57700 Federal Register / Vol. 64, No. 206 / Tuesday, 26, 1999 / Rules and Regulations

DEPARTMENT OF HEALTH AND CFR 101.70) establishes a process for tentatively concluded that the publicly HUMAN SERVICES petitioning the agency to authorize by available data supported an association regulation the use of health claims about between diets low in saturated fat and Food and Drug Administration a substance-disease relationship cholesterol and reduced risk of CHD (56 (§ 101.70(a)) and sets out the types of FR 60727 at 60737), and it confirmed 21 CFR Part 101 information that any such petition must that conclusion in the saturated fat/ [Docket No. 98P±0683] include (§ 101.70(f)). cholesterol final rule (58 FR 2739 at In response to the 1990 amendments, 2751). Food Labeling: Health Claims; Soy FDA also conducted an extensive Based on its review using the stated Protein and Coronary Heart Disease review of the evidence on 10 substance- criteria, and on its consideration of disease relationships. As a result of its comments received in response to the AGENCY: Food and Drug Administration, review, FDA has authorized claims for proposed rule entitled ‘‘Health Claims; HHS. 8 of these 10 relationships, one of which Dietary Fiber and Cardiovascular ACTION: Final rule. focused on the relationship between Disease’’ (56 FR 60582), FDA concluded SUMMARY: The Food and Drug dietary saturated fat and cholesterol and that the publicly available scientific Administration (FDA) is authorizing the reduced risk of CHD. CHD is the most information supported an association use, on food labels and in food labeling, common, most frequently reported, and between diets low in saturated fat and of health claims on the association most serious form of cardiovascular cholesterol and high in fruits, between soy protein and reduced risk of disease (CVD) (58 FR 2739, 6, vegetables, and grain products (i.e., coronary heart disease (CHD). Based on 1993). Further, although the agency foods that are low in saturated fat and its review of evidence submitted with denied the use on food labeling of cholesterol and that are good sources of comments to the proposed rule, as well health claims relating dietary fiber to dietary fiber) and reduced risk of heart as evidence described in the proposed reduced risk of CVD (58 FR 2552), it disease (58 FR 2552 at 2572). In the rule, the agency has concluded that soy authorized a health claim relating diets 1993 dietary fiber and CVD final rule, in protein included in a diet low in low in saturated fat and cholesterol and response to a comment regarding the saturated fat and cholesterol reduce high in fruits, vegetables, and grain apparent hypocholesterolemic products that contain dietary fiber properties of specific food fibers, FDA the risk of CHD by lowering blood (particularly soluble fiber) to a reduced again articulated its criteria for cholesterol levels. risk of CHD. evaluating diet and CHD relationships DATES: This regulation is effective In the proposed rule entitled ‘‘Health (58 FR 2552 at 2567). FDA agreed that October 26, 1999, except for Claims and Label Statements; Lipids the effectiveness of naturally occurring § 101.82(c)(2)(ii)(B), which contains and Cardiovascular Disease’’ (56 FR fibers in foods in reducing the risk of information collection requirements that 60727, , 1991) (hereinafter CHD may be documented for specific have not been approved by the Office of referred to as the saturated fat/ food products. Further, the agency Management and Budget (OMB). Upon cholesterol proposed rule), FDA set out indicated that if manufacturers could approval, the FDA will publish a criteria for evaluating evidence on diet document, through appropriate studies, document in the Federal Register and CVD relationships. The agency that dietary consumption of the soluble announcing the effective date of those focused on those aspects of the dietary fiber in a particular food has a beneficial requirements. lipid and CVD relationship for which effect on blood lipids predictive of CHD FOR FURTHER INFORMATION CONTACT: the strongest scientific evidence risk, they should petition for a health Susan M. Pilch, Center for Food Safety andagreement existed. FDA noted that, claim for that particular product. In and Applied Nutrition (HFS–465), Food because of the public health importance response to two petitions that and Drug Administration, 200 C St. SW., of CHD, identification of ‘‘modifiable’’ documented such evidence, FDA has Washington, DC 20204, 202–205–4500. risk factors for CHD had been the authorized health claims for soluble SUPPLEMENTARY INFORMATION: subject of considerable research and fiber from certain foods and reduced public policy attention. The agency also risk of CHD in § 101.81 (21 CFR 101.81) I. Background Information noted that there is general agreement (62 FR 3600, , 1997, and On November 8, 1990, the President that elevated blood cholesterol levels amended at 62 FR 15344, March 31, signed into law the Nutrition Labeling are one of the major ‘‘modifiable’’ risk 1997, and 62 FR 8119, 18, and Education Act of 1990 (the 1990 factors in the development of CHD. FDA 1998). amendments) (Public Law 101–535). cited Federal Government and other In the Federal Register of November This new law amended the Federal reviews that concluded that there is 10, 1998 (63 FR 62977), and in response Food, Drug, and Cosmetic Act (the act) substantial epidemiologic and clinical to a petition from Protein Technologies in a number of important ways. One evidence that high blood levels of total International, Inc. (Ref. 1 and Ref. 2), the notable aspect of the 1990 amendments and low density lipoprotein (LDL)- agency proposed § 101.82 to provide for was that they provided procedures cholesterol are a cause of atherosclerosis health claims on the relationship of soy whereby FDA is to regulate health and represent major contributors to protein and reduced risk of CHD claims on food labels and in food CHD. Further, factors that decrease total (hereinafter referred to as the soy labeling. blood cholesterol and LDL-cholesterol protein proposed rule). In the soy In the Federal Register of , will also decrease the risk of CHD. FDA protein proposed rule, FDA considered 1993 (58 FR 2478), FDA issued a final concluded that it is generally accepted the relevant scientific studies and data rule that implemented the health claim that blood total and LDL-cholesterol presented in the petition as part of its provisions of the act (hereinafter levels are major risk factors for CHD, review of the scientific literature on soy referred to as the 1993 health claims and that dietary factors affecting blood protein and CHD. The agency final rule). In that final rule, FDA cholesterol levels affect the risk of CHD. summarized this evidence in the soy adopted § 101.14 (21 CFR 101.14), High intakes of dietary saturated fat and, protein proposed rule and presented the which sets out rules for the to a lesser degree, of dietary cholesterol rationale for a health claim on this food- authorization and use of health claims are consistently associated with disease relationship as provided for by regulation. Additionally, § 101.70 (21 elevated blood cholesterol levels. FDA under the significant scientific

VerDate 12-OCT-99 17:23 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00002 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm03 PsN: 26OCR2 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations 57701 agreement standard in section containing one or more comments, from One comment reviewed additional 403(r)(3)(B)(i) of the act and § 101.14(c) consumers, consumer organizations, sources of information and reached the of FDA’s regulations. professional organizations, government same conclusion. Proposed § 101.82(c)(2)(ii)(A) agencies, industry, trade associations, In the soy protein proposed rule, FDA identified the substance that is the health care professionals, and research also tentatively concluded that soy subject of the proposed claim as soy scientists. protein from Glycine max satisfied the protein from the legume seed Glycine About half of these submissions preliminary requirement of max. The soy protein proposed rule supported the proposed rule without § 101.14(b)(3)(i) that the substance be a included qualifying criteria for the providing grounds for this support other food that contributes taste, aroma, or purpose of identifying soy protein- than those provided by FDA in the nutritive value (63 FR 62977 at 62978). containing foods eligible to bear the preamble to the soy protein proposed Sources of soy protein identified in the proposed health claim. The proposal rule. The majority of the remaining soy protein proposed rule included also specified mandatory content for comments were generally supportive, foods composed of or derived from health claim statements; identified but requested modification of one or whole soybeans and foods that contain additional, optional information for more provisions of the proposed rule. processed soy protein ingredients: such statements; and provided model Some comments provided additional Isolated soy protein (ISP), soy protein health claims. data on the relationship between soy concentrate (SPC), soy flour (SF), In its evaluation of the scientific protein and CHD, including one texturized soy protein, or texturized evidence for a relationship between submission, originally submitted as a vegetable protein (TVP). In addition to consumption of soy protein and blood health claim petition and converted to protein, these foods and ingredients total and LDL-cholesterol levels, the a comment on the soy protein proposed contain other naturally occurring soy agency found the data suggestive but not rule (Ref. 3), that included a constituents, such as isoflavones, fiber, sufficient to establish a dose-response comprehensive review of available and saponins. The specific processing for this relationship. However, the scientific evidence about the steps employed determine the extent of agency did find consistent, clinically relationship. Some of the comments that retention of such naturally occurring significant reductions of total and LDL- disagreed with the soy protein proposed constituents in the final product. cholesterol levels in controlled trials rule provided specific support for their In assessing whether the petitioner that used at least 25 grams (g) of soy positions. Some of the comments were had demonstrated that soy protein is protein per day. Thus, the agency received after the date for submitting safe and lawful at the level necessary to proposed to base the qualifying level of comments had passed. Although the justify the claim, FDA noted that the soy protein on a total daily intake of 25 agency is not obligated to respond to petitioner stated that soy protein g, as suggested by the petitioner. late comments, in the interest of ingredients were in common use in food Therefore, in § 101.82(c)(2)(iii)(A), FDA assessing the totality of the available before , 1958, and that they are proposed the qualifying criterion for a data, it has considered each of these generally recognized as safe (GRAS) by food to bear the claim as 6.25 g of soy comments to the extent that it provided self-determination (63 FR 62977 at protein per reference amount complete information for review or 62978). Because the fractionation customarily consumed (RACC) (i.e., 25 references accessible to the agency and procedures used to convert vegetable g divided by 4 eating occasions per day). addressed issues not raised in earlier flours to vegetable protein isolates and In the soy protein proposed rule, FDA comments. The agency has summarized concentrates were commonplace prior had tentatively indicated its intention to and addressed the relevant issues raised to 1958, the petitioner also asserted that use a specific analytical method to in the comments in the sections of this ISP and SPC can be defined as soy flour measure soy protein for assessing document that follow. ‘‘subject only to conventional compliance with the qualifying In response to the soy protein processing as practiced prior to January criterion. Comments persuaded the reproposal, the Agency received 1, 1958.’’ In addition, FDA reviewed agency that the method would be approximately 10 submissions, each information submitted by the petitioner inadequate for many products. containing one or more comments. The about potential risks of consuming soy Therefore, in the Federal Register of agency has summarized and addressed products: allergenicity (Refs. 9 and 10), 23, 1999 (64 FR 45932), FDA these comments in section II.C.2 of this exposure to trypsin inhibitors (Refs. 11 issued a proposed rule to provide for an document. through 16), reduced bioavailability of alternative procedure for assessing minerals (Refs. 13, 17, 18, 19, and 20), A. Eligibility of Soy Protein as the compliance (hereinafter referred to as and hormonal disturbances due to soy Subject of a Health Claim the soy protein reproposal). In the soy isoflavones (Refs. 21 through 26). Based protein reproposal, in In the soy protein proposed rule, the on the totality of the evidence and, in § 101.82(c)(2)(ii)(B) FDA proposed that agency assessed whether soy protein particular, its common use in food, the it would rely on measurement of total satisfied the preliminary requirement agency did not take issue with the protein and require manufacturers, that a substance that is the subject of a petitioner’s view that the use of soy when soy is not the sole source of health claim is associated with a disease protein is safe and lawful as required in protein in foods, to maintain records for which the U.S. population is at risk § 101.14(b)(3)(ii). Thus, FDA tentatively that document the amount of soy (63 FR 62977 at 62978). Based on concluded that the petitioner provided protein in products and to make these analyses presented in earlier evidence that satisfied the requirement records available to appropriate rulemakings and its review of data on in § 101.14(b)(3)(ii) that use of soy regulatory officials for inspection and the mortality, morbidity, and costs of protein at the levels necessary to justify copying upon request. CHD and prevalence of ‘‘high risk’’ and a claim is safe and lawful under the ‘‘borderline high’’ total and LDL- applicable food safety provisions of the II. Summary of Comments and the cholesterol levels in the United States act (63 FR 62977 at 62979). Agency’s Responses (Refs. 4 through 8), the agency Several comments agreed with the In response to the soy protein tentatively concluded that, as required agency’s conclusion and some provided proposed rule, the agency received in § 101.14(b)(1), CHD is a disease for the rationale for their support. A approximately 130 submissions, each which the U.S. population is at risk. number of comments disputed the

VerDate 12-OCT-99 17:23 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00003 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm03 PsN: 26OCR2 57702 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations petitioner’s assertion of GRAS status for use in food before January 1, 1958, in action, and the subject of the soy protein and raised questions about conformance with § 201(s) of the act. notification was soy isoflavone extract, the safety of soy protein-containing The comment also noted that, although rather than soy protein. At the foods. The specific aspects of soy protein is not listed as GRAS or company’s request, FDA ceased disagreement are summarized and prior sanctioned in Title 21 of the CFR, evaluation of the GRAS Notification discussed in the following sections of FDA has noted that these lists ‘‘do not pending the company’s updating of the this document. include all substances generally file (Ref. 75). Thus, this comment was recognized as safe for their intended incorrect. 1. Concerns About the Safety of Soy use’’ and, as stated at 21 CFR 182.1, ‘‘[i]t (Comment 5). A comment asserted Protein-Based Infant Formulas is impracticable [for FDA] to list all that petitioner’s basis for GRAS self- (Comment 1). Many of the comments substances that are GRAS for their determination of the use of soy protein that raised concerns about the safety of intended use.’’ This comment also as a dietary protein ingredient (i.e., consuming soy protein-containing foods agreed with the petitioner’s conclusion common use in food before January 1, addressed the safety of soy protein- that fractionation procedures used to 1958) was incorrect. Because the 1979 based infant formulas. The observed or convert vegetable flours to vegetable Select Committee on GRAS Substances hypothesized detrimental effects of such protein concentrates and isolates were (SCOGS) report (Ref. 76) determined formulas discussed in these comments commonplace in various sectors of the that, at the time of the report, likely included: hormonal disturbances due to grain industry, such as corn processing, average dietary exposure to soy protein estrogenic effects of soy isoflavones; well before 1958. Therefore, SPC and isolate was only about 150 milligrams thyroid abnormalities; altered mineral ISP can be defined as soy flour ‘‘subject (mg) from food items, the comment balance, especially for zinc; and only to conventional processing as asserted that soy protein isolates could diabetogenic effects in infants. practiced prior to January 1, 1958.’’ The not have been in common use before FDA is aware of concerns raised about comment concluded that SF (including 1958. the safety of soy infant formulas, but steam-treated SF), SPC, and ISP all fall FDA finds that this comment is notes that these are speculative at this within the category of ingredients that groundless and inaccurately time, pending the results of definitive are GRAS through experience based on characterizes the findings of the SCOGS. research. FDA also notes that the their common use. Several comments The 1979 SCOGS report includes the American Academy of Pediatrics (Ref. objected to the petitioner’s self- background statement ‘‘Edible soy 73) and the New Zealand Ministry of determination of GRAS status, citing a protein isolates for food uses appeared Health (Ref. 74) have recently issued variety of reasons. As stated previously, about 1957 as a major article of guidelines for the safe and suitable use FDA does not take issue with the commerce.’’ The 1979 SCOGS Report of soy-based infant formulas. Some petitioner’s self-determination of GRAS also cited a 1972 National Research issues regarding effects of infant formula status, and the comments, discussed Council survey of GRAS ingredients that are unique because infants may be below, have not convinced the agency to listed 14 food categories in which soy entirely dependent on formula as a sole change that conclusion. protein isolates were used and source of nutrition and the relevance of (Comment 3). Some comments raised calculated an average daily intake of such issues for soy protein consumed as objections on the basis that FDA has not several grams. Soy protein isolates part of a mixed diet by the general U.S. approved the GRAS status of soy represent only one of several possible population is not clear. protein. sources of soy protein in foods. In In any case, concerns about effects of Although FDA has not ruled formally addition, for purposes of determining if soy protein specific to infant formulas on the GRAS status of soy protein a substance is GRAS, common use is not are beyond the scope of the current rule, ingredients, it has not challenged restricted to common use in the United which authorizes a health claim about determinations that soy’s use as dietary States. the relationship of soy protein and CHD protein is GRAS. Food ingredients (Comment 6). A comment supporting for foods intended for use by the general whose use is generally recognized as the petitioner’s self-determination of population. Health claims are not safe by qualified experts are not GRAS status noted that use of soy as a permitted on foods represented or required by law to receive FDA food dates to about the 11th century BC purported for use by infants and approval. Under the health claim in the eastern half of north China. From toddlers less than 2 years of age unless petition process, FDA evaluates whether about the first century AD to the 15th- specifically provided for in the the substance is ‘‘safe and lawful’’ under 16th century, soybeans were introduced authorizing regulation (21 CFR the applicable food safety provisions of in Korea, Japan, , the 101.14(e)(5)). Diets restricted in fat, the act (§ 101.14(b)(3)(ii)). As discussed Philippines, , , saturated fat, and cholesterol are not in greater detail below, FDA did not Malaysia, Burma, Nepal, and northern recommended for infants and young receive sufficient evidence from India. Soybeans first grew in the United children, and the current rule (§ 101.82) comments to challenge the petitioner’s States in 1765 and were used then to contains no provisions for use of the assertion that soy protein ingredients manufacture soy sauce and vermicelli health claim about the relationship are GRAS by self-determination. The (soybean paste) (Ref. 77). A comment between soy protein and CHD on foods petitioner met the showing required by that disputed the petitioner’s self- for infants and toddlers. § 101.14(b)(3)(ii) that the substance be determination of GRAS status ‘‘safe and lawful.’’ speculated that the species of soybean 2. Comments on Petitioner’s Self- (Comment 4). One comment claimed grown early in its history in Asia may Determination of GRAS Status for Soy that the Center for Food Safety and have differed significantly in its content Protein Applied Nutrition recently returned a of nutrients and other active (Comment 2). One comment petition requesting GRAS recognition components from the modern species specifically agreed with the petitioner’s for soy protein. that is cultivated in this country. assertion that soy protein-containing The document referred to by the FDA does not find this comment food ingredients are generally comment was a notification by Archer compelling. Although the composition recognized as safe (GRAS) by self- Daniels Midland Company (GRN of soybeans has likely changed over determination and based on common 000001), rather than a petition for FDA time, modern soybean species and

VerDate 12-OCT-99 17:23 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00004 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm03 PsN: 26OCR2 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations 57703 cultivars are, in any case, encompassed harmful components of soy are FDA notes that many natural and within the period of common use of soy discussed below. processed foods contribute to the total and soy protein in food. human intake of nitrite. In an appendix 3. Lysinoalanine: Potential Toxic Effects (Comment 7). One comment titled ‘‘Health Aspects of Nitrites in Soy questioned whether the Asian (Comment 9). A few comments noted Protein Isolates,’’ the SCOGS report experience could provide assurance that concerns about the presence of (Ref. 76) presented an estimate of the soy is safe. Drawing parallels with lysinoalanine in soy protein isolates and consumer exposure to nitrite herbal medicine in terms of attitudes, cited the SCOGS report (Ref. 76), which contributed by soy protein in monitoring deficiencies, and the general indicated that lysinoalanine was perspective to nitrite from other dietary difficulty in detecting toxicities with implicated as a renal toxic factor in rats. sources and that formed in the long latency, this comment concluded FDA finds that the comments gastrointestinal tract by reduction of that the long history of apparent safe use inaccurately reflected the findings of the salivary and dietary nitrate. The SCOGS of soy products cannot assure they are SCOGS report. The SCOGS report noted report estimated the maximum daily without risk (Ref. 78). that the relatively severe alkali nitrite consumption for a vegetarian The comment did not provide treatment used to modify viscosity and eating meat alternatives prepared from evidence to document that soy products, adhesive properties of soy protein soy protein to be 0.04 mg/kilogram (kg) consumed at levels necessary to justify isolates used as sizing and coating body weight (or 2.8 mg for a 70-kg the claim, are not generally recognized adhesives in the production of paper person). The report estimated daily per as safe. Moreover, considerable research and paperboard products can cause capita intake of nitrite from other foods is underway at this time because of the formation of lysinoalanine. The report of plant origin and cured meats to be hypothesized benefits of the historical evaluated the risk of lysinoalanine about 2.4 mg and daily exposure to use of soy products by certain exposure from soy protein adhesives nitrite from saliva to be 15 mg. The population groups. FDA supports the and binders used in paper and report estimated that nitrite formed in ongoing research to clarify the effects, paperboard food packaging. The 1979 the intestine from reduction of ammonia both potentially beneficial and SCOGS report noted that, ‘‘For edible or organic nitrogen compounds potentially adverse, of soy and agrees isolated protein production, extraction contributed about 90 mg/day. Given the that any effects due to changes in the is usually carried out at a pH below 9 relatively minor potential contribution conditions of use should be monitored. to avoid hydrolytic or rheological of soy protein to total nitrite exposure, However, the information currently changes’’ and concluded that, while and the fact that no data were submitted available does not lead FDA to object to relatively low levels of lysinoalanine to document the current levels of the petitioner’s self-determination of had been reported in some samples of nitrites or nitrosamines in soy protein GRAS status of soy protein. food grade soy protein isolate, available isolates, FDA is not persuaded of the (Comment 8). Several other comments information indicated that the levels of necessity for establishing specifications for acceptable levels of these asserted that the proposal did not lysinoalanine in food grade soy protein compounds. adequately establish the GRAS status of isolates pose no hazard to the consumer soy protein food ingredients in that the (Ref. 76). 5. Trypsin Inhibitors: Potential Effects proposal did not include a thorough FDA notes that the comments that on Pancreatic Function evaluation of the safety of potentially expressed concern about lysinoalanine (Comment 11). A number of harmful components, e.g., in soy protein ingredients did not comments presented evidence that lysinoalanine, nitrites and nitrosamines, provide any information about modern heat treatment and other trypsin inhibitors, phytate, and lysinoalanine levels in food grade soy processing do not entirely eliminate the isoflavones. protein ingredients nor about use of activity of trypsin inhibitors in soy FDA notes that the 1979 SCOGS alkali-processed soy protein as a food protein-containing products. Additional report (Ref. 76) discussed several of ingredient. FDA finds that the potential references provided in comments (Refs. these components extensively and presence of lysinoalanine in soy protein 79, 80, 81, and 82) suggested that the recommended that it would be prudent isolates used for sizing and coating mechanism of feedback regulation of to develop food grade specifications for adhesives in paper and paperboard pancreatic enzyme secretion may be soy protein isolates that would set products is not relevant to the safe and responsible for deleterious effects on the acceptable limits on the levels of lawful use of soy protein in food. FDA pancreas—hyperplasia and formation of lysinoalanine, nitrites, and also notes that the production of small nodules—seen in animal studies. nitrosamines. But, the possible presence amounts of lysinoalanine during alkali Further, Leiner (Ref. 80) demonstrated of these components in soy protein processing has also been documented that infusion of high levels of isolated isolates did not lead the SCOGS panel with casein and lactalbumin, so it is not trypsin inhibitor in humans can evoke to recommend against GRAS status of unique to soy. Good manufacturing this mechanism but noted that further soy protein isolates. practices are and should be employed to research was needed to assess whether As noted above, the agency finds the minimize the production of frequent exposures to low levels of petitioner met the showing required by lysinoalanine because of its deleterious trypsin inhibitors consumed in the diet § 101.14(b)(3)(ii) that soy protein is effects on protein quality. could have the same effect. Other ‘‘safe and lawful.’’ The agency lacks 4. Nitrites and Nitrosamines: Potential comments cited evidence for potential documented evidence of adverse effects Carcinogenic Effects anticarcinogenic effects of these and in humans and has received no other protease inhibitors (Ref. 83). information about actual levels of (Comment 10). Some comments Leiner (Ref. 82) hypothesized that any potentially harmful components or expressed concerns about the potential anticarcinogenic effect of protease about threshold levels for adverse presence of nitrites in soy protein and inhibitors would likely be manifested at effects in humans. Accordingly, the the potential their presence poses for levels too low to evoke their adverse agency has no basis to conclude that soy the in vivo formation of nitrosamines, effects on the pancreas. protein is not safe and lawful. The which have been shown to be FDA notes that the observed adverse specific comments about potentially carcinogenic in experimental animals. effects have been limited to animal

