for over forty years as a result of antenatal , processed low-fat meats, whipped cream, cottage cheese cottage cheese
a soft, uncured cheese made from soured skim milk; most of the lactose is removed with the whey. Used in low-residue diets for dogs and cats. , ice cream, and yogurt, as well as in other products. From its original use several centuries ago as a thickener in Irish pudding and its incorporation into blancmange blanc·mange
A flavored and sweetened milk pudding thickened with cornstarch.
[Middle English blankmanger, a dish made with almond milk, from Old French blanc mangier : , the food additive use has extended widely and cuts across both low-fat and high-fat diets. It is often combined with other gums, such as locust bean gum Locust bean gum is a galactomannan vegetable gum extracted from the seeds of the Carob tree. It is used as a thickener and gelling agent in food technology. It is also called Carob Gum. External links
In 1977, data obtained by the survey of industry on the use of food additives produced an estimate of daily carrageenan intake of 100 mg for individuals older than 2 years. The 1971 survey of industry had indicated that formula-fed infants in the first 5 months of life had an intake of 108 mg/day (21,43). Informatics, Inc., in a report prepared for the Food and Drug Administration, cited daily carrageenan consumption of 45 mg (19); this is similar to the reported intake of 50 mg/day of carrageenan in France (45). Nicklin and Miller (20) reported intake of 0-1.5 g/day, depending on choice of diet and total food consumed. Although the Food and Nutrition Food and Nutrition
See also cheese; dining; milk.
Rare. the act or habit of reclining at meals.
Medicine. thescience of nutrition.
Pathology. Board of the National Research Council of the National Academy of Sciences of the United States in 1971 initially estimated 367 mg/day for carrageenan intake for individuals older than 2 years in the United States, this was subsequently revised to 11 mg/day. The wide range of estimates may be attributed to inconsistencies in how industry has reported carrageenan production and consumption data, variation in processed food formulations with regard to extent of incorporation of carrageenan, and changes in use of carrageenan in nonfood non·food
Of, relating to, or being something that is not food but is sold in a supermarket, as housewares or stationery. products. Daily individual consumption of between 50 mg/day and 100 mg/day is consistent with total consumption in the United States of 7,700 metric tons, as estimated for 1997 (46).
The content of carrageenan in several commonly consumed food products is summarized in Table 2. Because manufacturing practices vary and change over time and the food formulae are proprietary, carrageenan content is indicated by a range (12,13,47-49). The content is expressed as the percent by weight of carrageenan used in the production of the food.
Experimental Results in Animal Models
Intestinal lesions after exposure to carrageenan in animal models. Table 3 summarizes the laboratory investigations that associate exposure to carrageenan with the occurrence of intestinal lesions (50-93). Several animals were tested, including guinea pig guinea pig (gĭn`ē), domesticated form of the cavy, Cavia porcellus, a South American rodent. It is unrelated to the pig; the name may refer to its shrill squeal. , rat, monkey, mouse, rabbit, and ferret. The guinea pig seemed most susceptible to ulceration ulceration /ul·cer·a·tion/ (ul?ser-a´shun)
1. the formation or development of an ulcer.
2. an ulcer.
1. Development of an ulcer.
2. and the rat most susceptible to malignancy. Many studies used exposure to carrageenan in a drinking fluid, at concentrations generally of 1%. Some were feeding studies, in which carrageenan was added to a solid diet. Some studies used gastric or duodenal duodenal /du·o·de·nal/ (doo?o-de´n'l) (doo-od´ah-n'l) of or pertaining to the duodenum.
Refers to the duodenum, or the first part of the small intestine. intubation intubation /in·tu·ba·tion/ (in?too-ba´shun) the insertion of a tube into a body canal or hollow organ, as into the trachea.
endotracheal intubation to ensure intake at a specified level; however, this method may have affected the way that carrageenan was metabolized by gastric acid gastric acid,
n the hydrochloric acid secreted by the gastric glands in the stomach; aids in the preparation of food for digestion. (74,82-84,91). Feeding of carrageenan with milk may also have affected study results, because carrageenan binds tightly to milk proteins (caseins), affecting its metabolism (12-15, 22,41,42,47). The degraded carrageenan used in most of the experiments had molecular weight from 20,000 to 40,000. Several major findings in relation to neoplasia neoplasia /neo·pla·sia/ (-pla´zhah) the formation of a neoplasm.
cervical intraepithelial neoplasia and ulceration were observed in these animal studies. All of these studies observed the effects of carrageenan in comparison to appropriate control animals.
In the footnote to Table 3, several subdivisions of the table are indicated with citation of the entries from the table. The subdivisions include: a) studies in which carrageenan alone induces abnormal proliferation or malignancy, b) studies in which carrageenan alone induces intestinal ulcerations, c) studies in which carrageenan appears to be a promoter of malignancy in association with another agent, d) studies using a rat model, e) studies using a guinea pig model, f) studies using degraded carrageenan, g) studies using undegraded carrageenan, h) studies indicating uptake of carrageenan into an extraintestinal site(s), i) studies indicating intestinal breakdown of carrageenan into lower molecular weight forms, and j) studies demonstrating ulcerations in rats using degraded carrageenan. In the table, the classification of the carrageenan used in the experiments as [kappa], [lambda], or [iota] is indicated when this information is clear from the original report.
Neoplasia. Wakabayashi and associates (72) demonstrated the appearance of colonic tumors in 32% of rats fed 10% degraded carrageenan in the diet for less than 24 months. The lesions included squamous cell carcinomas squamous cell carcinoma
A carcinoma that arises from squamous epithelium and is the most common form of skin cancer. Also called cancroid, epidermoid carcinoma. , adenocarcinomas, and adenomas. With exposure to 5% degraded carrageenan in drinking water drinking water
supply of water available to animals for drinking supplied via nipples, in troughs, dams, ponds and larger natural water sources; an insufficient supply leads to dehydration; it can be the source of infection, e.g. leptospirosis, salmonellosis, or of poisoning, e.g. , there was a 100% incidence of colonic metaplasia metaplasia /meta·pla·sia/ (met?ah-pla´zhah) the change in the type of adult cells in a tissue to a form abnormal for that tissue. after 15 months. Metastatic Metastatic
The term used to describe a secondary cancer, or one that has spread from one area of the body to another.
Mentioned in: Coagulation Disorders
pertaining to or of the nature of a metastasis. squamous cell carcinoma was observed in retroperitoneal retroperitoneal /ret·ro·peri·to·ne·al/ (-per?i-to-ne´al) posterior to the peritoneum.
Situated behind the peritoneum. lymph nodes Lymph nodes
Small, bean-shaped masses of tissue scattered along the lymphatic system that act as filters and immune monitors, removing fluids, bacteria, or cancer cells that travel through the lymph system. in this experiment. In addition, macrophages Macrophages
White blood cells whose job is to destroy invading microorganisms. Listeria monocytogenes avoids being killed and can multiply within the macrophage. that had metachromatic staining consistent with carrageenan uptake were observed in liver and spleen spleen, soft, purplish-red organ that lies under the diaphragm on the left side of the abdominal cavity. The spleen acts as a filter against foreign organisms that infect the bloodstream, and also filters out old red blood cells from the bloodstream and decomposes .
Other studies have demonstrated the development of polypoidal lesions and marked, irreversible squamous metaplasia squamous metaplasia
See epidermalization. of the rectal mucosa, the extent of which was associated with duration and concentration of carrageenan exposure (67,70). Oohashi et al. (67) observed a 100% incidence of colorectal squamous metaplasia that progressed even after degraded carrageenan intake was discontinued in rats fed 10% degraded carrageenan for 2, 6, or 9 months and sacrificed at 18 months.
Fabian et al. (84) observed adenomatous adenomatous /ad·e·nom·a·tous/ (ad?e-nom´ah-tus)
1. pertaining to an adenoma.
2. pertaining to nodular hyperplasia of a gland.
1. and hyperplastic polyps as well as squamous metaplasia of the anorectal a·no·rec·tal
Relating to the anus and the rectum.
pertaining to, emanating from or affecting the anorectum.
see perianal fistula. region and the distal colon in rats given 5% carrageenan as a drinking fluid. Similarly, Watt and Marcus (90) observed hyperplastic Hyperplastic
Mentioned in: Adenoid Hyperplasia
characterized by a state of hyperplasia, e.g. hyperplastic enteritis, hyperplastic cholangitis, hyperplastic endometritis, hyperplastic gingivitis. mucosal changes and polypoidal lesions in rabbits given carrageenan as drinking fluid for 6-12 weeks at a concentration of 0.1-5%. Focal and severe dysplasia dysplasia
Abnormal formation of a bodily structure or tissue, usually bone, that may occur in any part of the body. Several types are well-defined diseases in humans. of the mucosal epithelium was observed in rabbits after 28 months of 1% degraded carrageenan in their drinking fluid (58).
Promotion of neoplasia. Several studies demonstrated an increased occurrence of neoplasia in relation to exposure to undegraded or degraded carrageenan and associated exposure to a known carcinogen carcinogen: see cancer.
Agent that can cause cancer. Exposure to one or more carcinogens, including certain chemicals, radiation, and certain viruses, can initiate cancer under conditions not completely understood. . Experimental data with undegraded carrageenan included enhanced incidence of colonic tumors in rats treated with azoxymethane (AOM AOM Academy of Management
AOM Age of Mythology (Ensemble Studios game)
AOM Acute Otitis Media (middle ear infection)
AOM Acupuncture and Oriental Medicine
AOM America on the Move ) and nitrosomethylurea (NMU NMU - Non-Maintainer Upload ), when carrageenan was added to the diet. Groups of rats received control diet; control diet with 15% carrageenan; 15% carrageenan plus 10 injections of AOM given weekly; carrageenan plus NMU; NMU alone; and AOM alone. AOM or NMU with carrageenan led to 100% incidence of tumors, versus 57% with AOM alone and 69% with NMU alone (p < 0.01). Controls had 0%, and carrageenan alone led to an incidence of 7%. In addition, when undegraded carrageenan was combined with AOM, there was a 10-fold increase in the number of tumors per rat (73). (Figure 1)
Using undegraded carrageenan as a solid gel at concentration 2.5% for 100 days, Corpet et al. (50) found that after exposure to azoxymethane, there was promotion of aberrant aberrant /ab·er·rant/ (ah-ber´ant) (ab´ur-ant) wandering or deviating from the usual or normal course.
1. crypt crypt (krĭpt) [Gr.,=hidden], vault or chamber beneath the main level of a church, used as a meeting place or burial place. It undoubtedly developed from the catacombs used by early Christians as places of worship. foci by 15% (p = 0.019). Exposure of rats to 6% undegraded carrageenan in the diet for 24 weeks, with 1,2-dimethylhydrazine (1,2-DMH) injections weekly, was associated with an increase in tumors from 40% to 75% and with the more frequent occurrence of larger and proximal tumors (57).
