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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
n.
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.

carcinogenicity

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
n.
The production of cancer.



carcinogenesis

production of cancer.


biological carcinogenesis
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.
polysaccharide

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:
  • Morbidity & Mortality, a term used in medicine
  • Morbidity and Mortality Weekly Report, a medical publication
See also
  • Morbidity, a medical term
  • Mortality, a medical term
 in the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. . Even with improvements in treatment and cancer screening, colorectal cancer colorectal cancer

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
artificial additive

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.

hex·ose
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.

e·mul·si·fi·er
n.
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.
Purpose

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.

Notes:
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.

di·e·tet·ic
adj.
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  
n.
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
  • LSBU carob gum webpage
, to improve the texture of foods (12-14,22,41,42).

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.

accubation

Rare. the act or habit of reclining at meals.

alimentology

Medicine. thescience of nutrition.

allotriophagy

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  
adj.
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.


ul·cer·a·tion
n.
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.
Duodenal
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
n.
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


metastatic

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.

ret·ro·per·i·to·ne·al
adj.
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
n.
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.


ad·e·nom·a·tous
adj.
1.
 and hyperplastic polyps as well as squamous metaplasia of the anorectal a·no·rec·tal
adj.
Relating to the anus and the rectum.



anorectal

pertaining to, emanating from or affecting the anorectum.


anorectal abscess
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
Overgrown.

Mentioned in: Adenoid Hyperplasia


hyperplastic

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.
carcinogen

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.

ab·er·rant
adj.
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
n.
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.

2. glanular.


glan·du·lar
adj.
1.
 areas.

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.

thy·mi·dine
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 2.7.1.75. 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.
abbr.
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.

ulcerative

pertaining to or characterized by ulceration.
 lesions appeared initially in distal colon and rectum rectum: see intestine.
rectum

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.


ce·cal
adj.
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
adj.
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.


mu·cous
adj.
1.
 in stools, and visible or occult blood occult blood
n.
Blood that is present in amounts too small to be seen and can be detected only by chemical analysis or microscopic examination.


Occult blood
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
pl.n.
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
adj.
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
(līssōmz),
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
adj.
Containing vacuoles or a vacuole.



vacuolated

containing vacuoles.
. It appeared that colonic ulcerations developed as a result of macrophage lysosomal lysosomal

pertaining to or emanating from lysosomes.


lysosomal enzymes
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
adj.
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.


in·fil·trate
v.
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
n.
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  
n.
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.

met·a·chro·mat·ic
adj.
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.

sul·fa·tase
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.
Microflora
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.


microbial digestion
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.

pretreatment estimate,
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
n.
See alimentary canal.


Digestive tract
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.

fe·cal
adj.
Relating to or composed of feces.



fecal

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.

bu·ty·rate
n.
A salt or ester of butyric acid.



butyrate

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
n.
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.

plan·tar
adj.
Of, relating to, or occurring on the sole.
 surface of a rat's paw (tool) PAW - Physics Analysis Workbench. , pleural cavity pleural cavity
n.
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.

sub·cu·ta·ne·ous
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.

bleb
n.
A large flaccid vesicle.



bleb

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 vi·tro
adj.
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
n.
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
adj.
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.

in vi·vo
adj.
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
adj.
1. Relating to body fluids, especially serum.

2. Relating to or arising from any of the bodily humors.


Humoral
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
n.
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.
Endothelial
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.

mam·ma·ry
adj.
Of or relating to a breast or mamma.



mammary

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
n.
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.
Description

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.

tes·tic·u·lar
adj.
Of or relating to a testicle or testis.



testicular

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
n.
The quality or state of being toxic to kidney cells.


nephrotoxicity(ne·fr
 (4).

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
adj.
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.[1] 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.

Conclusion

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.

mutagenicity

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
n.
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
n.
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
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.

am·y·lo·pec·tin
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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(15.) Daniel JR, Voragen ACJ ACJ American Committee on Jerusalem
ACJ Asociación Cristiana de Jóvenes (Christian Youth Association, Guatemala)
ACJ American Communication Journal
ACJ Acromioclavicular Joint
ACJ Advisory Circular Joint
ACJ Artificially Constructed Junction
, Pilnik W. Starch and other polysaccharides. In: Ullmann's Encyclopedia of Industrial Chemistry, Vol A 25 (Elvers B, Hawkins S, Russey W, ads). New York:VCH VCH Victoria County History
VCH Vertical Clitoral Hood (piercing)
VCH Volunteer Clearing House (University of Colorado)
VCH Vliegclub Hoogeveen
VCH Virtual Channel Handler
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(16.) Substances that are generally recognized as safe Generally Recognized as Safe (GRAS) is a United States of America Food and Drug Administration (FDA) designation that a chemical or substance added to food is considered safe by experts, and so is exempted from the usual Federal Food, Drug, and Cosmetic Act (FFDCA) food . Fed Reg FED REG Federal Register  21:9368-9370.