VerDate 12-OCT-99 17:23 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00005 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm03 PsN: 26OCR2 57704 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations studies. To date, deleterious effects of meal by soy protein caused a decrease studies. Moreover, many factors affect consumption of low levels of soybean in the absorption of nonheme iron and the absorption of these minerals, trypsin inhibitors have not been an increase in the absorption of heme including the amount consumed in a documented in humans. For example, iron (Ref. 88), so that overall iron meal, the enhancing and inhibiting Mills et al. (Ref. 84) conducted a absorption was not compromised. effects of other components of the meal, prospective study of fatal pancreas Another comment reported that human and the nutritional status of the subject. cancer among 34,000 California feeding studies with soy protein that Animal studies suggest that zinc status Seventh-day Adventists, a group with have examined measures of iron status is a strong determinant of effects of high soy consumption. Compared to all have not shown detrimental effects (Ref. phytate/soy on zinc absorption: zinc U.S. whites, Adventists experienced 89). absorption is more impaired with zinc decreased risk from pancreas cancer A comment raised concerns about the deficiency, in contrast to the effect of death, which was not statistically effect of soy protein on zinc status based low iron status, which enhances iron significant. Although there was a on studies of absorption of zinc from absorption. However, given the lack of suggestive relationship between soy infant formula (Ref. 90) and a study documented evidence for impaired iron increasing meat, egg, and coffee that showed decreased serum thymulin and zinc status in humans consuming consumption and increased pancreatic in subjects fed a low-zinc, soy protein- soy protein as part of a mixed diet, FDA cancer risk, these variables were not based experimental diet designed to is not persuaded of the necessity for the significantly related to risk after produce mild zinc deficiency (Ref. 91). suggested labeling with respect to the controlling for cigarette smoking. As noted earlier, issues specific to infant phytate: zinc molar ratio. Nor is it However, increasing consumption of formula are outside the scope of this persuaded that many consumers would vegetarian protein products, beans, rulemaking and the experimental diet in find the suggested information, which is lentils, and peas as well as dried fruit the latter study (Ref. 91) is of limited highly technical, useful at this time. was associated with highly significant relevance to the likely conditions of 7. Soy Isoflavones: Estrogenic Effects protective relationships to pancreas consumption of soy protein in the cancer risk. population that is the target of the Many comments addressed concerns Therefore, FDA finds that the health claim. Another comment cited about the possible deleterious information presented in these two studies (Refs. 92 and 93) showing consequences of phytoestrogen effects of comments has not documented no adverse effects of soy protein on the soy isoflavones, genistein and deleterious effects of dietary intake of absorption of zinc from meals in daidzein. Most of these addressed trypsin inhibitors from soy in humans subjects with adequate zinc status. proliferative (and potentially and, thus, does not lead the agency to One comment provided additional carcinogenic) effects on estrogen- take issue with the petitioner’s information on the mechanism of sensitive tissues, effects on circulating conclusion that the use of soy protein is phytate interference with zinc hormone levels and potential safe and lawful as required by homeostasis (Ref. 94) and characterized deleterious effects on fertility, and § 101.14(b)(3)(iii). the problem as more than a matter of potentially adverse effects on sexual decreased bioavailability of the zinc development. 6. Phytate: Effects on Mineral Balance consumed in a meal. The comment a. Proliferative effects. (Comment 13). Comments raised concerns about the noted that phytate can remove from the Several comments cited a number of potential deleterious effect of soy duodenum zinc that is mainly derived studies of in vitro effects of individual protein and its phytate content on from pancreatic secretions, that is, zinc isoflavones on proliferation of estrogen- mineral status. Phytate, the salt of that may have been consumed 1–2 sensitive cells. For example, Dees et al. phytic acid or inositol hexaphosphate, weeks earlier. Although these data are (Ref. 96) found that genistein increased is a natural plant constituent containing derived from animal studies, the a number of indices for proliferative six negatively charged phosphate groups comment indicated that the physiology activity in MCF–7 human breast cancer that can form strong complexes with of zinc homeostasis is not qualitatively cells. As the authors noted, these divalent cations such as calcium, different across species. findings are consistent with the magnesium, iron, zinc, and copper. This comment expressed concern that conclusion that dietary estrogens at low Concerns relative to soy have high consumption of soy protein might concentrations do not act as concentrated mainly on iron and zinc, exacerbate marginal zinc deficiency, antiestrogens, but act like estradiol to based primarily on studies of the which is difficult to diagnose, and stimulate human breast cancer cells to absorption and bioavailability of these suggested that labeling should include enter the cell cycle. However, many minerals. the content of both zinc and phytate so other studies (reviewed in Refs. 97 and (Comment 12). One comment cited a consumers can be educated that a molar 98) have found that the phytoestrogens study in which a soy protein-based ratio of phytate:zinc of less than 10 is present in soybeans inhibit breast purified diet induced iron deficiency in needed to avoid detrimental effects on cancer cell proliferation in vitro (at monkeys (Ref. 85). The same comment zinc status, as suggested by research in lower concentrations, closer to also noted two studies in humans—one animals (including Ref. 95). The physiological levels) and inhibit that found inhibition of the absorption comment acknowledged that education mammary cancer development in of nonheme iron from both would be needed for the public to various animal models. FDA concludes semisynthetic meals and meals utilize such labeling. The agency that studies in transformed cells cannot comprising conventional foods by recognizes that adequacy of iron and predict with certainty whether effects various soy protein-containing zinc status in largely plant-based diets will be beneficial or detrimental in ingredients (Ref. 86), and one that found is a legitimate concern. humans consuming soy protein. increasing inhibition of nonheme iron FDA finds that the evidence of (Comment 14). Comments argued that absorption with increasing amounts of potential adverse effects of soy protein two reports showed effects of dietary phytate in liquid formula meals that on iron and zinc status is equivocal. intake of soy isoflavones on breast tissue contained soy protein isolates (Ref. 87). Interpretation of the evidence is difficult in women. Petrakis et al. (Ref. 99) In a study cited in another comment, the because findings in human studies are studied 24 normal pre- and substitution of some meat in a mixed often inconsistent with results of animal postmenopausal white women, ages 30

VerDate 12-OCT-99 17:23 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00006 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm03 PsN: 26OCR2 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations 57705 to 58 years, who underwent monthly (Comment 16). Comments cited the Faber and Hughes, 1993 (Ref. 107) as nipple aspiration of breast fluid and study of Cassidy et al. 1994 (Ref. 105) showing alterations in LH regulation gave blood and 24-hour urine samples as suggesting the potential for following developmental treatment with for biochemical studies. The women deleterious effects on human fertility. genistein, suggesting that during consumed no soy in months 1–3 and These investigators examined the pregnancy in humans, isoflavones could 10–12. During months 4–9 the women influence of a diet containing soy be a risk factor for abnormal brain and ingested daily 38 grams (g) of soy protein on the hormonal status and reproductive tract development. This protein isolate containing 38 mg of regulation of the menstrual cycle in six study involved injection of 0, 1, 10, 100, genistein (daidzein content was not premenopausal women. Soy protein (60 200, 400, 500, or 1,000 micrograms of reported). This study’s findings g containing 45 mg isoflavones) given genistein into neonatal rats on days 1– indicated that prolonged consumption daily for 1 month significantly (p<0.01) 10. Because of the differences in of soy protein isolate had a stimulatory increased follicular phase length and/or developmental stages between rodents effect on the breast of premenopausal delayed menstruation. Midcycle surges and humans, this type of experiment is women, characterized by increased of luteinizing hormone (LH) and used as a model for prenatal (third secretion of breast fluid and elevated follicle-stimulating hormone (FSH) were trimester) effects of diethylstilbestrol levels of plasma estradiol. The study significantly suppressed during dietary (DES). Increased exposure to genistein also detected evidence of epithelial intervention with soy protein. Plasma led to decreased LH secretion; the proliferation (hyperplasia) in 7 of the 24 estradiol concentrations increased in the volume of the sexually dimorphic subjects during consumption of soy. follicular phase and cholesterol nucleus of the preoptic area increased McMichael-Phillips et al. (Ref. 100) concentrations decreased 9.6 percent. compared to controls only in animals examined the effects of dietary soy The authors concluded that responses to that received the two highest doses of supplementation on the proliferation soy protein are potentially beneficial genistein. An earlier paper by Faber and rate of premenopausal, histologically with respect to risk factors for breast Hughes 1991 (Ref. 108) showed that normal breast epithelium and the cancer and may in part explain the low effects elicited by neonatal injections of expression of progesterone receptor. incidence of breast cancer and its 1000 micrograms of genistein were Women (n = 48) with benign or correlation with a high soy intake in similar to those of 0.1 micrograms of malignant breast disease were randomly Japanese and Chinese women. One of DES. The comment also cited studies assigned to receive their normal diet the comments that cited this study using a similar experimental model by either alone or with a 60-g soy acknowledged that it is unclear whether Medlock et al. (Refs. 109 and 110) as supplement (containing 45 mg these soy effects are beneficial or demonstrating that equol (a metabolite isoflavones) taken daily for 14 days. adverse. FDA notes that the study found of daidzein in some individuals) acts as Serum concentrations of the isoflavones that soy did not interfere with ovulation an endocrine disruptor during genistein and daidzein increased in the and the study did not assess effects on development. FDA finds that the soy group at 14 days. The proliferation fertility. relevance of these studies to an rate of breast lobular epithelium In a similar study with a longer assessment of potential prenatal effects significantly increased after soy duration, Duncan et al. (Ref. 106) of dietary soy protein during pregnancy supplementation when both the day of studied effects of isoflavone is uncertain. menstrual cycle and the age of patient consumption in 14 premenopausal (Comment 18). One comment cited were accounted for. Progesterone women. The women consumed the study of Harrison et al. (Ref. 111) receptor expression increased isoflavones in soy protein powders that showed pregnant Rhesus monkeys significantly in the soy group. The (control diet, 10; low isoflavone diet, 64; fed genistein had serum estradiol levels authors concluded that further studies high isoflavone diet, 128 mg/day) for 50 to 100 percent higher than the are required to determine whether the three menstrual cycles plus 9 days in a controls in three different areas of the short-term stimulation of breast randomized cross-over design. The low maternal circulation. The comment also proliferation is due to estrogen agonist isoflavone diet decreased LH and FSH noted the finding that the fetuses of activity and to examine the long-term levels during the periovulatory phase. genistein fed monkeys had a 70 percent effects of soy on both the pituitary gland The high isoflavone diet decreased free higher serum estradiol level than did and breast. T3 and dehydroepiandrosterone sulfate the controls. In this study, five monkeys FDA finds that the detection of levels during the early follicular phase were fed genistein (amount not proliferative effects in these two studies and estrone levels during the specified) during pregnancy and suggests the need for additional midfollicular phase. No other significant compared to five controls. No research. The findings do not, however, changes were observed in hormone differences were reported in maternal establish that the observed effects are concentrations or in the length of the weight gain, fetal weights at delivery, or detrimental and are not supported by menstrual cycle, follicular phase, or placental weights. Significant the findings of epidemiologic studies of luteal phase. Endometrial biopsies differences in estradiol levels (but not soy intake and risk of premenopausal performed in the luteal phase of cycle progesterone) were noted at delivery in breast cancer (Ref. 101). 3 of each diet period revealed no effect maternal peripheral blood, uterine b. Fertility and Hormone Levels. of isoflavone consumption on veins, ovarian veins, and the fetus, and (Comment 15). Some comments histological dating. FDA notes that in maternal blood during pregnancy, but referenced a number of studies that although this study’s findings varied values were not reported. FDA received reported reduced fertility in animals somewhat from those of Cassidy et al. only an abstract describing this study. exposed to phytoestrogens (including (Ref. 105), it also did not directly Without more complete documentation, Refs. 102, 103, and 104). Some of these address the effect of soy on human the merits or weaknesses of this study studies involved phytoestrogens other fertility. FDA finds that these two cannot be evaluated. Therefore, FDA has than those found in soy or consumption studies do not provide sufficient not used this study to evaluate the of soy under extreme or unusual evidence to address the effect of soy concerns raised in this comment. conditions. FDA is not convinced of the protein on human fertility. FDA notes that, in another study that relevance of these studies to human c. Developmental Effects. (Comment examined dietary effects, Fritz et al. consumption of soy protein. 17). One comment cited the study of (Ref. 112) fed female rats genistein from

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Moreover, the produces the thyroid hormones T3 and consuming a traditional high soy diet) report does not provide information on T4, and indicated that its inhibition can enhances cell differentiation, resulting total soy intake or what variables were be expected to generate thyroid in programming of mammary gland cells controlled in the analysis. If tofu or soy abnormalities. Other comments, for reduced susceptibility to chemically were implicated in Alzheimer’s disease, however, noted the lack of evidence for induced mammary cancer, with no its prevalence would be expected to be consequential effects of TPO inhibition observed toxicity to the fertility of dams higher in Japan than in Hawaii, but (i.e., high prevalence of goiter) in or the reproductive tract of female White et al. (Ref. 115) found the populations with high soy consumption. offspring. FDA finds that these dietary prevalence of Alzheimer’s disease was One comment noted that there exists studies in animals do not provide higher in Hawaii than in Japan. a body of animal data that demonstrates evidence for detrimental developmental Therefore, FDA is not persuaded by the goitrogenic and even carcinogenic effects in humans. comment raising concerns about effects of soy products and cited the (Comment 19). Another comment potential adverse effects of soy protein study by Kimura et al. (Ref. 120). These raised the possibility that soy in dementia and brain atrophy in older researchers developed malignant goiter phytoestrogens could be responsible for persons. inducing premature puberty and cited in rats by feeding diets containing 40 the case-control study of estrogenic (Comment 21). One comment percent defatted soybean and no iodine. exposures by Freni-Titulaer et al. (Ref. addressed the general issue of threshold No deleterious effects were seen in 113) of patients with premature effects for estrogenic compounds, citing controls fed the same diet with iodine thelarche seen in Puerto Rico between a study (Ref. 116) that showed no added. 1978 and 1981. In subjects 2 years of age threshold dose for estradiol-induced sex Comments noted the existence of a or older at the onset of thelarche, the reversal of turtle embryos. It also cited number of case reports in the older study found no statistically significant a study (Ref. 117), available in abstract literature of soy inducing goiter in associations. In subjects with onset form, that reviewed 31 dose-response infants (Refs. 121 through 125). Van before 2 years of age, statistically curves for hormone-mimicking Wyk et al. (Ref. 121) studied one infant significant positive associations were chemicals that also failed to show a who developed goiter on a soybean found with a maternal history of ovarian threshold. The report of this study did formula and tested the same product in cysts, consumption of soy-based not include mention of soy isoflavones 12 adults. In adults, the product did not formula, and consumption of various and did not specify the estrogenic interfere with iodine absorption, impair meat products. A statistically significant effects examined. FDA does not find iodine uptake, interfere with oxidation negative association was found with this evidence particularly useful. The of iodine in the thyroid, or (in most consumption of corn products. The relevance of the turtle model to humans subjects) interfere with the release of authors concluded that these statistical is uncertain and the other cited protein-bound iodine into the blood. associations were not sufficient to evidence was available only in abstract Hydovitz (Ref. 12) provided a single explain the reported increase in form. case report; Shepard et al. (Ref. 123) described three cases and presented premature thelarche because in over 50 e. Conclusion. Soy isoflavones and percent of the case subjects there was no evidence that soybean goiter was caused other dietary phytoestrogens are known by iodine deficiency. Pinchera et al. exposure to any of the risk factors for to exert hormonal effects—both which statistical associations were (Ref. 124) reported on a case of a estrogenic and antiestrogenic— congenitally hypothyroid infant and found. depending on the amount and type Thus, FDA concludes that this study found high fecal losses of thyroxine. consumed and endogenous hormonal provides no convincing evidence that Addition of adequate iodine to soy- status of the organism studied; they are soy was responsible for premature based infant formulas in the 1960’s much less potent than endogenous thelarche. Moreover, FDA notes that the generally resolved or prevented goiter. estrogen or synthetic estrogens such as study documents no deleterious effects However, Chorazy et al. (Ref. 125) more DES. There is considerable variability of consuming soy protein at the levels recently reported on a hypothyroid from person to person in the absorption, necessary to justify the health claim in infant who was semi-refractory to metabolism, and disposition of the soy population groups that are the target of thyroid hormone therapy while isoflavones, genistein and daidzein (Ref. the claim. consuming soy formula. d. Other. (Comment 20). One 118), and researchers have found that Several comments cited the study of comment cited a study associating their metabolism and excretion depend Ishizuki et al. (Ref. 126) as evidence for intake of tofu in mid-life by Japanese- on the duration of ingestion and the goitrogenic effects of soy in adults. This American men in Hawaii with vascular subject’s sex (Ref. 119). study is published in Japanese and the dementia and brain atrophy in old age Overall, the evidence for proliferative available English abstract is poorly (Ref. 114). This comment hypothesized effects, effects on fertility and hormone translated. As described in that abstract, that isoflavone inhibition of aromatase, levels, and developmental and other the design and findings are unclear: which catalyzes the conversion of effects in humans due to the estrogenic goiters were said to occur in half the testosterone to estradiol, may provide a effects of soy isoflavones is very limited. subjects eating 30 g soybeans daily for mechanistic explanation for this Both possible beneficial effects and 3 months, though ‘‘various parameters finding. The report cited (Ref. 116) is an possible detrimental effects are still of serum thyroid hormones remained abstract that indicates the researchers hypothetical. FDA finds that the unchanged by taking soybeans.’’ The found an association of high tofu intake information presented in the comments soybean preparation used (reported in with low cognitive test scores and with has not adequately documented some comments to be roasted, pickled Alzheimer’s disease, rather than deleterious effects of dietary intake of soybeans), iodine intake, and other vascular dementia. soy isoflavones in humans. dietary changes were not reported.

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In one comment, researchers that infants who develop cow’s milk of the soy protein studies submitted in indicated that they had identified allergies or intolerance are frequently the petition. genistein and daidzein as the prescribed soy substitutes and a small Based on these studies, FDA goitrogenic isoflavonoid components of subset of these high-risk children also concluded there was scientific evidence soy and defined the mechanisms for develop soy protein allergy. for a consistent, clinically significant inhibition of TPO-catalyzed thyroid FDA finds that the comments that effect of soy protein on blood total and hormone synthesis using in vitro studies noted concerns about the allergenicity LDL-cholesterol levels (63 FR 62977 at of the pure isoflavones (Refs. 127 and of soy protein cited these concerns as 62989). The hypocholesterolemic effect 128). The comment noted that the evidence that consumption of soy is of soy protein was seen in addition to observed irreversible inactivation of unsafe, but did not propose that any the effects of a low saturated fat and low TPO by isoflavones, through covalent particular action be taken by the agency cholesterol diet. The degree of lowering binding to TPO, raises the possibility of as a consequence to protect consumers of blood total and LDL-cholesterol was neoantigen formation. The comment with soy allergies. FDA does not believe consistently and highly dependent on also noted that anti-TPO is the principal that, because some persons may have initial levels, within and across studies autoantibody present in autoimmune allergic reactions to a food, it is unsafe. of subjects with normal, moderately thyroid disease and proposed that this FDA has previously stated that the elevated, and severely elevated blood hypothetical mechanism is consistent declaration of an allergenic substance in lipid levels, with persons having higher with the reports of Fort et al. (Refs. 129 the ingredient statement on the food blood lipid levels showing greater and 130) of a doubling of risk for label provides adequate information for effects. Soy protein consistently caused autoimmune thyroiditis in children who consumers regarding the presence of the only statistically nonsignificant effects had received soy formulas as infants allergenic ingredient in the product (63 or slight elevations in high density compared to infants receiving other FR 8103 at 8113), and sees no reason to lipoprotein (HDL)-cholesterol levels. forms of milk. However, the studies of change this view with respect to soy. The intervention studies indicated that a minimum level of approximately 25 g Fort et al. were retrospective case- FDA notes, in agreement with one of the of soy protein was needed to have a control analyses of early feeding comments received, that authorization clinically significant effect on total and practices in children with diabetes (Ref. of a health claim for soy protein and LDL-cholesterol levels. 129) or autoimmune thyroid disease CHD will highlight the presence of soy (Ref. 130). The studies did not establish protein in those food products that bear 1. Additional Data Submitted With a cause-and-effect relationship or assess the claim. The agency, therefore, Comments and New Studies medical indications for use of soy anticipates that persons with known soy (Comment 25). Several comments formula in these children. allergies will be able more easily to FDA notes that no data or other included submissions of additional avoid soy protein based products. information presented in the comments studies of the effects of soy protein on documents deleterious effects on B. Updated Review of Scientific total and LDL-cholesterol or directed thyroid function of consuming soy Evidence and Issues Related to the FDA to studies published since it issued protein at the levels necessary to justify Evidence the soy protein proposed rule. FDA the health claim in population groups reviewed these studies and found that that are the target of the claim. In the soy protein proposed rule, FDA two (Refs. 136 and 137) meet its criteria conducted a comprehensive review of for consideration. 9. Allergenicity of Soy Protein the human studies submitted in the One comment included an (Comment 23). One comment petition (Refs. 27 through 66) (63 FR unpublished paper by Teixeira et al., disputed the statement in the soy 62977 at 62980). Of these, the agency 1999 (Ref. 136) that examined the effects protein proposed rule that soy allergies gave particular weight to 14 clinical of feeding four graded levels of soy are often outgrown. FDA finds that the trials (Refs. 27, 28, 30 (1 trial), 31, 36, protein in moderately comment cited data that did not directly 37 (1 trial), 40 (2 trials), 44, 49, 51, 54, hypercholesterolemic men. After a address this issue but documented the 58, and 59). These 14 trials met the three-week lead-in on a National following with respect to soy: a case criteria for selection set out by the Cholesterol Education Program (NCEP) report of an anaphylactic reaction to soy agency (63 FR 62977 at 62980): they Step 1 diet, subjects were randomly in an adult (131); severe reactions to soy included subjects representative of the assigned to one of five experimental in several Swedish children and general U.S. population; were well groups. Each group received 50 g adolescents, who had known severe controlled; reported information on protein daily, provided in a variety of reactions to peanuts and asthma but had intakes of saturated fat and cholesterol; baked goods and ready-to-mix not reacted previously to soy (Refs. 132 and avoided problems associated with beverages, from ISP or casein in and 133); cross reactivity of some soy small sample size, lack of a placebo, and different proportions for 6 weeks. The and peanut allergens (Ref. 134); and an other design problems. The agency proportions of protein were 50, 40, 30, outbreak of gastrointestinal illness summarized these studies in Table 1 of 20, and 0 g (for control) as ISP and 0, associated with consumption of an the soy protein proposed rule (63 FR 10, 20, 30, and 50 g as casein, improperly processed soy protein tuna 62977 at 62998). The agency also respectively. At 3 weeks, statistically salad extender in which only a few summarized seven clinical trials in significant (p<0.05) reductions in total individuals exhibited signs of true adults (Refs. 33, 35, 46, 55, 56, 60, and and non-HDL-cholesterol were seen hypersensitivity reactions (Ref. 135). 64) and three trials in children (Refs. 34, only in the groups consuming 40 and 50 (Comment 24). One comment noted 42/45, and 63) with type II or familial g of soy protein. At 6 weeks, statistically that use of soy protein health claims hypercholesterolemia in Table 2 of the significant reductions (p<0.05) from will highlight the presence of soy soy protein proposed rule (63 FR 62977 baseline were found for non-HDL protein in foods. Another comment at 63011). In addition, FDA reviewed cholesterol levels in all soy protein- noted that any food protein can the results of one epidemiological study consuming groups and, in all except the stimulate a food allergy and that such (Ref. 65 and 63 FR 62977 at 62986) and 40 g soy protein group, for total allergies are commonly due to milk, egg, a meta-analysis (Ref. 66 and 63 FR cholesterol level. Although a reduction and nut proteins. This comment noted 62977 at 62987) that included a number in total cholesterol was noted in this

VerDate 12-OCT-99 17:23 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00009 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm03 PsN: 26OCR2 57708 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations latter group, it was non-significant diet (which provided 33 grams of soy protein and fat to bring dietary (p=0.07). The authors noted that neither protein from a variety of commercially cholesterol levels to the moderate range. non-compliance with the diet nor available foods) resulted in a 6 percent Diets containing soy protein decreased alterations in blood isoflavone content decrease in total cholesterol and a 7 LDL-cholesterol but the effect was of could account for this result. The study percent decrease in LDL-cholesterol borderline statistical significance. FDA also showed that levels of HDL- levels. The second study (Ref. 140) used notes that the small number of subjects cholesterol were not affected by dietary a similar design but was only available and the unusual dietary conditions treatment at any soy consumption level as an abstract that contained too little employed in these two studies limit investigated. detail for the agency to evaluate it. their usefulness in adding to the body FDA also noted the recently FDA finds that neither of these of evidence about the effects of soy published study by Wong et al., 1998 studies can provide support for a protein on circulating lipid levels. (Ref. 137), who conducted a well hypocholesterolemic effect of soy In summary, although most of the designed and controlled trial using protein per se because both soy protein new studies considered had flawed or NCEP Step 1 diets with most protein and soluble fiber were varied unusual designs that compromised their provided by soy (50 g/day of soy concurrently. However, these studies do evaluation, the two better designed and protein) or animal protein. Subjects suggest that inclusion of these specific controlled studies (Ref. 136 and Ref. were 13 normocholesterolemic and 13 components can further enhance the 137) provide additional support for the hypercholesterolemic men aged 20–50 lipid-lowering effect of a low saturated cholesterol lowering effects of inclusion years and the trial was a randomized, 2- fat, low cholesterol diet. of reasonable amounts of soy protein in part, crossover study. Subjects were fed (Comment 28). A comment also diets low in saturated fat and either an NCEP Step I soy protein- submitted the recent study by Washburn cholesterol. containing diet or an NCEP Step I et al., 1999 (Ref. 141) for consideration. 2. Interpretation of the Clinical Trial animal protein diet for 5 weeks. After a In this randomized, double-blind Data for Soy Protein washout period of 10–15 weeks, the crossover trial, 51 subjects were fed the alternate diet for normocholesterolemic, perimenopausal (Comment 29). One comment raised 5 weeks. The study found the women consumed supplements for 6- concerns about the apparent hypocholesterolemic effect of soy week periods of 20 g of complex inconsistency in FDA’s application of protein to be independent of age, body carbohydrate, 20 g of soy protein its review selection criteria, especially weight, pretreatment plasma lipid containing 34 mg of phytoestrogens with respect to giving the greatest concentrations, and sequence of dietary given in a single dose, and 20 g of soy weight in evaluation of the health claim treatment. Regardless of plasma lipid protein containing 34 mg of to those studies that reported status, the soy protein diet was phytoestrogens split into two doses. information about the dietary intake of associated with a statistically significant Significant declines in total cholesterol constituents known to have the greatest decrease in the plasma concentrations of level (6 percent lower) and LDL- influence on total and LDL-cholesterol LDL cholesterol (p=0.029). FDA finds cholesterol level (7 percent lower) were levels. The comment noted that values these two studies supportive of the observed with both soy treatments for dietary saturated fat and cholesterol relationship of soy protein to reduced compared to the carbohydrate placebo were not reported for some studies and risk of CHD. control. However, no dietary that an outmoded description of (Comment 26). One comment cited assessments were performed; thus, FDA polyunsaturated fatty acid to saturated two metabolic ward studies by cannot determine whether the women fatty acid ratio was reported for some Fumagalli et al. 1982 (Ref. 138), may have modified their usual dietary studies. designed to examine fecal steroid intake in response to the supplements FDA agrees that values for these excretion in adults with familial type II and whether and how intake of dietary dietary constituents were not reported hypercholesterolemia, that had not been constituents may have differed among explicitly in all of the studies selected reviewed by FDA in the soy protein the treatment groups. for review. In such cases, FDA relied proposed rule, as supportive of the FDA identified two additional upon other documentation contained in ability of soy protein to lower total recently published studies for the study publications regarding the cholesterol levels. However, FDA finds consideration. Nilausen and Meinertz, contents of the test and control diets, these studies had a very small number 1998 (Ref. 142) employed liquid formula such as sample menus and reported of subjects, short duration of treatment, diets containing a very high level of manipulations of sources of saturated fat and reported insufficient information to protein (150 g/day) with soy or casein and cholesterol, for assurance that determine the amounts of soy protein in as the sole protein source to examine dietary saturated fat and cholesterol did the diets consumed. These studies failed individual variability in lipemic not differ significantly in the test to meet FDA’s selection criteria for response in a small metabolic study of conditions. review and, so, FDA has not considered normocholesterolemic men. In most (Comment 30). One comment them further. subjects effects of soy protein on both questioned the appropriateness of (Comment 27). Comments included LDL- and HDL-cholesterol levels were including studies in which only total information on two studies by Jenkins et favorable, but considerable variability in cholesterol levels were measured. al. 1999 (Refs. 139 and 140) that response was observed. Duane, 1999 As noted above, in earlier assessed the effects of inclusion of soy (Ref. 143) also conducted a small rulemakings on diet and CHD protein and soluble dietary fiber in an metabolic ward study in relationships, FDA concluded that it is NCEP Step II diet in normocholesterolemic men that generally accepted that blood total and hypercholesterolemic subjects in a compared effects of (1) a control diet LDL-cholesterol levels are major risk randomized crossover design. Dietary with ‘‘standard’’ amounts of dietary factors for CHD, and that dietary factors saturated fat (less than 7 percent of cholesterol, (2) a diet with essentially no affecting blood cholesterol levels affect energy) and cholesterol (less that 80 mg/ dietary cholesterol and all animal the risk of CHD. FDA notes that a few day) did not differ in the test and sources of protein substituted by TVP, of the older studies that it considered control metabolic diets (Ref. 139). and (3) a diet similar to the second one and reviewed in the soy protein Compared with the control diet, the test with eggs isocalorically substituted for proposed rule, and in previous