Degraded carrageenan in the diet of rats at a 10% concentration in association with exposure to 1,2-DMH weekly for 15 weeks was associated with an increase in small intestinal tumors from 20% to 50% and in colonic tumors from 45% to 60% (64). Iatropoulos et al. (77) found that in rats given 5% degraded carrageenan in the drinking water for less than 30 weeks in association with injections of 1,2-DMH weekly, there were increases in poorly differentiated poorly differentiated Oncology adjective Referring to a malignancy in which the malignant cells bear minimal resemblance to the cell from which they arose. Cf Well-differentiated. adenocarcinomas and in tumors of the ascending and transverse colon transverse colon
The part of the colon that lies across the upper part of the abdominal cavity. , as well as increased proliferation of cells in the deep glandular glandular /glan·du·lar/ (glan´du-ler)
1. pertaining to or of the nature of a gland.
Several investigators have measured the effect of carrageenan on thymidine thymidine /thy·mi·dine/ (thi´mi-den) thymine linked to ribose, a rarely occurring base in rRNA and tRNA; frequently used incorrectly to denote deoxythymidine. Symbol T.
n. incorporation and colonic cell proliferation. Wilcox et al. (51) observed a 5-fold increase in thymidine kinase Thymidine kinase TK, is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 18.104.22.168. It can be found in most living cells. It is present in two forms in mammalian cells, TKI and TKII. activity in colon cells with 5% undegraded or 5% degraded carrageenan. There was an associated 35-fold increase in proliferating cells in the upper third of crypts with degraded carrageenan and an 8-fold increase with undegraded carrageenan (51). With 5% [lambda]-undegraded carrageenan fed to rats for 4 weeks, Calvert and Reicks (55) observed a 4-fold increase in thymidine kinase activity in the distal 12 cm of the colon (p < 0.001). Fath fath or fath.
fathom et al. (59) observed a 2-fold increase in colonic epithelial epithelial /ep·i·the·li·al/ (-the´le-al) pertaining to or composed of epithelium.
epithelial (ep´ithē´lē cell proliferation, with increase in labeling indices in both proximal and distal colon and extensive increase of the proliferative compartment in the proximal colon to the upper third of the intestinal crypt, after exposure of mice to 10% degraded carrageenan in drinking water for 10 days.
Ulceration. Many studies have demonstrated significant ulceration of the cecum cecum (sē`kəm): see intestine. and/or large intestine large intestine
End section of the intestine. It is about 5 ft (1.5 m) long, is wider than the small intestine, and has a smooth inner wall. In the first half, enzymes from the small intestine complete digestion, and bacteria produce many B vitamins and vitamin K. after oral exposure to carrageenan in guinea pigs, rabbits, mice, rats, and rhesus monkeys (34,35,53,56,58,59,62,63,65,68,70,71,75, 78-80,82,83,86-93). Ulcerations arose in association with exposure to either degraded or undegraded carrageenan. Lesions occurred initially in the cecum of guinea pigs and rabbits, but could be induced in more distal parts of the colon of the guinea pig, as in an experiment in which carrageenan was introduced directly into the colon after ileotransversostomy (63). In rats, the ulcerative ulcerative /ul·cer·a·tive/ (ul´se-ra?tiv) (ul´ser-ah-tiv) pertaining to or characterized by ulceration.
pertaining to or characterized by ulceration. lesions appeared initially in distal colon and rectum rectum: see intestine.
End segment of the large intestine (see digestion) in which feces accumulate just prior to discharge. It is 5–6 in. (13–15 cm) long and lined with mucous membrane. (8). Undegraded and degraded carrageenan have been associated with epithelial cell loss and erosions in rats (51,65,70,87,93).
Watt et al. (34) first observed ulcerations in response to carrageenan exposure in animal models more than three decades ago. They noted that 100% of guinea pigs given 2% degraded carrageenan as liquid for 20-30 days had colonic ulcerations and that 75% of the animals > 200 ulcers (34). When guinea pigs were given 1% undegraded carrageenan as liquid for 20-30 days, 80% developed colonic ulcerations (92). The lesions were routinely produced with carrageenan concentrations of 0.1-1%, which is similar to the concentration in a variety of food products (7,12-14).
Grasso et al. (83) demonstrated pinpoint cecal cecal /ce·cal/ (se´k'l)
1. ending in a blind passage.
2. pertaining to the cecum.
Of, relating to, or having the characteristics of the cecum. and colonic ulcerations in guinea pigs and rabbits given 5% undegraded, as well as degraded, carrageenan in the diet for 3-5 weeks. Lesions were not observed in ferrets and squirrel monkeys given degraded carrageenan by gastric intubation gastric intubation Gavage, oral intubation Insertion of a nasogastric tube into the stomach to administer or withdraw substances from the stomach (83). Other investigators have also observed ulcerations after exposure to either degraded or undegraded carrageenan (75,88). Engster and Abraham (75) observed ulceration of cecum in guinea pigs given ??-carrageenan of molecular weight 21,000-107,000, demonstrating ulcerations were also caused by higher molecular weight carrageenan. Cecal ulcerations were not found with exposures to [Kappa] or [lambda] carrageenan of molecular weight varying from 8,500-314,000.
Investigators have noted that carrageenan-induced ulcerations of the colon are dose dependent and related to duration of exposure (52,53,67,68,70,89,90). Kitsukawa et al. (52) observed small epithelial ulcerations in guinea pigs who received carrageenan in their drinking fluid at two days. Olsen and Paulsen (68) observed cecal lesions after 24 hr and confluent con·flu·ent
1. Flowing together; blended into one.
2. Merging or running together so as to form a mass, as sores in a rash. ulcerations after 7 days in guinea pigs that ingested in·gest
tr.v. in·gest·ed, in·gest·ing, in·gests
1. To take into the body by the mouth for digestion or absorption. See Synonyms at eat.
2. a 5% carrageenan solution. In rats, superficial erosions were observed at the anorectal junction at 24 hr after 10% dietary carrageenan (70); these extended more proximally over time. In 5 days of feeding with a 5% carrageenan solution, Jensen et al. (62) observed as many as 111 ulcerations/[cm.sup.2] over the mucosal surface of the cecum in the guinea pig.
Benitz et al. (82) observed a dose effect when degraded carrageenan was given at concentrations of 0.5-2% in drinking fluid to rhesus monkeys for 7-14 weeks. Watt and Marcus (89) observed that in rabbits given 0.1% degraded carrageenan as drinking fluid, 60% of the animals developed ulcerations, whereas 100% of those given 1% carrageenan had ulcerations when exposed for 6-12 weeks.
Resemblance to ulcerative colitis ulcerative colitis
Inflammation of the colon, especially of its mucous membranes. The inflamed membranes develop patches of tiny ulcers, and the diarrhea contains blood and mucus. . Several investigators have noted the resemblance between the ulcerative lesions and accompanying inflammatory changes induced by carrageenan and the clinical spectrum of ulcerative colitis (56,94-99). Since the development of the carrageenan-induced model of ulcerative disease of the colon in 1969, carrageenan exposure has been used to model ulcerative colitis and to test for response to different treatments (52,62,100,101).
Clinical features in the experimental animals exposed to carrageenan have included weight loss, anemia, diarrhea, mucous mucous /mu·cous/ (mu´kus)
1. pertaining to or resembling mucus.
2. covered with mucus.
3. secreting, producing, or containing mucus.
1. in stools, and visible or occult blood occult blood
Blood that is present in amounts too small to be seen and can be detected only by chemical analysis or microscopic examination.
Presence of blood that cannot be seen with the naked eye. in stools. The absence of small intestinal lesions and the lack of remission and exacerbation are also characteristic features of the carrageenan model (99,102).
Onderdonk (94) discussed the similarity between the carrageenan model of colitis and ulcerative colitis in humans and considered whether animal models for inflammatory bowel disease were also models for intestinal cancer intestinal cancer Colorectal cancer, see there because of the increased risk of colon cancer colon cancer, cancer of any part of the colon (often called the large intestine). Colon cancer is the second most common cancer diagnosed in the United States. in individuals with ulcerative colitis. He reviewed the findings from carrageenan-treated animals, including loss of haustral folds, mucosal granularity, crypt abscesses crypt abscesses
Abscesses that are characteristic of ulcerative colitis, and are located in the mucosa of the large intestine. , lymphocytic lymphocytic
pertaining to, characterized by or of the nature of lymphocytes. See also lymphocytic-plasmacytic.
lymphocytic choriomeningitis (LCM) infiltration, capillary congestion The condition of a network when there is not enough bandwidth to support the current traffic load.
congestion - When the offered load of a data communication path exceeds the capacity. , pseudopolyps, and strictures. Other observations have demonstrated an apparent sequence from colitis to squamous metaplasia and then to tumors of the colorectum (67,72,102). Atypical epithelial hyperplasia Focal epithelial hyperplasia is an oral infection caused by a virus similar to the wart-producing papillomavirus. This infection causes many pink or whitish and often flat-topped mucosal masses to arise. These masses are painless and very contagious. in the vicinity of carrageenan-induced ulcerations resembled findings from human ulcerative colitis that provide a link to intestinal neoplasia (86,98).
Proposed mechanism of development of lesions. A common feature observed in the animal models of ulceration in association with carrageenan exposure is macrophage macrophage /mac·ro·phage/ (mak´ro-faj) any of the large, mononuclear, highly phagocytic cells derived from monocytes that occur in the walls of blood vessels (adventitial cells) and in loose connective tissue (histiocytes, phagocytic infiltration (35,56,63,65,68,75,76,78-81, 83,84,88,92,102-104). Fibrillar fi·bril·lar or fi·bril·lar·y
1. Relating to a fibril.
2. Relating to the fine rapid contractions or twitchings of fibers or of small groups of fibers in skeletal or cardiac muscle. material and metachromatic staining of the macrophages were observed. Notably, the macrophage lysosomes lysosomes
n the self-contained organelles found inside most cells, which contain hydrolytic enzymes that aid in intracellular digestion. appeared to take up the fibrillar material and to become distorted and vacuolated vacuolated /vac·u·o·lat·ed/ (vak´u-o-lat?ed) containing vacuoles.
vac·u·o·lat·ed or vac·u·o·late
Containing vacuoles or a vacuole.
containing vacuoles. . It appeared that colonic ulcerations developed as a result of macrophage lysosomal lysosomal
pertaining to or emanating from lysosomes.
enzymes located in the lysosomes.
lysosomal phospholipidosis disruption, with release of intracellular enzymes, subsequent macrophage lysis lysis /ly·sis/ (li´sis)
1. destruction or decomposition, as of a cell or other substance, under influence of a specific agent.
2. mobilization of an organ by division of restraining adhesions.
3. , and release of intracellular contents that provoked epithelial ulceration (75, 76, 79, 84, 85, 88, 105,106). In the rhesus monkey, Mankes and Abraham (76) observed vacuolated macrophages with fibrillar material when the animals were given undegraded carrageenan of molecular weight 800,000 as a 1% solution in their drinking fluid, demonstrating the occurrence of these changes after exposure to undegraded as well as to degraded carrageenan.