(17.) Food and Drugs: Food Additives. 21 C.F.R. 121.101,121.1063,121.1066,121.1067,121.1069,1969.

(18.) Proposed Revision of Food Additive Regulations and Deletion of Chondrus Extract (Carrageenin car·ra·geen·an also car·ra·geen·in  
n.
Any of a group of closely related colloids derived from Irish moss and several other red algae, widely used as a thickening, stabilizing, emulsifying, or suspending agent in industrial, pharmaceutical, and
) from Generally Regarded as Safe (GRAS) List. 37 Fed Reg 15434.

(19.) Informatics, Inc. Carrageenan. Arlington, VA:National Technical and Information Service, 1972;1-68.

(20.) Nicklin S, Miller K. Intestinal uptake and immunological effects of carrageenan--current concepts. Food Addit Contain 6(4):425-436 (1989).

(21.) Food and Nutrition Board, National Research Council. Estimating Distribution of Daily Intakes of Chondrus Extract (Carrageenan): Committee on GRAS List Survey--Phase III. Appendix C. Washington, DC:National Academy of Sciences, 1976;1-7.

(22.) Stanicoff DJ, Renn DW. Physiological effects of carrageenan. In: ACS (Asynchronous Communications Server) See network access server.  Symposium Series (15): Physiological Effects of Food Carbohydrates (Gould RF, ed). Washington, DC:American Chemical Society The American Chemical Society (ACS) is a learned society (professional association) based in the United States that supports scientific inquiry in the field of chemistry. Founded in 1876 at New York University, the ACS currently has over 160,000 members at all degree-levels and in , 1975; 282-295.

(23.) Pintauro SJ, Gilbert SW. The effects of carrageenan on drug-metabolizing enzyme system activities in the guinea-pig. Food Chem Toxicol 28:807-611 (1990).

(24.) Carrageenan, Salts of Carrageenan and Chondrus Extract (Carrageenin); Withdrawal of Proposal and Termination of Rulemaking Proceeding. Fed Reg 44:40343-40345.

(25.) International Food Additives Council and FMC See fixed mobile convergence.  Corporation-Marine Colloids Division, filing of Food Additive Petitions; Hercules, Inc.; Notice of Receipt of Citizen Petition; Request for Comments. Fed Reg 57:49483-49485.

(26.) National Research Council. Food Chemical Codex. 2nd ed, suppl 2. Washington, DC:National Academy of Science, 1975.

(27.) National Research Council. Food Chemical Codex. 4th ed. Washington, DC:National Academy of Science, 1996.

(28.) Tong H-K H-K Hunter-Killer , Lee K-H, Wong H-A. The molecular weight and viscosity of the water-soluble polysaccharide(s) from Eucheuma spinosum. Carbohydr Res 81:1-6 (1980).

(29.) Weiner ML. Toxicological properties of carrageenan. Agents Actions 32(1/2):48-51 (1991).

(30.) Food and Drugs: Food Additives Permitted for Direct Addition to Food for Human Consumption. 21 C.F.R. 172.620,172.626,172.655,172.660, 2000.

(31.) Food and Drugs: Substances Generally Regarded as Safe. 21 C.F.R. 182.7255,1999.

(32.) Food and Drugs: New Drugs. 21 C.F.R. 310.545, 1999.

(33.) Food and Drugs: 21 C.F.R. 133.178, 133.179, 136.110, 139.121,139.121,139.122, 150.141,150.161,176.170 (2000).

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(35.) Marcus SN, Marcus AJ, Marcus R, Ewen SWB SWB Stadtwerke Bonn
SWB Scranton Wilkes-Barre (Pennsylvania region)
SWB Short Wheel Base
SWB Southwestern Bell
SWB Subjective Well-Being (psychology)
SWB Switchboard
SWB Social Well-Being
, Watt J. The pre-ulcerative phase of carrageenan-induced colonic ulceration in the guinea-pig. Int J Exp Pathol 73:515-526 (1992).

