Use of Herbal Products in Pregnancy, Breastfeeding, and Childhood Workshop 

December 16, 2003
Sheraton Atlanta
Atlanta, GA

This meeting was held in conjunction with the National Children's Study, which is led by a consortium of federal agency partners: the U.S. Department of Health and Human Services (including the National Institute of Child Health and Human Development [NICHD] and the National Institute of Environmental Health Sciences [NIEHS], two parts of the National Institutes of Health, and the Centers for Disease Control and Prevention [CDC]) and the U.S. Environmental Protection Agency (EPA).

Co-Chairs: Margaret A. Honein, Ph.D., National Center on Birth Defects and Developmental Disabilities, CDC, DHHS, and Allen A. Mitchell, M.D., Slone Epidemiology Center, Boston University

Opening Remarks

Dr. Mitchell welcomed the workshop participants and introduced Dr. Honein as co-chair. He said that the purpose of the workshop is to discuss whether the use of herbal products in pregnancy, breastfeeding, and childhood could be incorporated into the National Children's Study. The workshop should not address issues such as safety, efficacy, or appropriateness of herbal products but should attempt to develop a rational framework of how to examine the use these products in Study participants. Dr. Mitchell identified several other topics to address during the workshop:

• What are herbal products?
• How are herbal products used?
• What are the patterns and prevalence of use?
• How are patterns of use changing?
• What kind of herbal use can be expected in the Study?

Dr. Mitchell explained that these topics and several others would be addressed in eight presentations; that because of limitations of time, participants would have a working lunch; and that the workshop would end with a discussion of the best approach for examining use of herbal products for the Study, given the information presented.

Herbal Use in Pregnancy: A Tale of Two Studies
Carol Louik, Sc.D., Slone Epidemiology Center, Boston University

Dr. Louik began her presentation by acknowledging and thanking her co-workers at the Slone Epidemiology Center. The presentation summarized information on herbal use during pregnancy from two studies: (1) the National Birth Defects Study (NBDPS), which was conducted by the Centers for Disease Control and Prevention, and (2) the Pregnancy Health Interview Study, which was conducted by the Slone Epidemiology Center.

NBDPS was a multi-site case-control study of major birth defects in eight states. Information was gathered during detailed maternal interviews about exposures from three months before pregnancy through the end of pregnancy. Mothers were interviewed between six weeks and 24 months after expected date of delivery. The study analyzed births from October 1, 1997, through December 31, 2000. During this period, 2,599 control mothers were interviewed. A question specifically on herbal use was added in mid-2000. The results indicated that, of those interviewed before the specific herbal question was added, 5.4 percent of mothers reported using an herbal product from three months before pregnancy through the end of pregnancy, whereas after the question was added, 12.8 percent reported using an herbal product. The prevalence of any herbal use during pregnancy was 4.3 percent before the specific question was added and 10.9 percent after the question was added. Data on prevalence of herbal use during pregnancy by site, maternal age, maternal education, maternal race/ethnicity, and pregnancy month appear in Attachment A. The most commonly reported herbal products were:

• Chamomile
• Herbal tea
• Unspecified herbal/folk remedy
• Vicks VapoRub®
• Echinacea
• Ginger
• Peppermint
• Ginseng
• One-source multi-vitamin.

The objective of the Pregnancy Health Interview Study was to describe prevalence and patterns of herbal treatment used among pregnant women in the Slone Epidemiology Center Births Defects Study. Study subjects were participants in an ongoing case-control surveillance for birth defects and included infants with congenital malformations and a sample of nonmalformed infants identified at birth and at tertiary care hospitals in areas around Boston, Philadelphia, Toronto, and San Diego. Mothers were interviewed by telephone within six months of birth. Questions specifically addressing herbal product use were added in 1998. The definitions of herbal products in this study are given in Attachment A.

Of the 10,219 women interviewed between 1998 and 2002, 15.8 percent reported using any herbal preparation at any time during pregnancy. The most commonly reported indications for herbal use were:

• Cold or flu (3.1 percent)
• Vitamin (1.9 percent)
• Nausea and vomiting (0.7 percent)
• Weight reduction (0.3 percent).

The most commonly reported single component herbal treatments were:

• Echinacea
• Ginger
• Herbal tea
• Avena sativa
• Herbal, not otherwise stated.

The most commonly reported multi-component herbal products were:

• Vitamins
• Cough drops
• Topicals
• Metabolife®
• Xenadrine®.

Because herbal products can now be found in multi-component vitamins, Dr. Louik explained that not all herbal use is voluntary; some use may be inadvertent. Data on prevalence of type of herbal use according to education, race/ethnicity, marital status, and body mass index appear in Attachment A. The study also examined several trends in use (see Attachment A).

According to Dr. Louik, both studies are compatible in the following terms:

• Overall use (11—15 percent)
• Increasing use with increasing age
• Increasing use with increasing level of education
• Variability with geographic region.

The findings of the Pregnancy Health Interview Study revealed the following:

• Approximately 25 percent of herbal exposure occurs as a component in a multi-vitamin.
• Most common indications include pregnancy-related conditions, for example, nausea and vomiting.
• Use of herbal products increases with body mass index.

In concluding, Dr. Louik noted that for any individual herbal product, rates of use are low (the highest being echinacea at 0.7 percent) and that trends in the use of specific products are unpredictable.

Use of Herbal Products for Weight Loss by Reproductive-Age Women
Heidi L. Blanck, Ph.D., National Center for Chronic Disease Prevention and Health Promotion, CDC, DHHS

Dr. Blanck presented the results of four studies that examined herbal use among women of childbearing age. Dr. Blanck explained that successful weight loss and maintenance depend on long-term lifestyle changes, such as reducing calories and increasing physical activity. However, because these changes are difficult, easily obtained nonprescription (NP) weight loss products are appealing to the increasingly overweight U.S. population. NP weight loss products include both over-the-counter products and dietary supplements that include herbal products. She noted that herbal products are regulated as dietary supplements under the 1994 Dietary Supplement Health and Education Act (DSHEA). Under DSHEA, the burden of proof is not on the manufacturer, but on the Food and Drug Administration (FDA), which must demonstrate that a product is unsafe before it can take regulatory action. The data sources for this presentation were the Behavioral Risk Factor Surveillance Survey (BRFSS) and the National Physical Activity and Weight Loss Survey (NPAWLS). Both data sources were telephone surveys of noninstitutionalized adults 18 years of age and older. Details on these surveys and the specific survey questions appear in Attachment B. Additional information on BRFSS can be found at www.cdc.gov/brfss. The survey results were presented as four separate studies:

• NP weight loss product use: Results from a multi-state survey, BRFSS 1996-1998
• NP weight loss product use: Results from a multi-state survey, BRFSS 2001-2003
• NP weight loss product use: Results from a national survey, NPAWLS 2002
• Medicinal herb use: Results from North Carolina BRFSS 2000-2001.