In an effort to clarify further the precise pathogenic changes that occurred, Marcus et al. (35) evaluated pre-ulcerative lesions after exposure of guinea pigs to degraded carrageenan for only 2-3 days. The animals received 3% drinking solution of carrageenan, with an average daily carrageenan intake of 5.8 g/kg. Early focal lesions were observed macroscopically mac·ro·scop·ic also mac·ro·scop·i·cal
1. Large enough to be perceived or examined by the unaided eye.
2. Relating to observations made by the unaided eye. in the cecum in only one animal with this brief exposure. However, in all test animals, a diffuse cellular infiltrate infiltrate /in·fil·trate/ (in-fil´trat)
1. to penetrate the interstices of a tissue or substance.
2. the material or solution so deposited.
1. , with macrophages and polymorphonuclear leukocytes polymorphonuclear leukocytes (pol´ēmôr´fōnoo´klēr loo´kō-sīts),
n. , was apparent microscopically. Inflammatory changes in the cecum and ascending colon ascending colon
The part of the colon between the ileocecal orifice and the right colic flexure. were present in all animals, and in the distal colon and rectum in three of four animals. Metachromatic staining material was noted in the lamina propria lamina pro·pri·a
A thin vascular layer of connective tissue beneath the epithelium of an organ.
[New Latin l of the colon and surface epithelial cells Epithelial cells
Cells that form a thin surface coating on the outside of a body structure.
Mentioned in: Corneal Transplantation from cecum to rectum, as well as in colonic macrophages. The surface epithelial cells and the macrophages contained vacuoles filled with the metachromatic metachromatic /meta·chro·mat·ic/ (-kro-mat´ik) staining differently with the same dye; said of tissues in which a dye gives different colors to different elements.
1. material, which was not found in the controls and not seen in more advanced lesions in previous studies. These early lesions suggested that the presence of degraded carrageenan within surface epithelial cells might be associated with the subsequent breakdown of the mucosa and to ulceration by a direct toxic effect on the epithelial cells (35).
Hence, a model of mechanical cellular destruction by disruption of lysosomes from carrageenan exposure arises from review of the experimental studies in animals. The observed changes in the lysosomes resemble the characteristic changes observed in some lysosomal storage diseases lysosomal storage diseases A heterogeneous group of diseases with specific lysosomal enzyme defects. Cf Inborn errors of metabolism. , in which there is accumulation of sulfated metabolites Metabolites
Substances produced by metabolism or by a metabolic process.
Mentioned in: Interactions that cannot be processed further due to sulfatase sulfatase /sul·fa·tase/ (sul´fah-tas) an enzyme that catalyzes the hydrolytic cleavage of inorganic sulfate from sulfate esters.
n. enzyme deficiency (107-110). Table 4 presents a proposed mechanism of the effects of carrageenan.
Possible role of intestinal bacteria. The relationship between the intestinal microflora microflora /mi·cro·flo·ra/ (-flor´ah) the microscopic vegetable organisms of a special region.
The bacterial population in the intestine. and the biologic activity of carrageenan has been reviewed (111,112). Investigators have examined the impact of antibiotics and alteration of the resident microbial microbial
pertaining to or emanating from a microbe.
the breakdown of organic material, especially feedstuffs, by microbial organisms. flora on the activity of carrageenan. Grasso et al. (83) studied the impact of neomycin neomycin (nē'ōmī`sĭn), broad spectrum antibiotic effective against both gram positive and gram negative bacteria (see Gram's stain). treatment on the development of ulcerations by carrageenan. Pretreatment pretreatment,
n the protocols required before beginning therapy, usually of a diagnostic nature; before treatment.
n See predetermination. against coliforms failed to attenuate To reduce the force or severity; to lessen a relationship or connection between two objects.
In Criminal Procedure, the relationship between an illegal search and a confession may be sufficiently attenuated as to remove the confession from the protection afforded by the the course of carrageenan-associated ulcerations (80,83). Pretreatment with metronidazole metronidazole /met·ro·ni·da·zole/ (-ni´dah-zol) an antiprotozoal and antibacterial effective against obligate anaerobes; used as the base or the hydrochloride salt. It is also used as a topical treatment for rosacea. was effective in preventing carrageenan-induced colitis in another experiment, although there was no benefit in established colitis (71). Aminoglycosides administered after carrageenan exposure were associated with reduced mortality, but not with reduction in the number of colonic ulcerations (94). Hirono et al. (65) found increased ulcerations and squamous metaplasia from the anorectal junction to the distal colon in germ-free rats fed 10% carrageenan for less than 63 days.
Additional considerations about the mechanism of action of carrageenan involved the role of production of hydrogen sulfide hydrogen sulfide, chemical compound, H2S, a colorless, extremely poisonous gas that has a very disagreeable odor, much like that of rotten eggs. It is slightly soluble in water and is soluble in carbon disulfide. gas from metabolism of carrageenan in the digestive tract digestive tract
See alimentary canal.
The organs that perform digestion, or changing of food into a form that can be absorbed by the body. . Because carrageenan is heavily sulfated (up to 40% by weight), bacterial sulfatases and sulfate reductases can produce hydrogen sulfide gas or H[S.sup.-] from carrageenan. Carrageenan, as well as other sulfated polysaccharides, has been shown to stimulate [H.sub.2]S production from fecal fecal /fe·cal/ (fe´k'l) pertaining to or of the nature of feces.
Relating to or composed of feces.
pertaining to or of the nature of feces. slurries (113). Sulfide has been implicated im·pli·cate
tr.v. im·pli·cat·ed, im·pli·cat·ing, im·pli·cates
1. To involve or connect intimately or incriminatingly: evidence that implicates others in the plot.
2. in the development of ulcerative colitis, perhaps attributable to interference with butyrate butyrate /bu·ty·rate/ (bu´ti-rat) a salt, ester, or anionic form of butyric acid.
A salt or ester of butyric acid.
a salt of butyric acid. oxidation by colonic epithelial cells (114,115). Butyrate has been shown to induce intestinal cellular differentiation Cellular differentiation is a concept from developmental biology describing the process by which cells acquire a "type". The morphology of a cell may change dramatically during differentiation, but the genetic material remains the same, with few exceptions. , suppress intestinal cell growth, and decrease expression of c-myc, among other functions in colonic epithelial cells (116-118).
No fermentation of carrageenan was reported after testing with 14 strains of intestinal bacteria. The increase in sulfide production observed arising from incubation of [kappa]-carrageenan with colonic bacteria demonstrates that intestinal metabolism of carrageenan does occur. However, data pertaining to breakdown of carrageenan by fecal organisms are limited (112,113).
Extraintestinal manifestations of carrageenan exposure. Trace amounts of undegraded carrageenan have been reported to cross the intestinal barrier, with accumulation of label in intestinal lymph nodes (61,74). Several investigators have noted uptake of carrageenan by intestinal macrophages with subsequent migration of these macrophages to lymph nodes, spleen, and liver (61,67,74,78,82,84,85).
In association with carrageenan-induced intestinal ulcerations, Delahunty et al. (56) observed an increased permeability to large molecules, such as [[sup.3]H]PEG (polyethylene glycol polyethylene glycol (PEG): see glycol. )-900. This finding suggested that the intestinal changes induced by carrageenan may be a factor in subsequent absorption of carrageenan or other large molecules.
Other experimental data. Because it can induce acute inflammation acute inflammation
Inflammation having a rapid onset and coming to a crisis relatively quickly, with a clear and distinct termination. , carrageenan has been widely used in experimental models of inflammation, to assess activity of anti-inflammatory drugs Anti-inflammatory drugs
A class of drugs that lower inflammation and that includes NSAIDs and corticosteroids.
Mentioned in: Antirheumatic Drugs and to study mediators of inflammation (4,61,106,119,120). Injected into an experimental site, such as the plantar plantar /plan·tar/ (plan´tar) pertaining to the sole of the foot.
Of, relating to, or occurring on the sole. surface of a rat's paw (tool) PAW - Physics Analysis Workbench. , pleural cavity pleural cavity
The potential space between the parietal and visceral layers of the pleura. Also called pleural space.
Pleural cavity , or subcutaneous subcutaneous /sub·cu·ta·ne·ous/ (sub?ku-ta´ne-us) beneath the skin.
adj. Abbr. s.c., SQ
Located, found, or placed just beneath the skin; hypodermic. air bleb bleb (bleb) a large flaccid vesicle, usually at least 1 cm. in diameter.
A large flaccid vesicle.
a large flaccid vesicle, usually at least 0. , carrageenan induces an inflammatory response, with edema edema (ĭdē`mə), abnormal accumulation of fluid in the body tissues or in the body cavities causing swelling or distention of the affected parts. , migration of inflammatory cells, predominantly polymorphonuclear leukocytes, and possibly granuloma granuloma /gran·u·lo·ma/ (gran?u-lo´mah) pl. granulomas, granulo´mata an imprecise term for (1) any small nodular delimited aggregation of mononuclear inflammatory cells, or (2) such a collection of modified macrophages formation (61,120). Undegraded carrageenans in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment.
In an artificial environment outside a living organism. can inhibit binding of basic fibroblast growth factor Basic fibroblast growth factor, also known as bFGF or FGF2, is a member of the fibroblast growth factor family.
In normal tissue, basic fibroblast growth factor is present in basement membranes and in the subendothelial extracellular matrix of blood (bFGF), transforming growth factor [beta]-1, and platelet-derived growth factor platelet-derived growth factor
A substance in platelets that is mitogenic for cells at the site of a wound, causing endothelial proliferation. but not insulin-like growth factor-1 or transforming growth factor- transforming growth factor–β1, –β2 Molecular biology Factors responsible for positive and negative autocrine growth regulation [alpha] (121).
Macrophage injury and destruction caused by carrageenan may be a factor in the reduced cytotoxic cy·to·tox·ic
Of, relating to, or producing a toxic effect on cells.
cyto·tox·ic lymphocytic response associated with carrageenan exposure in vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body.
Within a living organism.
in vivo adv. (122). In addition to depression of cell-mediated immunity cell-mediated immunity
n. Abbr. CMI
Immunity resulting from a cell-mediated immune response. Also called cellular immunity. , impairment of complement activity and of humoral hu·mor·al
1. Relating to body fluids, especially serum.
2. Relating to or arising from any of the bodily humors.
Pertaining to or derived from a body fluid. responses have been reported. Prolongation of graft survival and potentiation potentiation /po·ten·ti·a·tion/ (po-ten?she-a´shun)
1. enhancement of one agent by another so that the combined effect is greater than the sum of the effects of each one alone.
2. posttetanic p. of tumor growth have been attributed to the cytopathic effect Cytopathic effect (CPE) refers to degenerative changes in cells (especially in tissue culture) associated with the multiplication of certain viruses. When in tissue culture, the spread of virus is restricted by an overlay of agar (or other suitable substance) and thus the on macrophages (96,123). Because of its effect on T-cells, carrageenan has been studied for its impact on viral infections with herpes simplex virus Herpes simplex virus
A virus that can cause fever and blistering on the skin, mucous membranes, or genitalia.
Mentioned in: Conjunctivitis
herpes simplex virus types 1 and 2 (124) and HIV-1 (125,126), as well as infections with Chlamydia trachomatis Chlamydia tra·cho·ma·tis
A species of Chlamydia that causes trachoma, inclusion conjunctivitis, lymphogranuloma venereum, nonspecific urethritis, and proctitis in humans. (127).