(36.) Sarwar G, Matoyoshi S, Oda H. Purification of a [kappa]-carrageenase from marine cytophaga species. Microbiol Immunol 31:869-877 (1987).

(37.) Weigl J, Yaphe W. The enzymic hydrolysis of carrageenan by pseudomonas carrageenovora: purification of a [kappa]-carrageenase. Can J Microbiol 12:939-947 (1986).

(38.) Potin P, Sanseau A, LeGall Y, Rochas C, Bloareg B. Purification and characterization of a new [kappa]-carrageenase from a marine cytophaga-like bacterium. Eur J Biochem 201:241-247 (1991).

(39.) McLean MW, Williamson FB. [kappa]-Carrageenase from Pseudomonas carrageenovora. Eur J Biochem 93:553-558 (1979).

(40.) Johnston KH, McCandless EL. Enzymic hydrolysis of the potassium chloride potassium chloride, chemical compound, KCl, a colorless or white, cubic, crystalline compound that closely resembles common salt (sodium chloride). It is soluble in water, alcohol, and alkalies.  soluble fraction of carrageenan: properties of "lambda carrageenases" from Pseudomonas carrageenovora. Can J Microbiol 19(7):779-788 (1973).

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  • John C. Wiley, American ambassador
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(42.) Meer WA. Plant hydrocolloids. In: Food Colloids (Graham HD, ed). Westport, CT:AVI Publishing Company, Inc., 1977;522-539.

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(44.) Anderson W. Carrageenan: structure and biological activity. Can J Pharm Sci 2:81-90 (1967).

(45.) Comite "Additifs Alimentaires" du CNERNA. Toxicological evaluation of carrageenans. 10-Conclusions: acquired knowledges and problems requiring further researches. Sciences des aliments ALIMENTS. In the Roman and French law this word signifies the food and other things necessary to the support of life, as clothing and the like. The same name is given to the money allowed for aliments. Dig. 50, 16, 43.
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(46.) Will R, Zuanich J, DeBoo A, Ishikawa Y. Water-soluble polymers. Menlo Park Menlo Park.

1 Residential city (1990 pop. 28,040), San Mateo co., W Calif.; inc. 1874. Electronic equipment and aerospace products are manufactured in the city. Menlo College and a Stanford Univ. research institute are there.

2 Uninc.
, CA:Chemical Economics Handbook - SRI International (company) SRI International - One of the world's largest contract research firms. Founded in 1946 in conjuction with Stanford University as the Stanford Research Institute, they later became fully independent and were incorporated as a non-profit organisation under U.S. , 1999;582.0000E-582.0003V.

(47.) Piculell L Gelling carrageenans. In: Food Polysaccharides and Their Applications. New York:Marcel Dekker Marcel Dekker is a well-known encyclopedia publishing company with editorial boards found in New York, New York. They are part of the Taylor and Francis publishing group.

Initially a textbook publisher, they went to encyclopedia publishing in the late 1990's.
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(48.) Food and Nutrition Board, National Research Council. 1977 Survey of Industry on the Use of Food Additives. Summarized Data: Committee on GRAS List Survey-Phase III. Washington, DC:National Academy of Sciences, 1979;978-987.

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(50.) Corpet DE, Tache S tache (tahsh) [Fr.] a spot or blemish.tachet´ic

tache blanche  (blahnsh) a white spot on the liver in certain infectious diseases.
, Preclaire M. Carrageenan given as a jelly, does not initiate, but promotes the growth of aberrant crypt foci in the rat colon. Cancer Lett 114:53-55 (1997).

(51.) Wilcox DK, Higgins J, Bertram TA. Colonic epithelial cell proliferation in a rat model of nongenotoxin-induced colonic neoplasia. Lab Invest 67:405-411 (1992).

(52.) Kitsukawa Y, Saito H, Suzuki Y, Kasanuki J, Tamura Y, Yoshida S. Effect of ingestion ingestion /in·ges·tion/ (-chun) the taking of food, drugs, etc., into the body by mouth.

in·ges·tion
n.
1. The act of taking food and drink into the body by the mouth.

