Note: The entire meeting was open to the public. Copies of written information provided to the Committee for consideration are available from the Committee Staff. This includes written materials received from public participants. A transcript of this meeting is available from the FDA Dockets Management Branch (HFA-305), 12420 Parklawn Drive, Rockville, MD 20857.
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Special Working Group members present: Dr. E. Wayne Askew (Special Working Group Chair), Dr. Ara Der Marderosian, Dr. David Earnest, Dr. Marion Nestle, and Dr. Patricia M. Rodier
Special Working Group members absent: None
Food and Drug Administration representatives: (Center for Food Safety and Applied Nutrition) Dr. Lynn A. Larsen, Executive Secretary of the Food Advisory Committee; Dr. Kaye Wachsmuth, Deputy Director for Programs; Ms. Catherine DeRoever, Ms. Linda Hayden, and Ms. Joyce Perticone, Committee Staff; Ms. Margaret Binzer, Ms. Elizabeth Campbell, Dr. Sara Henry, Dr. James Hoadley, Dr. Michael Kashtock, Dr. Patricia Rohan, Dr. William Obermeyer, and Dr. Terry Troxell; (FDA Western Regional Office, San Francisco, CA) Dr. Wallace Winters.
Guest Speakers: Dr. Susan Loscutoff, Department of Health Services, State of California; Dr. James Wirth, Johns Hopkins University, Baltimore, MD.
Public Speaker: Dr. Alvin Segelman, Vice President of Health Science, Nature Sunshine Products, Provo, Utah.
Agenda
Dr. Askew, Chairman of the Special Working Group, convened the meeting at 8:35 a.m. Wednesday, June 7, 1995. The issue before the Special Working Group was the potential for public health problems associated with food products (particularly certain teas) containing certain ingredients (e.g., senna, aloe, cascara, buckthorn, rhubarb) that may produce stimulant laxative effects. The agenda for the first day focussed on the scientific and medical basis for concern, the legal basis for action, and the options for action developed by FDA. The meeting was recessed at 3:15 p.m. and reconvened the next morning at 8:30 a.m. On the second day, the Special Working Group developed its responses to the questions posed by FDA. The Special Working Group, in addition, developed a "model" label statement that incorporated all the elements the Group felt should be addressed. The Special Working Group adjourned at 11:25 a.m., Thursday, June 8, 1995.
Presentations - FDA
Dr. Troxell, Office of Plant and Dairy Foods and Beverages (OPDFB), introduced the issue to the Special Working Group. He explained that while the substances of concern occur in both food and drug products, the issue before the Group was not the regulatory category, but rather the potential for public health problems when the substances are in products FDA considers to be foods. Dr. Troxell went on to discuss the various considerations that must be made in assessing the risk of these substances in foods. He noted that FDA's tentative assessment is that such foods, as presently labeled, present a public health problem that may require some Agency action. He outlined what he called potential "risk management" approaches to the problem. He concluded by asking the Special Working Group, if it agreed with FDA's assessment, what message or messages should be conveyed on the labels of such products and why, and whether educational efforts should be part of the strategy to protect the public health.
Dr. Rohan, Office of Special Nutritionals (OSN), reviewed the reports FDA has received on adverse events associated with use of the foods of concern. She noted that the 48 complaints received by the Agency over the past three years tended to fall into three categories: acute gastrointestinal (GI) events, chronic GI events, and serious events of some other nature (syncope, colon surgery, death). Dr. Rohan reviewed in more detail the medical records and known facts about product use for the cases where death occurred.
Dr. Obermeyer, OPDFB, briefly described the chemical structures of several anthraquinone-derived stimulant laxatives. He presented an overview of the botanical sources, the plant parts used, the particular laxative-active derivatives in each, and the history of use. The plants include senna, cascara and the related plants buckthorn, aloe, rhubarb, castor bean, and may apple. He concluded his presentation with a chart showing that concentrations of anthraquinone-type compounds in senna, cascara and buckthorn can commonly reach 3-6% of dry weight, and in aloe 19-21%.
Dr. Henry, OPDFB, outlined what is known from the literature on the toxicology and pharmacokinetic mechanisms of the cathartic anthraquinone derivatives from the plants in question. Almost all the literature information comes from studies of the group of compounds known as sennosides. The glycoside forms of these substances are more potent than the aglycone forms, largely because they are transported, unabsorbed, directly to the site of action in the colon. Intestinal microflora metabolize the glycosides to the active end products. Dr. Henry noted that the mechanism(s) by which the substances cause laxation is not clear. Possible mechanisms include a disturbance of balance in colonic water absorption and secretion, cytotoxicity to the intestinal mucosa, and a direct stimulation of peristaltic activity. Demonstrated motility and secretion effects appear to occur independently. Dr. Henry very briefly covered the general animal toxicology data that are available.