In experimental systems, undegraded carrageenan has produced destruction of several different cell types in addition to macrophages, including small intestine small intestine
Long, narrow, convoluted tube in which most digestion takes place. It extends 22–25 ft (6.7–7.6 m), from the stomach to the large intestine. epithelial cell monolayers (54), androgen-dependent malignant prostatic cells (128), bFGF-dependent endothelial endothelial /en·do·the·li·al/ (-the´le-al) pertaining to or made up of endothelium.
A layer of cells that lines the inside of certain body cavities, for example, blood vessels. cell line (128), rat mammary mammary /mam·ma·ry/ (mam´ah-re) pertaining to the mammary gland, or breast.
Of or relating to a breast or mamma.
pertaining to the mammary gland. adenocarcinoma adenocarcinoma: see neoplasm. 13762 MAT cells (129), and human mammary myoepithelial cells myoepithelial cells cells (sometimes referred to as Myoepithelium) are cells usually found in glandular epithelium as a thin layer above the basement membrane but generally beneath the luminal cells. (130). Lysosomal inclusions and vacuolation vacuolation /vac·u·o·la·tion/ (vak?u-o-la´shun) the process of forming vacuoles; the condition of being vacuolated.
vac·u·o·la·tion or vac·u·o·li·za·tion
1. have been observed in macrophages, intestinal epithelial cells, and myoepithelial cells exposed to carrageenan (79,85,131).
Injections of carrageenan were noted to induce sarcomas Sarcomas Definition
A sarcoma is a bone tumor that contains cancer (malignant) cells. A benign bone tumor is an abnormal growth of noncancerous cells.
A primary bone tumor originates in or near a bone. , as well as mammary tumors in animal models, in an early study (132). In other experiments, mammary and testicular testicular /tes·tic·u·lar/ (tes-tik´u-lar) pertaining to a testis.
Of or relating to a testicle or testis.
pertaining to the testis. tumors have been observed (69,133). Carrageenan has also been noted to have anticoagulant anticoagulant (ăn'tēkōăg`yələnt), any of several substances that inhibit blood clot formation (see blood clotting). activity, and large systemic doses have been fatal through nephrotoxicity neph·ro·tox·ic·i·ty
The quality or state of being toxic to kidney cells.
Mechanisms for Production of Degraded Carrageenan from Undegraded Carrageenan
Gastrointestinal metabolism of carrageenan to form smaller molecular weight components has been observed by several investigators, who reported that carrageenan of high molecular weight changed during intestinal passage, compatible with hydrolysis yielding lower molecular weight components (9,10,74,75).
Under conditions such as might occur in digestion, 17% of food-grade carrageenan degraded to molecular weight < 20,000 in 1 hr at pH 1.2 at 37 [degrees] C. At pH 1.9 for 2 hr at 37 [degrees] C, 10% of the carrageenan had molecular weight less than 20,000 (9). These data suggest that substantial fractions of lower molecular weight carrageenan are likely to arise during normal digestion.
Table 5 presents data with regard to contamination of food-grade carrageenan by lower molecular weight carrageenan. Twenty-five percent of total carrageenans in eight food-grade carrageenans were found to have molecular weight < 100,000, with 9% having molecular weight < 50,000 (9). In addition, several bacteria have been identified that are able to hydrolyze carrageenan into smaller products, including tetracarrabiose. These bacteria, including Cytophaga species and Pseudomonas Pseudomonas
A genus of gram-negative, nonsporeforming, rod-shaped bacteria. Motile species possess polar flagella. They are strictly aerobic, but some members do respire anaerobically in the presence of nitrate. carrageenovora, are of marine origin; it is unknown whether the human microbial flora can perform similar hydrolysis reactions (36-40,134).
Extent of Human Exposure to Carrageenan
Indirect evidence relating exposure to carrageenan and the occurrence of ulcerative colitis and intestinal neoplasms consists of the similar geographic distribution between higher consumption of carrageenan and higher incidence of inflammatory bowel disease and colorectal cancer. Ulcerative colitis is more common in North America North America, third largest continent (1990 est. pop. 365,000,000), c.9,400,000 sq mi (24,346,000 sq km), the northern of the two continents of the Western Hemisphere. , the United Kingdom, and Scandinavia; and less common in Central and Southern Europe Southern Europe or sometimes Mediterranean Europe is a region of the European continent. There is no clear definition of the term which can vary depending on whether geographic, cultural, linguistic or historical factors are taken into account. , Asia, and Africa (135). This incidence distribution is similar to distributions for colorectal malignancy and for carrageenan consumption, providing some ecologic evidence to support a potential etiologic role of carrageenan in human disease (46,136).
The reported T[D.sup.50] (tumorigenic tu·mor·i·gen·ic
Capable of causing tumors. dose 50% = the dose rate, in milligrams per kilogram kilogram, abbr. kg, fundamental unit of mass in the metric system, defined as the mass of the International Prototype Kilogram, a platinum-iridium cylinder kept at Sèvres, France, near Paris. body weight per day, which will halve halve
tr.v. halved, halv·ing, halves
1. To divide (something) into two equal portions or parts.
2. To lessen or reduce by half: halved the recipe to serve two.
3. the probability of remaining tumorless over the life span of the exposed animal) by the Carcinogenic Potency Database for degraded carrageenan is 2,310 mg/kg body weight/day, based on rodent rodent, member of the mammalian order Rodentia, characterized by front teeth adapted for gnawing and cheek teeth adapted for chewing. The Rodentia is by far the largest mammalian order; nearly half of all mammal species are rodents. experiments (137,138). This extrapolates to 138.6 grams for a 60-kg individual. If the total carrageenan intake per person in the United States is about 100 mg a day (43), about 9 mg of carrageenan with molecular weight < 50,000 is likely to be ingested through contamination of food-grade carrageenan by degraded carrageenan, and at least 8 mg with molecular weight < 20,000 is likely to arise during normal digestion (simulated by exposure to pH 1.9 with pepsin pepsin, enzyme produced in the mucosal lining of the stomach that acts to degrade protein. Pepsin is one of three principal protein-degrading, or proteolytic, enzymes in the digestive system, the other two being chymotrypsin and trypsin. for 1 hr at 37 [degrees] C). This suggests an average intake of about 10 mg/day of degraded carrageenan for an individual older than 2 years of age in the United States.
An important issue is whether 10 mg/day degraded carrageenan is safe to ingest in·gest
tr.v. in·gest·ed, in·gest·ing, in·gests
1. To take into the body by the mouth for digestion or absorption. See Synonyms at eat.
2. . By the Delaney clause Delaney Clause Public health An addition to the US Food, Drug & Cosmetics Act, prohibiting the use of food additives known to be carcinogenic in experimental animals. See Alar, Ames test, Food & Drug Administration, Risk assessment. , no carcinogen should be permitted in food. The Food Quality Protection Act (FQPA FQPA Food Quality Protection Act ) established a usage level for negligible risk associated with pesticide residue Pesticide residue refers to the pesticides that may remain on or in food after they are applied to food crops. Regulation of pesticide residue in the US in food at 1 ppm (139,140). Applying this standard to the extrapolated T[D.sub.50] for degraded carrageenan for a 60-kg person, the anticipated average intake of 10 mg/day is 70-fold greater than this standard (138.6 g/[10.sup.6]/day). These calculations do not take into consideration possible exposure to furcellaran (molecular weight 20,000-80,000), or the wide range of possible intakes of carrageenan.
Inflammatory bowel disease and colorectal malignancy represent major sources of morbidity and mortality in the United States. A possible factor in the etiology of these pathologies is exposure to carrageenan.
Several investigators have expressed their concerns about the use of undegraded carrageenan in food products (6-10), yet no legislative protection to restrict incorporation of low molecular weight fractions has been enacted. In fact, there has been no substantive review by the Food and Drug Administration of carrageenan since the studies undertaken more than two decades ago. However, there has been increased evidence regarding the cancer-promoting activity of undegraded carrageenan and further confirmation of the carcinogenic potential of degraded carrageenan.
Evidence for the role in carcinogenesis of carrageenan appears to support a nongenotoxic model based on direct toxic effects, for carrageenan has been nonmutagenic in Salmonella mutagenicity mutagenicity /mu·ta·ge·nic·i·ty/ (-je-nis´it-e) the property of being able to induce genetic mutation.
the property of being able to induce genetic mutation. testing and nongenotoxic by DNA repair DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light can cause DNA damage, resulting in as many as 1 tests (60,102). A model of cellular destruction--from disruption of lysosomes by accumulation of carrageenan by-products or by interference with normal cellular oxidation-reduction processes from sulfate metabolites--emerges from review of the experimental studies. The impact of sulfatases, of either bacterial or human origin, on the metabolism of carrageenan requires further investigation. By interference with the normal intracellular feedback mechanisms associated with arylsulfatase activity, including steroid sulfatase Steroid sulfatase (or steryl-sulfatase) is an sulfatase enzyme involved in the metabolism of steroids. Pathology
A deficiency is associated with X-linked ichthyosis. , the highly sulfated carrageenan may have an impact on the availability of active, unsulfated hormones, such as dehydroepiandrosterone, derived from dehydroepiandrosterone-sulfate, and estrone-1, derived from estrone-1 sulfate.
Genetic characteristics that affect sulfatase and hydrolysis reactions as well as the individual intestinal microflora may influence how carrageenan is metabolized and how its effects are manifested. These factors may determine how carrageenan is metabolized differently by different individuals, but these characteristics may not be accessible to manipulation. A basic factor that can be controlled is the intake of carrageenan, which is amenable to dietary modification or food additive regulation.
Although carrageenan is widely used as a food additive for its texture-enhancing properties, other gums, some of which are used in combination with carrageenan, such as locust bean gum, gum arabic gum Arabic,
n Latin name:
Acacia senegal; part used: gum; uses: lower cholesterol, kidney conditions, gum disease, oral health, sore throat, diarrhea; precautions: none known. Also called
Egyptian thorn or
senega. , alginate alginate /al·gi·nate/ (al´ji-nat) a salt of alginic acid; water-soluble alginates are useful as materials for dental impressions. , guar gum guar gum
A water-soluble paste made from the seeds of the guar plant and used as a thickener and stabilizer in foods and pharmaceuticals.
guar gum , or xanthan gum xan·than gum
A natural gum of high molecular weight produced by culture fermentation of glucose and used as a stabilizer in commercial food preparation. , potentially can be used alone or in different combinations as substitutes for carrageenan (41,46). Alternatively, higher fat composition can lead to changes in food properties that may compensate for exclusion of carrageenan. Other hydrocolloids that are used as stabilizers and thickeners have not been associated with harmful gastrointestinal effects, and it is reasonable to expect that they could replace carrageenan in many food products. Although the dietary fibers pectin pectin, any of a group of white, amorphous, complex carbohydrates that occur in ripe fruits and certain vegetables. Fruits rich in pectin are the peach, apple, currant, and plum. Protopectin, present in unripe fruits, is converted to pectin as the fruit ripens. and psyllium psyllium /psyl·li·um/ (sil´e-um)
1. a plant of the genus Plantago.