VerDate 12-OCT-99 17:23 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00010 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm03 PsN: 26OCR2 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations 57709 rulemakings, measured only total consistency is notable in light of the In one study, Balmir et al. (Ref. 147) cholesterol levels. FDA concluded that different experimental designs and diets fed male rats diets containing protein inclusion of these studies for review studied, the different forms and from ethanol-acetone extracted ISP, was desirable in order to assess the amounts of soy protein tested, and the nonextracted ISP, casein, or casein to totality of the publicly available variability in initial cholesterol levels of which the ethanol-acetone extract was scientific evidence on the relationship the subjects. The modest lowering of added. Rats fed either ISP diet had of soy protein and risk of CHD, even total and LDL-cholesterol levels lower serum total cholesterol though LDL-cholesterol levels are now generally observed in these studies can concentrations compared with those fed considered to be a more powerful risk effect a significant reduction in CHD either casein diet. Lower serum LDL- factor than total cholesterol levels. risk. cholesterol concentrations were found (Comment 31). A few comments (Comment 32). Other comments in rats fed either ISP diet and in rats fed disagreed with FDA’s tentative decision reviewed various possible mechanisms casein plus extract compared with those to authorize a health claim for the for the cholesterol-lowering effects of fed casein. Sugano and Koba (Ref. 148) relationship between soy protein and soy protein and some argued that until found that a methanol-extracted soy CHD because not all of the studies the mechanism of action of soy protein fraction was not as effective as the reviewed in the soy protein proposed is clearly established, no health claim unextracted fraction in maintaining low rule showed significant reductions of should be authorized. FDA notes, plasma cholesterol levels in rats. Kirk et total and plasma cholesterol levels. however, that such knowledge is not al. (Ref. 149) showed that a soy protein- A recent review and meta-analysis of necessarily required for authorization of based isoflavone-containing diet the effectiveness of NCEP Step 1 and a health claim. resulted in a reduction in cholesterol Step 2 dietary interventions in free- levels in C57BL/6 mice compared to a living subjects by Yu-Poth et al. (Ref. 3. Role of Soy Isoflavones in and Effect of Processing on the diet containing alcohol-washed soy 144) noted an appreciable range of protein, although it had no effect on response to the dietary interventions Hypocholesterolemic Effect of Soy Protein cholesterol levels in transgenic mice with the maximal effect being more than that lacked the LDL receptor. In another In the soy protein proposed rule, FDA twice the average response reported in study, Balmir et al. (Ref. 147) fed male examined the limited evidence that controlled feeding studies with Step 1 Golden Syrian hamsters diets containing addressed whether the diets. The interventions reviewed were protein from ISP, ISP with added hypocholesterolemic effects of soy designed to achieve reduction of dietary ethanol-acetone extract, casein, or protein intake were dependent, as saturated fat and cholesterol and weight casein with added extract. Lower serum suggested by the petitioner, on reduction, factors known to have a total cholesterol and LDL cholesterol concomitant intake of a specified level major impact on circulating cholesterol concentrations were observed in levels. (The hypocholesterolemic effects of naturally occurring soy isoflavones, hamsters fed ISP, ISP with extract, or of soy protein, like those of soluble fiber i.e., 2 mg isoflavones per g of soy casein with extract compared with those from whole oats and psyllium seed, are protein (Refs. 22, 28, 31, 70, and 71). fed casein. Addition of the extract to of a lesser magnitude than those of FDA also took note of a letter to the casein at higher levels did not lower reduced dietary saturated fat and editor from Sirtori et al. (Ref. 72), who serum lipids relative to casein. Tovar- cholesterol.) Denke (Ref. 145), in an conducted a number of trials in which Palacio et al. (Ref. 150) fed gerbils one editorial comment on the study by Yu- soy protein exhibited of five experimental diets containing Poth et al., notes that cholesterol- hypocholesterolemic effects and either casein or alcohol-washed ISP lowering dietary therapy is subject to asserted that the products used in those provided alone, or ISP supplemented profound individual variation in trials were essentially devoid of response. In metabolic ward studies of isoflavones. Given the limited number with one of three different levels of an subjects with unselected cholesterol of studies and the contradictory alcohol extract of isolated soy protein levels, 5 percent of individuals had no outcomes, FDA was not persuaded that contributing either 2.1, 3.6 or 6.2 mg cholesterol-lowering response to dietary the isoflavone component of soy protein isoflavones/g protein. Gerbils fed all of modification and the percentage of was a relevant factor to the diet-disease the soy-based diets had significantly nonresponders increased to 10–25 relationship. Rather, FDA tentatively lower total and LDL + very low density percent in outpatient studies (Denke, concluded that the evidence from a lipoprotein (VLDL)-cholesterol levels 1995, Ref. 146). Such nonresponse can wide range of studies using differently than those fed casein. The additions of result in a significant underestimation processed soy protein was supportive of the alcohol extract to ISP did not reduce of the effectiveness of dietary a relationship between soy protein per serum cholesterol levels any further. intervention when only the mean se and reduced risk of CHD. This study suggests that, in gerbils, response is considered. The small (Comment 33). Several comments consumption of an isoflavone- metabolic ward study of Nilausen and reviewed and discussed the animal and containing extract does not contribute to Meinertz (Ref. 142), described above, human studies that examined effects of the hypocholesterolemic effect of documented evidence for considerable isoflavones directly or that compared alcohol-extracted soy protein. These inter-individual variability in the the effects of ISP processed with and reports did not characterize the nature response of cholesterol levels to diets without alcohol extraction that can of the extracts used in the studies. containing soy protein. remove essentially all isoflavones. Some Overall, FDA finds that studies in these Based on the studies reviewed in the of these studies examined effects on animal models do not clarify the role of soy protein proposed rule and the new parameters in addition to cholesterol isoflavones in the hypocholesterolemic studies reviewed in this document, FDA levels, such as measures of lipid-related effect of soy protein. concludes that the totality of the gene expression, atherosclerosis, and Comments noted a series of studies available scientific evidence supports a vascular reactivity. Because the health conducted in monkeys that examined consistent, if not universal, claim for soy protein and CHD is based the effect of removal of isoflavones and hypocholesterolemic effect of soy on the hypocholesterolemic effect of soy other alcohol-extractable compounds protein included in a low saturated fat protein, only that aspect of the studies from soy protein on its cholesterol- and low cholesterol diet. The degree of is summarized below. lowering activity. Anthony et al. (Ref.

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22) fed peripubertal male and female administered daidzein and genistein to group. HDL-cholesterol was also rhesus monkeys moderately atherogenic 23 male and female subjects with an significantly increased (p<0.05) in both diets in which the source of dietary average cholesterol level of 243 mg/ soy groups compared to the control. The protein was a soy protein isolate, either deciliter (dL) in a blinded crossover level of isoflavones did not affect any of containing isoflavones or with the design. Nestel et al. (Ref. 52) studied 21 the blood lipid levels measured. isoflavones removed by alcohol women in a randomized cross-over FDA also previously reviewed the extraction, in a crossover design with design with two active treatment unpublished study by Crouse et al., each period lasting for 6 months. The periods (80 mg of isolated soy which was subsequently accepted and intact soy protein (compared with the isoflavones) and one 5-week placebo published (Ref. 31), in the soy protein extracted soy protein) significantly period, while they consumed a soy-free proposed rule (63 FR 62977 at 62987). reduced LDL+VLDL-cholesterol levels diet. Hodgson et al. (Ref. 153) This study examined the effect of soy in both males and females and conducted a randomized, blinded, protein containing different levels of significantly increased HDL-cholesterol placebo-controlled trial of 8 weeks isoflavones in hypercholesterolemic levels for females. Honore´ et al. (Ref. 23) duration and a two-way parallel design men and women. Subjects with fed young adult rhesus monkeys with that tested the administration of 55 mg qualifying serum lipid levels (LDL- pre-existing diet-induced of soy isoflavones to 46 men and 13 cholesterol greater than 140 mg/dL) after atherosclerosis one of two soy-based postmenopausal women. Plasma lipid one month and who were compliant diets, which were identical in levels were not affected by soy with the study regimen were composition except that the isoflavones isoflavones in any of these studies. FDA randomized into one of five treatment were extracted from one and intact in notes that these studies do not support groups. The treatment groups received the other, for 6 months. Total and LDL- a role for isolated isoflavones in 25 g protein from ISP prepared from soy cholesterol levels were significantly cholesterol lowering. with different levels of isoflavones Three studies submitted in comments lower in females fed the intact soy (either 1.0, 1.6, or 2.5 mg total aglycone examined the effects of variation of protein than in those fed the extracted isoflavones/g protein), or 25 g protein isoflavone content in soy protein- soy protein. The same trend was seen in from alcohol-washed ISP that contained containing diets in human subjects. males, but the difference was not essentially no isoflavones (0.2 mg total Cassidy et al. (Ref. 154) conducted statistically significant for total aglycone isoflavones/g protein) or 25 g metabolic ward studies of the effects of cholesterol. Anthony et al. (Ref. 70) protein from casein (no isoflavones) in various soy products with and without studied young male cynomolgus beverages for 9 weeks. Results indicated macaques fed one of three moderately isoflavones in small numbers of healthy, nonvegetarian, premenopausal women. that compared to casein the ISP atherogenic diets for 14 months. The containing the highest level of groups differed only in the source of During one (control) menstrual cycle, the women ate a constant diet isoflavones significantly lowered total dietary protein, which was either (p<0.05) and LDL-cholesterol (p<0.05), casein/lactalbumin, soy protein with the containing no soy products. Then, over a second complete cycle six subjects by 4 percent and 6 percent, respectively, isoflavones intact, or soy protein with while HDL-cholesterol was not altered. the isoflavones mostly extracted. consumed a similar diet into which 60 g TVP/day, containing 45 mg conjugated In subjects with LDL-cholesterol in the Animals fed intact soy protein had top half of the study population, serum significantly lower total and isoflavones, was incorporated. Three participants had 50 g miso, containing total and LDL-cholesterol were reduced LDL+VLDL-cholesterol levels compared 25 mg unconjugated isoflavones, added by 9 percent (p<0.03) and 12 percent with the other two groups. The animals daily to their diet over a menstrual (p<0.03), respectively, by the ISP with fed intact soy protein had the highest cycle, and six others consumed 28 g the highest isoflavone content, and by 8 HDL-cholesterol level, the casein group TVP/day, containing 23 mg conjugated percent (p<0.03) and 9 percent (p<0.03), had the lowest level, and the group fed isoflavones. Five participants completed respectively by the ISP with the second the extracted soy protein was a third diet period in which they were highest isoflavone content, while HDL- intermediate. Anthony et al. (Ref. 151) randomly assigned to consume either cholesterol concentrations were randomized male and female macaques the control diet over a cycle, or a similar maintained. The authors reported a to groups fed a casein-containing diet or diet incorporating 60 g of a ISP from dose-response effect of increasing diets with soy protein with the which the isoflavones had been amounts of isoflavones on total and LDL isoflavones intact or extracted. Fat and chemically extracted. A significant cholesterol level. One comment cholesterol were identical in all diets. reduction in total cholesterol was found included a reanalysis of the dose- The LDL+VLDL-cholesterol levels were with 45 mg conjugated isoflavones, but response data that did not include data highest in the casein group, slightly not with 23 mg conjugated isoflavones for the casein diet, in order to control lower in the group fed extracted soy or isoflavone-free ISP. for an independent effect from soy protein, and significantly lower in the As previously reviewed in the soy protein itself, and found no significant group fed intact soy protein. The HDL- protein proposed rule (63 FR 62977 at effect based on isoflavone content. A cholesterol levels were significantly 62988), the study of Baum et al. (Ref. 28) comment from the petitioner disagreed higher in both soy protein groups than investigated the impact of soy protein as with this analysis. It also indicated that in the casein group. FDA notes that the ISP containing different levels of the study did not eliminate the alcohol extraction procedure used by isoflavones in hypercholesterolemic, possibility that isolated soy protein per these researchers, which was not postmenopausal women. Adjusted mean se has cholesterol-lowering properties, characterized in the study reports, differences in the change from baseline but rather suggested that soy protein appeared to diminish the for total serum cholesterol level did not with higher levels of isoflavones might hypocholesterolemic effect of ISP. differ in the two soy groups and the have even greater effects. FDA finds that Comments submitted three human control group. However, there was a the disparity in these comments does studies of isolated isoflavones that statistically significant reduction of 8–9 not clarify the equivocal nature of the examined their role in cholesterol percent in non-HDL (LDL+VLDL)- available evidence. FDA finds that these lowering. In a study published only as cholesterol in both of the ISP treatment studies do not provide sufficiently an abstract, Colquhoun et al. (Ref. 152) groups (p<0.05) compared to the control consistent results to cause the agency to

VerDate 12-OCT-99 17:34 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00012 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm03 PsN: 26OCR2 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations 57711 change the conclusion reached in the some credence to the knowledge of the The additional evidence about the soy protein proposed rule. investigator about the products used in role of isoflavones is contradictory and (Comment 34). One comment objected his studies, but agrees that the letter to inconclusive and has not persuaded to FDA’s consideration of the letter to the editor does not provide sufficient FDA to alter its original conclusion the editor by Sirtori et al. (Ref. 72) documentation to permit an about the inability to identify a specific because the reference substantiating the unequivocal conclusion that the contribution of soy isoflavones to the technique for processing the soy protein products found to be devoid of cholesterol-lowering effects of soy product was missing from the letter, the isoflavones were identical to those used protein. At the same time, the evidence products were not tested for isoflavone in the clinical studies. shows a clear relationship between soy content at the time of the studies, (Comment 35). One comment asserted protein and reduced risk of CHD despite different soy products (isolate and flour) that most of the studies reported by lack of a clearly defined mechanism for were used to manufacture the textured Sirtori’s group were performed using a its effect. soy protein used in the studies, and the textured soy protein based on steam- (Comment 37). Several comments references for studies cited in the letter treated soy flour; this treatment would interpreted the evidence as showing that alcohol extraction used in the did not match the ones cited by FDA in be expected to remove isoflavones. The the soy protein proposed rule. FDA processing of certain soy protein comment also included a letter from agrees that the reference for the patented ingredients (to the extent that they are Sirtori (Ref. 157) stating that essentially procedure for the production of the rendered essentially devoid of all of his group’s studies beginning in TVP, described as making use of rapid isoflavones) impairs or eliminates the 1980 were with products without heating under high pressure, was hypocholesterolemic effects of soy isoflavones. However, the patent omitted in the letter by Sirtori et al. (Ref. protein and recommended that the referenced in this letter was not 72) and that the isoflavone content of health claim not be allowed for alcohol- included with this submission. Thus, the products reported (Cholsoy and washed products. Comments also raised FDA cannot verify that the process used Croksoy) was not measured at the time some questions about the extent to to produce the products used in Sirtori’s the studies in which they were used which extensively alcohol-washed studies over time was the same used to were conducted. products, such as those used in the The letter by Sirtori et al. (Ref. 72) produce the products analyzed recently animal studies, are available cites two older studies—Sirtori et al., for isoflavone content. commercially. One comment asserted 1979 (Ref. 55) and Sirtori et al., 1979 (Comment 36). The interpretation of that some of ISP products used in the (Ref. 155)—as well more recent the data available on the role of soy primate studies were subjected to studies—Sirtori et al., 1995 (Ref. 156)— isoflavones in and the effects of additional alcohol extraction by the conducted by their group. The five processing on the hypocholesterolemic investigators, but the agency could not studies of Sirtori’s group that FDA effect of soy protein varied widely in the independently verify this assertion. This reviewed and cited in the soy protein comments. Several comments agreed comment also stated that all commercial proposed rule as using products that with FDA’s conclusion that the sources of soy protein contain some contained essentially no isoflavones evidence did not support a significant isoflavones. (Refs. 33, 34, 35, 46, and 56) are role for soy isoflavones in cholesterol- FDA examined the recently compiled included in the reference list of Sirtori lowering effects of soy protein. One USDA-Iowa State University Isoflavone et al., 1995 (Ref. 156), which is a review comment supported the petitioner’s Database (Ref. 158), which documents article. The agency did not review original conclusion that a level of 2 mg the following ranges of total isoflavone Sirtori et al., 1979 (Ref. 155) in the soy aglycone isoflavones per g soy protein content for various soy protein- protein proposed rule, and it did not was necessary for cholesterol lowering. containing ingredients, and found that cite Sirtori et al., 1977 (Ref. 55) because In a comment, the petitioner agreed most, but not all, contained levels of it specifically indicated use of a soy with FDA ‘‘that a relationship exists isoflavones higher than those that protein product different from those between soy protein per se and reduced would result from harsh alcohol tested for isoflavone content. FDA gives risk of CHD.’’ extraction procedures:

TABLE 1

Aglycone isoflavones Product (mg/100 g edivle portion

Soy flour, textured ...... 4.40±295.55 Soy flour, defatted ...... 73.72±168.09 Soy flour, full-fat, raw ...... 59.80±264.84 Soy flour, full-fat, roasted ...... 131.70±260.50 Soy protein concentrate, aqueous washed ...... 61.23±167.00 Soy protein concentrate produced by alcohol extraction ...... 2.08±31.82 Soy protein isolate ...... 46.50±199.25 Instant beverage, soy powder ...... 100.10±125.00

FDA agrees that the data from the insufficient to permit any conclusions products from eligibility to bear the animal studies reviewed suggest that about the impact of processing by health claim. alcohol washing of soy protein can alcohol extraction on the (Comment 38). One comment noted reduce its hypocholesterolemic effects. hypocholesterolemic effect of soy that several clinical trials designed to With respect to human studies, FDA protein. Thus, FDA concludes it would resolve questions about the impact of finds the available evidence is be premature to exclude alcohol-washed processing and isoflavone content are

VerDate 12-OCT-99 11:58 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00013 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm04 PsN: 26OCR2 57712 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations currently in progress. Many of the normocholesterolemic individuals and general U.S. population is at risk. The comments on these issues urged that that this should be indicated as part of risk of dying from CHD is related to FDA proceed with the health claim the claim. serum cholesterol levels in a continuous regulation as proposed, but monitor FDA agrees that the available data on and positive manner, increasing slowly research developments and make the hypocholesterolemic effects of soy for levels between 150 mg/dL and 200 changes in the regulation as warranted protein do not permit a dose-response mg/dL and more rapidly when the by the results. assessment. However, FDA notes that cholesterol level exceeds 200 mg/dL As noted above, FDA finds that, in dose-response data are not required to (Ref. 37). The public health policy light of the evidence that soy protein establish the qualifying criteria for a articulated by the NCEP, National Heart, processed in various ways, containing substance that is the subject of a health Lung, and Blood Institute, is to extend unknown amounts of isoflavones, has claim. Under § 101.70, which describes the benefits of cholesterol lowering to hypocholesterolemic effects, FDA is not the requirements for health claim the population as a whole by promoting applying any criteria for inclusion of petitions, the petition must address adoption of eating patterns that can help naturally occurring isoflavones or whether there is an optimum level of lower the blood cholesterol levels of excluding alcohol-washed products the particular substance to be consumed most Americans (Ref. 67). A dietary from eligibility to bear the health claim beyond which no benefit would be intervention that lowers blood on soy protein and CHD. expected (§ 101.70(f)(B)(1)). This cholesterol levels only in persons with (Comment 39). A few comments information may or may not be based on high levels would, like an intervention suggested that, regardless of the dose-response data. For example, in its that lowers cholesterol levels across the conclusions about the significance of evaluation of the scientific evidence for entire population range, cause a shift in soy isoflavones to the reduction of CHD a relationship between consumption of the population distribution of blood risk, food products that bear the soy soluble fiber from psyllium seed husk cholesterol levels resulting in a decrease protein health claim be allowed or and blood total and LDL-cholesterol in the mean value for the blood required to state the isoflavone content levels, the agency found no reliable data cholesterol level in the general of the product on the label. The to establish a dose-response for this population (Ref. 67). The anticipated comments did not provide any evidence relationship (62 FR 28234 at 28240). effect of such a shift would be to reduce that persuaded the agency that However, the agency did find that, in the morbidity from CHD and to produce consumers would find this information placebo-controlled studies that tested an a continued or accelerated decline in helpful in making healthful dietary intake of 10.2 g of psyllium seed husk the CHD mortality rate in the United choices. Accordingly, the agency is not per day as a part of a diet low in States. The agency is persuaded by the adopting this suggestion. saturated fat and cholesterol, there were evidence it has reviewed in this 4. Amount of Soy Protein Required for consistently significant effects of rulemaking that the consumption of soy Significant Effect on Cholesterol Levels psyllium husk on blood total and LDL- protein, as part of a low saturated fat cholesterol levels. Therefore, the agency and cholesterol diet, can be a useful Based on the limited data reviewed based the qualifying level of soluble public health measure to assist in the that supported a dose-response and the fiber from psyllium seed husk on a total national policy of promoting eating data that showed clinically significant daily intake of 10.2 g husk or about 7 patterns that will help in achieving or reductions in total and LDL-cholesterol g of soluble fiber. maintaining desirable blood cholesterol with soy protein ingestion in the range The qualifying level of 25 g/day has levels in the general population. of 17–31 g/day, and recognizing that the been demonstrated to have a consistent, Therefore, it concludes that the health hypocholesterolemic effects of soy clinically significant effect on total and claim need not indicate that protein were dependent on initial blood LDL-cholesterol levels. This 25 g/day hypercholesterolemic individuals may lipid levels, the agency tentatively level of intake for cholesterol lowering be more responsive to consumption of concluded that 25 g/day represented a is confirmed by the new study of soy protein than normocholesterolemic reasonable, effective amount of soy Teixeira et al. (Ref. 136), which showed individuals. In addition, consistent with protein (63 FR 62977 at 62992). In significant hypocholesterolemic effects the agency’s conclusions in rulemaking addition, the agency noted that an of 20 g/day of soy protein. Therefore, on the dietary saturated fat and amount of 25 g/day of soy protein the agency disagrees with the comments cholesterol/CHD claim (58 FR 2739 at represents half of the Reference Daily suggesting that dose-response data are 2745, January 6, 1993), the wording of Intake (RDI) of 50 g for protein and is needed before the agency can authorize the health claim as ‘‘ ‘may’ or ‘might’ a reasonable level of consumption in the a health claim. The totality of scientific reduce the risk of heart disease’’ context of the total daily diet. Thus, data, which establish a clinically adequately represents the fact that not FDA tentatively concluded that the significant reduction in blood all persons will realize the same amount of soy protein associated with cholesterol based on an intake of at least magnitude of benefit from adopting the reduction in total and LDL-cholesterol 25 g/day of soy protein, provides an dietary change. levels and, thus, with reduced risk of adequate basis for establishing a CHD was 25 g or more of soy protein per qualifying level for soy protein- 5. Summary of the Scientific Evidence day (63 FR 62977 at 62992). containing products. FDA reviewed human studies (Comment 40). Many comments The agency agrees that the available submitted by the petitioner and in agreed with the agency’s conclusion that data indicate that the comments that evaluated the effects on 25 g or more of soy protein per day was hypocholesterolemic effect of soy serum cholesterol and LDL-cholesterol associated with reduction in total and protein may be dependent on initial levels of dietary interventions with soy LDL-cholesterol levels. Several cholesterol levels, but notes that protein in subjects with normal to comments raised concerns about the moderately hypercholesterolemic elevated serum cholesterol levels and adequacy of the available data to individuals are generally more that met the agency’s criteria for support an assessment of dose-response. responsive to dietary interventions than selection. One comment expressed concern that normocholesterolemic individuals. As Most intervention trials in subjects higher levels of soy protein are needed the leading cause of death in this with total cholesterol levels less than to modify cholesterol levels in country, CHD is a disease for which the 300 mg/dL found that soy protein