BRFSS 1996—1998 results indicated that overall use of NP weight loss products was common among women, especially young obese women, with more than 25 percent reporting use. The rates of NP weight loss product use in the two years prior to the survey were:

• 18-34 years    17.3 percent
• 35-54 years    12.8 percent.

The rates for the use of ephedra/ephedrine products were:

• 18-34 years    1.9 percent
• 35-54 years    1.0 percent.

The rates for the use of Dexatrim®/Acutrim® products were:

• 18-34 years    3.0 percent
• 35-54 years    2.2 percent.

Dr. Blanck noted that the BRFSS survey did not collect information as to the dose, duration or frequency of use, prior use of these products, name of products, adverse effects, amount of weight loss attributable to product, or whether users of NP weight loss products told their physicians about use.

BRFSS 2001-2003 results indicated that:

• 11.2 percent of all women surveyed had used NP weight loss products in the previous 2 years
• 44.0 percent of NP products named by users contained the herb ephedra
• When these users were asked whether the product they took contained the herb ephedra:
  • 49.0 percent reported "yes"
  • 28.4 percent reported "no"
  • 22.6 percent reported, "I do not know or I'm not sure."

According to Dr. Blanck, these results suggest that many NP ephedra weight loss product users do not think or are unsure that they are taking a diet product with this herb.

NPAWLS 2002 results indicated the following prevalence of NP weight loss product use, ever:

• 18-34 years     25.7 percent
• 35-54 years     24.6 percent.

The objective of the North Carolina BRFSS 2000-2001 was to estimate the prevalence and frequency of medicinal herb use among adults, describe the reasons for use, and determine the proportion of adults who gave herbs to their children. The prevalence of medicinal herb use among women was:

• 18—34 years     23.0 percent (past year)     27.7 percent (daily use)
• 35—54 years     23.6 percent (past year)     33.9 percent (daily use).

This study revealed that among adults with at least one child younger than 18 years of age in their household, 5 percent reported giving their children herbal medicines in the past 12 months. Adults who were older than 35 years of age had higher odds of giving their children herbal medicines in the past 12 months compared with those 18-34 years of age. In addition, adults without health coverage anytime in the past 12 months had higher odds of having given their children medicinal herbs in the past 12 months, compared with parents with consistent health coverage. As expected, parents who had themselves not used herbs in the past 12 months had much lower odds of giving medicinal herbs to their children compared with parents who had used herbs in the past 12 months.

Dr. Blanck listed the following conclusions on the use of herbal weight loss products:

• Prevalence of past-two-year use of NP product use ranges from 11 percent to 17 percent among women of reproductive age.
• There is a higher prevalence of use among women who are trying to lose weight.
• Of reproductive-age women, 25 percent have used a weight loss product at some time.
• About half of the women surveyed are unsure of or do not know product ingredients.

Herbal and Dietary Supplement Use During Lactation
Katherine Shealy, M.P.H., IBCLC, RLC, National Center for Chronic Disease Prevention and Health Promotion, CDC, DHHS

Ms. Shealy explained that the prevalence, characteristics, and impact of use of herbal and dietary supplemental products during the perinatal period is complex, not well understood, and only just now beginning to be studied. She presented an overview of some of the most important issues of use of these products during breastfeeding from the surveillance, clinical, and epidemiologic perspectives. Details of Ms. Shealy's presentation are in Attachment C.

A group of herbal preparations called galactogogues has been consistently linked to human lactation throughout history. Although prevalence estimates for the United States are especially vague, there is indication that as breastfeeding prevalence has increased, so has use of galactogogues. Ms. Shealy noted that although many people believe they understand what is meant by an herbal or dietary supplement, the practical application of such definitions and labels is not clear-cut. This is particularly true for many of the commonly used and discussed herbal and dietary supplements during lactation and is especially problematic in terms of surveillance. Whether an item is considered food, herbal product, or dietary supplement often depends on how and why it is being used. Therefore, it is important to differentiate between a definition of galactogogues as items that increase milk production versus items used to increase milk production, as far more items are used than are known to actually affect milk production.

Most of the herbs used specifically related to lactation are galactogogues, although a few herbs are widely acknowledged to inhibit milk production and are thus used by women during weaning. Some other herbs are used to help alleviate gas in the infant. These can be administered directly to the infant or to the mother to be taken in by the infant through milk. Often these are the same herbs that are used as galactogogues. Herbs used as galactogogues are more widely used for general gastrointestinal issues.

Two main prescription galactogogues are used in the United States. Until recently, metoclopramide was most predominant, but in the last few years domperidone has become increasingly preferred.

Ms. Shealy noted that there are four main categories NP galactogogues:

• Herbal teas
• Herbal tablets/pills
• "Medicinal" foods
• Herbal tinctures.

To complicate things further, these most common NP galactogogues can vary significantly by region, ethnic group, parity, and population density. NP galactogogues include items such as:

• B-complex vitamins (tablet)
• Brewer's yeast (tablet, medicinal food)
• Nonalcoholic beer (medicinal food)
• Red raspberry leaf (tea, tablet)
• Oatmeal (medicinal food)
• Blessed thistle (tea, tablet, tincture)
• Coriander (tea, tablet, medicinal food)
• Fenugreek (tea, tablet, medicinal food, tincture)
• More Milk Plus® (tincture)
• Mother's Milk Tea® (tea).

Ms. Shealy explained that some galactogogues might include extra items, the prevalence of which depends on a variety of factors. She listed three galactogogues that are prevalent among Latinas in Texas, but which may not be related to consumption in other Latina groups in other areas of the United States. Examples of Latina galactogogues are:

• Te de Manzanilla (chamomile tea)
• Agua de Arroz (rice milk made of strained rice, condensed milk, water, cinnamon, and vanilla)
• Atole (a thick, porridge-like drink made of cornmeal, water, sugar, cinnamon, molasses, and vanilla).

Ms. Shealy said that determining the prevalence of use of herbs throughout breastfeeding would a challenge for the Study. Population-based breastfeeding data are limited in distribution and limited in scope in that existing data have not assessed herbal or dietary supplement use in this context. There is no consensus as to which products are of interest. Some studies were primarily concerned with potentially harmful herbs, yet few data confirm which herbs these are. There is no consensus on definitions. Some studies have been primarily concerned with the behavior of herb use with potential effect as a secondary concern, whereas others are concerned first with biologic effect. These approaches change the range of items of interest.