2. the husk (psyllium husk) or seed (plantago or psyllium seed) of various species of Plantago affect intestinal motility motility /mo·til·i·ty/ (mo-til´ite) the ability to move spontaneously.mo´tile
Motility is spontaneous movement. , ulcerations or neoplasms have not been induced with either these or the other water-soluble polymers used as food additives. In contrast, other highly sulfated polysaccharides, amylopectin amylopectin /am·y·lo·pec·tin/ (am?i-lo-pek´tin) a highly branched, water-insoluble glucan, the insoluble constituent of starch; the soluble constituent is amylose.
n. sulfate and dextran dextran /dex·tran/ (dek´stran) a high-molecular-weight polymer of d-glucose, produced by enzymes on the cell surface of certain lactic acid bacteria. sulfate sodium, have induced ulcerations and neoplasia, suggesting that the degree of sulfation and polysaccharide molecular weight may be critical for induction of the observed effects (102).
The major pieces of evidence that support an argument to reconsider the advisability of use of carrageenan as a GRAS food additive are:
* Degraded carrageenan is a known carcinogen in animal models
* Undegraded carrageenan is a known co-carcinogen in animal models of carcinogenesis
* In animal models, both degraded and undegraded carrageenan have been associated with development of intestinal ulcerations that resemble ulcerative colitis
* Hydrolysis such as may occur by exposure to gastric acid in the human stomach can lead to the depolymerization depolymerization /de·po·lym·er·iza·tion/ (de?po-lim?er-i-za´shun) the conversion of a polymer into its component monomers.
depolymerization of undegraded carrageenan and the availability of degraded carrageenan
* Food-grade carrageenan may be contaminated contaminated,
v 1. made radioactive by the addition of small quantities of radioactive material.
2. made contaminated by adding infective or radiographic materials.
3. an infective surface or object. with low molecular weight, degraded carrageenan that may arise during food processing Food processing is the set of methods and techniques used to transform raw ingredients into food for consumption by humans or animals. The food processing industry utilises these processes.
* The use of a viscosity measurement to characterize a carrageenan sample is insufficient because the presence of a small number of large molecules (and undegraded carrageenan may have molecular weight in the millions) may obscure a significant low molecular weight fraction.
The potential role of carrageenan in the development of gastrointestinal malignancy and inflammatory bowel disease requires careful reconsideration of the advisability of its continued use as a food additive.
Table 1. Characteristics of carrageenan (4,12-15,27,28,41-49). Chemical composition Hydrocolloid composed of [alpha]-D-1,3 and [beta]-D-1,4 galactose residues that are sulfated at up to 40% of the total weight. Strong negative charge over normal pH range. Associated with ammonium, calcium, magnesium, potassium, or sodium salts. Solubility [lambda] is readily soluble in cold or hot aqueous solution; [kappa] is soluble in hot solution; treatment of aqueous solution with potassium ion precipitates [kappa]-carrageenan. Gel formation [lambda] does not form gels; [lambda] and [iota] form right-handed helices; potassium chloride promotes gel formation of [kappa]; calcium ion promotes gel formation of [iota]. Metabolism Hydrolysis of glycosidic linkages at lower pH, especially pH [less than or equal to] 3.0; also desulfation by sulfatases. Viscosity Near logarithmic increase in viscosity with increasing concentration. Viscosity of food- grade carrageenan defined as not less than 5 cps at 75 [degrees] C for a 1.5% solution; viscosity ranges from 5 to 800 cps for 1.5% solution at 75 [degrees] C. Source Red algae; predominantly aqueous extraction from Chondrus, Gigartina, and various Eucheuma species. Molecular weight Discrepancies in definitions. Native carrageenan reported to have average molecular weight of 1.5 x [10.sup.6] - 2 x [10.sup.7]; food-grade carrageenan reported as 100,000-800,000 or 200,000-400,000. Degraded carrageenan (poli- geenan) has average molecular weight of 20,000- 30,000; furcellaran has average molecular weight 20,000-80,000. Properties [lambda] and [kappa] combine easily with milk proteins to improve solubility and texture; serve as thickening agent, emulsifier, stabilizer. Synergistic effects With locust bean gum, increase in gel strength. Other hydrocolloids may also affect gel strength and cohesiveness. Concentration in 0.005-2.0% by weight. food products Major uses Milk products, processed meats, dietetic formulations, infant formula, toothpaste, cosmetics, skin preparations, pesticides, laxatives Table 2. Range of content of carrageenan in some commonly consumed foods. Percent carrageenan Food (g/100 g food) Bakery products 0.01-0.1 Chocolate milk 0.01-0.2 Cottage cheese 0.02-0.05 Frosting base mix 3-4 Ice cream, frozen custard, sherbets, etc. 0.01-0.05 Jams and jellies 0.5-1.2 Liquid coffee whitener 0.3 Pie filling 0.1-1.0 Pimento olive stuffing 2.0 Processed cheese 0.01-0.06 Processed meat or fish 0.2-1.0 Pudding (nondairy) 0.1-0.5 Relishes, pizza, barbecue sauces 0.2-0.5 Yogurt 0.2-0.5 Because manufacturing processes vary and there can be substitutions of one hydrocolloid for another, the content of carrageenan for any individual product may differ from these estimates. Unpublished manufacturers' data indicate that these content estimates for processed cheese, frozen dairy dessert, cottage cheese, and jams and jellies are significantly lower than current usage (4, 13, 14,47). Table 3. Experimental data related to intestinal effects of dietary carrageenan exposure. Experiment Type of carrageenan, Dose molecular weight Animal %CG (g/kg bw/day) 1. Undegraded (a,d) Rat 10 27.4 Undegraded (a,d) Rat 0.25 0.2 2.5 4 2. Undegraded Rat 0.5, 1.5, [iota], >100,000 5 (a,b) Degraded [iota], Rat 0.5, 1.5, 20,000 (a,b) 5 3. Degraded [iota], Guinea pig 2, 2.5, 5 30,000 (c) 4. Degraded, Guinea pig 3 5.8 20,000-30,000 (c) 5. Degraded (c) Guinea pig 1, 2, 3 2, 3, 4 6. Degraded (c) Rat ileal 0-1.5 g/L cell monolayers 7. Undegraded Rat 5 [lambda], 300,000 (a,b) 8. Degraded Rat, 5 [iota] (c) Guinea pig 5 9. Undegraded Rat 6 0.8 [kappa] (a,d) 10. Degraded Rabbit 1 [lambda] (a,b,c) 11. Degraded Mice 10 (a,b,c) 12. Degraded, Cultured 1 mg/10 mL (20,000-40,000), rat hepa- or and tocytes or 1 mg/100 mL Undegraded (a) intestinal mucosal cells 13. Undegraded Rat 0.5 0.15-0.25 [kappa], [lambda], and [iota] (e) 14. Degraded (c) Guinea pig 5 15. Degraded (c) Guinea pig 5 16. Degraded (a,d) Rat 10 17. Degraded, Rat 10 15 (20,000-40,000) (a,b,c,g) 18. Degraded Guinea pig 3 [kappa], [lambda], [iota] 19. Degraded (20,000-40,000) Rat 10 (a,b,e) 20. Degraded (c) Guinea 5 pig 21. Undegraded, Rat, 0.5, 2.5, 5 0.36, 2, 4 (800,000) hamster (largely [kappa]) 22. Degraded Rat 10 (a,b,c,g) 23. Degraded (c) Guinea 2 pig 24. Degraded (c) Guinea 5 pig 25. Degraded Rat 10, 5, 1 (20,000-40,000) (a,b) 5 1 or 5 26.Undegraded Rat 15 [lambda] (a,d) 27. [iota], Rat 0.5 (8,700-145,000) (e,f) Undegraded [kappa]/ Rat 5 [lambda], (186,000-214,000) [iota], Guinea pig 2 (5,000-145,000) [iota], Guinea pig 1 (5,000-145,000) [kappa] Guinea pig 1 (8,500-275,000) [lambda] Guinea pig 1 (8,500-275,000) Undegraded [kappa]/ [lambda] Rhesus 0.05, 0.2, 0.5 (185,000) monkey [iota] 0.2 28.[kappa] (c) Guinea 1 (314,000) pig (51,500) (8,500) [lambda], (275,000) (74,800) (20,800) [iota], (145,000) (107,000) (88,000) (39,000) (21,000) (8,700) (5,000) 29. Degraded Rhesus 2 [iota] (C16), monkey (20,000) Undegraded Rhesus 1 [kappa][lambda] monkey mixture, (800,000) 30. Degraded Rat 5 ([iota], C16), 7.5 g, (10,000-30,000) (a,d) then 5 g 31. Degraded (c,e) Rat 0.2, 0.5, 5 Guinea pig 0.25, 0.5 32. Degraded Guinea pig 2, 0.2, 0.02 ([iota], C16) (c) Guinea pig 2 Rat 5 Monkey 2 33. Degraded (c) Guinea pig 2, 5 1.7-3.3 34. Undegraded Pig 0.05, 0.2, 0.5 [kappa], (200,000) 35. Degraded Rhesus 0.5-2 0.7, 1.4, 2.9 (C16, [iota]), (c) monkey (20,000) Undegraded Rhesus 1 1.3 (largely [kappa]), monkey (800,000) 1-3 0.05-1.25 36. Undegraded Guinea pig 5 Rabbit 5 Degraded (c) Guinea pig 1, 2, 5 Rabbit 2 Degraded Humans 5-g dose Ferret 1.5 Squirrel 1.5 monkey Rabbit, 1.5 mouse Rat 1 Rat 5 Undegraded Rat 5 Hamster 5 37. Degraded Rat 5 6-10 (c16, [iota]), 0.5-5.0 (20,000-30,000) (a,b,e) 38. Undegraded Rhesus 1 ([kappa]:[lambda] monkey = 70:30), (800,000) (e) Degraded Rhesus 0.5, 1, 2 (C16, [iota]), monkey (20,000-30,000) (e) 39. Degraded (c) Guinea 5 [less than or pig equal to] 2 g 40. Degraded (a,b,c,g) Rat 5 41. Undegraded (c) Guinea 5 pig Degraded (c) Guinea 1 pig 42. Degraded (a,b,c) Rabbit 0.1, 1, 5 0.07, 0.8, 1.4 43. Degraded (c) Guinea 4-5 pig Degraded Rat [less than or equal to] 16.5 Degraded, Rat, 0.07-4 Undegraded mouse 44. Undegraded Guinea pig 1 [less than or equal to] 1.5 Degraded Guinea [less than [less than or pig or equal equal to] 2 to] 5 45. Degraded Guinea pig 0.1-5 Rabbit Rat Mouse Type of Experiment carrageenan, molecular weight Animal Duration Route 1. Undegraded (a,d) Rat 8 days, Jelly sacrificed at 30 days Undegraded (a,d) Rat 100 days Liquid 100 days Solid gel 2. Undegraded Rat [less than Diet [iota], >100,000 or equal to] (a,b) 91 days Degraded [iota], Rat [less than Diet 20,000 (a,b) or equal