2.
 of eicosapentaenoic acid eicosapentaenoic acid /ei·co·sa·pen·ta·eno·ic ac·id/ (EPA) (i-ko?sah-pen?tah-e-no´ik) an omega-3, polyunsaturated, 20-carbon fatty acid found almost exclusively in fish and marine animal oils.  ethyl ethyl (ĕth`əl), CH3CH2, organic free radical or alkyl group derived from ethane by removing one hydrogen atom.  ester on carrageenan-induced colitis in guinea pigs. Gastroenterology gastroenterology

Medical specialty dealing with digestion and the digestive system. In the 17th century Jan Baptista van Helmont conducted the first scientific studies in the field; William Beaumont published his own observations in 1833.
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(53.) Marcus A J, Marcus SN, Marcus R, Watt J. Rapid production of ulcerative disease of the colon in newly-weaned guinea-pigs by degraded carrageenan. J Pharm Pharmacol 41:423-426 (1989).

(54.) Ling [kappa]-Y, Bhalla D, Hollander D. Mechanisms of carrageenan injury of IEC (International Electrotechnical Commission, Geneva, Switzerland, www.iec.ch) An organization that sets international electrical and electronics standards founded in 1906. It is made up of national committees from over 60 countries.

IEC - International Electrotechnical Commission
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(55.) Calvert RJ, Reicks M. Alterations in colonic thymidine kinase enzyme activity Enzyme activity
A measure of the ability of an enzyme to catalyze a specific reaction.

Mentioned in: Glucose-6-Phosphate Dehydrogenase Deficiency
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(56.) Delahunty T, Recher L, Hollander D. Intestinal permeability changes in rodents: a possible mechanism for degraded carrageenan-induced colitis. Food Chem Toxicol 25:113-118 (1987).

(57.) Arakawa S, Okumua M, Yamada S, Ito M, Tejima S. Enhancing effect of carrageenan on the induction of rat colonic tumors by 1,2-dimethylhydrazine and its relation to [beta]-glucuronidase activities in feces feces
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Solid bodily waste discharged from the colon through the anus during defecation. Normal feces are 75% water. The rest is about 30% dead bacteria, 30% indigestible food matter, 10–20% cholesterol and other fats,
 and other tissues. J Nutr Sci Vitaminol (Tokyo) 32:481-485 (1986).

(58.) Kitano A, Matsumoto T, Hiki M, Hashimura H, Yoshiyasu K, Okawa K, Kuwajima S, Kobayashi K. Epithelial dysplasia of the rabbit colon induced by degraded carrageenan. Cancer Res 46:1374-1376 (1986).

(59.) Fath RB, Deschner EE, Winawer SJ, Dworkin BM. Degraded carrageenan-induced colitis in C[F.sub.1] mice. Digestion 29:197-203 (1984).

(60.) Mori H, Ohbayashi F, Hirono I, Shimada T, Williams GM. Absence of genotoxicity Genotoxic substances are a type of carcinogen, specifically those capable of causing genetic mutation and of contributing to the development of tumors. This includes both certain chemical compounds and certain types of radiation.  of the carcinogenic sulfated polysaccharide carrageenan and dextran sulfate in mammalian DNA repair and bacterial mutagenicity assays. Nutr Cancer 6:92-97 (1984).

(61.) Nicklin S, Miller K. Effect of orally administered food-grade carrageenans on antibody-mediated and cell-mediated immunity in the inbred in·bred
adj.
1. Produced by inbreeding.

2. Fixed in the character or disposition as if inherited; deep-seated.



inbred

said of offspring produced by inbreeding.
 rat. Food Chem Toxicol 22:615-621 (1984).

(62.) Jensen BH, Andersen JO, Poulsen SS, Olsen PS, Rasmussen SN, Hansen SH, Hvidberg DF. The prophylactic prophylactic /pro·phy·lac·tic/ (pro?-fi-lak´tik)
1. tending to ward off disease; pertaining to prophylaxis.

2. an agent that tends to ward off disease.


pro·phy·lac·tic
n.
 effect of 5-aminosalicylic acid and salazosulphapyridine on degraded-carrageenan-induced colitis in guinea pigs. Scand J Gastroenterol 19:299-303 (1984).

(63.) Olsen PS, Kirkegaard P, Poulsen SS. The effect of ileotransversostomy on carrageenan-induced colitis in guinea pig. Scand J Gastroenterol 18:407-410 (1983).

(64.) Kawaura A, Shibata M, Togei K, Otsuka H. Effect of dietary degraded carrageenan on intestinal carcinogenesis in rats treated with 1,2-dimethylhydrazine dihydrochloride. Tokushima J Exp Med 29:125-129 (1982).