Clinical expert opinion on galactogogues use comes from two main sources: (1) experts in drugs and lactation and (2) experts in lactation management. According to one researcher (Hale), at least 15 percent of breastfeeding women use herbal galactogogues at some point. Users are diverse and include working mothers, mothers with babies in neonatal intensive care units, and mothers who are highly educated. Little is known of biologic outcomes from the use of galactogogues. The known side effects are extremely limited. The use of fenugreek has possible links with:

• Asthma
• Diarrhea in mother and possibly in baby
• Gastrointestinal bleeding
• Reduced blood glucose.

Ms. Shealy described a recent effort by the Maternal and Child Nutrition Branch, National Center for Chronic Disease Prevention and Health Promotion, CDC, DHHS, to complete cognitive testing of some herbal questions for the national Infant Feeding Practices Survey that is being designed in conjunction with the FDA. Some of the as-of-yet unresolved issues include surveillance dilemmas such as ethical and logistical issues. There is discomfort in including a list that may be seen as recommended items for breastfeeding mothers, especially given that some of the items FDA wishes to include would be included because of safety concerns, such as star anise. In fact, in cognitive testing, mothers looked over the list and said things like "Oh! I didn't know these were for breastfeeding! Maybe I should try these!" Beyond the specific potential risk of some items included in the list, other items were included that are widely acknowledged to inhibit lactation. This poses the ethical problem of leaving a mother thinking that anything on that list is good for breastfeeding. Researchers have toyed with the idea of a disclaimer, which only seems to draw more attention to the list and the issues, and in fact even the wording of the disclaimer is problematic.

Ethical issues include:

• Perceived "recommendation" when asked
• Inclusion of items clinically acknowledged to adversely affect lactation
• Disclaimers.

Beyond the ethical quandary is a logistical problem of both how long a list to include when researchers do not know which items should be included, as well as the potential of totally different lists for different areas of the country. Furthermore, there is concern among those designing the Survey regarding which types of herbal and dietary supplements should be included or which forms. Some feel that only "dangerous" items should be included, although researchers do not really know which these are. Others feel that only "effective" items should be included, although researchers do not know which these are. Some feel that only "potent" formulations (that is, pill versus tea versus tincture) of items should be included, although this differs across items and a wide variety of other factors.

Logistical issues include:

• Length of the list
  • Completeness versus response potential
  • Ethnic and geographic variation
• Content of the list
  • "Dangerous" items only
  • "Effective" items only
  • "Potent" formulations only.

Ms. Shealy commented on long-chain polyunsaturated fatty acid (LCPUFA) supplements. Some breastfeeding mothers consume herbal and dietary supplements to "improve" the quality of their breast milk. In the United States, medicinal foods or herbal or dietary supplements taken to improve the quality versus quantity of breast milk are relatively rare. The main sources used by breastfeeding mothers are flaxseed oil and fish oil, in either tablet or medicinal food form.

All infant formula manufacturers have released new products containing artificial formulations of LCPUFAs. The national Infant Feeding Practices Survey includes items related to use of these new infant formulas as part of larger questions about infant formula use, in response to concerns about possible elevated rates of adverse effects of these formulas over typical infant formula. Clinical trials have demonstrated beneficial effects of these formulations only on preterm infants. The Infant Feeding Practices Survey will track sources of infant formula brand information, as well as formula brand and formulation switching.

Maternal tablets/medicinal foods include:

• Flaxseed oil
• Fish oil.

LCPUFA-enhanced infant formulas include:

• Enfamil® LIPIL® (Mead Johnson)
• Similac® Advance® (Ross/Abbott)
• Good Start Supreme® (Nestle)
• Various store brands (Wyeth).

Ms. Shealy concluded by stating that:

• Herbs, dietary supplements, and medicinal foods are widely used during lactation.
• Little is known about prevalence of use.
• Little is known about effects of use.
• Herbs, dietary supplements, and medicinal foods need to be better studied and understood, especially in the perinatal period.

Herbal Use in the U.S. Pediatric Population: The Slone Survey
Carol Louik, Sc.D., Slone Epidemiology Center, Boston University

Dr. Louik began her second presentation by briefly reviewing four previous studies on the use of herbal products in pediatric populations. The results of these studies indicated a prevalence of herbal products ranging from 2.8 percent for "dietary supplement" use to 9 percent for one-year prevalence. Two of the studies revealed 5 percent and 7 percent lifetime use. Details of these studies are given in Attachment D.

The primary focus of Dr. Louik's presentation was to present results from the Slone Study. The objective of the Slone Survey is to provide comprehensive, ongoing data on the use of all medications in the U.S. population, including:

• Prescription
• Nonprescription
• "Dietary supplements."

The Slone Survey is a random-digit dialing anonymous telephone survey of medication use in the U.S. population. Eligible subjects are residents of households in 48 states and the District of Columbia with telephones. The study has no age restrictions, but the survey is limited to one subject per household selected at random. Parents provide information for subjects under 14 years of age; subjects 14-17 years old may be interviewed directly, with parental permission. Data collection began in 1998 and is continuing. The survey collects the following information:

• Age
• Sex
• Details of all medications taken in the previous week, including prescriptions, over-the-counter (OTC) medications, and "dietary supplements"
• Race and Hispanic origin (U.S. Census categories)
• Years of education
• Income
• Zip code of residence
• Pregnancy status and last menstrual period (women 18-50 years old)
• Insurance coverage of medications.

Details of the drug information obtained includes the following:

• Drug names confirmed from bottles/packaging whenever possible
• Perceived reason for use
• Route of administration
• Number of days taken during the week
• Total duration of use for one or more day per week
• Dose and number of pills each day during the week for selected drugs (aspirin, acetaminophen, ibuprofen, naproxen, conjugated estrogens).

The demographic representativeness of Slone Survey 1998-2002, compared with U.S. Census 2000 data, is as follows:

	U.S. Census 2000	Slone Survey
Sample size ( n)	281,421,906	10,408
Age (median, in years)	35	34
Sex (male)	49%	46%
Race
White	75%	75%
African American	12%	10%
Native American	2%	1%
Asian/Pacific	7%	3%
Other/refused	4%	11%
Hispanic	13%	12%

The available data from the Slone Survey include information obtained from interviews completed between February 1998 and June 2003 ( n = 12,535):

Adults		10,162
Children (< 18 years)		2,331
Refused		42
Participation rate*		67 percent

*The average participation rate in other academic surveys is 50 percent (range 22-70 percent).

The pediatric sample included 2,331 children, from birth to 17 years of age. The number of pediatric subjects by year ranged from 591 to 360 (average = 466.2). The median age was nine years. The percentage of male subjects ranged from 57-47 percent.

For the survey, a dietary supplement was defined as a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients:

• An herb or other botanical
• An amino acid
• A dietary substance for human use to supplement the diet by increasing the total dietary intake
• A concentrate, metabolite, constituent, extract, or combination of any ingredient described above.