to] 91 days 3. Degraded [iota], Guinea pig 7 days Drink 30,000 (c) 4. Degraded, Guinea pig 2-3 days Drink 20,000-30,000 (c) 5. Degraded (c) Guinea pig 2 weeks Drink 6. Degraded (c) Rat ileal 19, 30, Media cell 54 hr monolayers 7. Undegraded Rat 4 weeks Diet [lambda], 300,000 (a,b) 8. Degraded Rat, 4 months Drink [iota] (c) Guinea pig 3 weeks Drink 9. Undegraded Rat 24 weeks diet [kappa] (a,d) 10. Degraded Rabbit 8 weeks, Drink [lambda] (a,b,c) 12 months, 28 months 11. Degraded Mice 10 days Drink (a,b,c) 12. Degraded, Cultured 20 hr (20,000-40,000), rat hepa- and tocytes or 2 hr Undegraded (a) intestinal mucosal cells 13. Undegraded Rat 90 days Drink [kappa], [lambda], and [iota] (e) 14. Degraded (c) Guinea pig 5 days Drink 15. Degraded (c) Guinea pig 14 days Drink 16. Degraded (a,d) Rat 2 weeks Diet 17. Degraded, Rat < 63 days Diet (20,000-40,000) (a,b,c,g) 18. Degraded Guinea pig 3 weeks Drink [kappa], [lambda], [iota] 19. Degraded 2, 6, 9 Diet (20,000-40,000) Rat months (a,b,e) sacrificed at 18 months 20. Degraded (c) Guinea [less than Drink pig or equal to] 28 days 21. Undegraded, Rat, Lifetime Diet (800,000) hamster (largely [kappa]) 22. Degraded Rat 1 day to 12 Diet (a,b,c,g) weeks, some sacrificed at 27 weeks 23. Degraded (c) Guinea 2 weeks Drink pig 24. Degraded (c) Guinea 21 days pig 25. Degraded Rat [less than Diet (20,000-40,000) (a,b) or equal to] 24 months 15 months drink 15 months Stomach tube 26.Undegraded Rat [less than Diet [lambda] (a,d) or equal to] 40 weeks 27. [iota], Rat 9 months Gavage (8,700-145,000) (e,f) Undegraded [kappa]/ Rat 13 weeks Diet [lambda], (186,000-214,000) [iota], Guinea pig 7-10 weeks Diet (5,000-145,000) [iota], Guinea pig 2-3 weeks Drink (5,000-145,000) [kappa] Guinea pig 2-3 weeks Drink (8,500-275,000) [lambda] Guinea pig 2-3 weeks Drink (8,500-275,000) Undegraded [kappa]/ [lambda] Rhesus Stomach tube (185,000) monkey [iota] Stomach tube 28.[kappa] (c) Guinea (314,000) pig 2 weeks Drink (51,500) 2 weeks Drink (8,500) 2 weeks Drink [lambda], (275,000) 2 weeks Drink (74,800) 2 weeks Drink (20,800) 2 weeks Drink [iota], (145,000) 2 weeks Drink 10 weeks Diet (107,000) 2 weeks Drink 10 weeks Diet (88,000) 2 weeks Drink (39,000) 2 weeks Drink 10 weeks Diet (21,000) 2 weeks Drink 10 weeks Diet (8,700) 2 weeks Drink 10 weeks Diet (5,000) 2 weeks Drink 29. Degraded Rhesus 10 weeks Drink [iota] (C16), monkey (20,000) Undegraded Rhesus 10 weeks Drink [kappa][lambda] monkey mixture, (800,000) 30. Degraded Rat [less than Drink, ([iota], C16), or equal to] diet (10,000-30,000) (a,d) 30 weeks 31. Degraded (c,e) Rat [less than Drink or equal to] 12 weeks Guinea pig [less than Drink or equal to] 4 weeks 32. Degraded Guinea pig 12 months, Drink ([iota], C16) (c) 10 months Guinea pig 3 months In milk Rat 3 months Drink Monkey 10 weeks Drink 33. Degraded (c) Guinea pig 30-44 days Drink 34. Undegraded Pig 83 days Jelly [kappa], (200,000) 35. Degraded Rhesus 7-14 weeks, Drink (C16, [iota]), (c) monkey then reco- (20,000) very for 20- 24 weeks for some before sacrificed Undegraded Rhesus 7-14 weeks, Drink (largely [kappa]), monkey then 11 (800,000) weeks reco- very [less than Tube or equal to] 12 weeks, after reco- very 36. Undegraded Guinea pig 1-45 days Diet Rabbit Diet Degraded (c) Guinea pig 1-45 days Drink Rabbit Drink Degraded Humans 10 days Diet Ferret 28 days Tube Squirrel 28 days Tube monkey Rabbit, 28 days Tube mouse Rat 56 days Drink Rat Undegraded Rat 56 days Diet Hamster 6 months Diet 37. Degraded Rat [greater Drink (c16, [iota]), than or equal to] 25 weeks (20,000-30,000) (a,b,e) 1-15 months Tube 38. Undegraded Rhesus 7-12 weeks Drink ([kappa]:[lambda] monkey = 70:30), (800,000) (e) Degraded Rhesus 7-12 weeks Drink (C16, [iota]), monkey (20,000-30,000) (e) 39. Degraded (c) Guinea 20-45 days Drink pig 40. Degraded (a,b,c,g) Rat 6 months Drink 41. Undegraded (c) Guinea 2-4 weeks Diet pig Degraded (c) Guinea 2-4 weeks Drink pig 42. Degraded (a,b,c) Rabbit 6-12 weeks Drink 43. Degraded (c) Guinea Drink pig Degraded Rat Drink Degraded, Rat, 28 days- Tube Undegraded mouse 6 months 44. Undegraded Guinea pig 20-30 days Drink Degraded Guinea 20-30 days Drink pig 45. Degraded Guinea pig 30 days- Drink Rabbit 1 year Drink Rat Drink Mouse Drink Experiment Effects Type of carrageenan, Additional Digestive/ molecular weight Animal exposure systemic 1. Undegraded (a,d) Rat AOM injection Less weight (5 mg/kg ip) gain with 2.5% CG Undegraded (a,d) Rat AOM injection (20 mg/kg ip) prior to CG 2. Undegraded Rat [iota], >100,000 (a,b) Degraded [iota], Rat 20,000 (a,b) 3. Degraded [iota], Guinea pig Eicosapen- 2% led to FOB+ 30,000 (c) taenoic acid at 7 days; 5% (300 mg/kg/day) led to 38% at 14 days mortality 4. Degraded, Guinea pig 20,000-30,000 (c) 5. Degraded (c) Guinea pig 6. Degraded (c) Rat ileal cell monolayers 7. Undegraded Rat [lambda], 300,000 (a,b) 8. Degraded Rat, [iota] (c) Guinea pig 9. Undegraded Rat 1,2-DMH [kappa] (a,d) (20 mg/kg bw) SC x 16 wks 10. Degraded Rabbit [lambda] (a,b,c) 11. Degraded Mice Bloody diarrhea (a,b,c) 12. Degraded, Cultured (20,000-40,000), rat hepa- and tocytes or Undegraded (a) intestinal mucosal cells 13. Undegraded Rat [kappa], [lambda], and [iota] (e) 14. Degraded (c) Guinea pig 15. Degraded (c) Guinea pig With ileo- transvers- ostomy 16. Degraded (a,d) Rat 1,2-DMH weekly injections for 15 weeks (10 mg/kg bw) with DCG vs. DMH alone 17. Degraded, Rat Germ-free vs. (20,000-40,000) conventional (a,b,c,g) gut flora 18. Degraded Guinea pig Diarrhea after [kappa], [lambda], 7 days. Mori- [iota] bund after 9 days of [iota] DCG. 19. Degraded Basal diet after (20,000-40,000) Rat DCG exposure (a,b,e) 20. Degraded (c) Guinea pig 21. Undegraded, Rat, Diarrhea in (800,000) hamster some (largely [kappa]) 22. Degraded Rat (a,b,c,g) 23. Degraded (c) Guinea Loose stools by pig 2 weeks 24. Degraded (c) Guinea 17/22 died pig by day 21 25. Degraded Rat (20,000-40,000) (a,b) 26.Undegraded Rat NMU 2 mg twice [lambda] (a,d) weekly rectally for 3 weeks; AOM (8 mg/kg bw) SC for 10 weeks; UCG with NMU, UCG with AOM 27. [iota], Rat (8,700-145,000) (e,f) Undegraded [kappa]/ Rat [lambda], (186,000-214,000) [iota], Guinea pig (5,000-145,000) [iota], Guinea pig (5,000-145,000) [kappa] Guinea pig (8,500-275,000) [lambda] Guinea pig (8,500-275,000) Undegraded [kappa]/ [lambda] Rhesus (185,000) monkey [iota] 28.[kappa] (c) Guinea (314,000) pig (51,500) (8,500) [lambda], (275,000) (74,800) (20,800) [iota], (145,000) (107,000) (88,000) (39,000) (21,000) (8,700) (5,000) 29. Degraded Rhesus [iota] (C16), monkey (20,000) Undegraded Rhesus [kappa][lambda] monkey mixture, (800,000) 30. Degraded Rat 1,2-DMH Watery, bloody ([iota], C16), (20 mg/kg) stools (10,000-30,000) (a,d) SC/wk 31. Degraded (c,e) Rat Severe diarrhea in 3 days with 5% Guinea pig Diarrhea 32. Degraded Guinea pig ([iota], C16) (c) Guinea pig Rat Monkey 33. Degraded (c) Guinea pig Trimethoprim/ Blood in stools Sulfame- thoxazole 34. Undegraded Pig [kappa], (200,000) 35. Degraded Rhesus Diarrhea, (C16, [iota]), (c) monkey hemorrhage (20,000) Undegraded Rhesus (largely [kappa]), monkey (800,000) 36. Undegraded Guinea pig Neomycin Diarrhea, Rabbit (0.1%) added hemorrhage Degraded (c) Guinea pig Rabbit Degraded Humans Ferret Squirrel monkey Rabbit, mouse Rat SI diarrhea Rat Diarrhea Undegraded Rat SI diarrhea Hamster Diarrhea 37. Degraded Rat FOB+ by (c16, [iota]), 3-7 days with > 5 g/kg/day; gross blood (20,000-30,000) (a,b,e) by 2-3 weeks 38. Undegraded Rhesus ([kappa]:[lambda] monkey = 70:30), (800,000) (e) Degraded Rhesus (C16, [iota]), monkey (20,000-30,000) (e) 39. Degraded (c) Guinea FOB+, pig diarrhea by 1 week 40. Degraded (a,b,c,g) Rat 41. Undegraded (c) Guinea pig Degraded (c) Guinea pig 42. Degraded (a,b,c) Rabbit Diarrhea, blood by day 7, weight loss 43. Degraded (c) Guinea pig Degraded Rat Degraded, Rat, Undegraded mouse 44. Undegraded Guinea pig FOB+ Degraded Guinea Diarrhea by pig 10 days, FOB+ 45. Degraded Guinea pig Weight loss in Rabbit guinea pig and Rat rabbit, not rat Mouse or mouse. Blood and mucous in stool. Type of Effects carrageenan, molecular weight Animal Histopathologic changes 1. Undegraded (a,d) Rat Undegraded (a,d) Rat 2. Undegraded Rat Epithelial cell loss, macrophage [iota], >100,000 infiltration, loss of crypts, (a,b) Degraded [iota], Rat 20,000 (a,b) 3. Degraded [iota], Guinea pig Cecal ulcerations; foamy 30,000 (c) macrophages; small epithelial ulcerations at 2 days. 4. Degraded, Guinea pig Microscopic mucosal changes from 20,000-30,000 (c) cecum to rectum; apparent macro- molecule absorption by colonic epithelium, macrophage infiltra- tion, macrophages with vacuoles. 5. Degraded (c) Guinea pig 100% had cecal ulceration after 3% for 4 days; crypt abscesses. 6. Degraded (c) Rat ileal cell monolayers 7. Undegraded Rat 3/8 had slight congestion [lambda], and erythema of distal colon. 300,000 (a,b) 8. Degraded Rat, Increased permeability to [iota] (c) Guinea pig ([sup.3] H) PEG-900; ulcerations in guinea pig, crypt abscesses, macrophage infiltration. 9. Undegraded Rat [kappa] (a,d) 10. Degraded Rabbit Ulcerative lesions at 8 wks; at [lambda] (a,b,c) 12 months had chronic inflammatory changes. 11. Degraded Mice Ulceration in proximal and distal (a,b,c) colon, with dilatation of cecum and ascending colon. 