(65.) Hirono I, Sumi SUMI Software Usability Measurement Inventory (measures software quality from the user's point of view)  Y, Kuhara K, Miyakawa M. Effect of degraded carrageenan on the intestine in germfree germ·free  
adj.
Free of microorganisms.

Adj. 1. germfree - free from germs or pathogenic organisms; sterile; "a germfree environment"
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(66.) Norris AA, Lewis AJ, Zeitlin IJ. Inability of degraded carrageenan fractions to induce inflammatory bowel ulceration in the guinea pig. J Pharm Pharmacol 33:612-613 (1981).

(67.) Oohashi Y, Ishioka TT, Wakabayashi K, Kuwabara N. A study of carcinogenesis induced by degraded carrageenan arising from squamous metaplasia of the rat colorectum. Cancer Lett 14:267-272 (1981).

(68.) Olsen PS, Poulsen SS. Stereomicroscopic and histologic his·tol·o·gy  
n. pl. his·tol·o·gies
1. The anatomical study of the microscopic structure of animal and plant tissues.

2. The microscopic structure of tissue.
 changes in the colon of guinea pigs fed degraded carrageenan. Acta Pathol Microbiol Scand Sect A 88:135-141 (1980).

(69.) Rustia M, Shubik P, Patil K. Lifespan carcinogenicity tests with native carrageenan in rats and hamsters. Cancer Lett 11:1-10 (1980).

(70.) Oohashi Y, Kitamura S, Wakabayashi K, Kuwabara N, Fukuda Y. Irreversibility of degraded carrageenan-induced colorectal squamous metaplasia in rats. Gann 70:391-392 (1979).

(71.) Onderdonk AB, Hermos JA, Dzink JL, Bartlett JG. Protective effect of metronidazole in experimental ulcerative colitis. Gastroenterology 74:521-526 (1978).

(72.) Wakabayashi K, Inagaki T, Fujimoto Y, Fukuda Y. Induction by degraded carrageenan of colorectal tumors in rats. Cancer Lett 4:171-176 (1978).

(73.) Watanabe K, Reddy BS, Wong CQ, Weisburger JH. Effect of dietary undegraded carrageenan on colon carcinogenesis in F344 rats treated with azoxymethane or methylnitrosourea. Cancer Res 38:4427-4430 (1978).

(74.) Pittman KA, Golberg L, Coulston F. Carrageenan: the effect of molecular weight and polymer type on its uptake, excretion and degradation in animals. Food Cosmet Toxicol 14:85--93 (1976).

(75.) Engster M, Abraham R. Cecal response to different molecular weights and types of carrageenan in the guinea pig. Toxicol Appl Pharmacol 38:265-282 (1976).

(76.) Mankes R, Abraham R. Lysosomal dysfunction in colonic submucosal submucosal /sub·mu·co·sal/ (-mu-ko´sal)
1. pertaining to the submucosa.

2. beneath a mucous membrane.
 macrophages of rhesus monkeys caused by degraded iota carrageenan. Proc Soc Exp Biol Med 150:166-170 (1975).

(77.) Iatropoulos MJ, Golberg L, Coulston L. Intestinal carcinogenesis in rats using 1,2-dimethylhydrazine with or without degraded carrageenan. Exp Mol Pathol 23:386--401 (1975).

(78.) Grasso P, Gangolli SD, Butterworth KR, Wright MG. Studies on degraded carrageenan in rats and guinea-pigs. Food Cosmet Toxicol 13:195-201 (1975).

(79.) Abraham R, Fabian RJ, Golberg MB, Coulston F. Role of lysosomes in carrageenan-induced cecal ulceration. Gastroenterology 67:1169-1181 (1974).

(80.) Van der Waaif D, Cohen cohen
 or kohen

(Hebrew: “priest”) Jewish priest descended from Zadok (a descendant of Aaron), priest at the First Temple of Jerusalem. The biblical priesthood was hereditary and male.
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(81.) Poulsen E. Short-term peroral peroral /per·oral/ (per-or´al) performed or administered through the mouth.

per·o·ral
adj.
Performed or administered through or by way of the mouth.
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(82.) Benitz [kappa]-F, Golberg L, Coulston F. Intestinal effects of carrageenans in the rhesus monkey. Food Cosmet Toxicol 11:565-575 (1973).

(83.) Grasso P, Sharratt M, Carpanini FMB FMB
abbr.
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).