The results on the use (percentage) of medications in prior week indicated:

	Any use	Three or more
Any prescription, OTC,     or dietary supplement	55%	13%
Any dietary supplement	1.8%	0.2%

Details on the use of herbal and nonherbal dietary supplements during the previous week by age group, the use of herbals in prior week according to age and sex, and the use of herbals and nonherbal dietary supplements during the previous week by survey year are presented in Attachment D.

From 1998 through 2003, the top 10 dietary ingredients listed as being used in the previous week were as follows:

Ananas comosus		0.3 percent
Eucalyptus		0.3 percent
Broccoli		0.3 percent
Carrot		0.3 percent
Echinacea		0.3 percent
Parsley		0.3 percent
Malus species		0.3 percent
Spinacia		0.3 percent
Amylase		0.2 percent
Lipase		0.2 percent

The most common indications for use of herbals were as follows:

"Vitamin"/diet supplement		29 percent
Specific condition		8 percent
"Health"		13 percent
"Good for you"		6.7 percent.

Other indications for herbal use included:

• Prevent colds
• Immune booster
• Joints
• Help digestion
• Increase appetite
• Lose weight
• Keep arteries clean.

Dr. Louik concluded by summarizing some observations from the Slone Study:

• 11-year old male reported three products for treatment of attention deficit disorder: Mela-leuca mel-vita, Mela-leuca mela-cal, and Attend.
• Youngest reported herbal user was one-month-old male using Hyland's colic tabs. Ingredients for this product include Colocynth (bitter apple), Matricaria recutita (chamomile), and Dioscorea villosa (wild yam).
• Many subjects use multiple products.
  • Among the 41 subjects <18, 10 (25 percent) used more than one.
• Substantial use is as an ingredient in a multi-vitamin product.
  • Of the 45 distinct products identified, 19 (42 percent) include vitamins.
  • Of the 41 subjects, 15 (37 percent) were classified as herbal users only due to a vitamin product.
• Echinacea was used by five subjects.
  • There was no evidence of secular trend observed in pregnancy exposures.
• Among children, use of dietary supplements (apart from vitamins) varies by age, but overall is infrequent and does not appear to be dramatically increasing.

Herbal Products and Dietary Supplements: Use in Healthy and Chronically Ill Children
Laurie J. Moyer-Mileur, Ph.D., R.D., University of Utah Health Sciences Center

Dr. Moyer-Mileur began her presentation by reviewing what is currently known about the prevalence of herbal products and dietary supplements among children. She noted that dietary supplements now make up one of seven domains identified by the National Center for Complementary and Alternative Medicine, NIH, DHHS. Dietary supplements include:

• Vitamins and minerals
• Botanicals (that is, herbal and plant-derived products)
• Pre-probiotics
• Enzymes
• Amino acids/proteins
• Fatty acids.

In providing some background information, Dr. Moyer-Mileur said that the prevalence of dietary supplement use is reflected in sales figures:

• 1998-1999 (Hartman Group)
  • $10.4 billion
  • 71 percent of households reported some use
• 1999 ( Nutrition Business Journal) $120 million spent on children's products
• 2000 ( Prevention Magazine)
  • $8.5 billion
  • 58 million Americans.

Some of the sales figures for herbal remedies are as follows:

• 1999 (Reuters)
  • $15 billion
• 2000 (American Botanical Society)
  • $600 million at major grocery and drug stores
• 1994-1998, sales doubled.

Dr. Moyer-Mileur summarized the prevalence of herbal product use in children as follows:

• In the general pediatric population: 20-30 percent for dietary supplements in general
• In adolescents:
  • 50-75 percent use complementary and alternative medicine (CAM)
  • Herbals used by 75 percent of teens that use CAM
• In chronically ill children:
  • 19-70 percent
  • Limited to specific illness/disease, for example, cancer, asthma, juvenile rheumatoid arthritis.

A study by Sikand and Laken (1998; see Attachment E for details) revealed that few pediatricians ask patients about the use of herbal products. Of the pediatricians studied:

• 85 percent believed their patients were using CAM.
• 33 percent felt herbal remedies may be effective.
• 29 percent thought herbal remedies may be harmful.

In the next part of her presentation, Dr. Moyer-Mileur described the results from a pilot study to investigate the nature and prevalence of dietary supplement use by children and adolescents in Utah. She commented that the legislation that deregulated the dietary supplement industry was cosponsored by the senior Senator from Utah. The Dietary Supplement Health and Education Act of 1994 (DSHEA; P.L. 103-417) amends the Federal Food, Drug, and Cosmetic Act to establish standards with respect to dietary supplements and stipulates that manufacturers are not required to pre-market test their products. The State of Utah has the largest number of dietary supplement manufacturers per capita in the United States, and there is broad cultural acceptance of natural products throughout the state.

Dr. Moyer-Mileur listed the specific aims of the Utah pilot study:

• To determine prevalence of dietary supplement use by children in health and disease
• To identify supplements taken and rationale for their use
• To document perceived benefits and problems associated with supplement use.

The study method consisted of a 32-item self-report survey completed by a parent. Of the subjects surveyed, 638 were healthy children who had visited one of five private-practice or community clinics in the Salt Lake City metropolitan area. There were 505 chronically ill subjects who visited outpatient clinics at the Primary Children's Medical Center, University of Utah Health Sciences Center. The survey was conducted from February 2001 to February 2002.

The survey questions were concerned with:

• Demographics
• Health history
• Type of supplement
  • Vitamin/minerals
  • Herbal products
  • Probiotics
• Perceived benefit
• Perceived side effects
• Information source
• Monthly cost
• Use discussed with health care provider?

Characteristics of the study populations included the following:

Healthy Subjects	Chronically Ill Subjects
n = 638 52% male Reason for visit : Routine check-up (46%) Acute illness (37%) Injury (15%)	n = 505 56% male Reason for visit : Asthma Cancer (solid tumors and leukemia) Cystic fibrosis Diabetes Liver/renal transplant Neurobiological disorders Rheumatologic disorders Seizures

Demographics on the study populations are given in Attachment E.

The survey results revealed that for healthy subjects, 45 percent were currently using vitamin/mineral supplements and that 10 percent had used vitamins/minerals within the past 6 months. Approximately 13 percent of healthy subjects were currently using herbal products, and approximately 4 percent had used herbal products within the past six months. Of the chronically ill subjects, 39 percent were currently using vitamin/mineral supplements, and about 3 percent had used vitamins/minerals within the past six months. Approximately 17 percent of chronically ill subjects were currently using herbal products, and about 3 percent had used herbal products in the past 6 months. Of the chronically ill subjects, those with cystic fibrosis had the highest percentage of dietary supplement use. Additional information on the distribution of nonprescribed dietary supplement in chronically ill children is presented in Attachment E.