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The evidence currently the qualifying criterion set forth in the 137) or slightly increased (Refs. 28, 44, available, as reviewed in section II.B.3 petition would be appropriate (63 FR 58, and 59). In some cases (Refs. 27, 44, of this document, does not permit a 62977 at 62992). and 49), decreases in total and LDL- conclusion regarding how significantly Most comments agreed that the cholesterol were statistically significant alcohol processing may affect the qualifying level of 6.25 g soy protein per only in subsets of subjects with the hypocholesterolemic effects of soy RACC was appropriate. Many of these higher initial blood lipid levels. Results protein. The intervention studies comments also indicated that a in normocholesterolemic subjects (Refs. reviewed indicate that a minimum level sufficient number and variety of soy 30, 36, 58, 59, and 53) were more of approximately 25 g of soy protein per protein-containing foods are available to variable than those in day results in a clinically significant enable consumers to select suitable hypercholesterolemic subjects (Refs. 31, effect on total and LDL-cholesterol products to consume a total of 25 g soy 28, 27, 51, 44, 40, 37, 49, 54, 29, 43, and levels. protein per day. 136) except in the study of Wong et al. With respect to the scientific data and (Comment 41). Several comments (Ref. 137), in which information about the relationship of suggested rounding the qualifying level normocholesterolemic and moderately soy protein and CHD, the relevant data to 6 or 7 g of soy protein per RACC, in hypercholesterolemic subjects were are provided by well controlled and keeping with the requirements for the equally responsive. The outcome of an well designed studies. Soy protein, the labeling of protein in the Nutrition Facts epidemiologic study (Ref. 65) also food substance that is the subject of the panel. supported a relationship between higher claim, is measured in those studies. The FDA, however, notes that the levels of soy protein intake and lower relationship of the biomarkers Nutrition Facts panel contains the blood lipid levels. evaluated—total and LDL-cholesterol— amount of total protein per serving of Most of the studies in subjects with to the risk of CHD is validated and the the product, regardless of the source total cholesterol levels less than 300 mg/ studies measured the biomarkers ingredient. For many products that may dL used low saturated fat and low appropriately. Finally, a consistent body bear the claim, soy protein may not be cholesterol diets (Refs. 31, 28, 27, 51, of evidence from a variety of studies is the sole contributor to total protein. 44, 30, 36, 53, 29, 43, 136, and 137), but available. Accordingly, the agency is Therefore, FDA finds that the amount of some used ‘‘usual’’ diets (Refs. 37, 49, able to conclude, based on the totality soy protein in a serving of a food that 54, 36, 58, and 59). Although soy of the publicly available scientific may bear the health claim will neither be required nor permitted to appear in protein was found to lower blood lipid evidence, that there is significant the Nutrition Facts panel. The levels in some of the studies using scientific agreement that soy protein, qualifying level need not conform to ‘‘usual’’ diets, hypocholesterolemic included at a level of 25 g/day in a diet requirements specific to the Nutrition effects of soy protein were more low in saturated fat and cholesterol, can Facts Panel. consistently observed with diets low in help reduce total and LDL-cholesterol saturated fat and cholesterol. Given the (Comment 42). One comment received levels, and that such reductions may in response to the soy protein variability of amounts and forms in reduce the risk of CHD. which soy protein was provided in the reproposal indicated that food diets, the response of blood lipid levels C. Nature of the Food Eligible to Bear processors will be required to declare appears robust and notably consistent, the Claim the corrected amount of protein and the percent Daily Value of protein on the particularly in subjects with moderate 1. The Qualifying Amount of Soy Nutrition Facts panel, in accordance hypercholesterolemia. Protein Data from studies of adults with type with 21 CFR 101.9(c)(7)(i). This II and familial forms of Using 25 g of soy protein as the comment noted that, in nearly all cases, hypercholesterolemia (and total qualifying amount for a CHD claim, the the amount of protein declared will be cholesterol levels in excess of 300 mg/ petitioner suggested that a single serving lower than the quantity of protein dL) (Refs. 55, 33, 64, 56, 64, 46, and 35) of a soy protein-containing product (i.e., present in the product and may, in some were also consistent in showing large one RACC) should provide 1⁄4 of this instances, be lower than the qualifying and statistically significant decreases in amount (based on four servings a day). amount of soy protein. total and LDL-cholesterol, accompanied Thus, a soy protein-containing product FDA notes that compliance with the by no changes or slight increases in would have to contain at least 6.25 g soy requirements of this regulation will be HDL-cholesterol levels. Nearly all of the protein (1⁄4 × 25 g) per RACC. The based on the actual amount of soy subjects in these trials consumed low petitioner stated that this approach was protein present in the food and not on saturated fat and low cholesterol diets reasonable because it would permit a the amount of protein declared on the during the studies and had consumed wide variety of low fat, soy protein- nutrition label. such diets prior to studies with soy containing products to bear the health (Comment 43). One comment protein. Soy protein was tested in a claim. The petitioner provided a list of suggested that the qualifying level variety of foods but produced fairly products on the market that currently should be increased to 12.5 g soy consistent results regardless of the food meet the proposed requirements and a protein per RACC because of concerns form fed and apparent differences in list of products that could be modified that consumers would not choose soy processing techniques. to meet them (Ref. 1, Appendix V). The protein-containing foods frequently The FDA concludes, based on the agency has generally made the enough during a day to reach a total of evidence submitted and reviewed, that assumption that a daily food 25 g and might believe that the health soy protein, included in a diet low in consumption pattern includes three benefit may be attained by eating a saturated fat and cholesterol, can lower meals and a snack (see 58 FR 2302 at single serving of a food that provided no blood total and LDL-cholesterol levels, 2379, January 6, 1993). The agency more than 6.25 g soy protein. Several

VerDate 12-OCT-99 11:58 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00015 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm04 PsN: 26OCR2 57714 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations other comments also raised concerns soluble fiber from whole oats and CFR 101.12(g)) require that, ‘‘The that consuming soy protein-containing soluble fiber from psyllium seed husks). reference amount [i.e., the reference foods up to four times daily would FDA finds that these comments did amount customarily consumed] * ** represent a significant change from the not provide a compelling rationale for shall be used in determining whether a typical American diet that might not be selecting an appropriate number of product meets the criteria * * * for selected by many consumers. eating occasions on any other basis. The health claims.’’ In a previous FDA cannot assess how many agency has not limited its previous rulemaking, FDA had considered consumers would be interested in determinations of an appropriate permitting this option, but comments making such a change, but it is qualifying level of a substance that does persuaded the agency that the most persuaded that it will be feasible for not have a Daily Value in a food to be reasonable approach was to base claim motivated consumers to do so. Doubling eligible to bear a health claim to evaluations on the reference amount (58 the qualifying level of soy protein per consideration of the number of FR 2229 at 2287). FDA agreed with the RACC would greatly and unnecessarily individual foods or classes of food comments that claims should reflect the restrict the number of foods potentially products then available that might bear true characteristics of a product, and eligible to bear the health claim. the claim. Rather, in determining what that those characteristics do not change Because § 101.82(c)(2)(i)(G) requires that constitutes a level of the substance if the product is packaged in a different the claim specify both the daily dietary sufficiently high to justify the claim, size container. The comment received in intake of soy protein that is necessary to FDA considers factors such as the response to the soy protein proposed reduce the risk of coronary heart disease number of servings likely to be rule did not provide a convincing and the contribution that one serving of consumed and the feasibility of rationale to justify a change in this the product makes to the specified daily developing a variety of foods that decision. dietary intake, consumers will not be contain a significant proportion of the total daily intake needed for the claimed 2. Method for Determining Qualifying misled about the amount of soy protein Amount of Soy Protein in Foods needed for the health effect. benefit. For example, when the psyllium claim was authorized, FDA was aware In the soy protein proposed rule (63 (Comment 44). A number of of only one conventional food product FR 62977 at 62992), FDA proposed use comments suggested that greater that would have been eligible to bear the of the Association of Official Analytical flexibility in meeting the recommended claim and concluded that, if various Chemists (AOAC) official method of total daily intake of 25 g soy protein per psyllium-containing foods were analysis No. 988.10 to measure soy day could be achieved by permitting a available, consumption of four servings protein in foods. As described in the soy lower qualifying level on the basis of daily could be achieved. Based on protein reproposal (64 FR 45932 at increasing the number of servings or experience with that claim and other 45933), each of the comments on this eating occasions per day from four to health claims, FDA believes that proposed analytical method disagreed five or six or more. Several of these manufacturers will be encouraged by with its use and concluded that the comments proposed that the qualifying the availability of a health claim for soy method was unlikely to produce a level of soy protein should be reduced protein and CHD to develop new reliable measure of the soy protein to 4 g per RACC; one suggested lowering products that will be eligible to bear the content in every food. The comments the qualifying level to 2.5 g per RACC. claim. The agency is not persuaded by noted a variety of problems with the Most of these comments indicated that the comments received that it should assay. These comments persuaded the 4 g soy protein per RACC is the abandon its assumption that a daily agency that AOAC official method of maximum amount of soy protein from food consumption pattern includes analysis No. 988.10 was not an soy flour that can be incorporated in three meals and a snack (see 58 FR 2302 appropriate method for the quantitation baked products that consumers find at 2379, January 6, 1993) and that one of soy protein in many of the products palatable and acceptable. These serving of a soy protein-containing that may be eligible to bear the health comments suggested that lowering the product could reasonably be consumed claim. qualifying level would stimulate at each eating occasion. As noted in the In the soy protein reproposal, FDA manufacturers to develop a wider range discussion above of the comments that discussed the alternative approaches of products and indicated that use of expressed concerns about the suggested in comments for assessing ISP in baked products would be willingness of consumers to select soy compliance with the qualifying level of prohibitively expensive. One comment protein-containing foods as many as soy protein in products that bear the challenged FDA’s assertion that four times a day, such an eating pattern health claim. Based on this information, consumers would be able to consume an represents a considerable change from a the agency provided its tentative effective amount of soy protein from a typical American diet. Although one of rationale for a procedure employing variety of products, including baked the comments included detailed menus measurement of total protein and, for goods. FDA based the assertion on its that illustrated the possibility of products containing sources of protein observation that baked products had consuming more than one soy protein- other than soy, calculation of the soy been used to provide soy protein in containing product per eating occasion, protein content based on information some studies the agency relied upon to FDA has concluded that it should not contained in manufacturers’ records (64 justify authorization of the health claim lower the amount of soy protein FR 45932 at 45934). Thus, in the soy (Refs. 27, 28, and 51); in one study (Ref. required for a food to be eligible to bear protein reproposal, FDA modified 27), the authors indicated that 25 g soy the health claim. previously proposed § 101.82(c)(2)(ii)(B) protein daily was provided in four (Comment 45). One comment to provide for this alternative approach muffins. ISP was the source of soy suggested that the amount of soy protein for compliance assessment that relied, protein in the baked products used in required for eligibility to bear the health in some cases, on records that the these studies. Some comments stated claim be permitted to be determined on agency could inspect. that FDA need not base the qualifying the basis of serving size as well as The agency received approximately level on four eating occasions per day as RACC. 10 comments in response to the soy the agency had done for other health This comment is outside the scope of protein reproposal. One of the claims for substances (beta-glucan this rulemaking. Current regulations (21 comments did not address the proposed

VerDate 12-OCT-99 11:58 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00016 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm04 PsN: 26OCR2 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations 57715 procedure for compliance assessment FR 296). Comments received in analytical method for measuring total but, rather, reiterated concerns raised in response to that proposal persuaded protein as a measure of soy protein in comments on the soy protein proposed FDA to change the substance of its final foods that contain soy as the only source rule about the safety of soy isoflavones. rule to beta-glucan soluble fiber from of protein. Absent an appropriate Among the materials it referenced were whole oats (62 FR 3584). The agency has analytical methodology, each of these two documents authored by FDA staff addressed the earlier comments on the comments supported the need for that the comment characterized as role of isoflavones in the manufacturers to have and keep records ‘‘reports.’’ FDA could not identify one of hypocholesterolemic effect of soy to substantiate the amount of soy these documents from the citation given protein in Section II.B.3 of this protein in a food that bears the health and the other was a letter submitted as document. claim and contains sources of protein a comment to Docket 98P–0683 in (Comment 48). Two comments other than soy, and to make such response to the soy protein proposed objected to any use of recordkeeping for records available to appropriate rule. Another comment raised concerns compliance assessment, questioning regulatory officials upon request. These about the GRAS status of soy protein. whether it could be an appropriate comments noted that in cases where FDA has addressed the issues raised in substitute for analytical methods to records are needed to substantiate label the earlier comments regarding GRAS assess the truthfulness of health claims. claims, food manufacturers have status and safety in Section II.A of this One of these comments also reiterated historically provided such records document. In addition to commenting objections to authorization of the health voluntarily upon request to the FDA and about the reproposal, one comment claim, because of concerns about could be expected to continue to do so raised a technical issue about the incomplete scientific understanding of in the future. They argued that FDA nutrition labeling declaration of protein the biological activity of soy need not assert broad records inspection that is addressed in Section II.C.1. components, in terms of both safety and authority in order to obtain the (Comment 46). Two comments contribution to the protective effect of information needed for compliance objected to the 30-day comment period soy protein in CHD. The agency has assessment. They noted 21 CFR allowed for the soy protein reproposal. addressed these concerns, which were 101.13(j)(ii)(A), which requires firms to FDA stated its rationale and authority raised in comments on the soy protein have substantiation for the basis of for selecting this period in the soy proposed rule, in Sections II.A and nutrient reference values in comparative protein reproposal (64 FR 45932 at II.B.3, respectively, of this document. nutrient content claims and to make 45936 and 45937) and notes that these The other comment asserted that an such substantiation available to comments were submitted and received approved, scientifically accurate appropriate regulatory officials upon in timely fashion. One of these methodology is needed for any health request, as a model for requests of comments asserted that after the claim. However, it also indicated that records. FDA should finalize its regulation as comment period for the soy protein FDA agrees that a manufacturer must originally proposed, but did not propose proposed rule had passed, no new have substantiation that a qualifying an alternative for compliance submissions or evidence after that date amount of soy protein is present in a other than that of FDA origin (or from verification other than suggesting that a product that bears the health claim and published scientific documents manufacturer might voluntarily share that such records can serve as the basis accessed by FDA) was acceptable. As analytical data with the agency if for substantiation of use of the health noted in the introduction of Section II questions about compliance were raised. claim. FDA noted in the Federal of this document, FDA disagrees with FDA does not agree with the Register of February 2, 1996 (61 FR this assertion. FDA considered contention that an analytical method is 3885 at 3886) several examples of comments received after the initial an absolute requirement for a health regulations that implemented the 1990 comment period, regardless of source, to claim, even though it is the preferred amendments in which the agency could the extent that each provided complete means for verifying compliance with the not independently, using analytical information for review or references requirements of a health claim accessible to the agency and addressed regulation and substantiating the methodology, verify the basis for issues not raised in earlier comments. truthfulness of all label statements. statements on the food label, but instead (Comment 47). A comment asserted (Comment 49). Many other comments would rely on access to a that the issue of the method FDA will supported continued work to develop manufacturers’ information supporting use to verify that foods contain the appropriate analytical methodology for its labeling claims. These include access qualifying amount of soy protein is measuring the content of soy protein in to: irrelevant because FDA was required to foods, and urged FDA, in collaboration (1) A detailed protocol and records of consider and evaluate only the claims with other government agencies, all data used to derive a density- made for the substance identified in the industry, and scientific organizations, to adjusted reference amount for aerated petition, soy protein with naturally pursue this effort. As noted in the soy foods (58 FR 2229 at 2272 and occurring isoflavones. protein reproposal, FDA intends to do § 101.12(e)); This comment misunderstands FDA’s so, to the extent that resources permit. (2) Information that provides the basis responsibility to review and evaluate Also, as noted in the soy protein for deriving reference nutrient values for the available scientific evidence and reproposal, and as urged in a number of comparative nutrient content claims reach appropriately supported comments, FDA would propose to such as ‘‘light’’ (58 FR 2302 at 2365 and conclusions about the substance-disease amend its regulation to provide for § 101.13(j)(1)(ii)(A)); relationship based on information compliance verification based on one or (3) Specific information with respect provided in the petition, accessed in the more analytical methodologies when to the caloric content of new products public scientific literature, and received such methods have been validated. with reduced digestibility (58 FR 2079 in comments. FDA notes, for example, (Comment 50). Several of the at 2087 and 2111 and that in response to a petition for oat comments specifically addressed the § 101.9(c)(1)(i)(D)); and bran and oatmeal, it proposed to method for assessing compliance set out (4) Information supporting nutrient authorize a health claim on the in the soy protein reproposal. None of content claims for restaurant foods (58 relationship of those foods and CHD (61 these comments objected to use of an FR 2302 at 2388 and § 101.13(q)(5)(ii)).

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In each of these cases, verification of soy protein to total protein. By listing regulation to provide access to records the truthfulness of a label claim can be the types of records that could provide for compliance verification. These assessed by FDA only with access to such documentation in the soy protein comments noted that such an action information known only by the reproposal, FDA did not intend to would give unfair advantage to certain manufacturer. The same is true, in the indicate that it would request all of products, unfairly penalize products absence of a validated analytical method these records and subject them to that were equally beneficial, and dilute to measure the amount of soy protein in inspection, or even that it would specify the potential benefit of the health claim the presence of other proteins, for any particular records when it requests to consumers. Because the agency has verifying that the qualifying amount of them. Instead, FDA intended to suggest authorized the claim for any food that soy protein to bear the health claim is the types of records a manufacturer contains adequate amounts of soy present in a food that contains sources might use to substantiate the levels of protein, without regard to other sources of protein in addition to soy. Thus, the soy protein in its foods. Accordingly, of protein, these comments are moot. agency concludes, in agreement with FDA has modified § 182(c)(2)(ii)(B) to (Comment 56). One comment noted these comments, that it is appropriate to clarify that the manufacturer is to that, in addition to providing FDA, require access to manufacturers’ records identify these materials. upon request, information regarding substantiating the ratio of soy protein to (Comment 52). One comment substantiation of the claim, food total protein for foods that contain questioned whether FDA might request processors may, on a voluntary basis, sources of protein in addition to soy to records for products in which soy is the present information on the food label or assess their compliance with this only source of protein and urged FDA in labeling that may support the regulation. Also, in agreement with to specify that it would not request eligibility of the product to bear the these comments, the agency concludes records for such products. claim and facilitate an FDA compliance that it need not assert broad records FDA agrees that, because review. Such information might take the inspection authority to have access to measurement of total protein provides form of statements about the percentage appropriate records. The agency adequate assessment of compliance for composition of soy protein in a serving disagrees, however, with comments that products in which soy is the sole source of food. The agency agrees that indicate that reliance on the voluntary of protein, that it would not, under the manufacturers may voluntarily provide provision of records by manufacturers is regulation, request records for such truthful and not misleading sufficient to meet the agency’s need to substantiation of the amount of soy information and that the provision of verify compliance. Rather, the agency is protein in such products. The agency such information may aid consumer taking the approach of codifying a believes that the proposed language understanding of the claim. requirement for the manufacturer to adequately communicates this point and (Comment 57). Several of the provide appropriate records, on request, has made no changes to the regulatory comments strongly objected to the as the agency has done previously. language in response to this comment. proposal for records inspection on the Although most of the comments (Comment 53). One comment basis that FDA lacks the statutory supported the use of records, in requested that FDA identify what authority to require access to records for principle, for compliance assessment, circumstances would precipitate a foods. Another comment argued that, they also raised concerns about the request for records. Although FDA once the agency determined that a types of records that FDA might request, cannot specify all such circumstances, it substance-disease relationship meets the the circumstances under which FDA notes, as did another of the comments, standard of significant scientific would request records, and the legal that a substantial proportion of its agreement, the act requires the agency to authority of the FDA to require records enforcement actions are undertaken in authorize a claim, and the agency may and records inspection. response to trade complaints. not require that manufacturers maintain (Comment 51). Several comments (Comment 54). One comment asked records or that FDA be able to request indicated that FDA had used overly that the agency specify that any records or inspect them. This comment also broad and imprecise language in the soy requested could be provided on site asserted that, were FDA to require protein reproprosal to describe the types without the need for reproduction or recordkeeping, record production, or of records that FDA would request. duplication by the investigator. Another records inspection, it would violate the They indicated that a manufacturer is comment, however, objected to FDA First Amendment by conditioning the best able to determine the nature of the making requests for information on site, exercise of speech rights on the records that would be needed to arguing that most companies would recordkeeping, record production, or substantiate the amount of soy protein have the necessary information at records inspection requirement. in its own products and urged that headquarters rather than at production FDA disagrees with these comments. manufacturers be allowed the flexibility facilities. This comment urged that FDA Other comments have convinced the to determine how to document make any such requests in writing and agency that, in this instance, it need not substantiation. One comment argued allow the manufacturers to provide assert its rulemaking authority to that a recipe-based system would be too appropriate substantiation within a provide for inspection of records. This complex and burdensome for baked reasonable period of time. As FDA will issue is therefore moot. The agency goods in particular. Other comments not require inspection of records on site, maintains, however, that it has the legal expressed concern that FDA would, in the concern about reproduction or authority, using section 701(a) of the all cases, require inspection of a wide duplication is moot. FDA agrees that act, to promulgate record inspection variety of records, including nutrient making a request for records in writing requirements for the efficient data bases or analyses, recipes or is appropriate and has modified the enforcement of the act. The formulations, purchase orders for regulation accordingly. requirements that records be maintained ingredients, and others. (Comment 55). Some comments and submitted to the agency upon FDA agrees that the manufacturer will objected to the alternative offered in the request pass the test in National be in the best position to know which soy protein reproposal that FDA would Confectioners Association v. Califano, of its records provide documentation of authorize the claim only for products 569 F.2d 690, 693 & n.9 (D.C. Cir. 1979). the amount of soy protein in its that contain soy as the sole source of First, these requirements are limited to products, and specifically the ratio of protein, if it could not proceed with a those records that the manufacturer

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They interest in permitting the use of health products would not lead to an increase focus only on those foods for which an claims on foods and they are narrowly in the intake of saturated fat or adequate analytical method is not tailored to do so. In addition, when used cholesterol and, thus, negate the health available. They allow FDA to verify that on a food, the authorized soy protein benefits of soy protein. In addition, they the authorized soy health claim is health claim must identify the amount would serve as sources of the essential truthful and not misleading when it is of soy protein in a serving of food. fatty acids, linoleic acid and linolenic used on such foods. The requirements, Accordingly, the provisions also permit acid. therefore, assist in the effective and FDA to assure that the claim as it As noted above, the FDA has required efficient enforcement of the act. Third, appears on a food is not false and that foods bearing any of the previously these requirements are not unduly misleading. authorized CHD health claims meet the burdensome. They require maintenance requirements for ‘‘low saturated fat,’’ 3. Requirement that Food Meets the of records that manufacturers should ‘‘low cholesterol,’’ and ‘‘low fat.’’ In the Criterion for Low Fat already have to validate that their food saturated fat/cholesterol proposed rule, product may lawfully bear the claim, In § 101.82(c)(2)(iii)(B), the agency FDA proposed that in order for a food and they permit them to identify the proposed, consistent with other to bear the health claim, the food must records that substantiate their claim. authorized heart disease health claims, also meet the requirements for a ‘‘low’’ FDA requests copies of the records in that foods bearing the health claim meet claim relative to total fat content (56 FR writing without inspection. These the requirements for ‘‘low saturated fat,’’ 60727 at 60739). The agency noted that, burdens are not unreasonably onerous. ‘‘low cholesterol,’’ and ‘‘low fat.’’ In the while total fat is not directly related to With respect to significant scientific preamble to the final rule authorizing increased risk for CHD, it may have agreement, the comment misreads the the fruits, vegetables, and grain products significant indirect effects. Low fat diets statute. Under section 403(r)(3)(B)(i) of and heart disease claim (§ 101.77, 58 FR facilitate reductions in the intake of the act, FDA authorizes a claim about a 2552 at 2572), the agency stated that saturated fat and cholesterol to substance-disease relationship only if populations with diets rich in these low recommended levels. Furthermore, the the standard of significant scientific saturated fat and low cholesterol foods agency noted that obesity is a major risk agreement is met. Under that section, experience many health advantages, factor for CHD, and dietary fats, which significant scientific agreement is a including lower rates of heart disease. In have more than twice as many calories necessary condition, but not a sufficient the preamble to the saturated fat/ per gram as proteins and carbohydrates, one, for FDA to authorize a health cholesterol proposed rule (56 FR 60727 are major contributors to total calorie claim. FDA may impose other at 60739), the agency stated that while intakes. For many adults, maintenance requirements in accordance with section total fat is not directly linked to of desirable body weight is more readily 403(r) of the act. increased risk of CHD, it may have achieved with moderation of intake of The agency also disagrees that the significant indirect effects. Foods that total fat. The agency also concluded that recordkeeping and record access are low in total fat facilitate reductions this approach would be most consistent provisions violate the First Amendment. in intakes of saturated fat and with the U.S. Dietary Guidelines and Under section 201(g)(1) of the act, a food cholesterol to recommended levels. other dietary guidance that recommends is not a drug solely because its labeling Therefore, the agency tentatively diets low in saturated fat, total fat, and contains a health claim authorized and concluded that proposed cholesterol. In the saturated fat/ made in accordance with the § 101.82(c)(2)(iii)(B) set forth cholesterol final rule (58 FR 2739 at requirements of section 403(r) of the act. appropriate requirements for foods to be 2742), FDA reiterated the requirement Section 201(g)(1) provides no such eligible to bear the soy protein and CHD for ‘‘low fat,’’ but allowed for the provision for a food whose labeling claim. exception that fish and game meats contains a health claim that is not (Comment 58). No comments objected could meet the requirement for ‘‘extra authorized and made in accordance to the requirements that a food meet the lean,’’ because these foods are with the requirements of section 403(r) criteria for ‘‘low saturated fat’’ and ‘‘low appropriately included in a diet low in of the act. Congress provided for the use cholesterol’’ in order to bear a health fat, saturated fat, and cholesterol. FDA on foods of health claims authorized claim about the relationship of soy also noted that the ‘‘low fat’’ under and made in accordance with the protein and CHD. However, many requirement for foods to make the requirements of section 403(r) of the act comments objected to the requirement saturated fat/cholesterol and heart to promote the public health by, in part, that a food meet the criterion for ‘‘low disease health claim would limit a helping consumers maintain balanced fat,’’ mainly on the basis that all foods manufacturer’s ability to increase trans- and healthful diets (58 FR at 2514). FDA made from whole soybeans would be fatty acid levels in foods, since any has required that foods whose labels disqualified by virtue of the inherent substitution of trans-fatty acids for contain an authorized health claim must ratio of protein to fat (approximately 2 saturated fatty acids would have to be contain a sufficiently high level of the to 1) in soybeans. Several of these accomplished within the 3 g per RACC substance that is the subject of the claim comments noted that makers of such or per 50 g limit for total fat. The agency in question (see 21 CFR foods would have to use soy protein considered this approach unlikely to 101.14(d)(2)(vii)). This provision assures isolates to develop qualifying products. result in significantly increased levels of that a food bearing the claim in fact The comments that provided additional trans-fatty acids in foods bearing the contributes to the claimed effect (56 FR rationale argued that saturated fat and health claim (58 FR 2739 at 2744). at 60553) and so may help consumers to cholesterol were properly restricted for The latter consideration is not maintain a balanced and healthful diet. a CHD claim, but that total fat need not applicable to the case of foods made Absent the recordkeeping and access be restricted to the same degree because from whole soybeans. No substitution of provisions, FDA could not assure that, it is not directly related to risk of CHD. one type of fatty acid for another is