(84.) Fabian RJ, Abraham R, Coulston F, Golberg L. Carrageenan-induced squamous metaplasia of the rectal mucosa in the rat. Gastroenterology 65:265-276 (1973).

(85.) Abraham R, Golberg L, Coulston F. Uptake and storage of degraded carrageenan in lysosomes of reticuloendothelial reticuloendothelial /re·tic·u·lo·en·do·the·li·al/ (-en?do-the´le-al) pertaining to the reticuloendothelium or to the reticuloendothelial system.

re·tic·u·lo·en·do·the·li·al
adj.
 cells of the rhesus monkey. Exp Mol Pathol 17:77-93 (1972).

(86.) Watt J, Marcus R. Carrageenan-induced ulceration of the large intestine in the guinea pig. Gut 12:164-171 (1971).

(87.) Marcus R, Watt J. Colonic ulceration in young rats fed degraded carrageenan. Lancet 2:765-766 (1971).

(88.) Sharratt M, Grasso P, Carpanini F, Gangolli SD. Carrageenan ulceration as a model for human ulcerative colitis. Lancet 2:932 (1970).

(89.) Watt J, Marcus R. Ulcerative colitis in rabbits fed degraded carrageenan. J Pharm Pharmacol 22:130-131 (1970).

(90.) Watt J, Marcus R. Hyperplastic mucosal changes in the rabbit colon produced by degraded carrageenin. Gastroenterology 59:760-768 (1970).

(91.) Maillet M, Bonfils S, Lister RE. Carrageenan: effects in animals. Lancet 2:414-415 (1970).

(92.) Watt J, Marcus R. Ulcerative colitis in the guinea-pig caused by seaweed extract. J Pharm Pharmacol 21:187S-188S (1969).

(93.) Marcus R, Watt J. Seaweeds and ulcerative colitis in laboratory animals. Lancet 2:489-490 (1969).

(94.) Onderdonk AB. The carrageenan model for experimental ulcerative colitis. Prog Clin Biol Res 186:237-245 (1985).

(95.) Ottet NK. On animal models for inflammatory bowel disease. Gastroenterology 62:1269-1272 (1972).

(96.) Watt J, Marcus R. Progress report: Experimental ulcerative disease of the colon in animals. Gut 14:506-510 (1973).

(97.) Sharratt M, Grasso P, Carpanini F, Gangolli SD. Carrageenan ulceration as a model for human ulcerative colitis. Lancet 1:192-193 (1971).

(98.) Mottet NK. On animal models for inflammatory bowel disease. Gastroenterology 62:1269-1271 (1971).

(99.) Kim H-S, Berstad A. Experimental colitis in animal models. Scand J Gastroenterol 27:529-537 (1992).

(100.) Watt J, Marcus SN, Marcus AJ. The comparative prophylactic effects of sulfasalazine sulfasalazine /sul·fa·sal·a·zine/ (-sal´ah-zen) a sulfonamide used in the treatment and prophylaxis of inflammatory bowel disease and the treatment of rheumatoid arthritis. , prednisolone prednisolone /pred·nis·o·lone/ (pred-nis´ah-lon) a synthetic glucocorticoid derived from cortisol, used in the form of the base or the acetate, sodium phosphate, or tebutate ester in replacement therapy for adrenocortical insufficiency, , and azathioprine azathioprine: see metabolite.  in experimental ulceration. J Pharm Pharmacol 32:873-874 (1980).

(101.) Kitano A, Matsumoto T, Oshitani N, Nakagawa M, Yasuda K, Watanabe Y, Tomobuchi M, Obayashi M, Tabata A, Fukushima R, et al. Distribution and anti-inflammatory effect of mesalazine on carrageenan-induced colitis in the rabbit. Clin Exp Pharmacol Physiol 23:305-309 (1996).

(102.) Ishioka T, Kuwabara N, Oohashi Y, Wakabayashi K. Induction of colorectal tumors in rats by sulfated polysaccharides. CRC (Cyclical Redundancy Checking) An error checking technique used to ensure the accuracy of transmitting digital data. The transmitted messages are divided into predetermined lengths which, used as dividends, are divided by a fixed divisor.  Crit Rev Toxicol 17:215-244 (1987).

(103.) Gangolli SD, Wright MG, Grasso P. Identification of carrageenan in mammalian tissues: an analytical and histochemical study. Histochem J 5:37-48 (1973).