The most commonly used dietary supplements in study subjects are summarized below:

Healthy Subjects	Chronically Ill Subjects
Vitamin/mineral Multi-vitamin/mineral Fluoride Calcium Iron Herbal products Echinacea (55% White) Herbal teas/infusions (95% Hispanic) Chamomile Chaparrel Mint Garlic	Vitamin/mineral Multi-vitamin/mineral Single vitamin/mineral Calcium Fat-soluble vitamins Iron, magnesium Herbal products Echinacea Mixture Dietary Supplement Probiotics Anti-oxidants Enzymes Disease-specific (such as Nutravene D)

The study subjects listed the following reasons as motivation for use of dietary supplements:

Healthy Subjects		Chronically Ill Subjects
General health Supplement diet Prevent disease		General health Supplement diet Treat disease Prevent exacerbation of disease Greater sense of control Holistic approach to care Dissatisfied with conventional treatment

In reviewing the information sources of dietary supplements for healthy and chronically ill, Dr. Moyer-Mileur commented on the diversity of sources: The information sources were not the same for every product. The information sources listed by subject population are as follows:

Healthy Subjects		Chronically Ill Subjects
MD Family Media Friend Other Internet		MD Pharmacy/store Media Support groups

When subjects were asked if they had discussed the use of dietary supplements with his or her health care provider, 62 percent of healthy subjects said they had, but distribution was not equal between non-Hispanic Whites and Hispanics. When asked "Why not?," healthy subjects responded as follows:

• Did not think important (45 percent)
• Used before MD involvement (22 percent)
• MD never asked (20 percent)
• Afraid MD would be negative (11 percent).

Among the chronically ill subjects, 80.2 percent said they had discussed the use of dietary supplements with their physicians. However, subjects with diabetes and asthma were least likely to discuss this issue with a doctor, and subjects with cystic fibrosis and transplant patients most likely to discuss this issue. When asked "Why not?," chronically ill subjects responded as follows:

• Did not think important (33 percent)
• Afraid MD would be negative (33 percent)
• MD never asked (21 percent)
• Used before MD involvement (10 percent).

Dr. Moyer-Mileur summarized the lessons learned from her review of prevalence of herbal products and dietary supplements among children:

• Herbal product and dietary supplement use
  • Differs between ethnic groups
  • Is more prevalent in chronically ill populations
• Identification of specific products, dosage, and actual use is problematic
• Parent and health care provider knowledge of herbal products and dietary supplements is limited.

The specific concerns about the use of herbal products and dietary supplements among children are:

• Efficacy
• Safety
• Drug-herb interactions
• Herb-herb interactions
• Children are not little adults.

In concluding, Dr. Moyer-Mileur listed some of the future needs for studies on use of herbal products and dietary supplements among children:

• Larger regional and national randomized surveys of use
• Target all CAM domains
• Repeated annually to identify trends and potential risks and/or benefits to normal growth and development.

What Do People Call Their Herbal Products, How Do They Use Them, and How Do These Vary by Culture and Geography?
Bonnie B. O'Connor, Ph.D., School of Medicine, Brown University

Using a more informal approach, Dr. Brown explained that, in investigating the use of herbal products, how a researcher asks a question often determines the answer. She noted that there are very culturally specific folk remedies and that there are often language barriers in conducting telephone surveys. Folk medicine is an academic term that may actually create a semantic barrier. For example, in posing questions on herbal use, a researcher may want to consider such phrases as "home remedies" or "traditional medicines used by your family." Asking whether someone uses "herbal products" may not elicit a response. Dr. O'Connor characterized herbal products and folk remedies as existing on a continuum of food to medicine and from medicine back to food. Better questions to pose during a survey might include the following:

• "How do you eat when you are pregnant?"
• "What do you do to take care of yourself?"
• "What do you make for yourself when you are not feeling well?"

Dr. O'Connor suggested that those investigating the use of herbal products would benefit from a uniform classification of foods and medicines. She said that health is often perceived as a state of balance that can be measured on a scale of symptoms. A standardized questionnaire may want to indicate "hot" conditions, for which remedies are begun or ended depending on their effects on a mother's symptoms. Standardizing questionnaires across cultures may be efficacious to researchers.

Dr. O'Connor distributed to the participants a variety of herbal concoctions from a number of cultural sources. These samples provided examples of folk remedies, foods, and medicines that may be outside the normal conceptual framework of academically oriented researchers. Given the nature of the samples, Dr. O'Connor offered another list of questions that may be successful in determining the use of herbal products across cultures:

• "What is the source of your folk remedy/folk medicine?"
• "Where did your folk remedy/folk medicine come from?"
• "How is your folk remedy/folk medicine prepared?"
• "What do you call your folk remedy/folk medicine?"
• "What other names does your folk remedy/folk medicine have?"
• "How do you use your folk remedy/folk medicine (for example, swallowed/ingested; as a bath, enema, or douche; washes; poultices)?"
• "For what symptom/condition did you use your folk remedy/folk medicine?"

Dr. O'Connor observed that patent medicines often contain herbal ingredients. Products such as sassafras tea may be used for corporal and spiritual purification. In certain cultures, herbal concoctions may be used by healers for their supernatural aspects or may be used for an individual's health and well-being (for example, for stress reduction). Some herbal products are believed to possess "energetic" properties, whereas others may have cosmological or spiritual aspects and connotations. Dr. O'Connor mentioned that the vitalistic forces of the body (often called "chi") may play a role in the use of herbal products.

Dr. O'Connor briefly discussed the notion of "side effects." Herbal products often have desired effects and some undesired effects; the use of other products is to often counterbalance desired and undesired effects. In a particular culture, single-ingredient herbal "prescriptions" are rare. The ingredients are tailor-made for a specific individual.

Another problem in determining use of herbal products is nomenclature/semantics. Products may have regional names, local names, or even family names. The names of herbal and botanical preparation may not always translate. A researcher may want to ask whether an herbal product is "cooked," and if so, how. The definitions of "tea" and "soup" may not be applicable across cultures.

Questions to Ascertain Herbal Use in Various Studies
Margaret A. Honein, Ph.D., National Center on Birth Defects and Developmental Disabilities, CDC, DHHS

Dr. Honein explained that the purpose of this short presentation was to examine some of the questions that previous studies have used to ascertain the use of herbal products. Dr. Honein reviewed the following studies:

• Behavioral Risk Factor Surveillance Study (BRFSS)
• National Health and Nutrition Examination Survey (NHANES) 1999-2000
• Infant Feeding Practices Survey 2 (IFPS)
• Slone Epidemiology Center's Drug Survey
• Slone Epidemiology Center's Birth Defects Study
• National Birth Defects Prevention Study.