12. Degraded, Cultured (20,000-40,000), rat hepa- and tocytes or Undegraded (a) intestinal mucosal cells 13. Undegraded Rat CG able to penetrate intestine; [kappa], [lambda], CG in mesenteric lymph node, and [iota] (e) and macrophages of villus and lamina propria. 14. Degraded (c) Guinea pig Small, superficial ulcerations over mucosal surface of cecum (1-111 ulcerations/ [cm.sup.2]). 15. Degraded (c) Guinea pig Ulcerations in cecum and proximal colon in unoperated. Postproce- dure, crypt abscesses in rectum and ulcerations in distal colon and rectum. Macrophage infiltra- tion. 16. Degraded (a,d) Rat 17. Degraded, Rat Erosions; aggregates of foamy (20,000-40,000) metachromatic macrophages (a,b,c,g) in submucosa and lamina propria. 18. Degraded Guinea pig No cecal or colonic [kappa], [lambda], lesions seen. [iota] 19. Degraded CG in mucosa (20,000-40,000) Rat and RE system. (a,b,e) 20. Degraded (c) Guinea Cecal lesions after 24 hr; pig confluent ulcerations after 7 days. Macrophage infiltration. 21. Undegraded, Rat, No difference in (800,000) hamster ulcerations from control. (largely [kappa]) 22. Degraded Rat Superficial erosions (a,b,c,g) at anorectal junction at 24 hr; at 2 weeks, more proximal erosions. 23. Degraded (c) Guinea 100% with colonic ulcerations; pig 75% had over 200 ulcers. 24. Degraded (c) Guinea All had mucosal ulcerations pig from cecum to rectum by day 14. 25. Degraded Rat (20,000-40,000) (a,b) 26.Undegraded Rat [lambda] (a,d) 27. [iota], Rat Av MW of CG in liver was (8,700-145,000) (e,f) at 10,000; all CG in feces Undegraded [kappa]/ Rat had MW < 100,000. [lambda], (186,000-214,000) [iota], Guinea pig (5,000-145,000) [iota], Guinea pig (5,000-145,000) [kappa] Guinea pig (8,500-275,000) [lambda] Guinea pig (8,500-275,000) Undegraded [kappa]/ [lambda] Rhesus (185,000) monkey [iota] 28.[kappa] (c) Guinea Cecal ulceration not seen with (314,000) pig [kappa] or [lambda,]; [iota] (51,500) fractions of MW 21,000-107,000 (8,500) led to ulcerations of cecum, [lambda], crypt abscesses, and epithelial (275,000) thinning. [iota] fractions (74,800) absorbed and seen in vacuolated (20,800) macrophages. Intense lysosomal [iota], enzymatic activity in macrophages (145,000) of lamina propria. (107,000) (88,000) (39,000) (21,000) (8,700) (5,000) 29. Degraded Rhesus Macrophages given DCG had [iota] (C16), monkey fibrillar material and (20,000) vacuolations. Undegraded Rhesus Vacuolations seen with UCG. [kappa][lambda] monkey mixture, (800,000) 30. Degraded Rat Distal rectum transformed ([iota], C16), to stratified squamous by (10,000-30,000) (a,d) DMH with DCG. 31. Degraded (c,e) Rat DCG contained within macrophages of spleen, liver, kidney, small and large intestine; cecal Guinea pig and colonic ulcerations at 4 weeks. 32. Degraded Guinea pig 2% CG in water, but not in ([iota], C16) (c) milk, led to cecal ulceration Guinea pig in guinea pig. DCG in macro- phages of submucosal layer in guinea pigs, rats, and monkeys. Rat No cecal ulceration seen in Monkey rats or monkeys. 33. Degraded (c) Guinea pig Cecum and distal colon had ulcerations, crypt abscesses; enlarged cecal or colonic lymph nodes; more extensive ulceration with 5%; fewer lesions with antibiotic. Infiltration of foamy macrophages. 34. Undegraded Pig Focal irregularities without [kappa], ulcerations; thickened lamina (200,000) propria; macrophage infiltration. 35. Degraded Rhesus Ulcerations of colon; hypertrophy (C16, [iota]), (c) monkey of mesenteric lymph nodes and (20,000) granulomas; multiple crypt abscesses; dose effect present. Undegraded Rhesus Without colonic changes. (largely [kappa]), monkey (800,000) 36. Undegraded Guinea pig Multiple pinpoint cecal and Rabbit colonic ulcerations after 3-5 Degraded (c) Guinea pig weeks in guinea pig and rabbit. Rabbit Macrophages increased; inclusions and vacuoles in macrophages; granulomas seen. Neomycin did not affect incidence of ulcers or time of onset. Degraded Humans Patients had colon malignancy with colectomy planned to follow CG exposure, no ulcerations seen. Ferret No lesions seen. Squirrel No lesions seen. monkey Rabbit, mouse No lesions seen. Rat Rat Undegraded Rat Hamster 37. Degraded Rat Metachromatic material (c16, [iota]), thought to be CG found in RE cells of liver, spleen, lymph nodes, macrophages (20,000-30,000) (a,b,e) of lamina propria and submucosa. No cecal lesions. 38. Undegraded Rhesus No changes in liver. ([kappa]:[lambda] monkey = 70:30), (800,000) (e) Degraded Rhesus Membrane-bound vacuoles (C16, [iota]), monkey with fibrillar material in RE (20,000-30,000) (e) cells of liver. 39. Degraded (c) Guinea Multiple ulcers in cecum, colon, pig and rectum in 100% of animals by day 30. 40. Degraded (a,b,c,g) Rat Ulceration of cecum in 4/12, associated with stricture; marked glandular hyperplasia at ulcer margins. 41. Undegraded (c) Guinea Ulceration of mucosa as pig consequence of macrophage Degraded (c) Guinea accumulation in lamina propria, pig then submucosa. 42. Degraded (a,b,c) Rabbit Ulceration of colon in 100% of those fed 1%; 60% of those fed 0.1%. 43. Degraded (c) Guinea Mucosal erosions in cecum, pig rarely into colon in guinea pig; without erosion in rat or mouse. Degraded Rat Degraded, Rat, Undegraded mouse 44. Undegraded Guinea pig Multiple ulcerations of cecum; 80% had ulcerations. Crypt abscesses present; macrophages, with metachromatic material. Degraded Guinea 100% had ulcerations; ulceration pig extended into distal colon and rectum. 45. Degraded Guinea pig Hemorrhagic and ulcerative Rabbit lesions in cecum, colon, or Rat rectum in all four species; Mouse crypt abscesses present. Effects Type of carrageenan, Refe- molecular weight Animal Neoplastic changes rence 1. Undegraded (a,d) Rat UCG jelly (10% x 8 days) (50) did not initiate tumor. Undegraded (a,d) Rat UCG solid gel promoted growth of aberrant crypt foci (+15%; p = 0.019). 2. Undegraded Rat 5-Fold increase in (51) [iota], >100,000 thymidine kinase (a,b) activity in colon cells Degraded [iota], Rat with 5% UCG or DCG. 20,000 (a,b) 35-Fold increase in proliferating cells in upper third of crypt with DCG, 8-fold with UCG. 3. Degraded [iota], Guinea pig (52) 30,000 (c) 4. Degraded, Guinea pig (35) 20,000-30,000 (c) 5. Degraded (c) Guinea pig (53) 6. Degraded (c) Rat ileal Retarded cell growth (54) cell caused cell death; monolayers at 0.25g/L inhibited DNA synthesis by 20%. 7. Undegraded Rat 4-Fold increase in (55) [lambda], thymidine kinase 300,000 (a,b) activity in distal 12 cm of colonic mucosa. 8. Degraded Rat, (56) [iota] (c) Guinea pig 9. Undegraded Rat More tumors with (57) [kappa] (a,d) UCG than control diet (75% vs. 40%); also larger, more proximal tumors. 10. Degraded Rabbit At 28 months, focal (58) [lambda] (a,b,c) and severe glandular atypism; precancerous changes seen. 11. Degraded Mice 2-Fold increase in (59) (a,b,c) colonic epithelial cell proliferation; increase in labeling indices and extension of prolifera- tive compartment to upper third of crypt. 12. Degraded, Cultured DCG and UCG nonmuta- (60) (20,000-40,000), rat hepa- genic in Salmonella and tocytes or mutagenicity test; DCG Undegraded (a) intestinal nongenotoxic by DNA mucosal repair test. cells 13. Undegraded Rat (61) [kappa], [lambda], and [iota] (e) 14. Degraded (c) Guinea pig (62) 15. Degraded (c) Guinea pig (63) 16. Degraded (a,d) Rat Increase in tumors (64) of small intestine (50% vs. 25%) and colon (60% vs. 45%) with CG than occurred with DMH alone. 17. Degraded, Rat Squamous metaplasia (65) (20,000-40,000) from anorectal junction (a,b,c,g) to distal colon. 18. Degraded Guinea pig (66) [kappa], [lambda], [iota] 19. Degraded 100% incidence of (67) (20,000-40,000) Rat colorectal squamous (a,b,e) metaplasia that prog- ressed after DCG intake discontinued. 20. Degraded (c) Guinea (68) pig 21. Undegraded, Rat, Increased incidence (69) (800,000) hamster of benign mammary (largely [kappa]) tumors and testicular neoplasms (at 2.5% level) in rats only. 22. Degraded Rat Squamous metaplasia (70) (a,b,c,g) of rectal mucosa at 2 weeks; extended after no longer being fed CG. 23. Degraded (c) Guinea (34) pig 24. Degraded (c) Guinea (71) pig 25. Degraded Rat Squamous cell (72) (20,000-40,000) (a,b) carcinomas, adenocarcinomas, adenomas. 32% and fed 10% diet had tumors. 100% incidence of meta- plasia with 5% drink. 26.Undegraded Rat 100% had tumors with (73) [lambda] (a,d) AOM and UCG vs. 57% with AOM alone. 100% had tumors with NMU and UCG vs. 59% with NMU alone. 0 tumors in control, 7% tumors with UCG alone. UCG with AOM had 10-fold increase in number of tumors per rat. 27. [iota], Rat (74) (8,700-145,000) (e,f) Undegraded [kappa]/ Rat [lambda], (186,000-214,000) [iota], Guinea pig (5,000-145,000) [iota], Guinea pig (5,000-145,000) [kappa] Guinea pig (8,500-275,000) [lambda] Guinea pig (8,500-275,000) Undegraded [kappa]/ [lambda] Rhesus (185,000) monkey [iota] 28.[kappa] (c) Guinea (75) (314,000) pig (51,500) (8,500) [lambda], (275,000) (74,800) (20,800) [iota], (145,000) (107,000) (88,000) (39,000) (21,000) (8,700) (5,000) 29. Degraded Rhesus (76) [iota] (C16), monkey (20,000) Undegraded Rhesus [kappa][lambda] monkey mixture, (800,000) 30. Degraded Rat DMH with DCG- (77) ([iota], C16), induced proliferation (10,000-30,000) (a,d) of deep glandular areas; more poorly differentia- ted adenocarcinomas; more frequently found tumors of ascending and transverse colon with DMH and DCG. 31. Degraded (c,e) Rat (78) Guinea pig 32. Degraded Guinea pig (79) ([iota], C16) (c) Guinea pig Rat Monkey 33. Degraded (c) Guinea pig (80) 34. Undegraded Pig (81) [kappa], (200,000) 35. Degraded Rhesus (82) (C16, [iota]), (c) monkey (20,000) Undegraded Rhesus (largely [kappa]), monkey (800,000) 36. Undegraded Guinea pig (83) Rabbit Degraded (c) Guinea pig Rabbit Degraded Humans Ferret Squirrel monkey Rabbit, mouse Rat Rat Undegraded Rat Hamster 37. Degraded Rat Adenomatous (84) (c16, [iota]), and hyperplastic polyps in one rat. Squamous metaplasia (20,000-30,000) (a,b,e) of anorectal region and distal colon. 