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The others proposed that FDA allow a the results of several studies showed amount by which foods made from variety of shortened claims that would that daily consumption of oat bran or whole soybeans that are otherwise effectively render this requirement an oatmeal lowered total cholesterol and eligible to bear the soy protein health optional element of the claim or that LDL-cholesterol levels, the agency noted claim would exceed the ‘‘low fat’’ FDA permit the information in this that the effects of dietary intake of oat criterion due to the inherent fat content requirement to be presented in a split bran or oatmeal were particularly of soybeans is small and well below the claim. evident when the diets were low in disqualifying level for total fat that a FDA disagrees with some of the saturated fat and cholesterol (61 FR 296 food bearing any health claim must characterizations of FDA’s requirements at 306). Thus, the agency tentatively meet (§ 101.14 (a)(4)). FDA is persuaded for currently authorized heart disease found it would be more helpful to that products derived from whole claims. The comment notes that the Americans’ efforts to maintain healthy soybeans are useful sources of soy agency requires a statement of the role dietary practices if the effect of oats on protein that they, like fish and game of low saturated fat and cholesterol diets serum lipids were described in the meats that are ‘‘extra lean,’’ can be in the reduction of risk of heart disease context of a healthy diet (61 FR 296 at appropriately incorporated in a diet that in three of the authorized claims’the 306). is low in fat, saturated fat, and dietary lipids claim (21 CFR 101.75), the This tentative conclusion was cholesterol. Thus, FDA is modifying claim for fruits, vegetables, and grain supported by many of the comments § 101.82(c)(2)(iii)(B) to require that all products that contain dietary fiber, received in response to the proposed products meet the criteria for ‘‘low particularly soluble fiber (21 CFR rule and described in the final rule saturated fat’’ and ‘‘low cholesterol’’ and 101.77), and the claim for soluble fiber authorizing a health claim for soluble adding § 101.82(c)(2)(iii)(C) to require from psyllium seed husks (21 CFR fiber from whole oats (62 FR 3584 at that a food meet the criterion for ‘‘low 101.81)—because the effect of the 3594). In the final rule, the agency noted fat’’ in order to bear the soy protein subject food substances had been that diets low in saturated fat and health claim, except for products established only in the context of such cholesterol are considered by expert consisting of or derived from whole a diet. However, the comment groups to be the most effective dietary soybeans without additional fat. maintained that evidence for the means of reducing heart disease risk, hypocholesterolemic effect of soluble and that while soluble fiber from whole D. Required Elements for the Claim fiber from whole oats showed it to be oats can contribute to this effect, its role 1. Context of the Total Daily Diet independent of other dietary changes. is generally recognized as being of Thus, in requiring that the claim for this smaller magnitude (Ref. 5). Further, In the soy protein proposed rule (63 substance be stated in the context of a expert groups saw selection of foods FR 62977 at 62991), the agency diet low in saturated fat and cholesterol with soluble fiber from whole oats as a tentatively found that, for the public to (21 CFR 101.81), the comment asserted useful adjunct to selection of diets low understand fully, in the context of the that FDA had failed to provide a claim in saturated fat and cholesterol (Ref. 5). total daily diet, the significance of that accurately and truthfully reflected The agency concluded that it would not consumption of soy protein on the risk the underlying science. be in the best interest of public health of CHD (see section 403(r)(3)(B)(iii) of FDA disagrees with this or consistent with the scientific the act), information about the total diet characterization. The petition for a evidence to imply that selecting diets must be included as part of the claim. health claim for oat products stated that with soluble fiber from whole oats is a Therefore, in § 101.82(c)(2)(i)(D), the there was significant scientific evidence substitute for consuming diets low in agency proposed to require that the to show that the effect of oats on saturated fat and cholesterol (62 FR claim include the fact that the effect of lowering serum lipids is independent of 3584 at 3594). Therefore, FDA dietary consumption of soy protein on a diet low in saturated fat and emphasized the importance of the the risk of CHD is evident when it is cholesterol. In light of this evidence, the dietary component of the health claim, consumed as part of a healthy diet and petitioner argued that any health claim i.e., the necessity for soluble fiber from that, consistent with other authorized that is authorized need not refer to such whole oats to be consumed as part of a health claims related to CHD, the fat a diet. In the proposed rule for a health low saturated fat, low cholesterol diet, component of the diet be specified as claim for oat products, the agency for a complete understanding of the ‘‘saturated fat’’ and ‘‘cholesterol.’’ acknowledged that there were a number claim (62 FR 3584 at 3594). (Comment 59). One comment objected of studies that showed that high intakes The comment also characterized the to this requirement on several grounds: of oat bran and oatmeal lowered blood claim for sodium/salt and hypertension that FDA has been inconsistent in total and LDL-cholesterol in subjects (21 CFR 101.74) as a claim about risk of requiring specification of the need to that otherwise consumed a typical heart disease and indicated that FDA consume diets low in saturated fat and American diet (61 FR 296 at 305). was not consistent because this claim is cholesterol in previously authorized However, the agency also recognized not required to be stated in the context CHD health claims; that the effect of soy that CHD is a major public health of a diet low in saturated fat and protein on blood cholesterol levels is concern in the United States, and that cholesterol. FDA disagrees with this independent of a low fat, low saturated the totality of the scientific evidence characterization of the claim and the fat, and low cholesterol diet; that the provides strong and consistent support conclusion that follows from it. This statutory requirement to place the claim that diets high in saturated fat and claim does not address the risk of heart in the context of the total daily diet cholesterol are associated with elevated disease, but rather is a claim specific for need only relate the labeled product to levels of blood total and LDL- hypertension. The scientific evidence the rest of the day’s diet; and that cholesterol, and thus CHD (56 FR 60727 does not suggest that dietary saturated consumers will conclude that soy at 60737). Dietary guidelines from both fat and cholesterol have a significant protein will be of no benefit to them if government and private scientific effect on blood pressure; thus, no they cannot reduce saturated fat and bodies conclude that the majority of the mention of that dietary context is cholesterol in their diets. Other American population would benefit required. In addition, FDA has stated comments raised similar objections to from decreased consumption of dietary (58 FR 2739 at 2746) that it has not been the requirement. This comment and saturated fat and cholesterol. Although presented with data that sodium intake

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FDA notes that 403(r)(1)(B) of the act unless it were relationship of the substance to the these comments did not suggest what specifically authorized by the agency. disease, the significance of the additional information might be helpful The agency does agree with the substance in affecting the disease, and to consumers in understanding the comment that it has not found that all the significance of the information in claim. the risk factors for CHD must be stated the context of the total daily diet. Thus, (Comment 61). Several comments in order to ensure that a heart disease a claim may need to address a wide suggested that the daily dietary intake of health claim is truthful and not variety of factors to fulfill these soy protein needed to reduce the risk of misleading. In fact, for CHD claims requirements, and the agency is not CHD be required to be described as ‘‘at authorized more recently (21 CFR limited to requiring only that least 25 g/day of soy protein’’ or ‘‘a 101.81), FDA has not required that CHD information that is necessary to prevent minimum of 25 g/day of soy protein.’’ be characterized in the claim as a a claim from being misleading. FDA is not persuaded to require that disease caused by many factors, in Finally, the agency is not persuaded such statements be used because it is contrast to the claims that FDA that requiring the soy protein claim to concerned about the need to balance authorized earlier as part of the initial be stated in the context of a total daily informing consumers about the effective NLEA reviews (21 CFR 101.75 and 21 diet low in saturated fat and cholesterol level of soy protein intake needed to CFR 101.77). will deter consumers who are interested provide the claimed health benefit In addition, FDA disagrees with the in dietary control of cholesterol levels, against encouraging excessive assertion that the cholesterol lowering and who have made unsuccessful consumption of a single food substance. effect of soy protein is independent of attempts to lower dietary intake of If consumers were to interpret the claim other dietary changes; the agency saturated fat and cholesterol, from erroneously as supporting consumption interprets the data differently. As noted incorporating soy protein into their of soy as the sole source of dietary in the discussion above, most of the diets. Consumers now have had protein or supplementing a diet already scientific evidence for an effect of soy experience with the claims for soluble adequate in protein from various protein on blood lipid levels is provided fiber from whole oats and psyllium seed sources with additional soy protein, by studies that used diets low in husks. These claims, like the soy protein then the two most important tenets of a saturated fat and cholesterol. Although claim, accurately draw the consumer’s healthful diet—variety and soy protein was found to lower blood attention to the dietary pattern moderation—would be violated. lipid levels in some of the studies using associated most strongly with reduction (Comment 62). One comment noted ‘‘usual’’ diets, hypocholesterolemic of risk from heart disease—a diet low in that, in the second model claim, the effects of soy protein were more saturated fat and cholesterol—and offer characterization of the total dietary consistently observed with diets low in choices of specific foods that can be intake of soy protein appeared to have saturated fat and cholesterol. The incorporated into this dietary pattern to omitted indication that the amount is agency concludes that the data enhance its beneficial effects. Thus, ‘‘per day.’’ FDA agrees. This omission supporting an independent effect for soy FDA is not modifying the requirement was inadvertent and the agency has protein are more limited than those that the health claim for soy protein be corrected § 101.82 (e)(1). supporting an independent effect of stated in the context of a diet low in Although comments generally viewed soluble fiber from whole oats in saturated fat and cholesterol. as desirable providing information on reducing cholesterol levels. Moreover, both the total daily dietary intake of soy 2. Daily Dietary Intake of Soy Protein because the hypocholesterolemic effects protein and the contribution of a single and Contribution of One Serving of soy protein are seen in addition to the serving of a food to the total intake, effects of a low saturated fat, low In the soy protein proposed rule (63 some comments urged that it need not cholesterol diet, combining the two FR 62977 at 62991), the agency be provided in one place on the label practices will provide enhanced proposed that § 101.82(c)(2)(i)(G) with all of the other required benefits. require that the claim specify the daily information. Many of these comments Nor does FDA agree with the dietary intake of soy protein needed to encouraged FDA to make provisions for comment’s assertion that the statutory reduce the risk of CHD and the the use of abbreviated claims that would requirement to place the claim in the contribution one serving of the product include a referral statement directing context of the total daily diet need only makes to achieving the specified daily the consumer elsewhere on the package relate the labeled product to the rest of dietary intake. The agency noted this for the full claim. Issues associated with the day’s diet. In the 1993 health claims requirement was consistent with abbreviated and split claims are final rule (58 FR 2478 at 2513), the requirements set forth in § 101.81 for addressed below. agency disagreed with comments that claims about soluble fiber from whole proposed that the requirement to enable oats and psyllium seed husks, food 3. Abbreviated/Split Claims the public to understand the substances that (like soy protein) do not (Comment 63). Although there were significance of the claim in the context have Daily Values that can serve as a not substantive objections regarding of the total daily diet would be fulfilled guide to consumers for appropriate most of the required elements FDA if a health claim merely characterized levels of intake. It is also required by specified, a large number of comments the level of a substance vis-a-vis a § 101.14(d)(2)(vii). objected to the model claims proposed disease, provided that there was (Comment 60). Almost all of the in § 101.82 (e), asserting that they are significant scientific agreement that that comments that addressed these excessively long, complicated, and level of intake of the substance was requirements supported the need for the cumbersome, and requested that FDA beneficial in reducing the risk of claim to contain this information. Some devise shorter claim statements. Many disease. Rather, FDA found that section comments expressed concern that even of these comments expressed concerns 403(r)(3)(B)(iii) of the act requires that a with this information some consumers that manufacturers would be reluctant regulation that authorizes a health claim might be misled into believing that a to use and consumers unlikely to read

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Thus, at this time, the evaluate all products with the same appearing on the principle display agency is making provision only for a ground rules. panel of the label together with a full claim. This assertion is incorrect. As the referral statement for the full claim agency explained in the 1993 health elsewhere on the package. As support E. Other Issues claims final rule (58 FR at 2506), the for these suggestions, many of the 1. Consideration of Health Claims for scientific standard for authorization of a comments cited the Keystone Dialog’s Benefits of Soy Protein in Addition to health claims is less stringent than the (Ref. 159) endorsement of shorter claims Effects on Cholesterol Levels and Risk of requirements for approval of a new drug and FDA’s own health claim consumer Coronary Heart Disease under section 505 of the act (21 U.S.C. research (Ref. 160), which the comments 355). (Comment 64). A few comments urged characterized as showing that short that FDA consider authorizing claims 3. Claims for Other Vegetable Proteins claims were more effective than long about other putative beneficial effects of claims and that splitting claims between (Comment 67). One comment the front and back panels made little soy protein or soy products on reviewed data on the possible difference. cardiovascular disease in addition to mechanisms for soy protein’s FDA notes, however, that the results cholesterol lowering as well as putative hypocholesterolemic effects and of its consumer research were more beneficial effects on other diseases or concluded that they may be due in part complicated than indicated by that brief health conditions such as cancer, to its amino acid composition, summary. The short and long claims osteoporosis, and menopausal specifically its high arginine and low studied differed in the inclusion of symptoms. One comment suggested that methionine content. The comment information about non-dietary risk statements derived from preliminary noted that other vegetable proteins, such factors and special populations at risk research on the putative beneficial as pea proteins, have a similar amino for the subject disease. The soy protein effects of soy isoflavones be allowed on acid profile and would likely have the health claim already lacks these food labels and in labeling. same effect on risk of CHD as soy requirements. The study also found that, These suggestions are beyond the protein. The comment proposed that for some products with an abbreviated scope of the present rulemaking. The qualifying levels of both arginine and claim and a referral statement on the present rulemaking is based on FDA’s isoflavones be required for the health principal display panel, subjects were review of information submitted in a claim and that the claim not be limited less likely to look at the back of the petition about the relationship of soy to soy protein. FDA finds that this package for the full claim. protein and reduced risk of CHD based suggestion is outside the scope of the Concerns about health claims being exclusively on studies of the cholesterol current rulemaking. FDA has not too wordy and too lengthy have been lowering effects of soy protein. The reviewed any data on the raised to the agency in various ways, agency has neither received nor hypocholesterolemic effects of specific including by a petition submitted by the reviewed relevant data for any other vegetable proteins other than soy. National Food Processors Association possible effects of soy protein relevant (Comment 68). Another comment that (NFPA) (Docket No. 94P–0390). In to risk of heart disease or of other also discussed the possible importance response to the NFPA petition, the diseases or health-related conditions. of the amino acid composition of soy agency proposed several changes to the Any interested person who has such protein to its cholesterol-lowering requirements for health claims in the data may submit a petition to the agency ability suggested that the title of the new Federal Register of 21, 1995 detailing the information for FDA’s claim should be ‘‘Protein from Certain (60 FR at 66206) (the 1995 proposal). At review and evaluation of whether such Foods and Reduced Risk of CHD’’ in that time, FDA stated that it had no information meets the requirements for anticipation that data will be generated desire for its regulations to stand in the authorization of a health claim. showing hypocholesterolemic effects of way unnecessarily of the use of health (Comment 65). At the same time, one other vegetable proteins with amino claims and the presentation of the comment expressed concern that the acid compositions similar to soy important information contained in authorization of a health claim on the protein. Having reviewed data only on them. The agency stated that, while relationship of soy protein and risk of soy protein and being aware of no health claims are being used on the CHD might be read by some consumers similar body of evidence about any label and in labeling, they could be used as an implied claim for other putative other vegetable protein, FDA finds this more extensively. The agency, therefore, benefits of soy foods. suggestion premature. proposed to provide for shorter health FDA concludes, however, that the claims by making optional some of the requirements it has set forth for the 4. Regulatory Issues Regarding Soy elements that are presently required. health claim already narrow the focus of Protein Claims in Other Countries FDA also proposed to authorize the use the claim sufficiently to the relationship (Comment 69). One comment of abbreviated claims. that FDA evaluated. Accordingly, provided extensive information about a FDA has reviewed the comments consumers should not be so misled by complaint brought against a company received in response to the 1995 the claim. regarding a particular television proposal on changing the requirements advertising campaign for a non-dairy for health claims, including permitting 2. Drug Claims vs. Health Claims for soy beverage product in New Zealand the use of abbreviated claims, but it has Foods that was alleged to be deceptive. This not completed work on the final rule. (Comment 66). One comment objected information included an unpublished Given that this rule is pending, and to FDA’s provision of a health claim for report of a study comparing the effects given its relevance to the issue of foods containing soy protein and of the non-dairy soy beverage to milk abbreviated claims, FDA has decided to reduced risk of CHD when FDA had not that was inadequate for assessing a

VerDate 12-OCT-99 11:58 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00022 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm04 PsN: 26OCR2 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations 57721 hypocholesterolemic effect for soy particular, these soybeans possess the Mandates Reform Act of 1995 requiring protein or the soy product itself because same nutritional profile as their parent cost benefit and other analyses. A dietary saturated fat and cholesterol or other commercially available significant rule is defined in 2 U.S.C. varied substantially in the two dietary soybeans, except that the high oleic acid 1532 (a) as ‘‘a Federal mandate that may treatments. Another comment raised soybean has a modified fat profile, as result in the expenditure by State, local concerns about the importation of foods intended. In addition, levels of and tribal governments in the aggregate, from the United States that may bear isoflavones, trypsin inhibitors, and or by the private sector, of $100,000,000 health claims in violation of Mexican endogenous allergens are unchanged. (adjusted annually for inflation) in any law. The agency therefore concludes that 1 year.’’ The FDA advises that violations of there is no basis to the comment’s Finally, in accordance with the Small laws or regulations of other countries assertion that currently available Business Regulatory Enforcement with respect to claims made on food bioengineered soybeans may raise Fairness Act, 5 U.S.C. 801(a)(1)(A)(ii), labels or labeling or claims made in additional safety concerns. Nor is there the Administrator of the Office of advertising are outside the scope of the any basis to require that bioengineered Information and Regulatory Affairs of present rulemaking. Companies doing soybeans be identified in food labeling the Office and Management and Budget business in other countries are as such. has determined that this final rule is not responsible for complying with the a major rule for the purpose of relevant statutory and regulatory III. Environmental Impact Congressional review. A major rule for requirements of those countries. The agency has previously considered this purpose is defined in 5 U.S.C. 804 5. Genetically Modified Soybeans the environmental effects of this rule as as one that the Administrator has announced in the soy protein proposed determined has resulted or is likely to (Comment 70). Two comments noted rule (63 FR 62977 at 62993) and the soy result in: (A) an annual effect on the that much of the current soybean crop protein reproposal (64 FR 45932 at economy of $100,000,000 or more; or (B) in the United States consists of 45935). The agency determined that this a major increase in costs or prices for genetically modified varieties of action is of a type that does not consumers, individual industries, soybeans. One comment requested that individually or cumulatively have a Federal, State, or local government products bearing the health claim be significant effect on the human agencies, or geographic regions; or (C) required to indicate on the label environment, and that neither an significant adverse effects on whether genetically modified soybeans environmental assessment nor an competition, employment, investment, were used. The other comment noted environmental impact statement is productivity, innovation, or on the that genetic modification may alter the required, but provided incorrect ability of United States-based content of isoflavones and other citations for categorical exclusion in the enterprises to compete with foreign- biologically active components of soy proposed rules. The correct citation is based enterprises in domestic or export and suggested that research was needed 21 CFR 25.32(p). No new information or markets. to determine if such genetic comments have been received that modifications raise additional safety would affect the agency’s previous B. Regulatory Options concerns. The comments provided no determination. FDA did not discuss regulatory data or other information to justify options in the analysis of the proposed labeling or substantiate any safety IV. Analysis of Economic Impacts rule, because no costs were identified in concerns. A. Cost-Benefit Analysis that analysis. Public comments on the FDA has considered these comments proposed rule raised a number of and disagrees with both, for the FDA has examined the impacts of this potential costs and a number of issues following reasons. FDA has stated its final rule under Executive Order 12866. that may affect the benefits of this rule. expectation that companies consult with Executive Order 12866 directs federal The comments also suggested a large the agency early in the process of agencies to assess the costs and benefits number of regulatory options. The developing a bioengineered food and of available regulatory alternatives and, primary options suggested in the that they provide the agency with a when regulation is necessary, to select comments were as follows: summary of safety data and a nutritional regulatory approaches that maximize (1) Take no new regulatory action. assessment for its review (Ref. 161). To net benefits (including potential (2) Take no action, but generate or date, three companies have consulted economic, environmental, public health wait for additional information on with the agency about bioengineered and safety effects; distributive impacts; which to base a future action. soybeans. Two companies developed and equity). According to Executive (3) Take proposed action. soybeans that are resistant to the Order 12866, a regulatory action is (4) Take proposed action, but specify herbicides glyphosate and glufosinate, ‘‘economically significant’’ if it meets a different minimum level of soy protein respectively. A third company modified any one of a number of specified for products bearing the claim. the oil composition of the soybean to conditions, including having an annual (5) Take proposed action, but specify increase its levels of oleic acid, and it effect on the economy of $100 million a minimum level of soy isoflavones in must be labeled as high oleic acid or adversely affecting in a material way addition to a minimum level of soy soybean. One company stopped further a sector of the economy, competition, or protein for products bearing the claim. development of a genetically modified jobs. A regulation is considered (6) Take proposed action, but revise soybean that involved the addition of a ‘‘significant’’ under Executive Order the wording of the claim or require that brazil nut protein when it discovered 12866 if it raises novel legal or policy warnings or other statements that the protein would cause allergic issues. FDA finds that this final rule is accompany the claim. reactions. neither an economically significant nor (7) Take proposed action, but specify The safety and nutritional a significant regulatory action as defined a different maximum total fat content or assessments of the three bioengineered by Executive Order 12866. grant an exemption from the maximum soybeans show that there are no In addition, FDA has determined that total fat requirement for foods made unintended effects of the genetic this rule does not constitute a with natural soy beans that have no modification (Refs. 162 through 167). In significant rule under the Unfunded added fat.

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(8) Take proposed action, but use a effects. According to these comments, contain soy protein may reduce, to some different procedure for determining potential health risks are associated degree, the number of soy-free products level of soy protein in particular with an increased intake of: (1) Soy that are available to those who are products. protein; (2) other components of allergic to soy protein. This reduction in soybeans including soybean trypsin product choice may lead to utility losses 1. Option One: Take No New Regulatory inhibitors and isoflavones such as for those consumers. However, a large Action genistein; (3) artifacts of particular number of products will continue to not By convention, the option of taking no methods of manufacturing soy protein contain soy protein, so this utility loss new regulatory action is the baseline in isolates or products containing soy will probably be modest. This rule may comparison with which the costs and protein, such as nitrates, nitrosamines, also increase the incidence of the benefits of the other options are and lysinolanine; and (4) artifacts of adverse health effects associated with determined. Therefore, neither costs nor genetically engineered soy protein. zinc deficiency, which is typically benefits are associated with taking no Among the potential health concerns related to largely plant-based diets, to new regulatory action. related to these substances mentioned in some degree. However, FDA has 2. Option Two: Take No Action, But the comments were the following: (1) insufficient information to estimate this Generate or Wait for Additional Allergenicity; (2) reduced bioavailability effect. Some comments suggested that this Information on Which To Base a Future of vitamins and minerals including zinc rule might indirectly increase the Action and iron; (3) hormonal alterations, including changes in fertility and incidence of CHD. According to these A number of comments suggested functioning of sex glands; (4) toxicity in comments, the proposed health claim delaying action until further research is estrogen sensitive tissues and an could lead some consumers to carried out on: (1) The mechanism by increase in estrogen-related diseases; (5) overestimate the role of soy protein in which soy protein reduces the risk of vascular dementia; (6) adverse effects on preventing CHD and to neglect other coronary heart disease (CHD), including the central nervous system and actions that have an equal or greater the role of soy isoflavones; (2) the effect behavioral changes; (7) thyroid effect on the risk of CHD. Other of particular methods of manufacturing abnormalities, including goiter; (8) comments argued that this rule might soy protein isolates and products cancer; (9) diabetes; (10) liver disease; lead to the adverse health effects caused containing soy protein; (3) the effect of (11) adverse effects on the immune and by poor nutrition because the proposed other characteristics of the diet such as endocrine systems; and (12) adverse health claim might lead some fiber or mineral content; (4) potential effects on metabolism. Other comments consumers to concentrate unduly on health risks associated with increased argued that no health concerns would foods containing soy protein and to intake of soy protein, soy isoflavones, be associated with the intake levels of neglect the other components of a other components of soybeans, and soy protein and the other substances balanced diet. Another comment argued artifacts of particular methods of that can be associated with soy protein, the proposed health claim could lead to manufacturing soy protein isolates and such as soy isoflavones or various by- miscellaneous adverse health effects products containing soy protein; (5) products of manufacturing soy protein because it might be interpreted by some consumption patterns of foods isolates, that are likely to result from the consumers as an endorsement of the containing soy protein and the proposed health claim. miscellaneous benefits that are percentage of such foods that meet the As discussed previously in the sometimes claimed for soy products, proposed requirements for the health preamble to this rule, FDA finds that such as the prevention of cancer or claim; and (6) methods of measuring the there is no evidence that any increase in osteoporosis. This comment argued that level of soy protein in foods. the intake of soy protein or the other this interpretation would lead some The cost of delay is the elimination of substances discussed in the comments consumers to neglect the actions that the benefits that would have been presents a risk of adverse health effects. reduce the risk of these other realized between the effective date of The availability of the health claim conditions. the non-delayed rule and the effective may increase the number of products Some consumers may misinterpret the date of the delayed rule. The potential containing soy protein. Increased proposed health claim (or any other benefits of delay are: (1) The reduction availability of products containing soy health claim). However, the fact that the of potential health risks, if any, protein may increase the likelihood that proposed health claim states that the associated with increased intake of soy those who are allergic to soy protein risk of CHD may be reduced by an protein and other relevant substances; may consume such products. The net unspecified degree by consuming a (2) the reduced likelihood of the effect of this rule on the incidence of specified level of soy protein per day, as potential reduction in the perceived allergic reactions to soy protein is part of a low saturated fat and low reliability of FDA-approved claims that unclear. As discussed earlier in the cholesterol diet, makes it unlikely that might occur if future research were to preamble, the presence of the health many consumers will neglect other require the soy protein health claim be claim will serve to notify consumers of activities that reduce the risk of CHD or revised; (3) the increase in the health the presence of soy protein in products neglect other types of foods. Similarly, benefits generated by a delayed health that bear the claim. However, some the fact that the health claim specifies claim that, potentially, would be more consumers who are allergic to soy CHD makes it unlikely that many accurate or complete. protein may not already know they are consumers will interpret the claim as an As discussed below, the comments allergic to soy protein and some endorsement of other benefits that are did not provide information establishing consumers who do know they are sometimes claimed for soy products. that the benefits of delaying the rule allergic may inadvertently consume The comments did not provide outweigh the costs. such products despite the presence of sufficient information to allow FDA to the health claim. FDA has insufficient estimate the likelihood of these effects. 3. Option Three: Take Proposed Action information to estimate the net effect on Furthermore, these potential effects are Costs the incidence of allergic reactions to soy no more likely to be associated with the A number of comments suggested that protein. In addition, the addition of soy proposed claim than with any other this rule might lead to adverse health protein to products that do not currently claim.