(104.) Pipy B. 9-Carraghenanes et macrophages. Sciences des aliments 4:415-428 (1984).

(105.) Catanzaro PJ, Schwartz HJ, Graham RD. Spectrum and possible mechanism of carrageenan cytotoxicity cytotoxicity /cy·to·tox·ic·i·ty/ (si?to-tok-sis´i-te) the degree to which an agent possesses a specific destructive action on certain cells or the possession of such action. . Am J Pathol 64:387-404 (1971).

(106.) Thomson AW, Fowler EF. Carrageenan: a review of its effect on the immune system immune system

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
n.
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.

lip·i·do·sis
n. pl.
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(108.) Ballabio A, Shapiro LJ. Steroid sulfatase deficiency and X-linked ichthyosis X-linked ichthyosis is an inborn error of metabolism characterized by a deficiency in microsomal sulfatase (steroid sulfatase). It is also referred to as placental sulfatase deficiency. . In: The Metabolic and Molecular Bases of Inherited Diseases (Scriver CR, Beaudet AL, Sly WS, Valle D, eds) 7th ed. New York: McGraw-Hill, Inc., 1995;2999-3022.

(109.) Cotran RS, Kumar V, Robbins SL, Schoen FJ. Genetic diseases. Robbins' Pathological Basis of Disease. 5th ed. Philadelphia:W.B. Saunders Company, 1994;123-171.

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(111.) Corpet DE. Toxicological evaluation of carrageenans. 5-Dietary carrageenans and intestinal microflora. Sciences des aliments 4:367-374 (1984).

(112.) Michel C, Macfarlane MacFarlane or Macfarlane is a surname shared by:
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  • Alexander Macfarlane (mathematician) (1851-1913), a Scottish-Canadian logician, physicist, and mathematician
 GT. Digestive fates of soluble polysaccharides from marine macroalgae: involvement of the colonic microflora and physiological consequences for the host. J Appl Bacteriol 1996;80:349-369 (1996).

(113.) Gibson GR, Macfarlane S, Cummings JH. The fermentability fer·ment  
n.
1. Something, such as a yeast, bacterium, mold, or enzyme, that causes fermentation.

2. Fermentation.

3.
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)
WEW Weather Effects Workstation
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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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  • Propionic acid
  • Isobutyric acid
  • Butyric acid
  • Isovaleric acid
  • Valeric acid
  • Caproic acid
  • Lactic acid
 beta-oxidation at acyl-CoA dehydrogenase acyl-CoA dehydrogenase /ac·yl-CoA de·hy·dro·gen·ase/ (de-hi´dro-jen-as) any of several enzymes that catalyze the oxidation of acyl coenzyme A thioesters as a step in the degradation of fatty acids.  level in colonocytes: implications for ulcerative colitis. Mol Cell Biochem 181:117-124 (1998).

(117.) Toscani A, Soprano DR, Soprano KJ. Molecular analysis of sodium butyrate-induced growth arrest. Oncogene oncogene

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.
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(118.) Glinghammar B, Holmberg K, Rafter J. Effects of colonic lumenal components on AP-1 dependent gene transcription Gene transcription
The process by which genetic information is copied from DNA to RNA, resulting in a specific protein formation.

Mentioned in: Gene Therapy
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(119.) Salyers AA, West SHE, Vercelotti JR, Wilkins TD. Fermentation of mucins and plant polysacchairds by anerobic bacteria from the human colon. Appl Environ Microbiol 334:529-533 (1977).

(120.) Di Rosa M. Review: Biological properties of carrageenan. J Pharm Pharmacol 24:89-102 (1972).

(121.) Hoffman R. Carrageenans inhibit growth-factor binding. Biochem J 289:331-334 (1993).

(122.) Cochran FR, Baxter CS. Macrophage-mediated suppression of T-lymphocyte proliferation induced by oral carrageenan administration. Immunology 53:221-227 (1994).

(123.) Thomson AW, Fowler EF. Potentiation of tumor growth by carrageenan. Transplantation 24:397-400 (1977).

(124.) Carlucci MJ, Pujol CA, Ciancia M, Noseda MD, Matulewicz MC, Damonte EB, Cerezo AS. Antiherpetic and anticoagulant properties of carrageenans from the red seaweed Gigartina skottsbergii and their cyclized derivatives: correlation between structure and biological activity. Int J Biol Macromol 20:97-105 (1997).