Ms. Campbell, Office of Food Labeling (OFL), began her presentation with a discussion of the legal distinction between foods and drugs, and the statutory authorities that devolve to the Agency for each. This was in response to questions by the Subcommittee, following earlier presentations, about such distinctions when both food and drug products contain the same pharmacologically active substances. The distinction often involves demonstrating intent of use, as evidenced by the label, labeling and advertising of a product. Ms. Campbell then went on to discuss the food labeling requirements of the Food, Drug, and Cosmetic Act (the Act), and the authority for FDA to take action under that act. She noted that if it is necessary for safe use of a food, appropriate label statements can be required. She cited as an example the advisory to persons with the condition phenylketonuria that must appear on products containing aspartame. Ms. Campbell stated that, in addition, the Act addresses misbranding not only with regard to what is stated on a label, but also by the material facts that may be missing from a label. In this context, she cited the warnings that must appear on some protein products used in weight reduction programs because of the dangers of very low calorie protein diets.
Further examples of labeling more relevant to the type of concerns for foods containing stimulant laxative substances were provided by Dr. Hoadley, Office of Premarket Approval (OPA). A special labeling requirement is triggered for foods containing any one of three ingredients (sorbitol, mannitol and polydextrose) when consumption of the food is expected to exceed specific levels. Under these circumstances, the label must bear an advisory statement regarding laxation potential. Dr. Hoadley described the physiological mode by which these substances can cause laxation, and the background for the labeling requirements. The requirement is triggered when reasonably foreseeable daily consumption of a food might result in ingestion of 50 grams of sorbitol or 20 grams of mannitol, or a single serving of a food would contain 15 grams of polydextrose.
Ms. Binzer, OSN, provided the Special Working Group with a succinct discussion of the provisions of the Act that guide FDA's determination that a product should be regulated as a food, as a dietary supplement (a special food category), as a food ingredient, or as a drug. She noted that the same ingredient may appear in both foods and drugs, and that it is the labeling and intended use which drive a determination of regulatory status. Ms. Binzer went on to describe the labeling information, or lack thereof, on products containing stimulant laxative substances, and the potential for consumer misuse of food products containing such substances in the absence of appropriate label statements.
Dr. Kashtock, OPDFB, concluded the FDA presentations by describing the regulatory options that FDA had tentatively concluded could address the public health concerns about use of food products containing stimulant laxative substances. He first described three conditions of use that pose concerns: use by individuals with medical conditions that compound potential risks, such as being nutritionally compromised; prolonged use that might lead to dependency; and short-term or single-use situations that may be accompanied by acute gastrointestinal effects. Dr. Kashtock presented several possible label statements of differing complexity. All the proposed options incorporated some initial alerting word such as "notice" or "warning," and all included a statement indicating the identity of the material of concern (e.g., senna). Dr. Kashtock indicated that the means of requiring such label statements might simply be through an FDA policy statement, or it might be through a regulation. He noted that educational efforts targeted at consumers and health professionals might either be an adjunct or an independent means of ensuring consumers are alerted to potential health problems from the products of concern.
Guest Speaker Presentations
Dr. Loscutoff spoke about the concerns about these products in the State of California, and actions the State had taken. She described three categories of users, and then discussed the adverse reactions reported for each. Dr. Loscutoff's first category was composed of first time users who are unaware that a product contains a stimulant laxative, treat the product like an ordinary tea, and suffer acute reactions. The second category included repeat users who remain (or claim to remain) unaware of the stimulant laxative properties of the foods and who suffer chronic GI distress. Grouped into the third category were dependent users who are utilizing the product as a laxative and who eventually suffer more severe GI problems. Dr. Loscutoff described analyses by the State which showed that the food products in question contained levels of laxative compounds comparable to those in approved over-the-counter drug products. She indicated the State's health concerns, among them being that first-time users don't always know they are taking a laxative product (and in a laxative dosage), and repeat users who don't understand the health risks from overuse of stimulant laxative substances. Dr. Loscutoff also noted that physicians often do not have the information needed to advise their patients about use/misuse of such products.
Dr. Wirth presented data on the eating disorders anorexia nervosa and bulimia. He indicated that individuals suffering from these conditions are particularly at risk from the effects and side effects of laxative abuse. Although the data are variable, the best information from a study of 15- to 19-year-old middle- and working-class white women indicates that the prevalence of anorexia in this age group is about 1 in 250. Data on bulimia are even less certain, but the best data suggest the incidence (sic) is about 1 in 100 in college-age women. Dr. Wirth also presented data from studies of teenagers and college students (men and women) from the general population. Use of laxatives was as high as 5-10% (among college women), and daily use within these subpopulations was as high as 1 in 100 (high school students). Use was generally associated with the desire to look thin or as a means of weight control. He went on to describe studies which showed that laxatives are not at all effective in preventing utilization of food calories. He concluded by summarizing the questions for which FDA was seeking responses from the Special Working Group.