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Some comments suggested that this However, in general, it is unclear that FDA believes this final rule will rule might indirectly increase the the failure to authorize a health claim generate benefits, this analysis will not incidence of miscellaneous adverse for one substance would reduce the attempt to quantify the effect of this rule health effects by decreasing the effectiveness of a health claim for on the incidence of CHD. perceived reliability of FDA-approved another substance. Some comments argued that health claims in general. Some A number of comments addressed the increasing soy intake would generate comments noted the presence of a method FDA proposed to use to benefits other than a reduction in the certain degree of uncertainty concerning determine the level of soy protein. Many risk of CHD, including reduction in the the mechanism by which soy protein of the comments recommended revising incidence of cancer, osteoporosis, and reduces the risk of CHD. One comment the proposed rule. These comments are menopausal symptoms. These types of argued that if further research on this discussed under Option 8 below. effects would be relevant to the estimation of the benefits of this rule. mechanism were to find that isoflavones C. Benefits or other components of soybeans are However, FDA has reviewed no involved, and the health claim were The analysis of the proposed rule scientific evidence to assess whether subsequently revised to reflect those discussed the benefit of this rule in such benefits exist or to estimate the findings, then FDA’s scientific terms of the value to consumers of the size of such benefits. reputation and the perceived value of information communicated in the proposed health claim. The comments 4. Option Four: Take Proposed Action, FDA-approved health claims could be but Specify a Different Minimum Level adversely affected. Other comments did not provide information directly relevant to estimating this value. of Soy Protein for Products Bearing the implied that uncertainty over the Claim mechanism means that future research However, a number of comments addressed the health and other benefits Many comments suggested revising might show that soy protein does not that might be generated by changes in the minimum level of soy protein that affect the risk of CHD. Other comments consumer behavior that might follow is required for a product to be able to argued that the proposed claim would from this rule. As discussed in the bear the proposed health claim. Some reduce FDA’s scientific credibility analysis of the proposed rule, the value comments addressed the significance of because it would mean that FDA is of these other benefits may be the 25 g per day of soy protein on which treating soy protein in a manner that is considered a lower bound on the value the proposed 6.25 g per RACC inconsistent with how FDA treats to consumers of the information requirement was based. One comment certain other substances that may communicated in the health claim. This noted that studies have found that soy reduce the risk of CHD, including value is a lower bound because some protein affects the risk of CHD at intake estrogens and linseed oil. consumers might want that information, levels of between 17 g and 31 g per day. Future research could lead to results but nevertheless choose not to modify Another comment argued that between that would lead FDA to revise the soy their behavior. In addition, the value of 30 g to 50 g of soy protein per day is health claim. However, the comments these other benefits may be considered necessary to produce clinically did not provide sufficient information to an appropriate independent metric for significant results on the incidence of allow FDA to estimate the likelihood of valuing the benefits of this rule because CHD. revisions or to assess the impact of these consumers may value the information in Specifying the particular daily intake revisions on the perceived reliability of the claim based on the usefulness of that of soy protein that will have a FDA-approved health claims in general. information for reducing the risk of CHD significant effect on the risk of CHD The latter relationship is highly but may underestimate or overestimate involves some uncertainty. However, speculative, because it depends on the usefulness of that information. FDA does not have sufficient consumers not knowing that scientific Many comments argued that this rule information to estimate the effect of knowledge is in a constant state of would lead to a reduction in the specifying different levels and the development. In addition, although incidence of CHD and provided comments did not provide sufficient some revisions may be necessary, it is information relevant to estimating that information to allow FDA to do so. As unlikely that future research will reduction. A few comments argued that discussed earlier in the preamble, FDA indicate that soy protein has no effect this rule would not lead to a reduction believes the 25 g soy protein per day on CHD. As stated earlier in the in the incidence of CHD because soy level is supported by the scientific preamble, FDA has concluded that the protein does not affect the risk of CHD. literature and disagrees that intake scientific evidence establishes that One comment argued that this rule levels of 30 g to 50 g per day is increased intake of soy protein reduces would generate benefits by obviating, in necessary to produce clinically the risk of CHD and that this effect is not some cases, the need for riskier and significant results on the incidence of simply an artifact of the substitution of more expensive pharmacological CHD. lower fat and cholesterol products for treatments for reducing the risk of CHD. Other comments did not address the higher fat and cholesterol products. The Thus, according to this comment, this 25 g soy protein per day target level but comment that suggested otherwise rule might generate benefits even if no did address the 6.25 g per RACC ignores the many studies in which fat, reduction in the incidence of CHD were requirement derived from the daily saturated fat, and cholesterol were the to take place. target level. Some comments argued that same in treatment and control groups Quantifying the effect of the proposed the per RACC requirement was overly and soy protein still exerted an effect on health claim on the incidence of CHD restrictive and that few products would the risk of CHD. Also, FDA disagrees would involve a number of qualify for the health claim under this that the only mechanism discussed in uncertainties and any ensuing estimate requirement. One comment analyzed the petition was the soy isoflavone would be imprecise. In addition, there the list of products that was presented mechanism. Finally, the comments did would be little value to generating such in the petition as qualifying for the not provide sufficient information to an estimate because, as discussed above, health claim and found that only 61 estimate the effect of the purported the comments did not provide sufficient products would qualify if multiple inconsistencies on the perceived value information to estimate the purported flavors of the same product were of FDA-approved health claims. costs of this rule. Therefore, although omitted, and that 88 products would

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In addition, products would themselves meet the bear the health claim might lead to FDA has insufficient information on the requirements for the proposed claim. additional benefits in terms of consumption patterns of the relevant Another comment noted that many of encouraging the consumption of products to determine whether lowering the qualifying products listed in the products from grain group of the USDA/ the per RACC level would lead more or petition were varieties of non-dairy soy DHHS Food Guide Pyramid, which this fewer consumers to consume 25 g soy beverages or tofu, which this comment comment claims are currently protein per day. argued have not been well accepted by underconsumed. Some comments noted that the American consumers. Other comments Other comments argued that the proposed health claim contains noted that most of the soy products that proposed per RACC requirement would information on (1) the daily intake level are available on the market that would effectively prevent other types of of soy protein that is associated with meet the proposed per RACC products from bearing the health claim. reduced risk of CHD and (2) the level of requirement are entree-type products One comment argued that it is difficult soy protein in a serving of the product that consumers would probably not to incorporate 6.25 g soy protein into a bearing the claim. According to these consume four times per day. Some single RACC of most such foods in a comments, the provision of this comments suggested that only way that it would be palatable to most information obviates the need to restrict vegetarian or soy burgers, shakes, tofu, American consumers, given current and the claim to products having 6.25 g or and non-dairy soy beverages would reasonably anticipated technology. more soy protein per RACC, because meet the proposed per RACC Some of the comments that argued consumers can easily determine the requirement. One comment noted that that few products would be able to meet relative significance of particular many of the products that meet the the 6.25 g per RACC requirement products as a source of soy protein. recommended lowering the minimum RACC requirements are specialty items These comments implied that specifying per RACC level to allow a wider variety that are only available at health food a much lower minimum level of soy of foods to qualify for the health claim stores. protein would increase benefits because and to make it easier for consumers to In contrast, other comments argued a wider variety of products would then achieve an intake of 25 g soy protein per that many existing soy products meet be able to bear the claim and consumers day. Some comments argued that a level the proposed per RACC requirement or would more easily be able to achieve an of 4 g per RACC would allow baked could easily be reformulated to meet intake of 25 g soy protein per day. that requirement. One comment goods, allow soy pasta, low-fat extended Allowing the claim to appear on suggested that the vast majority of meat products, and vegetarian burgers products containing very low levels of products containing soy protein that are made with soy flour and textured soy soy protein might increase the currently available on the market meet protein to bear the claim. These usefulness of the claim for consumers the proposed RACC level. These comments noted that assuming intake comments argued that the assumption of levels of 5 to 6 servings per day of these and might lead to a greater reduction in four eating occasions per day that was types of products would be reasonable CHD than would be produced by taking used to derive the 6.25 g per RACC and that 4 g per RACC would, therefore, the proposed action. The agency is requirement from the 25 g per day level be consistent with a daily intake of 25 unable to determine the likelihood of was reasonable. Among the products g per day. Another comment suggested this effect. listed in these comments were the that FDA has legal precedent for setting Other comments suggested revising following: tofu, soy-based beverages, soy the per RACC requirement as low as 2.5 the per RACC requirement for other burgers and other meat alternatives, g per RACC. reasons. One comment argued that the frozen deserts, protein bars, cheese and In contrast, some of the comments per RACC requirement should be yogurt alternatives, soybeans, soynut that argued that few products would changed to a requirement based on butter, soynuts, tempeh, miso, and soy meet the 6.25 g per RACC requirement serving size. This comment argued, for flour or soy protein powder. Another recommended raising the per RACC example, that a single veggie burger that comment implied that any product in level to reduce the number of servings contains 6.25 g of soy protein should which protein is normally consumed that would be necessary to obtain 25 g qualify for the health claim, even if the could easily be modified to meet the per soy protein per day. Some comments product does not meet the per RACC RACC requirements, including snack argued that if the primary source of soy requirement because the burger pattie is foods, breakfast cereals, burger patties, protein were from meals in which high larger than the applicable RACC. and more formal entrees. protein meat dishes are currently eaten, Changing the per RACC requirement Some comments argued that the 6.25 then the per RACC requirement should to a per serving requirement would g per RACC restrictions would be based on two or three servings per probably increase the number of effectively prevent baked products from day, rather than the proposed products that would be able to bear the bearing the claim. One comment noted assumption of four servings per day. proposed health claim and might, that achieving a level of 6.25 g per Thus, these comments suggested that therefore, increase the health benefits RACC in these products would require FDA revise the per RACC requirement generated by the claims. However, the incorporating soy flour at 15 percent from 6.25 g to either 8.3 g or 12.5 g. comments did not provide sufficient inclusion or greater and that would FDA has insufficient information on information to estimate this effect. In yield a product that would be the characteristics of the soy products addition, this revision would require unacceptable to consumers and would that are currently on the market to revision of the regulations at 21 CFR also be too costly to compete effectively determine the proportion of such 101.12(g), and is, therefore, beyond the with other products. Many comments products that would qualify for the scope of this rulemaking.

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One comment noted that the correct 6. Option Six: Take Proposed Action, exposures that exceeds established No declaration of 6.25 g soy protein is 6 g but Revise Wording of the Claim or Significant Risk Levels. One comment because current law mandates that the Require That Warnings or Other argued that manufacturers should amount of protein be rounded to the Statements Accompany the Claim voluntary provide information on nearest whole number. According to Some comments suggested that FDA product labels on various issues such as this comment, this rounding might require additional information be put on manufacturing methods and the use of confuse consumers. If consumers were the labels of product bearing the pesticides, because consumers have a confused about the level of soy protein proposed claim that explains the right to such information. FDA has determined that there is no in the RACC of a particular product and conditions under which soy protein evidence that health risks are associated the significance of that product for reduces the risk of CHD. For example, with increased intake of soy protein or meeting the specified daily intake level, some comments suggested that product the other substances discussed in the then the benefits of the health claim labels should make it clear that no comments. Label statements warning of might be lower than they would be benefits should be expected for daily otherwise. This comment suggested that possible allergic reactions to soy protein soy protein intake levels of less than 25 the per RACC requirement be revised would provide some potentially g. Some comments argued that the from 6.25 g to either 6 g or 7 g. As valuable information to consumers who beneficial effects of soy protein accrue discussed previously, the rounding do not realize they are allergic to soy only to consumers who have high requirement applies only to the protein or that such allergies are cholesterol levels and suggested that the Nutrition Facts Panel and soy protein possible. However, such labeling would proposed health claim be revised to content is not allowed to appear on the not provide useful information to those communicate this fact. Nutrition Facts Panel. consumers who are already aware of the Although requiring a label statement fact that allergies to common foods are 5. Option Five: Take Proposed action, clarifying that benefits should not be possible, and might discourage the but Specify a Minimum Level of Soy expected for daily soy protein intake consumption of soy protein by those Isoflavones in Addition to the Proposed levels of less than 25 g might generate who are not allergic to soy protein. FDA Minimum Level of Soy Protein for benefits, the marginal benefits of such a has insufficient information to estimate Products Bearing the Claim statement are unclear given that the the costs or benefits of such a warning Some comments argued that the effect proposed health claim relates health statement or to determine if such a of soy protein on the risk of CHD may effects to an intake of 25 g per day and warning statement would provide a net depend on the presence of soy not to the intake of any particular benefit to consumers. Associating isoflavones. These comments product. The comment did not provide warning statements with the proposed recommended that the health claim be sufficient information to estimate the health claim would generate no restricted to products that contain a marginal benefit of an additional marginal benefits for consumers who minimum level of total soy isoflavones, statement concerning the significance of know they are allergic to soy protein of particular isoflavones, of both total the 25 g per day intake level. Finally, as because the health claim would already isoflavones and particular isoflavones, discussed previously in this preamble, indicate the presence of soy protein. or of amino acids such as arginine and FDA has determined that the effect of Label statements addressed to the methionine. Some of the comments that soy protein on the risk of CHD may potential effect of increased argued that the beneficial effects of soy depend, in part, on initial cholesterol consumption of products containing soy protein may depend on the presence of levels, but does not accrue only to those protein on zinc deficiency, such as a soy isoflavones also noted that with high initial cholesterol levels. warning statement, indications of the particular manufacturing or processing Therefore, restricting the health claim to zinc and phytate content of products methods can affect the level of soy apply to only those with high initial containing soy protein, or recommended isoflavones. These comments cholesterol levels would not generate maximum daily intakes, might reduce recommended that the health claim be marginal benefits. the likelihood that increased restricted to products that have been Some of the comments that argued consumption of these products will lead manufactured or processed in particular that the increased consumption of to zinc deficiency. Earlier in the ways. For example, many comments products containing soy protein could preamble to this rule, FDA determined noted that alcohol washing reduces lead to health risks suggested that FDA that consumers would not find isoflavone content and suggested that require warning labels on those information relating to the zinc and products containing alcohol washed or products to alert consumers of the risks. phytate content of products containing extracted soy protein isolate should not Other comments suggested that various soy protein useful. The other suggested be authorized to bear the health claim. types of information relevant to the labeling approaches for addressing the Some comments added that there is no purported health risks be reported on effect of increased consumption of these evidence that adding purified soy product labels. For example, one products on zinc deficiency may be isoflavone extract back into such comment that argued that increased useful for some consumers. However, products is effective and argued that any intake of soy protein could lead to zinc again, the benefit of such labeling must isoflavone requirement should be based deficiency suggested that the labels of be compared to the possible costs in on naturally occurring isoflavones. products bearing the health claim terms of discouraging the use of such As discussed earlier in this preamble, indicate the phytate and zinc content products among those who are not at FDA finds that the scientific evidence per serving for those products. One risk of zinc deficiency. FDA has does not indicate that the effect of soy comment suggested that labels indicate insufficient information to estimate the protein on the risk of CHD varies with a recommended maximum daily intake costs or benefits of the other suggested the presence of soy isoflavones or amino of soy protein to prevent the health risks labeling approaches or determining acids. Therefore, no additional benefit associated with overconsumption of whether such approaches would would result from restricting the claim products containing soy protein. This generate net benefits. to products having particular levels of comment argued that daily consumption One comment suggested eliminating isoflavones, or produced using of between 25 g and 100 g of isolated the language relating the effect of soy particular methods of manufacture. soy protein could result in nitrosamine protein to diets low in saturated fat and

VerDate 12-OCT-99 11:58 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00027 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm04 PsN: 26OCR2 57726 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations cholesterol because the effect of soy bear the proposed health claim and the source of protein is soy and which, protein on the risk of CHD is benefits generated by the health claim therefore, need not provide FDA access independent of these other factors. The may be increased. The cost of this to records to establish the level of soy benefit of eliminating this language is revision is that the total fat content of protein in their products. that consumers who are not currently some products bearing the claim may be If FDA were to require the inspection eating a diet low in saturated fat and slightly higher than under the proposed and duplication of records that firms cholesterol may be more likely to react rule. As explained earlier in the attempting to use the soy protein health to the health claim if the effect of soy preamble, a reduction of total fat claim considered unnecessary to protein is not presented as applying facilitates maintenance of normal body establish compliance with the only to those eating diets low in weight and, therefore, reduces the risk requirements for making that claim, saturated fat and cholesterol. An of obesity. The reduction of this effect then those firms would have less increase in the number of consumers would cause an increase in the risk of incentive to use the claim and the likely to react to the health claim may obesity and, therefore, produce a benefits associated with allowing that increase the benefits of the health claim. countervailing increase in the risk of claim would be reduced. However, FDA However, the size of this marginal CHD. In this case, the benefit of has modified its proposal to inspect benefit is unclear because, as discussed increasing the number of products records to provide, instead, that earlier, the available data on the effects probably outweighs the slight increase manufacturers must identify and supply of soy protein show that soy protein has in the total fat content of qualifying to FDA, on written request, records that a more consistent effect on CHD for products. substantiate the amount of soy protein those consuming a low fat and in a food that bears the soy protein 8. Option Eight: Take Proposed Action, cholesterol diet than for others. The cost health claim if soy is not the sole source but Use a Different Procedure for of eliminating this language is that some of protein in the food. Therefore, this Determining Level of Soy Protein in consumers might believe that achieving rule will not require record inspection Particular Products. a certain intake of soy protein can or unnecessary duplication of records. substitute for eating a diet low in Many comments on the proposal This rule may generate some saturated fat and cholesterol and might, addressed the analytical method that distributive effects because it may put therefore, indirectly increase the intake FDA proposed to use to confirm the firms that are required to provide such of saturated fat and cholesterol. FDA has level of soy protein in products bearing records at a competitive disadvantage insufficient information to determine if the proposed health claim. These relative to firms that produce products eliminating the language relating the comments were discussed in the in which soy is the only source of effect of soy protein to diets low in reproposal. The reproposal specified protein. However, these effects will saturated fat and cholesterol would various types of records that might probably be small because generate net benefits or costs. allow FDA to calculate the level of soy manufacturers probably already Some comments suggested that the protein in particular products. FDA maintain the necessary records. proposed health claim was either too received a number of comments on the D. Small Entity Analysis long or too complicated to be effective. reproposal. Most of these comments Many comments argued that the health addressed the issue of which records FDA has examined the impacts of this claim would be more effective if it were FDA will use to determine the soy proposed rule under the Regulatory shortened or replaced by a ‘‘split protein content of foods. Many Flexibility Act. The Regulatory claim.’’ Many comments suggested comments argued that the reproposal Flexibility Act (5 U.S.C. 601–612) wording for a shorter health claim. appeared to allow FDA wide discretion requires federal agencies to consider Increasing the effectiveness of the health in determining which records to inspect alternatives that would minimize the claim would increase the benefits and duplicate. These comments also economic impact of their regulations on associated with the health claim and expressed the concern that FDA might small businesses and other small would not affect costs. However, FDA inspect and duplicate records of each of entities. No compliance costs are has insufficient information to analyze the various types that were specified as generated by this rule because this rule the effect of different labeling formats or potentially relevant in the reproposal, does not require any labels to be wording. Although FDA has studied the and might also inspect and duplicate as changed, or any product to be effectiveness of split claims for other yet unspecified records that FDA later reformulated. Therefore, small types of claims, the relevance of that determines are relevant. According to businesses will only relabel or information for a health claim on soy these comments, some of the resulting reformulate products if the benefits to protein is unclear. record inspection and duplication might those small businesses outweigh the be unwarranted. Many comments costs. FDA did not receive any 7. Option Seven: Take Proposed Action, suggested that the rule be revised to comments that challenged this but Specify a Different Maximum Total require manufacturers to provide FDA conclusion. Accordingly, pursuant to Fat Content or Grant an Exemption from with records that provide a reasonable the Regulatory Flexibility Act, 5 U.S.C. the Maximum Total Fat Requirement for basis for concluding that a particular 605(b), FDA certifies that this rule will Foods Made With Natural Soybeans product has sufficient soy protein not have a significant economic impact That Have No Added Fat content to bear the health claim. on a substantial number of small Many comments noted that the low According to these comments, this entities. fat requirement for products bearing the revision would eliminate the possibility proposed health claim would prevent that FDA will use the records V. Paperwork Reduction Act of 1995 soybeans and traditional soybean inspections clause to inspect and This final rule contains information products from bearing the health claim. duplicate records in situations in which collection provisions that are subject to This rule has been revised so that foods such actions are not strictly necessary. review by the Office of Management and made from whole soybeans with no One comment argued that the records Budget (OMB) under the Paperwork added fat are exempted from the low fat inspection provision would give an Reduction Act of 1995 (the PRA) (44 requirement. The benefit of this revision unfair market advantage to firms that U.S.C. 3501–3520). The title, is that more products will be able to manufacture products whose sole description, and respondent description

VerDate 12-OCT-99 11:58 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00028 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm04 PsN: 26OCR2 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations 57727 are shown below with an estimate of the visits. Comments received on the soy protein. Thus, FDA is requiring annual recordkeeping and reporting protein reproposal have been addressed manufacturers to have and keep records burden. Included in the estimate is the by the agency in section II.C.2 of this to substantiate the amount of soy time for reviewing instructions, document, and this rule reflects protein in a food that bears the health searching existing data sources, modifications made in response to those claim and contains sources of protein gathering and maintaining the data comments. This final rule requires a other than soy, and to make such needed, and completing and reviewing manufacturer of a product bearing the records available to appropriate each collection of information. soy protein health claim whose product regulatory officials upon written Title: Record Retention Requirements contains a source or sources of protein request. for the Soy Protein/CHD Health Claim in addition to soy to identify and retain Although no comments on the soy Description: The regulation set forth records that reasonably substantiate the protein reproposal specifically in this rule authorizes the use in food ratio of soy protein to total protein. The addressed the estimated burden of the labeling of a health claim about the rule also requires the manufacturer of information collection requirements, relationship between soy protein and such a food product to provide those several indicated that recordkeeping CHD. Section 403(r) of the act requires records upon written request to and record inspection would be that food bearing a health claim appropriate regulatory officials. burdensome. These comments authorized by regulation on a petition to FDA had submitted the information expressed concern about FDA’s record the agency be labeled in compliance collection requirements to OMB for inspection authority. In response to this with the regulation issued by FDA. In review under the PRA at the time the concern, FDA has determined that, in response to comments received on the August 1999 soy protein reproposal was this case, it need not assert record soy protein proposed rule (63 FR published. In response, OMB requested inspection authority in order to obtain 62977), the agency proposed an that FDA respond to the need for the the information needed for compliance alternative procedure for assessing collection and the burden hours that assessment. The comments also compliance with the requirement that a will be imposed as a result of this expressed concern about the potentially food contain a qualifying amount of soy collection. broad array of records that FDA might protein in the soy protein reproposal (64 To bear the soy protein and CHD demand. In response to this concern, FR 45932). This procedure would have health claim, foods must contain 6.25 g FDA clarified that it did not intend to required that a manufacturer of a soy protein per RACC. For foods that specify the records to be supplied. product bearing the proposed soy contain soy as the sole source of protein, Rather, the final rule indicates that protein health claim whose product analytical methods for total protein can records will be requested in writing and contains a source or sources of protein be used to quantify the amount of soy that manufacturers will be responsible in addition to soy retain the records that protein. At the present time, there is no for identifying the records that they permit the calculation of the ratio of soy validated analytical methodology have used to substantiate the proportion protein to other sources of protein in the available to quantify the amount of soy of soy protein in their products. food. The manufacturer of such a food protein in foods that contain other product would have been required to proteins. For these latter foods, FDA FDA estimates the burden of this make those records available for review must rely on information known only to collection of information as follows: and copying by appropriate regulatory the manufacturer to assess compliance Description of Respondents: officials upon request and during site with the qualifying amount of soy Businesses or others for-profit.

TABLE 2.ÐESTIMATED ANNUAL RECORDKEEPING BURDEN 1

Annual Total 21 CFR No. of frequency per annual Hours per Total Hours respondents response responses response

101.82(c)(2)(ii)(B) ...... 25 1 25 1 25 1 There are no capital costs or operating and maintenance costs associated with this collection.

TABLE 3.ÐESTIMATED ANNUAL REPORTING BURDEN 1

No. of Total 21 CFR Section No. of responses per annual Hours per Total hours respondents respondent responses response

101.82(c)(2)(ii)(B) ...... 5 1 5 1 5 1 There are no capital costs or operating and maintenance costs associated with this collection.