38. Undegraded Rhesus (85) ([kappa]:[lambda] monkey = 70:30), (800,000) (e) Degraded Rhesus (C16, [iota]), monkey (20,000-30,000) (e) 39. Degraded (c) Guinea (86) pig 40. Degraded (a,b,c,g) Rat (87) 41. Undegraded (c) Guinea (88) pig Degraded (c) Guinea pig 42. Degraded (a,b,c) Rabbit Hyperplastic 89, mucosal changes, 90) polypoidal lesions. 43. Degraded (c) Guinea (91) pig Degraded Rat Degraded, Rat, Undegraded mouse 44. Undegraded Guinea pig (92) Degraded Guinea pig 45. Degraded Guinea pig (93) Rabbit Rat Mouse Abbreviations: AOM, azoxymethane; bw, body weight, CG,carrageenan; DCG, degraded carrageenan; DMH, dimethylhydrazine; FOB, fecal occult blood; ip, intraperitoneal; NMU, nitrosomethylurea; PEG, polyethylene glycol; SC, subcutaneous; SI, slight; tube, gastric intubation; UCG, undegraded carrageenan. (a) Studies are associated with neoplastic changes, unlike studies predominantly demonstrating intestinal ulcerations. (b) Increased proliferation or neoplasm and carrageenan alone. (c) Ulcerations and carrageenan alone. (d) Neoplasms in which carrageenan promoted carcinogenesis. (e) Studies with uptake to lymph node or other site. (f) Study demonstrating breakdown to lower molecular weight. (g) Studies demonstrating ulcerations in rat using degraded carrageenan. Table 4. Proposed mechanism for effects of carrageenan (9,10,35,67,72,75,76,79,84-86,88,98,102,105,107-110,114,115). Site Effect Intestinal lumen Ingested carrageenan can undergo acid hydrolysis in stomach possible breakdown by intestinal bacteria. Intestinal Take up degraded carrageenan, as indicated by epithelial cells metachromatic staining from cecum to rectum. Vacuoles observed to contain metachromatic material. Epithelial cells may undergo lysis from effect of lysosomal disruption producing erosions. Inflammatory Polymorphonuclear cells and macrophages infiltrate infiltrate to site of intestinal inflammation. Macrophages have metachromatic staining associated with uptake of degraded carrageenan. Lysosomal vacuolation occurs as well as lysosomal disruption with release of intracellular enzymes from macrophage destruction, leading to intestinal ulcerations. Process of chronic inflammation, as with ulcerative colitis. Macrophage Macrophages may circulate and may lead to circulation extraintestinal effects related to carrageenan. Table 5. Experimental evidence for presence of low molecular weight carrageenan in food-grade carrageenan and production of low molecular weight carrageenan by acid hydrolysis or by bacteria. (9,10,36-40). Degraded carrageenan in food-grade carrageenan 25% of total carrageenans in eight food-grade [kappa]-carrageenans had MW < 100,000 9% of total carrageenan in eight food-grade [kappa]-carrageenans had MW < 50,000 Production of degraded carrageenan by acid hydrolysis of food-grade carrageenan In simulated gastric fluid (including pepsin and HCL}, [kappa]- carrageenan at pH 1.2, 37 [degrees] C for 1 hr leads to 17% degraded carrageenan with MW < 20,000 for 2 hr leads to 25% with MW < 20,000 In simulated gastric fluid (including pepsin and HCL), [kappa]- carrageenan at pH 1.9, 37 [degrees] C for 1 hr leads to 8% with MW < 20,000 for 2 hr leads to 10% with MW < 20,000 [kappa]-carrageenan in solution at pH 1.0, 37 [degrees] C, for 6 hours, leads to 25% with MW < 20,000 [iota]-carrageenan in solution at pH 1.0, 37 [degrees] C, for 6 hours, leads to 10% with MW < 25,000 Hydrolysis of carrageenan by bacterial carrageenases [kappa]- and [iota]-carrageenase from cell-free supernatant from culture of Cytophaga genus [kappa]-carrageenase isolated from cell-free medium of cultured Pseudomonas carrageenovora [lambda]-carrageenase from cell-free medium of Pseudomonas carrageenovora cultures MW, molecular weight.
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Performed or administered through or by way of the mouth. toxicity of undegraded carrageenan in pigs. Food Cosmet Toxicol 11:219-227 (1973).
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(83.) Grasso P, Sharratt M, Carpanini FMB FMB
Federal Maritime Board
FMB (US) n abbr (= Federal Maritime Board) → Dachausschuss der Handelsmarine , Gangolli SD. Studies on carrageenan and large-bowel ulceration in mammals. Food Cosmet Toxicol 11:555-564 (1973).
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adj. cells of the rhesus monkey. Exp Mol Pathol 17:77-93 (1972).
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Cells, cell products, organs, and structures of the body involved in the detection and destruction of foreign invaders, such as bacteria, viruses, and cancer cells. Immunity is based on the system's ability to launch a defense against such invaders. . Agents Actions 1:265-273 (1981).
(107.) Kolodny EW, Fluharty AL. Metachromatic leukodystrophy metachromatic leukodystrophy
An inherited metabolic disorder characterized by myelin loss, accumulation of metachromatic lipids in the white matter of the central and peripheral nervous systems, a marked excess of sulfatidates in white matter and in and multiple sulfatase deficiency: sulfatide lipidosis lipidosis /lip·i·do·sis/ (lip?i-do´sis) pl. lipido´ses any disorder of lipid metabolism involving abnormal accumulation of lipids in the reticuloendothelial cells.
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(112.) Michel C, Macfarlane MacFarlane or Macfarlane is a surname shared by:
(113.) Gibson GR, Macfarlane S, Cummings JH. The fermentability fer·ment
1. Something, such as a yeast, bacterium, mold, or enzyme, that causes fermentation.
a. A state of agitation or of turbulent change or development.
b. of polysaccharides by mixed human faecal fae·cal
adj. Chiefly British
Variant of fecal.
Adj. 1. faecal - of or relating to feces; "fecal matter"
fecal bacteria in relation to their suitability as [kappa]-forming laxatives. Lett Appl Microbiol 11:251-254 (1990).
(114.) Roediger WEW WEW Week-End Warriors (Arizona gaming clan)
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(115.) Richardson CJ, Magee EAM (1) (Enterprise Asset Management) The management and control of the information technology assets within the enterprise. The asset management repository includes a description of the asset as well as contract information pertaining to its acquisition. , Cummings JH. A new method for the determination of sulphide in gastrointestinal contents and whole blood by microdistillation and ion chromatography Ion-exchange chromatography (or ion chromatography) is a process that allows the separation of ions and polar molecules based on the charge properties of the molecules. . Clin Chim Acta 293:115-125 (2000).
(116.) Babidge W, Millard S, Roediger W. Sulfides impair short chain fatty acid Short chain fatty acids are a sub-group of fatty acids with aliphatic tails of less than six carbons. They include:
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Gene that can cause cancer. It is a sequence of DNA that has been altered or mutated from its original form, the proto-oncogene (see mutation). Proto-oncogenes promote the specialization and division of normal cells. Res 3:223-238 (1998).
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The process by which genetic information is copied from DNA to RNA, resulting in a specific protein formation.
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(128.) Hoffman R, Burns WW, Paper DH. Selective inhibition selective inhibition
See competitive inhibition. of cell proliferation and DNA synthesis DNA synthesis commonly refers to:
(129.) Coombe A coombe is a short, deep, generally bowl-shaped valley or hollow, see cirque.
Coombe may refer to one of these places in England:
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(130.) Tobacman JK. Filament filament, in astronomy: see chromosphere. disassembly dis·as·sem·ble
v. dis·as·sem·bled, dis·as·sem·bling, dis·as·sem·bles
To take apart: disassemble a toaster.
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(140.) Food Quality Protection Act of 1996. Public Law 104-170, 110 Stat. 1489.
Joanne K. Tobacman College of Medicine, University of Iowa, Iowa City, Iowa, USA
Address correspondence to J.K. Tobacman, Department of Internal Medicine, University of Iowa Not to be confused with Iowa State University.
The first faculty offered instruction at the University in March 1855 to students in the Old Mechanics Building, situated where Seashore Hall is now. In September 1855, the student body numbered 124, of which, 41 were women. Health Care, 200 Hawkins Drive, Iowa City, Iowa Iowa City is a city in Johnson County, Iowa, United States. It is the principal city of the Iowa City, Iowa Metropolitan Statistical Area which encompasses Johnson and Washington counties. 52242-1081, USA. Telephone: (319) 356-3702. Fax: (319) 356-3086. E-mail: joanne-tobacman@ uiowa.edu
Received 17 January 2001; accepted 17 March 2001.