(125.) Yamada T, Ogano A, Saito T, Watanabe J, Uchiyama H, Nakagawa Y. Preparation and anti-HIV activity of low-molecular-weight carrageenans and their sulfated derivatives. Carbohydr Polym 32:51-55 (1997).

(126.) Pearce-Pratt R, Phillips DM. Sulfated polysaccharides inhibit lymphocyte-to-epithelial transmission of human immunodeficiency immunodeficiency

Defect in immunity that impairs the body's ability to resist infection. The immune system may fail to function for many reasons. Immune disorders caused by a genetic defect are usually evident early in life.
 virus-1. Biol Reprod 54:173-182 (1996).

(127.) Zaretzky FR, Pearce-Pratt R, Phillips DM. Sulfated polyanions block Chlamydia trachomatis infection of cervix-derived human epithelia ep·i·the·li·a  
n.
A plural of epithelium.
. Infect Immun 63:3520-3526 (1995).

(128.) Hoffman R, Burns WW, Paper DH. Selective inhibition selective inhibition
n.
See competitive inhibition.
 of cell proliferation and DNA synthesis DNA synthesis commonly refers to:
  • DNA replication - DNA biosynthesis (in vivo DNA amplification)
  • Polymerase chain reaction - enzymatic DNA synthesis (in vitro DNA amplification)
  • Oligonucleotide synthesis - chemical synthesis of nucleic acids
 by the polysulphated carbohydrate ??-carrageenan. Cancer Chemother Pharmacol 36:325-334 (1995).

(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:
  • Coombe, Buckinghamshire
  • Coombe, Bude, Cornwall
  • Coombe, Camborne, Cornwall
  • Coombe, Liskeard, Cornwall
 DR, Parish CR, Ramshaw IA, Snowden JM. Analysis of the inhibition of tumour metastasis metastasis /me·tas·ta·sis/ (me-tas´tah-sis) pl. metas´tases  
1. transfer of disease from one organ or part of the body to another not directly connected with it, due either to transfer of pathogenic microorganisms or to
 by sulphated polysaccharides. Int J Cancer 39:82-88 (1987).

(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

v.tr.
To take apart: disassemble a toaster.

v.intr.
1.
 and loss of mammary myoepithelial cells after exposure to lambda-carrageenan. Cancer Res 57:2823-2826 (1997).

(131.) Tobacman JK, Walters K. Carrageenan exposure leads to mammary myoepithelial cell myoepithelial cell (mī″oep″īthē´lē  development of unusual intracellular inclusions. Proc Am Assoc Cancer Res 39:4722 (1999).

(132.) Cater DB. The carcinogenic action of carrageenin in rats. Br J Cancer 15:607-614 (1961).

(133.) Hopkins J. Carcinogenicity of carrageenan. Food Cosmet Toxicol 19:779-788 (1981).

(134.) Dyrset N, Lystad KQ, Levine DW. Development of a fermentation process for production of a kappa-carrageenase from Pseudomonas carrageenovora. Enzyme Microb Technol 20(6):418-423 (1997).

(135.) Irvine EJ, Farrokhyar F, Swarbrick ET. A critical review of epidemiological studies in inflammatory bowel disease. Scand J Gastroenterol 36(1):2-15 (2001).

(136.) Ferlay J, Bray F, Pisani P, Parkin parkin
Noun

Brit a moist spicy ginger cake usually containing oatmeal [origin unknown]
 DM. GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0. IARCCancerBase No. 5. Lyon:IARC Press, 2001. Limited version available: http://www-dep.iarc.fr/cgibin/exe-globom.exe [cited 2 March 2001].

(137.) Gold LS, Slone TH, Manley NB, Garfinkel GB, Rohrbach L, Ames BN. Carcinogenic potency database. In: Handbook of Carcinogenic Potency and Genotoxicity Databases (Gold LS, Zeiger E, ads). New York:CRC Press, Inc., 1997;116-117.

(138.) Gold LS, Slone TH, Ames BN. Summary of carcingogenic potency database by chemical. In: Handbook of Carcinogenic Potency and Genotoxicity Databases (Gold LS, Zeiger E, ads). New York:CRC Press, Inc., 1997;629.

(139.) Food Additives Amendment of 1958. Public Law 85-929, 72 Stat. 1784.

(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.
COPYRIGHT 2001 National Institute of Environmental Health Sciences
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2001, Gale Group. All rights reserved. Gale Group is a Thomson Corporation Company.

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Author:Tobacman, Joanne K.
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