Manufacturers must determine that manufacturers will need to use records, claims, FDA estimated that 25 firms their products are qualified to bear any e.g., the food’s formulation or recipe, to would market products bearing a soy claim used on foods labels or in determine if such a food contains 6.25 protein and CHD health claim and that labeling, including meeting the g per RACC. In this rule, FDA is one of each firm’s products would requirement for a qualifying amount of requiring that firms maintain the contain a source or sources of protein in soy protein to bear the health claim records they use to determine that a addition to soy. FDA received no authorized for use by this regulation. In food is qualified to bear the claim, and comments that challenged this estimate. the absence of a validated analytical that those records be submitted to FDA FDA estimates that, annually, it would methodology for soy protein in foods upon written request. Based upon its request records to assess compliance that contain other proteins, experience with the use of health from 20 percent of firms subject to the

VerDate 12-OCT-99 17:23 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00029 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm03 PsN: 26OCR2 57728 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations recordkeeping requirement. The records 9. Van Sickle, G. J., G. K. Powell, P. J. 25. Lee, H. P., L. Gourley, S. W. Duffy, J. that would be required to be retained by McDonald, and R. M. Goldblum, ‘‘Milk- and Esteve, J. Lee, and N. E. Day, ‘‘Dietary Effects § 101.82(c)(ii)(B)(2) are records that, as Soy Protein-induced Enterocolitis: Evidence on Breast-cancer Risk in Singapore,’’ Lancet, described above, FDA believes a for Lymphocyte Sensitization to Specific 337:1197–1200, 1991. Food Proteins,’’ Gastroenterology, 88:1915– 26. Cassidy, A., S. Bingham, and K. D. R. prudent and responsible manufacturer 1921, 1985. Setchell, ‘‘Biological Effects of a Diet of Soy uses and retains as a normal part of 10. Sampson, H. A. and S. M. Scanlon, Protein Rich in Isoflavones on the Menstrual doing business. Thus, the burden to the ‘‘Natural History of Food Hypersensitivity in Cycle of Premenopausal Women,’’ American food manufacturer would be that Children with Atopic Dermatitis,’’ Journal of Journal of Clinical Nutrition, 60:333–340, involved in assembling and providing Pediatrics, 115:23–27, 1989. 1994. the records to appropriate regulatory 11. Roebuck, B. D., ‘‘Trypsin Inhibitors: 27. Bakhit, R. M., B. P. Klein, D. - officials upon written request. The Potential Concern for Humans?’’ Journal of Sorlie, J. O. Ham, J. W. Erdman, Jr., and S. requirements contained in this rule Nutrition, 117:398–400, 1987. M. Potter, ‘‘Intake of 25 g of Soybean Protein 12. Anderson, R. L. and W. J. Wolf, With or Without Soybean Fiber Alters Plasma would require only a minimal burden, ‘‘Compositional Changes in Trypsin Lipids in Men With Elevated Cholesterol no more than one hour per response, Inhibitors, Phytic acid, Saponins and Concentrations,’’ Journal of Nutrition, from respondents. Isoflavones Related to Soybean Processing,’’ 124:213–222, 1994. The information collection provisions Journal of Nutrition, 125:581S–588S, 1995. 28. Baum, J. A., H. Teng, J. W. Erdman, Jr., of this final rule have been submitted to 13. Erdman, J. W., Jr. and R. M. Forbes, R. M. Weigel, B. P. Klein, V. W. Persky, S. OMB for review. FDA will publish a ‘‘Effects of Soya Protein on Mineral Freels, P. Surya, R. M. Bakhit, E. Ramos, N. notice in the Federal Register Availability,’’ Journal of the American Oil F. Shay, and S. M. Potter, ‘‘Long-term Intake announcing OMB’s decision to approve, Chemists’ Society, 58:489–493, 1981. of Soy Protein Improves Blood Lipid Profiles modify, or disapprove the information 14. Liener, I. ‘‘Significance for Humans of and Increases Mononuclear Cell Low- Biologically Active Factors in Soybeans and density-lipoprotein Receptor Messenger RNA collection provisions in this final rule. Other Food Legumes,’’ Journal of the in Hypercholesterolemic, Postmenopausal An agency may not conduct or sponsor, American Oil Chemists’ Society, 56:121–129, Women,’’ American Journal of Clinical and a person is not required to respond 1979. Nutrition, 68:545–551, 1998. to, a collection of information unless it 15. Kennedy, A. R., ‘‘The Evidence for Soy 29. Bosello, O., L. Cominacini, I. Zocca, U. displays a currently valid OMB control Products as Cancer Preventive Agents.’’ Garbin, R. Compri, A. Davoli, and L. Brunetti, number. Journal of Nutrition, 125:733S–743S, 1995. ‘‘Short-and Long-term Effects of Hypocaloric 16. Adlercreutz H. and W. Mazur, ‘‘Phyto- Diets Containing Proteins of Different VI. References oestrogens and Western Diseases,’’ Annals of Sources on Plasma Lipids and Apoproteins of The following references have been Medicine, 29:95–120, 1997. Obese Subjects,’’ Annals of Nutrition placed on display in the Dockets 17. Liener, I. E., ‘‘Factors Affecting the Metabolism, 32:206–214, 1988. Management Branch (address above) Nutritional Quality of Soya Products,’’ 30. Carroll, K. K., P. M. Giovannetti, M. W. Journal of the American Oil Chemists’ Huff, O. Moase, D. C. K. Roberts, and B. M. and may be seen by interested persons Society, 58:406–415, 1981. Wolfe, ‘‘Hypocholesterolemic Effect of between 9 a.m. and 4 p.m., Monday 18. Erdman, J. W., Jr. and E. J. Fordyce, Substituting Soybean Protein for Animal through Friday. ‘‘Soy Products and the Human Diet,’’ Protein in the Diet of Healthy Young 1. Protein Technologies International, Inc., American Journal of Clinical Nutrition, Women,’’ American Journal of Clinical ‘‘Health Claim Petition,’’ May 4, 1998 [CP1, 49:725–737, 1989. Nutrition, 31:1312–1321, 1978. vol. 1–3]. 19. Breslau, N. A., L. Brinkley, K. D. Hill, 31. Crouse, J. R., III, T. Morgan, J. G. Terry, 2. Protein Technologies International, Inc., and C. Y. C. Pak, ‘‘Relationship of Animal J. Ellis, M. Vitolins, and G. L. Burke, ‘‘A ‘‘Addendum to Health Claim Petition,’’ Protein-rich Diet to Kidney Stone Formation Randomized Trial Comparing the Effect of August 10, 1998 [CP1, vol. 4]. and Calcium Metabolism,’’ Journal of Clinical Casein with That of Soy Protein Containing 3. American Soybean Association, ‘‘Health Endocrinology and Metabolism, 66:140–146, Varying Amounts of Isoflavones on Plasma Claim Petition for Soy Protein,’’ October 29, 1988. Concentrations of Lipids and Lipoproteins,’’ 1998 [C1, vol. 8–12]. 20. Portale, A. A., B. P. Halloran, M. M. Archives of Internal Medicine, 159:2070– 4. DHHS, Public Health Service (PHS), Murphy, and R. C. Morris, Jr., ‘‘Oral Intake 2076, 1999. ‘‘The Surgeon General’s Report on Nutrition of Phosphorus Can Determine the Serum 32. Cruz, M. L. A., W. W. Wong, F. and Health,’’ U.S. Government Printing Concentration of 1,25-dihydroxy-vitamin D Mimouni, D. L. Hachey, K. D. R. Setchell, P. Office, Washington, DC, pp. 83–137, 1988. by Determining its Production Rate in D. Klein, and R. C. Tsang, ‘‘Effects of Infant 5. Food and Nutrition Board, National Humans.’’ Journal of Clinical Investigation, Nutrition on Cholesterol Synthesis Rates,’’ Academy of Sciences, ‘‘Diet and Health: 77:46–55, 1986. Pediatric Research, 35:135–140, 1994. Implications for Reducing Chronic Disease 21. Moule, G. R., ‘‘Clinical Aspects of 33. Descovich, G. C., C. Ceredi, A. Gaddi, Risk,’’ National Academy Press, Washington, Nutritional Infertility of Ewes,’’ Australian M. S. Benassi, G. Mannino, L. Colombo, L. DC, pp. 291–309 and 529–547, 1989. Veterinary Journal, 46:428–435, 1970. Cattin, G. Fontana, U. Senin, E. Mannarino, 6. DHHS, Public Health Service (PHS) and 22. Anthony, M. S., T. B. Clarkson, C. L. C. Caruzzo, E. Bertelli, C. Fragiacomo, G. National Institutes of Health, ‘‘National Hughes, Jr., T. M. Morgan, and G. L. Burke, Noseda, M. Sirtori, and C. R. Sirtori, Cholesterol Education Program: Population ‘‘Soybean Isoflavones Improve ‘‘Multicentre Study of Soybean Protein Diet Panel Report,’’ Bethesda, MD, pp. 1–40, 1990. Cardiovascular Risk Factors Without for Outpatient Hypercholesterolaemic 7. Sempos, C. T., J. I. Cleeman, M. D. Affecting the Reproductive System of Patients,’’ Lancet, 2:709–712, 1980. Carroll, C. L. Johnson, P.S. Bachorik, D. J. Peripubertal Rheusus Monkeys,’’ Journal of 34. A. Gaddi, G. C. Descovich, G. Noseda, Gordon, V. L. Burt, R. R. Briefel, C. D. Brown, Nutrition, 126:43–50, 1996. C. Fragiacomo, A. Nicolini, G. Montanari, G. K. Lippel, and B. M. Rifkind, ‘‘Prevalence of 23. Honore´, E. K., J. K. Williams, M. S. Vanetti, M. Sirtori, E. Gatti, and C. R. Sirtori, High Blood Cholesterol Among U.S. Adults. Anthony, and T. B. Clarkson, ‘‘Soy ‘‘Hypercholesterolaemia Treated by Soybean An Update Based on Guidelines From the Isoflavones Enhance Coronary Vascular Protein Diet,’’ Archives of Disease in Second Report of the National Cholesterol Reactivity in Atherosclerotic Female Childhood, 62:274–278, 1987. Education Program Adult Treatment Panel,’’ Macaques,’’ Fertility and Sterility, 67:148– 35. Gaddi, A., A. Ciarrocchi, A. Matteucci, Journal of the American Medical Association, 154, 1997. S. Rimondi, G. Ravaglia, G. C. Descovich, and 269:3009–3014, 1993. 24. Cline, J. M., J. C. Paschold, M. S. C. R. Sirtori, ‘‘Dietary Treatment for Familial 8. Ross, R., ‘‘Atherosclerosis,’’ in Cecil— Anthony, I. O. Obasanjo, and M. R. Adams, Hypercholesterolemia—Differential Effects of Textbook of Medicine, J. B. Wyndaarden, L. ‘‘Effects of Hormonal Therapies and Dietary Dietary Soy Protein According to the H. Smith, and J. C. Bennett, editors. Harcourt Soy Phytoestrogens on Vaginal Cytology in Apolipoprotein E Phenotypes,’’ American Brace Johanevich, Inc. Philadelphia, P. 293– Surgically Postmenopausal Macaques,’’ Journal of Clinical Nutrition, 53:1191–1196, 298, 1992. Fertility and Sterility, 65:1031–1035, 1996. 1991.

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36. Giovannetti, P. M., K. K. Carroll, and P. M. Laplaud, ‘‘Effects of Soy Protein and 60. Verrillo, A., A. de Teresa, P. C. B. M. Wolfe, ‘‘Constancy of Fasting Serum Casein in Low Cholesterol Diets on Plasma Giarrusso, and S. La Rocca, ‘‘Soybean Protein Cholesterol of Healthy Young Women Upon Lipoproteins in Normolipidemic Subjects,’’ Diets in the Management of Type II Substitution of Soy Protein Isolate for Meat Atherosclerosis, 72:63–70, 1988. Hyperlipoproteinaemia,’’ Atherosclerosis, and Dairy Protein in Medium and Low Fat 48. Meinertz, H., K. Nilausen, and O. 54:321–331, 1985. Diets,’’ Nutrition Research, 6:609–618, 1986. Faergeman, ‘‘Soy Protein and Casein in 61. Vessby, B., B. Karlstro¨m, H. Lithell, I. 37. Goldberg, A. P., A. Lim, J. B. Kolar, J. Cholesterol-enriched Diets: Effects on Plasma B. Gustafsson, and I. Werner, ‘‘The Effects on J. Grundhauser, F. H. Steinke, and G. Lipoproteins in Normolipidemic Subjects,’’ Lipid and Carbohydrate Metabolism of Schonfeld, ‘‘Soybean Protein Independently American Journal of Clinical Nutrition, Replacing Some Animal Protein by Soy- Lowers Plasma Cholesterol Levels in Primary 50:786–793, 1989. protein in a Lipid-lowering Diet for Hypercholesterolemia,’’ Atherosclerosis, 49. Mercer, N. J. H., K. K. Carroll, P. M. Hypercholesterolaemic Patients.’’ Human 43:355–368, 1982. Giovannetti, F. H. Steinke, and B. M. Wolfe, Nutrition: Applied Nutrition, 36A:179–189, 38. Gooderham, M. J., H. Adlercreutz, S. T. ‘‘Effects on Human Plasma Lipids of 1982. Ojala, K. Wa¨ha¨la¨, and B. J. Holub, ‘‘A Soy Substituting Soybean Protein Isolate for Milk 62. Wang, M. F., S. Yamamoto, H. M. Protein Isolate Rich in Genistein and Protein in the Diet,’’ Nutrition Reports Chung, S. Y. Chung, S. Miyatani, M. Mori, T. Daidzein and its Effects on Plasma Isoflavone International, 35:279–287, 1987. Okita, and M. Sugano, Concentrations, Platelet Aggregation, Blood 50. Meredith, L., M. Liebman, and K. ‘‘Antihypercholesterolemic Effect of Lipids and Fatty Acid Composition of Plasma Graves, ‘‘Alterations in Plasma Lipid Levels Undigested Fraction of Soybean Protein in Phospholipid in Normal Men,’’ Journal of Resulting from Tofu and Cheese Young Female Volunteers,’’ Journal of Nutrition, 126:2000–2006, 1996. Consumption in Adult Women,’’ Journal of Nutritional Science and Vitaminology, 39. Grundy, S. M. and J. J. Abrams, the American College of Nutrition, 8:573– 41:187–195, 1995. ‘‘Comparison of Actions of Soy Protein and 579, 1989. 63. Widhalm, K., G. Brazda, B. Schneider, Casein on Metabolism of Plasma 51. Potter, S. M., R. M. Bakhit, D. L. Essex- and S. Kohl, ‘‘Effect of Soy Protein Diet Lipoproteins and Cholesterol in Humans,’’ Sorlie, K. E. Weingartner, K. M. Chapman, R. Versus Standard Low Fat, Low Cholesterol American Journal of Clinical Nutrition, A. Nelson, M. Prabhudesai, W. D. Savage, A. Diet on Lipid and Lipoprotein Levels in 38:245–252, 1983. I. Nelson, L. W. Winter, and J. W. Erdman, Children with Familial or Polygenic 40. Holmes, W. L., G. B. Rubel, and S. S. Jr., ‘‘Depression of Plasma Cholesterol in Men Hypercholesterolemia,’’ Journal of Pediatrics, Hood, ‘‘Comparison of the Effect of Dietary by Consumption of Baked Products 123:30–34, 1993. Meat Versus Dietary Soybean Protein on Containing Soy Protein,’’ American Journal 64. Wolfe, B. M., P. M. Giovannetti, D. C. Plasma Lipids of Hyperlipidemic of Clinical Nutrition, 58:501–506, 1993. H. Cheng, D. C. K. Roberts, and K. K. Carroll, 52. Potter, J. M. and P. J. Nestel, ‘‘Greater Individuals,’’ Atherosclerosis, 36:379–387, ‘‘Hypolipidemic Effect of Substituting Bile Acid Excretion with Soy Bean Than with 1980. Soybean Protein Isolate for All Meat and Cow Milk in Infants,’’ American Journal of 41. Huff, M. W., P. M. Giovannetti, and B. Dairy Protein in the Diets of Clinical Nutrition, 29:546–551, 1976. M. Wolfe, ‘‘Turnover of Very Low-density Hypercholesterolemic Men,’’ Nutrition 53. Sacks, F. M., J. L. Breslow, P. G. Wood, Lipoprotein-Apoprotein B is Increased by Reports International, 24:1187–1198, 1981. and E. H. Kass, ‘‘Lack of an Effect of Dairy Substitution of Soybean Protein for Meat and Protein (Casein) and Soy Protein on Plasma 65. Nagata, C., N. Takatsuka, Y. Kurisu, Dairy Protein in the Diets of Cholesterol of Strict Vegetarians. An and H. Shimizu, ‘‘Decreased Serum Total Hypercholsterolemic Men,’’ American Experiment and a Critical Review,’’ Journal Cholesterol Concentration is Associated with Journal of Clinical Nutrition, 39:888–897, of Lipid Research, 24:1012–1020, 1983. High Intake of Soy Products in Japanese Men 1984. 54. Shorey, R. L., B. Bazan, G. S. Lo, and and Women,’’ Journal of Nutrition, 128:209– 42. Jacques, H., D. Laurin, S. Moorjani, F. F. H. Steinke, ‘‘Determinants of 213, 1998. ´ H. Steinke, C. Gagne, D. Brun, and P. J. Hypercholesterolemic Response to Soy and 66. Anderson, J. W., B. M. Johnstone, and Lupien, ‘‘Influence of Diets Containing Cow’s Animal Protein-based Diets,’’ American M. E. Cook-Newell, ‘‘Meta-analysis of the Milk or Soy Protein Beverage on Plasma Journal of Clinical Nutrition, 34:1769–1778, Effects of Soy Protein Intake on Serum Lipids in Children with Familial 1981. Lipids,’’ New Journal of Medicine, Hypercholesterolemia,’’ Journal of the 55. Sirtori, C. R., E. Agradi, F. Conti, O. 333:276–282, 1995. American College of Nutrition, 11 (suppl): Mantero, and E. Gatti, ‘‘Soybean-protein Diet 67. DHHS, National Heart, Lung, and Blood 69S–73S, 1992. in the Treatment of Type-II Institute, National Cholesterol Education 43. Jenkins, D. J. A., T. M. S. Wolever, G. Hyperlipoproteinaemia,’’ Lancet, 1:275–277, Program, ‘‘Report of the Expert Panel on Spiller, G. Buckley, Y. Lam, A. L. Jenkins, 1977. Population Strategies for Blood Cholesterol and R. G. Josse, ‘‘Hypocholesterolemic Effect 56. Sirtori, C. R., C. Zucchi-Dentone, M. Reduction (Population Panel Report),’’ of Vegetable Protein in a Hypocaloric Diet,’’ Sirtori, E. Gatti, G. C. Descovich, A. Gaddi, Chapter II. Background and Introduction, Atherosclerosis, 78:99–107, 1989. L. Cattin, P. G. Da Col, U. Senin, E. NIH Publication No. 93–3046, Bethesda, MD, 44. Kurowska, E. M., J. Jordan, J. D. Spence, Mannarino, G. Avellone, L. Colombo, C. 1993. S. Wetmore, L. A. Piche´, M. Radzikowski, P. Fragiacomo, G. Noseda, and S. Lenzi, 68. Food and Nutrition Board, National Dandona, and K. K. Carroll, ‘‘Effects of ‘‘Cholesterol-lowering and HDL-raising Academy of Sciences, ‘‘Diet and Health: Substituting Dietary Soybean Protein and Oil Properties of Lecithinated Soy Proteins in Implications for Reducing Chronic Disease for Milk Protein and Fat in Subjects with Type II Hyperlipidemic Patients,’’ Annals of Risk,’’ National Academy Press, Washington, Hypercholesterolemia, ‘‘Clinical Investigative Nutrition Metabolism, 29:348–357, 1985. DC, pp. 23–40, 1989. Medicine, 20:162–170, 1997. 57. Steele, M. G., ‘‘The Effect on Serum 69. Department of Health and Human 45. Laurin, D., H. Jacques, S. Moorjani, F. Cholesterol Levels of Substituting Milk with Services, ‘‘Guide to Clinical Preventive H. Steinke, C. Gagne´, D. Brun, and P. J. a Soya Beverage,’’ Australian Journal of Services: Report of the U.S Preventive Lupien, ‘‘Effects of a Soy-protein Beverage on Nutrition and Dietetics, 49:24–28, 1992. Services Task Force,’’ 2d edition, Plasma Lipoproteins in Children with 58. van Raaij, J. M. A., M. B. Katan, J. G. Washington, DC: Office of Public Health and Familial Hypercholesterolemia,’’ American A. J. Hautvast, and R. J. J. Hermus, ‘‘Effects Science, U.S. Department of Health and Journal of Clinical Nutrition, 54:98–103, of Casein Versus Soy Protein Diets on Serum Human Services, April 1989. 1991. Cholesterol and Lipoproteins in Young 70. Anthony, M. S., T. B. Clarkson, B. C. 46. Lovati, M. R., C. Manzoni, A. Canavesi, Healthy Volunteers,’’ American Journal of Bullock, and J. D. Wagner, ‘‘Soy Protein M. Sirtori, V. Vaccarino, M. Marchi, G. Clinical Nutrition, 34:1261–1271, 1981. Versus Soy Phytoestrogens in the Prevention Gaddi, and C. R. Sirtori, ‘‘Soybean Protein 59. van Raaij, J. M. A., M. B. Katan, C. E. of Diet-induced Coronary Artery Diet Increases Low Density Lipoprotein West, and J. G. A. J. Hautvast, ‘‘Influence of Atherosclerosis of Male Cynomolgus Receptor Activity in Mononuclear Cells from Diets Containing Casein, Soy Isolate, and Soy Monkeys,’’ Arteriosclerosis, Thrombosis, and Hypercholesterolemic Patients,’’ Journal of Concentrate on Serum Cholesterol and Vascular Biology, 17:2524–2531, 1997. Clinical Investigation, 80:1498–1502, 1987. Lipoproteins in Middle-aged Volunteers,’’ 71. Nestle, P. J., T. Yamashita, T. Sashara, 47. Meinertz, H., O. Faergeman, K. American Journal of Clinical Nutrition, S. Pomeroy, A. Dart, P. Komesaroff, A. Owen, Nilausen, M. J. Chapman, S. Goldstein, and 35:925–934, 1982. and M. Abbey, ‘‘Soy Isoflavones Improve

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Systemic Arterial Compliance but Not Nonheme Iron Absorption in Man,’’ 101. Wu, A.H., R.G. Ziegler, A.M.Y. Plasma Lipids in Menopausal and American Journal of Clinical Nutrition, Nomura, D.W. West, L.N. Kolonel, P.L. Horn- Perimenopausal Women,’’ Arteriosclerosis, 34:2622–2629, 1981. Ross, R.N. Hoover, and M.C. Pike, ‘‘Soy Thrombosis, and Vascular Biology, 17:3392– 87. Hurrell, R.F., M.A. Juillerat, M.B. Intake and Risk of Breast Cancer in Asians 3398, 1997. Reddy, S.R. Lynch, S.A. Dassenko, and J.D. and Asian Americans,’’ American Journal of 72. Sitori, C. R., E. Gianazza, C. Manzoni, Cook, ‘‘Soy Protein, Phytate, and Iron Nutrition, 69(suppl):1437S–1443S, 1998. M. R. Lovati, and P. A. Murphy, ‘‘Role of Absorption in Humans,’’ American Journal of 102. Setchell, K.D.R., S.J. Gossellin, M.B. Isoflavones in the Cholesterol Reduction of Clinical Nutrition, 56:573–578, 1992. Welsh, J.O. Johnston, W.F. Balistreri, L.W. Soy Proteins in the Clinic,’’ letter to the 88. Lynch, S.R., S.A. Dassenko, T.A. Kramer, B.L. Dresser, and M.J. Tarr, ‘‘Dietary editor, American Journal of Clinical Morck, J.L. Beard, and J.D. Cook, ‘‘Soy Estrogens—A Probable Cause of Infertility Nutrition, 65:166–167, 1997. Protein Products and Heme Iron Absorption and Liver Disease in Captive Cheetahs,’’ 73. American Academy of Pediatrics, in Humans,’’ American Journal of Clinical Gastroenterology, 93:225–233, 1987. Committee on Nutrition, ‘‘Policy Statement— Nutrition, 41:13–20, 1985. 103. Leopold, A.S., M. Erwin, J. Oh, and B. Soy Protein-based Formulas: 89. Bodwell, C.E., C.W. Miles, E. Morris, Browning, ‘‘Phytoestrogens: Adverse Effects Recommendations for Use in Infant E.S. Prather, W. Mertz, and J.J. Canary, on Reproduction in California Quail,’’ Feeding,’’ Pediatrics, 101:148–153, 1998. ‘‘Long-term Consumption of Beef Extended Science 191:98–99, 1976. 74. Ministry of Health, ‘‘Soy-based Infant with Soy Protein by Men, Women, and 104. Drane, H.M., D.S. Patterson, B.A. Formula,’’ Wellington, New Zealand. Children: II. Effects on Iron Status,’’ Plant Roberts, and N. Saba, ‘‘Oestrogenic Activity 75. Kahl, L., Office of Premarket Approval, Foods in Human Nutrition, 37:361–376, of Soya-bean Products,’’ Food and Cosmetic Center for Food Safety and Applied 1987. Toxicolology, 18:425–427, 1980 Nutrition, FDA, Letter to M. W. Empie, 90. Lo¨nnerdal, B., ‘‘Nutritional Aspects of 105. Cassidy, A., S. Bingham, and K.D.R. Archer Daniels Midland Company, Soy Formula,’’ Acta Pediatrica Supplement, Setchell, ‘‘Biological Effects of a Diet of Soy November 25, 1998. 402:105–108, 1994. Protein Rich in Isoflavones on the Menstrual 76. Select Committee on GRAS Substances, 91. Prasad, A.S., S. Mefta, J. Abadallah, J. Cycle of Premenopausal Women,’’ American Life Sciences Research Office, ‘‘Evaluation of Kaplan, G.J. Brewer, J.F. Bach, and M. Journal of Clinical Nutrition, 60:333–340, the Health Aspects of Soy Protein Isolates as Dardenne, ‘‘Serum Thymulin in Human Zinc 1994. Food Ingredients,’’ Prepared for the Bureau of Deficiency,’’ Journal of Clinical Investigation, 106. Duncan, A.M., B.E. Merz, X. Xu, T.C. Foods, Food and Drug Administration, 82:1202–1210, 1988. Nagel, W.R. Phillips, and M.S. Kurzer, ‘‘Soy Contract No. 223–75–2004, Federation of 92. Sandstrom, B. and A. Cederblad, ‘‘Zinc Isoflavones Exert Modest Hormonal Effects in American Societies for Experimental Biology, Absorption from Composite Meals. II. Premenopausal Women,’’ Journal of Clinical Bethesda, MD, 1979. Influence of the Main Protein Source,’’ Endocrinology and Metabolism, 84:192–197, American Journal of Clinical Nutrition, 1999. 77. Hymowitz, T. and J.R. Harlan, 33:1778–1783, 1980. 107. Faber, K.A. and C.L. Hughes, Jr., ‘‘Introduction of the Soybean to North 93. Solomons, N.W., M. Janghorbani, B.T. ‘‘Dose-response Characteristics of Neonatal America by Samuel Bowen in 1765, , Ting, F.H. Steinke, M. Christensen, R. Bijlani, Exposure to Genistein on Pituitary Gazette, 17, 1766,’’ article from N. Istfan, and V.R. Young, ‘‘Bioavailability of Responsiveness to Gonadotropin Releasing http/www.nsrl.uiuc.edu/beanhistory/ Zinc from a Diet Based on Isolated Soy Hormone and Volume of the Sexually intrnall.html. Protein: Application in Young Men of the Dimorphic Nucleus of the Preoptic Area 78. Sheehan, D.M., ‘‘Herbal Medicines, Stable Isotope Tracer, 70Zn,’’ Journal of (SDN–POA) in Postpubertal Castrated Female Phytoestrogens, and Toxicity: Risk:Benefit Nutrition, 112:1809–1821, 1982. Rats.’’ Reproductive Toxicology, 7:35–39, Considerations,’’ Proceedings of the Society 94. Oberleas, D., ‘‘Mechanism of Zinc 1993. for Experimental Biology and Medicine, Homeostasis,’’ Journal of Inorganic 108. Faber, K.A. and C.L. Hughes, Jr., ‘‘The 217:379–385, 1998. Biochemistry, 64:231–241, 1996. Effect of Neonatal Exposure to 79. Liener, I.E., ‘‘Trypsin Inhibitors: 95. Lo, G.S., S.L. Settle, F.H. Steinke, and Diethylstibestrol, Genistein, and Zearalenone Concern for Human Nutrition or Not?’’ D.T. Hopkins, ‘‘Effect of Phytate:Zinc Molar on Pituitary Responsivesness and Sexually Journal of Nutrition, 116:920–923, 1986. Ratio and Isolated Soybean Protein on Zinc Dimorphic Nucleus Volume in the Castrated 80. Liener, I.E., R.L. Goodale, A. Bioavailability,’’ Journal of Nutrition, Adult Rat,’’ Biology of Reproduction, 45:649– Deshmukh, T.L. Satterberg, G. Ward, C.M. 111:2223–2235, 1981. 653, 1991. DiPietro, P.E. Bankey, and J.W. Borner, 96. Dees, C., J.S. Foster, S. Ahamed, and J. 109. Medlock, K.L., W.S. Branham, and ‘‘Effect of a Trypsin Inhibitor from Soybeans Wimalasena, ‘‘Dietary Estrogens Stimulate D.M. Sheehan, ‘‘Effects of Coumestrol and (Bowman-Birk) on the Secretory Activity of Human Breast Cells to Enter the Cell Cycle,’’ Equol on the Developing Reproductive Tract the Human Pancreas,’’ Gastroenterology, Environmental Health Perspectives, of the Rat.’’ Proceedings of the Society for 94:419–427, 1988. 105(suppl 3):633–636, 1997. Experimental Biology and Medicine, 208:67– 81. Liener, I.E., ‘‘Possible Adverse Effects 97. Adlercreutz, C.H.T., B.R. Goldin, S.L. 71, 1995. of Soybean Anticarcinogens,’’ Journal of Gorbach, K.A.V. Ho¨ckerstedt, S. Watanabe, 110. Medlock, K.L., W.S. Branham, and Nutrition, 125:744S–750S, 1995. E.K. Ha¨ma¨la¨inen, M.H. Markanen, T.H. D.M. Sheehan, ‘‘The Effects of 82. Liener, I.E., ‘‘Soybean Protease Ma¨kela¨, K.W. Wa¨ha¨la¨, T.A. Hase, and T. Phytoestrogens on Neonatal Rat Uterine Inhibitors and Pancreatic Carcinogenesis,’’ Fotsis, ‘‘Soybean Phytoestrogen Intake and Growth and Development.’’ Proceedings of letter to the editor, Journal of Nutrition, Cancer Risk,’’ Journal of Nutrition, the Society for Experimental Biology and 126:582–583, 1996. 125(suppl):757S–770S, 1995. Medicine, 208:307–313, 1995. 83. Kennedy, A.R., ‘‘The Bowman-Birk 98. Barnes, S., ‘‘Effect of Genistein on In 111. Harrison, R. M., P. P. Phillippi, and Inhibitor from Soybeans as an Vitro and In Vivo Models of Cancer,’’ Journal M. C. Henson, ‘‘Effects of Genistein on Anticarcinogenic Agent,’’ American Journal of Nutrition, 125(suppl):777S–783S, 1995. Estradiol Production in Pregnant Rhesus of Clinical Nutrition, 68(suppl):1406S–1412S, 99. Petrakis N.L., S. Barnes, E.B. King; J. Monkeys (Macaca mulatta),’’ abstract, 1998. Lowenstein, J. Wiencke, M.M. Lee, R. Miike, American Journal of Primatology, 45:183, 84. Mills, P.K., W.L. Beeson, D.E. Abbey, M. Kirk, and L. Coward, ‘‘Stimulatory 1998. G.E. Fraser, and R.L. Phillips, ‘‘Dietary Habits Influence of Soy Protein Isolate on Breast 112. Fritz, W. A., L. Coward, J. Wang, and and Past Medical History as Related to Fatal Secretion in Pre- and Postmenopausal C. A. Lamartiniere, ‘‘Dietary Genistein: Pancreas Cancer Risk Among Adventists,’’ Women.’’ Cancer Epidemiology, Biomarkers, Perinatal Mammary Cancer Prevention, Cancer, 61:2578–2585, 1988. and Prevention, 5:785–794, 1996. Bioavailability and Toxicity Testing in the 85. Fitch, C.D., W.F. Harville, J.S. Dinning, 100. McMichael-Phillips, D.F., C. Harding, Rat.’’ Carcinogenesis, 19:2151–2158, 1998. and F.S. Porter, ‘‘Iron Deficiency in Monkeys M. Morton, S.A. Roberts, A. Howell, C.S. 113. Freni-Titulaer, L. W., J. F. Cordero, L. Fed Diets Containing Soybean Protein,’’ Potten, and N.J. Bundred, ‘‘Effects of Soy- Haddock, G. Lebron, R. Martinez, and J. L. Proceedings of the Society for Experimental protein Supplementation on Epithelial Mills, ‘‘Premature Thelarche in Puerto Rico. Biology and Medicine, 116:130–133, 1964. Proliferation in Histologically Normal A Search for Environmental Factors.’’ 86. Cook, J.D., T.A. Morck, and S.R. Lynch, Human Breast,’’ American Journal of Clinical American Journal of Diseases of Children, ‘‘The Inhibitory Effect of Soy Products on Nutrition, 68(suppl):1431S–1436S, 1998. 140:1263–1267, 1986.