Public Hearing Presentations
Dr. Alvin B. Segelman, Nature's Sunshine Products, Utah, raised the issue of whether the "melanosis coli" might mask early signs of colon cancer. Melanosis coli is a condition arising from deposition of anthraquinones in the intestinal mucosa. Dr. Segelman had received numerous calls from physicians concerned about the presence of these pigments. The ensuing dialog with the Special Working Group yielded the suggestion that rather than masking, the pigmentation might enhance detection, because the hyperplastic growths are not colored. He also addressed the issue of products with multiple components that might contribute, collectively, to adverse reactions. However, he supported the concept of a notice on the label of products with laxation potential.
Dr. Winters, FDA Pacific Regional Office, indicated that he was aware of approximately 60 reports of adverse events in consumers using certain food products containing stimulant laxative substances. Some are reports his office had received directly and are under investigation, while others are included in information he received from other parts of the country. He stated that he had heard of five more deaths reportedly associated with one of the products under discussion, but that he had no further information on these cases and had not actually seen any related records (including medical records) on these consumers.
Special Working Group Discussion
Throughout the course of the meeting the Special Working Group members entered into often extensive discussion with the various speakers. The members sought to better understand the uses of identical materials in both foods and drugs, the full range of health ramifications from the use of stimulant laxative materials (particularly the issues of the impact on blood potassium levels and of chronic use), and the finer points of FDA's legal authorities with respect to labeling.
Drs. Earnest and Wirth had been asked to review and report on the detailed files for the four cases where death had occurred. Unexplained hypokalemia appeared to be an important aspect in two cases; there was insufficient information to state conclusively that eating disorders were a factor. Both experts were concerned about what substances other than sennosides might be contained in the teas and might therefore be contributing to the clinical events.
Conclusions and other Suggestions
1. The Special Working Group agreed that based upon each member's expertise, knowledge and experience, and upon information presented at the meeting, food products containing ingredients such as senna, cascara, etc. may result in adverse effects, in particular, adverse effects associated with the gastrointestinal tract.
2. The Group likewise agreed that it is important for consumers to be made aware of these potential effects.
3. The Group had more difficulty with the question on whether an appropriately worded label statement would reduce the incidence of adverse reactions associated with the products of concern. There was general agreement that such a label statement would increase consumer knowledge about the possibility of adverse reactions. There was discussion, however, about the extent to which consumer behavior would actually be affected, whether this could be measured, and the absence of baseline information for comparison. All agreed that reduction of adverse reactions would be the intended result. After rephrasing the question to suggest that appropriate labeling may reduce the incidence of adverse reactions, there was general agreement among the Group that its answer was yes.
4. FDA's fourth question to the Group related to label instructions on some of the products and concerns about potential abuse or harm from prolonged or repeated use. This generated discussion about possible use of statements like those required for over-the-counter laxative drugs, and the problem of brewing herbal teas for longer times to obtain a stronger tasting beverage (and coincidentally - or perhaps also intentionally - a stronger dose of the laxating component). One concern was that directions for product use should be couched in terms of food beverage use rather than laxative (drug) use.
The Group concurred with the concept embodied in the question, but felt that the statement should be clearer and more understandable than that proposed by FDA. There was general agreement that there were three elements of caution that needed to be incorporated: one caution relating to concentration (e.g., from lengthy steeping, or use of more than one teabag or portion for a single serving) and unexpected effects on consumers who did not purchase the product for a laxative effect; a second caution on prolonged use for consumers who would buy the product for a laxative effect; and an advisory that such products do not significantly reduce calorie absorption.
5. The Group was divided in its opinions about the value of an educational effort in addition to, or instead of, labeling. The extent to which an education campaign might effect a behavior change among consumers was debated. Also of concern was the level of resources that would be required for a educational effort that might have a chance of success.
The Group concluded that a modest, targeted effort to provide information to professional groups would be useful, but recommended against an extensive and sweeping public health education campaign. The Group did not feel it could answer the question, "would a warning label and/or education program adequately protect the consumer?" The members concluded that a label statement will help improve the information to the consumer and may in some instances provide a certain amount of protection, but it will not be adequate to completely protect the consumer.
6. The Special Working Group went on to incorporate the issues about which members had expressed concern into a "model" label statement. Various members produced their own versions of a model label. The several versions were synthesized into a single "model" statement encompassing all the points of concern, although it was agreed that the statement would need to be shortened. The statement reads as follows:
"NOTICE (or WARNING): Contains herbs (insert whatever the herbs are) that can act as stimulant laxatives. Prolonged steeping time can increase the risk of adverse laxative effects including: nausea, vomiting, abdominal cramps, and diarrhea. Chronic use of laxatives can impair colon function. Use of laxatives may be hazardous in the presence of abdominal pain, nausea, vomiting, or rectal bleeding. Laxative-induced diarrhea does not significantly reduce absorption of food calories. Acute or chronic diarrhea may result in serious injury or death."
E. Wayne Askew Chair, Special Working Group on
Stimulant Laxative Substances in Foods
Food Advisory Committee
Lynn A. Larsen
Executive Secretary
Food Advisory Committee
This meeting was held in June 1995.
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