The BRFSS is the world's largest telephone survey and is used to track health risks in the United States. A module that included questions on herbal products used for weight loss was used in the BRFSS in Florida, Iowa, Michigan, West Virginia, and Wisconsin. The following statement was given as a preface to the survey questions:

"Now we would like you to tell us about any over-the-counter products such as pills, powders, and liquids, you have taken to lose weight. That is, products you do not need a prescription to purchase."

The first question asked was:

"In the past 2 years, have you taken any over-the-counter weight loss products?"

If the participant answered "yes" to this question, the investigator would then ask:

"Have you taken any of the following over-the-counter weight loss products in the past 2 years?"

• Herbal fen-phen (also known as natural fen-phen, or fen-fuel)?
• Acutrim® or Dexatrim®?
• Ma-huang?
• St. John's Wort?
• Ephedra?
• Or Other?

NHANES is a comprehensive survey to provide extensive data on the health and diet of people in the United States. For NHANES 1999-2000, the use of herbal supplements was ascertained during an in-person interview in the respondent's home. If a respondent indicated use of a supplement, he or she was then asked to show the supplement container to the interviewer. The interviewer entered the names of the supplement and the supplement's manufacturer. However, no ingredient information was recorded by the interviewer. The interviewer prefaced the survey question by making the following statement:

"The next questions are about your use of dietary supplements and medications during the past month."

The interviewer then asked:

"Have you used or taken any vitamins, minerals, or other dietary supplements in the past month? Include those products prescribed by a health professional such as a doctor or dentist, and those that do not require a prescription. This card lists some examples of different types of dietary supplements."

The card used by interviewers is the Handcard DSQ1; it lists approximately 36 vitamins, minerals, and dietary supplements, some of which are herbal products. Details of the NHANES Handcard DSQ1 are presented in Attachment F.

The third set of questions that Dr. Honein examined were the pilot questions for IFPS. The preface to questions was:

"The following question asks about feeding herbal or botanical supplements to babies. We are very interested in your honest recall of which herbal or botanical supplements you have fed your baby. None of the agencies involved with this research recommend use of herbs or any other medication without supervision from a health care provider. Some herbs may be safe for use by infants, but others may be dangerous."

The interviewer then asked: "Did you take any of the following herbal or botanical supplements from a month before delivery up through the time of the baby's birth?"

Bitter orange		Ginger
Black cohosh		Ginkgo biloba
Blue cohosh		Ginseng
Chamomile oil		Goldenseal
Cranberry concentrate or extract		Kava kava
Don quai		Lemongrass leaf
Echinacea		Pennyroyal
Ephedra		Peppermint oil
Evening primrose oil		Red raspberry leaf
Fennel seed		St. John's Wort
Garlic		Other (specify).

The Slone Epidemiology Center's Drug Survey is a telephone survey of drug use. It began by asking the following question:

"We are interested in all medicines which you have (your child has) taken in the past seven days. These include prescriptions that your doctor or clinic may have given to you, non-prescription medicines, vitamins, herbs or alternative medicines that you bought on your own or obtained from someone else."

The Slone Epidemiology Center's Birth Defects Study is also conducted via a telephone interview of women who have recently delivered an infant with a birth defect or a non-malformed infant. Participants are asked if they had any of a list of illnesses during the period from two months before last menstrual period to date of delivery. For each illness reported, the women were asked:

"Did you use any medications for (specified indication)? Please include medications prescribed by a health care provider and medications you might have obtained without a prescription from stores, pharmacies, friends, or relatives, as well as herbal or home remedies."

This question was repeated for a long list of indications including epilepsy, sexually transmitted diseases, nausea and/or vomiting, constipation, and smoking cessation. Interviewers selected responses from a drug dictionary or entered the exact response if no exact match was located.

The National Birth Defects Prevention Study is an ongoing case-control study of major birth defects. During the maternal telephone interview, participants are asked the following question:

"Between (-3) and (DOIB) did you use any herbs or folk medicines to treat any medical conditions, to lose weight, or just to keep you healthy?"

In this study, subjects were able to report herbals (or other medications) at any point during the interview. Interviewers selected responses from a drug dictionary or entered the exact response if no exact match was located.

Based on her examination of questions to ascertain herbal use in these studies, Dr. Honein made the following conclusions:

• There is no apparent consensus on how to ascertain herbal use.
• Many surveys are not yet specifically seeking to ascertain herbal products.
• There are clear differences in levels of ascertainment based on the specificity of questions included in the questionnaire.

Validation of Exposure: How Do We Know What Is Actually Ingested?
Joseph M. Betz, Ph.D., Office of Dietary Supplements, Office of the Director, NIH, DHHS

Dr. Betz began his presentation by reviewing the breadth and diversity of herbal products that are currently available in the commercial marketplace. According to Blumenthal (2001; see Attachment G for details), herbal retail sales in the food, drug, and mass-market arenas for2000-2001 included the following products:

Ginkgo		Valerian
Asian ginseng		Kava kava
Garlic		Evening primrose
Echinacea		Milk thistle
St. John's Wort		Grape seed
Saw palmetto		Bilberry
Soy		Black cohosh
Pycnogenol		Yohimbe
Green tea		Feverfew
Ginger		Hawthorn.

The American Herbal Products Association (AHPA) estimates that there are as many as 3,000 plant species in the commercial marketplace. Approximately 90 percent of the market is dominated by the top 30 or so plants. AHPA estimates that there are approximately 30,000-50,000 plant products available to the public. Because of DSHEA, there is little pre-market scrutiny and no product or formula registration. Manufacturers may change formulations as costs dictate. Dr. Betz provided an example of the "proprietary blend" concept. A product called Chomper® contains 14 botanicals:

Plantain (leaf)		Rhubarb (root)
Cascara sagrada (bark)		Golden Seal (root)
Barberry (bark)		Lobelia (leaf)
Sheep sorrel (leaf)		Cellulose
Fennel (seed)		Magnesium stearate
Ginger (root)		Kelp
Myrrh gum (resin)		Alfalfa.
Red raspberry (leaf)

However, the list of ingredients for Chomper® changes over time. Yet the manufacturer retains the product as a proprietary blend.

Even if the consumer knows the ingredients, Dr. Betz indicated that another issue of herbal products is quality. Although an herb or botanical may be listed as an ingredient, the consumer is not assured that the correct plant species has been used or that the correct plant part has been processed for the purchased product. In addition, many common plants have parts that contain natural toxins that may be dangerous if consumed. Several examples relating to quality are presented in Attachment G.

Dr. Betz listed the following as examples of some drugs/toxic substances that have been found in dietary supplements:

"PC SPES"		warfarin
"Sleeping Buddha"		Estazolam (a benzodiazepine)
"Black Pearl"		Hydrochlorothiazide, diazepam, indomethacin, mefenamic acid
Aristolochia fangchi		Aristolochic acid
Symphytum x uplandicum		Echimidine.