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114. White, L., H. Petrovitch, G. W. Ross, 129. Fort, P., R. Lanes, S. Dahlem, B. Supplementation on Serum Lipoproteins, and K. Masaki, ‘‘Association of Mid-life Recker, M. Wyman-Daum, M. Pugliese, and Blood Pressure, and Menopausal Symptoms Consumption of Tofu with Late Life F. Lifshitz, ‘‘Breast Feeding and Insulin- in Perimenopausal Women,’’ Menopause: Cognitive Impairment and Dementia: The dependent Diabetes Mellitus in Children,’’ The Journal of the American Menopause Honolulu:Asia Aging Study,’’ abstract, The Journal of the American College of Nutrition, Society, 6:7–13, 1999. Neurobiology of Aging, 17 (suppl 4), S121, 5:439–441, 1986. 142. Nilausen, K., and H. Meinertz, 1996. 130. Fort, P., N. Moses, M. Fasano, T. ‘‘Variable Lipemic Response to Dietary Soy 115. White, L., H. Petrovitch, G. W. Ross, Goldberg, and F. Lifschitz, ‘‘Breast and Soy- Protein in Healthy, Normolipidemic Men,’’ K. H. Masaki, R. D. Abbott, E. L. Teng, B. L. formula Feedings in Early Infancy and the American Journal of Clinical Nutrition, Rodriguez, P. L. Blanchette, R. J. Havlik, G. Prevalence of Autoimmune Thyroid Disease 68(suppl):1380S–1384S, 1998. Wergowske, D. Chiu, D. J. Foley, C. in Children,’’ Journal of the American 143. Duane, W.C., ‘‘Effects of Soybean Murdaugh, and J. D. Curb, ‘‘Prevalence of College of Nutrition, 9:164–167, 1990. Protein and Very Low Dietary Cholesterol on Dementia in Older Japanese-American Men 131. Monoz, L. A. and W. H. Yang, ‘‘Kunitz Serum Lipids, Biliary Lipids, and Fecal in Hawaii: The Honolulu-Asia Aging Study,’’ Soybean Inhibitor: A Specific Allergen in Sterols in Humans,’’ Metabolism, 48:489– Journal of the American Medical Association, Food,’’ New England Journal of Medicine, 494, 1999. 276:955–960, 1996. 302:1126–1128, 1980. 144. Yu-Poth, S., G. Zhao, T. Etherton, M. 116. Sheehan, D. M., E. Willingham, D. 132. Livsmedels Verket, National Food Naglak, S. Jonnalagadda, and P. M. Kris- Gaylor, J. M. Bergeron, and D. Crewes, ‘‘No Administration, Allergic Reactions to Food, Etherton, ‘‘Effects of the National Cholesterol Threshold Dose for Estradiol-induced Sex , 1997, report based on Foucard, T., Education Program’s Step I and Step II Reversal of Turtle Embryos: How Little is Too U. Edberg, and I. Malmheden Yman, ‘‘Fatal Dietary Intervention Programs on Much?’’ Environmental Health Perspectives, and Severe Food Hypersensitivity. Peanut Cardiovascular Disease Risk Factors: A Meta- 107:155–159, 1999. and Soya Underestimated Allergens,’’ analysis,’’ American Journal of Clinical 117. Sheehan, D. M., ‘‘Literature Analysis La¨ kartidningen, 94:2635–2638, 1997. Nutrition, 69:632–646, 1999. of No-threshold Dose-response Curves for 133. Malmheden Yman, I, Livsmedels 145. Denke, M. A., ‘‘Revisiting the Endocrine Disruptors,’’ abstract, Teratology, Verket, National Food Administration, Letter Effectiveness of the National Cholesterol 57:219, 1998. to Jane McLennan, Ministry of Health, New Education Program’s Step I and Step II Diets: 117A. Setchell, K. D. R., ‘‘Phytoestrogens: Zealand, May 30, 1997. Cholesterol-lowering Diets in a the Biochemistry, Physiology, and 134. Eigenman, P.A., A.W. Burks, G.A. Pharmaceutically Driven World,’’ American Implications for Human Health of Soy Bannon, and H.A. Sampson, ‘‘Identification Journal of Clinical Nutrition, 69:581–582, Isoflavones,’’ American Journal of Clinical of Unique Antigenic Fractions of Soy and 1999. Nutrition, 68 (suppl):1333S–1346S, 1998. Peanut,’’ abstract, Journal of Allergey and 146. Denke, M. A., ‘‘Review of Human Clinical Immunology, 97:328, 1996. Studies Evaluating Individual Dietary 118–119. Lu, L. J. and K. E. Anderson, ‘‘Sex 135. Gunn, R.A., P.R. Taylor, and E.J. Responsiveness in Patients with and Long-term Soy Diets Affect the Gangarosa, ‘‘Gastrointestinal Illness Hypercholesterolemia,’’ American Journal of Metabolism and Excretion of Soy Isoflavones Associated with Consumption of a Soy Clinical Nutrition, 62(suppl):471S–477S, in Humans,’’ American Journal of Clinical Protein Extender,’’ Journal of Food 1995. Nutrition, 68 (suppl):1500S–1504S, 1998. Protection, 43:525–527, 1980. 147. Balmir F., R. Staack, E. Jeffrey, M. D. 120. Kimura, S., J. Suwa, M. Ito, and H. 136. Teixeira, S., S.M. Potter, R. Weigel, S. Jimenez, L. Wang, and S. M. Potter, ‘‘An Sato, ‘‘Development of Malignant Goiter by Hannum, C.M. Hasler, and J.W. Erdman, Jr., Extract of Soy Flour Influences Serum Defatted Soybean with Iodine-free Diet in ‘‘Effects of Feeding 4 Levels of Soy Protein Cholesterol and Thyroid Hormones in Rats Rats,’’ Gann, 67:763–765, 1976. for 3 and 6 Weeks on Blood Lipids and and Hamsters,’’ Journal of Nutrition, 121. Van Wyk, J. J., M. B. Arnold, J. Wynn, Apolipoproteins in Moderately 126:3046–3053, 1996. and F. Pepper, ‘‘The Effects of a Soybean Hypercholesterolemic Men,’’ submitted. 148. Sugano, M., and K. Koba, ‘‘Dietary Product on Thyroid Function in Humans,’’ 137. Wong, W.W., E.O.B. Smith, J.E. Stuff, Protein and Lipid Metabolism: A Pediatrics, 24:752–760, 1959. D.L. Hachey, W.C. Heird, and H.J. Pownell, Multifunctional Effect,’’ Annals of the New 122. Hydovitz, J. D., ‘‘Occurrence of Goiter ‘‘Cholesterol-lowering Effect of Soy Protein York Academy of Sciences, 676:215–222, in an Infant on a Soy Diet,’’ New England in Normocholesterolemic and 1993. Journal of Medicine, 262:351–353, 1960. Hypercholesterolemic Men,’’ American 149. Kirk, E. A., P. Sutherland, S. A. Wang, 123. Shepard, T. H., G. E. Pyne, J. E. Journal of Clinical Nutrition, 68 A. Chait, and R. C. Leboeuf, ‘‘Dietary Kirschvink, and M. McLean, ‘‘Soybean (suppl):1385S–1389S, 1998. Isoflavones Reduce Plasma Cholesterol and Goiter: Report of Three Cases,’’ New England 138. Fumagalli, R., L. Soleri, R. Farina, R. Atherosclerosis in C57BL/6 Mice But Not Journal of Medicine, 262:1099–1103, 1960. Musanti, O. Mantero, G. Noseda, E. Gatti, and LDL Receptor-deficient Mice,’’ Journal of 124. Pinchera, A., M. H. MacGillivray, J. D. C.R. Sirtori, ‘‘Fecal Cholesterol Excretion Nutrition, 128:954–959, 1998. Crawford, and A. G. Freeman, ‘‘Thyroid Studies in Type II Hypercholesterolemic 150. Tovar-Palacio, C., S. M. Potter, J. C. Refractoriness in an Athyreotic Cretin Fed Patients Treated with the Soybean Protein Hafermann, and N. F. Shay, ‘‘Intake of Soy Soybean Formula,’’ New England Journal of Diet,’’ Atherosclerosis, 43:341–353, 1982. Protein and Soy Protein Extracts Influences Medicine, 273:83–87, 1965. 139. Jenkins, D. J. A., C. W. C. Kendall, C. Lipid Metabolism and Hepatic Gene 125. Chorazy, P. A., S. Himelhoch, N. J. C. Mehling, T. Parker, A. V. Rao, S. Agarwal, Expression in Gerbils,’’ Journal of Nutrition, Hopwood, N. G. Greger, and D. C. Postellon, R. Novokmet, P. J. H. Jones, M. Raeini, J. A. 128:839–842, 1998. ‘‘Persistent Hypothyroidism in an Infant Story, E. Furumoto, E. Vidgen, L. C. Griffin, 151. Anthony, M. S., G. L. Burk, C. L. Receiving a Soy Formula: Case Report and S. C. Cunnane, M. A. Ryan, and P. W. Hughes Jr., and T. B. Clarkson, ‘‘Does Soy Review of the Literature,’’ Pediatrics, 96:148– Connolly, ‘‘Combined Effect of Vegetable Supplementation Improve Coronary Heart 150, 1995. Protein (Soy) and Soluble Fiber Added to a Disease (CHD) Risk?’’ abstract, Circulation, 126. Ishizuki, Y., Y. Hirooka, Y. Murata, Standard Cholesterol-lowering Diet,’’ 91:I–925, 1995. and K. Togashi, ‘‘The Effects on the Thyroid Metabolism, 48:809–816, 1999. 152. Colquhoun, D. M., R. J. Hicks, and G. Gland of Soybeans Administered 140. Jenkins, D. J. A., C. W. C. Kendall, E. E. Kelly, ‘‘Lack of Effect of Isoflavones on Experimentally in Healthy Subjects,’’ Nippon Vidgen, C. C. Mehling, T. Parker, H. Seyler, Human Serum Lipids and Lipoproteins,’’ Naibunpi Gakkai Zasshi, 67:622–629, 1991. D. Faulkner, M. Garsetti, L. C. Griffin, S. abstract, Arteriosclerosis, 109:75, 1994. 127. Divi, R.L., H. C. Chang, and D. R. Agarwal, A. V. Rao, S. C. Cunnane, M. A. 153. Hodgson J. M., I. B. Puddey, L. J. Doerge, ‘‘Anti-thyroid Isoflavones from Ryan, P. W. Connolly, L. A. Leiter, V. Beilin, T. A. Mori, and K. D. Croft, Soybean: Isolation, Characterization, and Vuksan, and R. Josse, ‘‘The Effect on Serum ‘‘Supplementation with Isoflavonoid Mechanisms of Action,’’ Biochemical Lipids and Oxidized LDL of Supplementing Phytoestrogens Does Not Alter Serum Lipid Pharmacology, 54:1087–1096, 1997. Self-selected Low-fat Diets with Soluble Concentrations: A Randomized Controlled 128. Divi, R. L. and D. R. Doerge, Inhibition Fiber, Soy, and Vegetable Protein Foods,’’ Trial in Humans,’’ Journal of Nutrition, of Thyroid Peroxidase by Dietary submitted. 128:728–732, 1998. Flavonoids.’’ Chemical Research and 141. Washburn, S., G. L. Burke, T. Morgan, 154. Cassidy, A., S. Bingham, and K. Toxicology, 9:16–23, 1996. and M. Anthony, ‘‘Effect of Soy Protein Setchell, ‘‘Biological Effects of Isoflavones in

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Young Women: Importance of the Chemical PART 101ÐFOOD LABELING (2) Intakes of saturated fat exceed Composition of Soyabean Products,’’ British recommended levels in the diets of Journal of Nutrition, 74:587–601, 1995. The authority citation for 21 CFR part many people in the United States. One 155. Sirtori, C. R., E. Gatti, O. Mantero, F. 101 continues to read as follows: of the major public health Conti, E. Agradi, E. Tremoli, M. Sirtori, L. 1. Authority: 15 U.S.C. 1453, 1454, 1455; recommendations relative to CHD risk is Fraterrigo, L. Tavazzi, and D. Kritchevsky, 21 U.S.C. 321, 331, 342, 343, 348, 371. ‘‘Clinical Experience with the Soybean to consume less than 10 percent of Protein Diet in the Treatment of 2. Add § 101.82 to subpart E to read calories from saturated fat and an Hypercholesterolemia,’’ American Journal of as follows: average of 30 percent or less of total Clinical Nutrition, 32:1645–1658, 1979. calories from all fat. Recommended § 101.82 Health claims: Soy protein and 156. Sirtori, C. R., M. R. Lovati, C. daily cholesterol intakes are 300 mg or risk of coronary heart disease (CHD). Manzoni, M. Monetti, F. Pazzucconi, and E. less per day. Scientific evidence Gatti, ‘‘Soy and Cholesterol Reduction: (a) Relationship between diets that are demonstrates that diets low in saturated Clinical Experience,’’ Journal of Nutrition, low in saturated fat and cholesterol and fat and cholesterol are associated with 125(suppl):589S–605S, 1995. that include soy protein and the risk of lower blood total and LDL-cholesterol 157. Sirtori, C. R., Universita Degli Studi di CHD. (1) Cardiovascular disease means levels. Soy protein, when included in a Milano, letter to E. Gugger, Archer Daniels diseases of the heart and circulatory low saturated fat and cholesterol diet, Midland Company, May 25, 1997. system. CHD is one of the most common also helps to lower blood total and LDL- 158. USDA Food Composition Laboratory and serious forms of cardiovascular and Nutrition Data Laboratory, Department of cholesterol levels. disease and refers to diseases of the (c) Requirements. (1) All requirements Food Science and Human Nutrition of the heart muscle and supporting blood Iowa State University, ‘‘USDA-Iowa State set forth in § 101.14 shall be met. vessels. High blood total cholesterol and (2) Specific requirements—(i) Nature University Database on the Isoflavone low density lipoprotein (LDL)- Content of Foods—1999,’’ US Department of of the claim. A health claim associating Agriculture. cholesterol levels are associated with diets that are low in saturated fat and 159. ‘‘The Keystone National Policy Dialog increased risk of developing CHD. High cholesterol and that include soy protein on Food, Nutrition, and Health: Final CHD rates occur among people with with reduced risk of heart disease may Report,’’ Keystone, CO, 1996, pp. 57–70. high total cholesterol levels of 240 be made on the label or labeling of a 160. Levy, A., B. Derby, and B. Roe, milligrams per deciliter (mg/dL) (6.21 food described in paragraph (c)(2)(iii) of ‘‘Consumer Impacts of Health Claims: An millimole per liter (mmol/L)) or above this section, provided that: Experimental Study, FDA Center for Food and LDL-cholesterol levels of 160 mg/dL (A) The claim states that diets that are Safety and Applied Nutrition, Division of (4.13 mmol/L) or above. Borderline high low in saturated fat and cholesterol and Market Studies,’’ January 1997. risk total cholesterol levels range from 161. Office of Premarket Approval, Center that include soy protein ‘‘may’’ or 200 to 239 mg/dL (5.17 to 6.18 mmol/ ‘‘might’’ reduce the risk of heart disease; for Food Safety and Applied Nutrition and L) and 130 to 159 mg/dL (3.36 to 4.11 Office of Surveillance and Compliance, (B) In specifying the disease, the mmol/L) of LDL-cholesterol. The Center for Veterinary Medicine, Food and claim uses the following terms: ‘‘heart Drug Administration, ‘‘Guidance on scientific evidence establishes that diets disease’’ or ‘‘coronary heart disease’’; Consultation Procedures: Foods Derived from high in saturated fat and cholesterol are (C) In specifying the substance, the New Plant Varieties,’’ October, 1997. associated with increased levels of claim uses the term ‘‘soy protein’’; 162. Rulis, A. M., Office of Premarket blood total and LDL-cholesterol and, (D) In specifying the fat component, Approval, Center for Food Safety and thus, with increased risk of CHD. the claim uses the terms ‘‘saturated fat’’ Applied Nutrition, FDA, ‘‘Letter to Diane Re, (2) Populations with a low incidence and ‘‘cholesterol’’; The Agricultural Group of Monsanto,’’ of CHD tend to have relatively low (E) The claim does not attribute any January 27, 1995. blood total cholesterol and LDL- degree of risk reduction for CHD to diets 163. Food and Drug Administration, cholesterol levels. These populations that are low in saturated fat and ‘‘Memorandum of Conference,’’ Participants: also tend to have dietary patterns that cholesterol and that include soy protein; Monsanto and FDA, September 19, 1994. are not only low in total fat, especially 164. Rulis, A. M., Office of Premarket (F) The claim does not imply that Approval, Center for Food Safety and saturated fat and cholesterol, but are consumption of diets that are low in Applied Nutrition, FDA, ‘‘Letter to Sally L. also relatively high in plant foods that saturated fat and cholesterol and that Van Wert, AgrEvo USA Company,’’ , contain dietary fiber and other include soy protein is the only 1998. components. recognized means of achieving a 165. Food and Drug Administration, ‘‘Note (3) Scientific evidence demonstrates reduced risk of CHD; and to the File: BNF0055—Glufosinate-tolerant that diets low in saturated fat and (G) The claim specifies the daily Soybean Lines,’’ April 21, 1998. cholesterol may reduce the risk of CHD. dietary intake of soy protein that is 166. Rulis, A. M., Office of Premarket Other evidence demonstrates that the necessary to reduce the risk of coronary Approval, Center for Food Safety and addition of soy protein to a diet that is heart disease and the contribution one Applied Nutrition, FDA, ‘‘Letter to Edward low in saturated fat and cholesterol may serving of the product makes to the W. Raliegh, DuPont Agricultural Products,’’ also help to reduce the risk of CHD. , 1997. specified daily dietary intake level. The (b) Significance of the relationship 167. Food and Drug Administration, daily dietary intake level of soy protein ‘‘Memorandum of Conference,’’ Participants: between diets that are low in saturated that has been associated with reduced DuPont and FDA, , 1996. fat and cholesterol and that include soy risk of coronary heart disease is 25 protein and the risk of CHD. (1) CHD is grams (g) or more per day of soy protein. List of Subjects in 21 CFR Part 101 a major public health concern in the (ii) Nature of the substance. (A) Soy United States. It accounts for more Food labeling, Nutrition, Reporting protein from the legume seed Glycine deaths than any other disease or group and recordkeeping requirements. max. of diseases. Early management of risk (B) FDA will assess qualifying levels Therefore, under the Federal Food, factors for CHD is a major public health of soy protein in the following fashion: Drug, and Cosmetic Act and under goal that can assist in reducing risk of FDA will measure total protein content authority delegated to the Commissioner CHD. High blood total and LDL- by the appropriate method of analysis of Food and Drugs, 21 CFR part 101 is cholesterol are major modifiable risk given in the ‘‘Official Methods of amended as follows: factors in the development of CHD. Analysis of the AOAC International,’’ as

VerDate 12-OCT-99 11:58 Oct 25, 1999 Jkt 190000 PO 00000 Frm 00034 Fmt 4701 Sfmt 4700 E:\FR\FM\26OCR2.XXX pfrm04 PsN: 26OCR2 Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 / Rules and Regulations 57733 described at § 101.9(c)(7). For products (d) Optional information. (1) The their physicians for medical advice and that contain no sources of protein other claim may state that the development of treatment. If the claim defines high or than soy, FDA will consider the amount heart disease depends on many factors normal blood total and LDL-cholesterol of soy protein as equivalent to the total and may identify one or more of the levels, then the claim shall state that protein content. For products that following risk factors for heart disease individuals with high blood cholesterol contain a source or sources of protein in about which there is general scientific should consult their physicians for addition to soy, FDA will, using the agreement: A family history of CHD; medical advice and treatment; measurement of total protein content, elevated blood total and LDL- (6) The claim may include calculate the soy protein content based cholesterol; excess body weight; high information on the number of people in on the ratio of soy protein ingredients to blood pressure; cigarette smoking; the United States who have heart total protein ingredients in the product. diabetes; and physical inactivity. The disease. The sources of this information FDA will base its calculation on claim may also provide additional shall be identified, and it shall be information identified and supplied by information about the benefits of current information from the National manufacturers, such as nutrient data exercise and management of body Center for Health Statistics, the National bases or analyses, recipes or weight to help lower the risk of heart Institutes of Health, or ‘‘Nutrition and formulations, purchase orders for disease; Your Health: Dietary Guidelines for ingredients, or any other information (2) The claim may state that the Americans,’’ USDA and DHHS, GPO; relationship between intake of diets that that reasonably substantiates the ratio of (e) Model health claim. The following soy protein to total protein. are low in saturated fat and cholesterol and that include soy protein and model health claims may be used in Manufacturers must maintain records food labeling to describe the sufficient to substantiate the claim for as reduced risk of heart disease is through the intermediate link of ‘‘blood relationship between diets that are low long as the products are marketed and in saturated fat and cholesterol and that provide these records, on written cholesterol’’ or ‘‘blood total and LDL- cholesterol’’; include soy protein and reduced risk of request, to appropriate regulatory heart disease: officials. (3) The claim may include information from paragraphs (a) and (b) (1) 25 grams of soy protein a day, as (iii) Nature of the food eligible to bear of this section, which summarize the part of a diet low in saturated fat and the claim. (A) The food product shall relationship between diets that are low cholesterol, may reduce the risk of heart contain at least 6.25 g of soy protein per in saturated fat and cholesterol and that disease. A serving of [name of food] reference amount customarily include soy protein and CHD and the supplies ll grams of soy protein. consumed of the food product; significance of the relationship; (2) Diets low in saturated fat and (B) The food shall meet the nutrient (4) The claim may state that a diet low cholesterol that include 25 grams of soy content requirements in § 101.62 for a in saturated fat and cholesterol that protein a day may reduce the risk of ‘‘low saturated fat’’ and ‘‘low includes soy protein is consistent with heart disease. One serving of [name of cholesterol’’ food; and ‘‘Nutrition and Your Health: Dietary food] provides ll grams of soy (C) The food shall meet the nutrient Guidelines for Americans,’’ U.S. protein. content requirement in § 101.62 for a Department of Agriculture (USDA) and ‘‘low fat’’ food, unless it consists of or Department of Health and Human Dated: October 19, 1999. is derived from whole soybeans and Services (DHHS), Government Printing Margaret M. Dotzel, contains no fat in addition to the fat Office (GPO); Acting Associate Commissioner for Policy. inherently present in the whole (5) The claim may state that [FR Doc. 99–27693 Filed 10–20–99; 10:35 soybeans it contains or from which it is individuals with elevated blood total a.m.] derived. and LDL-cholesterol should consult BILLING CODE 4160±01±P

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