Other issues of quality involved the following:

• "High quality" raw material
  • Compendial standards?
  • USP(20-30), AHP(9), BHP, GP, EP
• Pathogen-free
• Adhere to established limits for non-pathogens (not filthy or decomposed), not moldy
• Aflatoxin, pesticide, toxic elements within acceptable range.

Dr. Betz then reviewed some issues of quality for a single plant product: ginkgo. These plants are cultivated and the plant parts (usually the leaves) must be collected at the proper time of year. Some ginkgo products may contain more than just ginkgo. Dr. Betz cited the ingredient lists from several commercial ginkgo biloba products.

Ginkgo Biloba Dietary Supplement (Natural Ginkgo biloba leaf formula) contains:

• Ginkgo Biloba Leaf, 300 mg
• Sclerotium Poriae Cocos, 100 mg
• Dioscoreae Oppositae Rhizoma, 100 mg
• No yeast, no corn, no soy, no salt, no sugar, no chemical, no preservative, no artificial color.

Each tablet of a product called Ginkgold® contains 60 mg of a patented ginkgo biloba dried extract. A third product, Ginkgo Special Formula Tea, states that each teabag contains:

• 30 mg of standardized Ginkgo leaf extract (24 percent ginkgoflavonglycosides)
• Ginkgo leaves
• Lemongrass
• Licorice root
• Other flavorful, synergistic herbs.

Herbal preparations are obtained by subjecting herbal raw materials to treatments such as extraction, distillation, expression, fractionation, purification, concentration, or fermentation. These include comminuted or powdered herbs, tinctures, extracts, essential oils, expressed juices, and processed exudates. According to Dr. Betz, the concept of "generic" does not exist in the world of herbal products. Extracts are preparations of liquid (liquid extracts and tinctures)—of either semi-solid (soft extracts) or solid (dry extracts) consistency—obtained from herbal drugs or animal matters, which are usually in a dry state. Standardized extracts are adjusted within an acceptable tolerance to a given content of constituents with known therapeutic activity. However, there is a shifting definition of standardized extracts. Standardization is achieved by adjustment of the extract with inert material or by blending batches of extracts.

Despite years of research, the actual "actives" remain unknown for most plants (even something as highly studied as St. John's Wort). Basic research into whether and how phytomedicines work is needed before true standardization can occur. Quantified extracts can be adjusted to a defined range of constituents of interest (such as marker compounds). Dr. Betz cautioned that the notion of quantified extracts is also a shifting science. Marker compounds are one or more constituents that occur naturally. They are selected for special attention by the researcher or manufacturer. The idea of marker compounds is an outgrowth of the concept of chemotaxonomy.

Chemotaxonomy:

• Used chemotaxonomic markers to establish plant identity and phylogenetic relationships
• Relied on uniqueness
• Made historical assumption that a unique compound is "active" even if not proven.

Dr. Betz listed the following benefits of markers:

• A botanical mfarker compound that is unique to a species can aid identification.
• Marker compounds can help detect adulteration (negative markers); for example Aristolochic acid.
• Marker compounds can serve as quality indicators during manufacturing, handling, and storage.
• Marker compounds can serve as shelf-life indicators.
• Marker compounds can help manufacturers produce a consistent product.

There are, however, pitfalls for the use of markers:

• Few or no reliable "off-the-shelf" analytical methods
• Few analytical reference materials
• Issues of markers versus "actives"
• Shifting science (for example, St. John's Wort).

To elaborate on the subject of "shifting science," Dr. Betz cited two published articles:

• "Remedy's U.S. Sales Zoom, But Quality Control Lags. St. John's Wort: Regulatory vacuum leaves doubt about potency, efforts of herb use for depression."—T. Monmaney, Los Angeles Times, August 31, 1998
• "1500% Variation Found in Strength of Garlic Supplements: Many labels not helpful, misleading." Consistently reports about 1/10 of non-herbal and 1/3 of herbal products fail to meet label claim. ConsumerLab.com, December 20, 2002.

Dr. Betz noted that for herbal products such as ginkgo biloba, there are variations in strength and chemical content (INDENA). He listed the following contents as examples:

Ginkgolides		2.5-4.5 percent
Bilobalide		2.6-3.2 percent
Flavonol glycosides		22-26 percent
Proanthocyanidins		1-10 percent
Ginkgolic acids		< 5 parts per million.

Another issue in assessing herbal products is the diversity of trade names. A standardized lipid extract of the berries of the saw palmetto, Serenoa repens (also known as the American dwarf palm tree and sometimes called Sabal serrulata) is often used to treat benign prostatic hyperplasia. Commercially available saw palmetto products are distributed worldwide. Different manufacturers and distributors label the same product with different names. The following list gives some examples of the daunting diversity in trade names for a single product:

France Permixon Belgium Prostaserene Prosta-Urgenin Urgenin Italy Permixon Rilaprost Germany Cefasabal Cystibosin Eviprostat-S Hewesabal Ju Cystan S Pascosabal N Prosta Fink N Prosta Urgenin uno Prostagutt forte Prostagutt mono Prostagutt uno Prostaselect Prostasyx Prosta-Gastreu

Prostata-Komplex Prostess/-uno Remiprostan Uno Rephaprossan Sabal Saburgen-N Seniovita aktiv Serenoa-ratiopharm Sita-Kapseln Steiprostat Strogen S Strogen Uno Talso/-uno Urologicum PMD Urotruws.

Dr. Betz concluded by quoting Voltaire: "The secret of being tiresome is to tell everything."

Regulation of Herbal Products
Susan J. Walker, M.D., Center for Food Safety and Applied Nutrition, FDA, DHHS

Dr. Walker said that the purpose of her presentation was to provide an overview of how supplements are regulated. Details of this presentation appear in Attachment H. Dr. Walker described the two main areas of her presentation:

• Regulatory pathways for herbal products
• Dietary supplement products
  • Labeling and claims
  • Safety
  • Enforcement.

The "facts" of regulatory life is defining where nutraceuticals, botanicals, and herbals products fit in regard to foods and drugs. Do they fall into a category with foods, which includes conventional foods and dietary supplements, or are they categorized as drugs, which includes prescription and OTC medications?

Dr. Walker suggested that the best path for defining these products might be by intended use because of the following:

• Different legal requirements
• Different safety considerations
• Different substantiation for claims.

The starting point would then be intended use defined by claims such as the following:

• Drug
  • Curing, preventing, treating, or mitigating a disease
• Dietary supplement
  • Reducing risk of disease
  • Structure/function claim
  • Dietary supplement labeling.

Depending on intended use, products would then fall into one of the following regulatory boxes:

• Drug products
  • OTC monograph
  • NDA approval
• Conventional foods
  • Food additives
  • GRAS program
• Dietary supplements
  • Pre 1994 (DSHEA)
  • New dietary ingredients.

Dr. Walker listed year 2000 dietary supplement estimated sales breakdown of $17.1 billion market as follows:

Vitamins		38 percent
Minerals		8 percent
Herbal/botanicals		32 percent
Other supplements		22 percent.

The enactment of DSHEA:

• Defined dietary supplements
• Made provisions for safety and GMPs
• Made provisions for labeling and claims.

In addition, dietary supplement products set a standard for "reasonable risk":

• Manufacturer responsible for ensuring product and ingredients are safe
  • No FDA premarket approval process
  • No FDA list of "approved ingredients"
• FDA to take action against unsafe products
  • Gather evidence; support need for action.

In response, the manufacturer's labeling had the following:

• Manufacturer obligated to ensure it contains what is declared on the label
• No federal "standards" for ingredients
• No "approval" of label.

Dr. Walker said that the herbal dietary supplement label must:

• Identify the part of the plant
• Conform to specifications of any official compendium listed on label (USP etc.)
• Contain identity and strength represented on label.

Herbal dietary supplements had no requirements for testing or preapproval in special populations:

• Breastfeeding
• Pregnancy
• Pediatrics.

As a result, manufacturers are responsible for safety of their products. The Food Drug and Cosmetic Act requires that:

• Statements in labeling are truthful and not be misleading.
• Products are safe for their intended use.

Claim statements that are truthful and not misleading fall into two categories:

• Structure/function claims—supplements
  • Describe the role of a nutrient or dietary ingredient intended to affect structure or function in humans
  • "This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease."
• Health claims—supplements
  • Reducing the risk of disease.

The primary question of whether an herbal product is safe for intended use remains: Who bears the safety burden?

Some of the challenges for botanical products are:

• Validation of analytical methods
• Validation of animal models
• Validation of interpretable biomarkers for population monitoring and surveillance
• Relative effects
• Multiple ingredient products.

Some of the postmarket safety challenges are:

• Under and incomplete reporting of adverse events
• Issues of product composition
• Consumer:
  • Use patterns
  • Individual sensitivities
• Causality
• Biological plausibility.

Some issues in postmarket surveillance are:

• Adverse events
• Peer-reviewed literature
• Medwatch
• FDA field offices
• Other.

FDA's dietary supplement enforcement report noted the following:

• Treatments for life threatening diseases
• Weight loss products
• Autism treatments
• Treatments for behavior disorders
• Treatments for mental retardation and Down syndrome
• Colloidal minerals
• Supplements for smokers
• Supplements for drinkers.

Enforcement tools include the following:

• "Cyber" letters—Issued to Web site operators who promote dietary supplements that claim to diagnose, mitigate, treat, cure, or prevent a disease or diseases
  • Electronic
  • Similar to traditional "warning" or "untitled" letters
  • Outline the alleged violation and request a formal response
• Hardcopy "cyber" letter also sent
  • Web site operator
  • U.S. Customs Service
  • Regulatory officials in country where operator is located.

Other aspects of enforcement include:

• Investigative tools
  • Statutory authority to conduct inspections
• Advisory tools
  • Warning letters
  • Untitled letters
• Judicial actions
  • Seizures
  • Injunctions
  • Prosecutions
• Detention without physical examination—imports.

FDA Commissioner McClellan's initiative of December 2002 on consumer health information for better nutrition was designed to:

• Encourage makers of conventional foods and dietary supplements to make accurate, science-based claims about the health benefits of their products
• Help eliminate bogus labeling claims by taking on those dietary supplement manufacturers who make false or misleading claims.

The Dietary Supplement Strategic Plan of January 2000 had the following key components:

• Safety
• Boundaries/claims
• Enforcement
• Research
• Outreach
• Budget-driven/leveraging and partners.

In concluding, Dr. Walker listed the essential elements of partnering/cooperation for the regulation of herbal products:

• Consumers
• Industry
• Foreign and domestic governmental and regulatory groups
  • Videoconferences with EMEA and Canada/Australia/New Zealand
  • NCTR/NIH-ODS
• Academia
• Science organizations.

Conclusion

Dr. Mitchell summarized the recommendations of the herbal workshop participants as follows:

• Collect herbals intensively for only a subsample of the Study.
• Because of the changing use of herbals over time, the Study cannot ask questions about use at only one point in time.
• A list of the most commonly used herbal products of concern should be created.
• Samples of herbal products could be taken from Study participants.
• Biologic samples should also be taken.
• Biomarkers should be identified and collected, when possible.
• Whether biomarkers alone or other "markers of exposure" are sufficient should be investigated.
• Ingredient lists of herbal products from available product containers should be recorded as useful information.
• Flags to denote changes in use of herbal products over time should be generated.
• Focus groups should examine the use of two groups of herbal products:
  • Vasoactive herbals used during pregnancy
  • Phytoestrogens used during pregnancy and breastfeeding.

Presenters

Joseph M. Betz, Ph.D., Office of the Director, NIH, DHHS
Heidi L. Blanck, Ph.D., National Center for Chronic Disease Prevention and Health Promotion,
   CDC, DHHS
Margaret A. Honein, Ph.D., National Center on Birth Defects and Developmental Disabilities,
   CDC, DHHS
Carol Louik, Sc.D., Boston University
Allen A. Mitchell, M.D., Boston University
Laurie J. Moyer-Mileur, Ph.D., R.D., University of Utah Health Sciences Center
Bonnie B. O'Connor, Ph.D., Brown University
Katherine Shealy, M.P.H., IBCLC, RLC, National Center for Chronic Disease Prevention and
   Health Promotion, CDC, DHHS
Susan J. Walker, M.D., Center for Food Safety and Applied Nutrition, FDA, DHHS

Observers and Other Participants

Christina D. Chambers, Ph.D., M.P.H., University of California, San Diego
Stanley A. Edlavitch, Ph.D., University of Missouri, Kansas City
Janet R. Hardy, M.P.H., M.Sc., University of Massachusetts
Jane Hildreth, B.A., Blaze Science Industries
Katherine E. Kelley, B.S.Pharm, R.Ph., Slone Epidemiology Center, Boston University
Diane L. Kennedy, R.Ph., M.P.H., Center for Drug Evaluation and Research, FDA, DHHS
Roberta Ness, M.D., M.P.H., University of Pittsburgh
Mary Frances A. Picciano, Ph.D., Office of the Director, NIH, DHHS
Paul J. Seligman, M.D., M.P.H., Center for Drug Evaluation and Research, FDA, DHHS
Robert M. Ward, M.D., University of Utah Health Sciences Center
Tara S. Wass, University of Tennessee, Knoxville
Sumner J. Yaffe, M.D., University of California, Los Angeles