Index
A
Abortifacients, 189, 193, 197, 199
Acceptable daily intake (ADI), 308
Adulterants, see Contaminants and adulterants
Adverse Event Reporting for Dietary Supplements: An Inadequate Safety Valve, 301
Adverse events, 299
see also Case reports and case series
cost factors, 129
defined, 126(n.1)
Dietary Supplement Health and Education Act (DSHEA), 135-136, 301-303
epidemiological studies and, 129, 148, 149
evidence, value as, 104, 112, 126, 127-136, 141, 152
glucosamine, 366
health care professionals, 16, 283, 303
historical use data and, 141
in vitro assays and, 224-225
integration of data, 255-257
international perspectives, 131(n.3)
MedWatch, 16, 39, 129, 302-303, 313, 484
Poison Control Centers, 16
prescription drugs, 130
prototype safety monographs, 272, 275, 279, 281, 283, 366, 368, 373, 377, 388-389, 432, 466
reporting, 16, 104, 126, 294, 301-303, 366
FDA, general, 16, 127-131 (passim), 133, 294, 301-303
spontaneously reported, 16, 127-136, 293, 373, 432
saw palmetto, 279, 377, 379, 432, 466
shark cartilage, 281
Special Nutritional Adverse Event Monitoring System (SN/AEMS), 272, 275, 279, 281, 300, 373, 389, 402, 436
vulnerable subpopulations, 112
Advisory committees, external
conflicts of interest, 46, 59, 65, 270
Framework review process, 8, 9, 10, 87, 91, 97-99, 123-124, 290, 296
prototype safety monographs, 290
Age factors, 248
see also Fetal development
children, 48, 64, 248, 365, 369, 370, 376
infants, 248-249, 311, 326, 368, 472
Tolerable Upper Intake Level (UL), 70
Agency for Toxic Substances and Disease Registry, 374-375
Alkaloids, 38, 179, 183, 186-204 (passim), 323-351 (passim)
Allergic reactions, 69-70, 191, 201, 324, 345, 350, 365, 388
American Botanical Council, 72
American Herbal Pharmacopoeia, 68-69
American Herbal Products Association, 69-70, 395
Botanical Safety Handbook, review approach, 51-54, 272
American Pharmaceutical Association’s Practical Guide to Natural Medicines, 61-63, 76
Androgens
melatonin, 377
saw palmetto ingestion by women, prototype monograph, 286, 450-477
Angiogenesis inhibitors, shark cartilage, 211, 281, 282, 381-384
Animal studies, 156-173
adverse event reporting and, 135, 163-164, 172
behavioral toxicity, 158, 159, 166
botanicals, 159-161, 390-391, 437-439, 453, 456, 457-458, 468-470, 476-477
carcinogenicity, 163, 164, 172, 368
chemical components and botanicals, taxonomic relatedness, 187-200 (passim), 210, 211
FDA, general, 157, 158, 167-168
Framework review process, 11, 94, 100, 101, 102, 103, 105, 106, 293
prototype safety monographs, 283, 285, 287, 358, 360, 364, 365, 368, 373, 381, 437-439, 453, 456, 457-458, 468-470, 476-477
glucosamine, 275-277, 283, 364, 365
melatonin, 368
oral administration of supplements, 156, 457-458, 468
pharmacokinetics and pharmacodynamics, 159, 161-162, 163, 172, 241-242
review approaches, various, 45, 49, 52, 55, 57, 59, 61, 63, 266-267, 312
saw palmetto, 453, 456, 457-458, 468-470, 476-477
teratogenicity, 248-249
veterinary medicine, 159-161, 164, 187-200 (passim)
Assays, see In vitro assays
Attitudes and beliefs
consumer beliefs, general, 22-23, 36
consumer expectations about supplement safety, 23-24
Recommended Dietary Allowance, 31
B
Behavioral toxicity, 484
prototype monographs, 278, 279, 369, 370
Bioavailability, 114-115, 162, 285, 383
Biological activity/mechanism of action
see also Metabolism and metabolites;
Pharmacokinetics and pharmacodynamics
adverse event reporting, 132, 136
chemically and botanically related substances, 176, 205
DSHEA review approaches, various, 17
functional relatedness of chemicals and related botanicals, 92, 175, 208, 210-212, 279-280, 283, 299, 392, 453, 476-477
Framework review process, 94, 96, 365
prototype safety monographs, 383, 456
glucosamine, 365
historical use of botanicals, 139
integration of data, 256-259
interactions, supplement-induced, 236-244
other review approaches, various, 48, 49, 53, 58, 60, 64
Botanical Safety Handbook, 51-54, 272
Botanicals, 175-214
see also Chaparral;
Chemical components and related botanicals;
Saw palmetto
animal studies, 159-161, 390-391, 437-439, 453, 456, 457-458, 468-470, 476-477
consumption, 22
contaminants and adulterants, 191, 195, 199, 201, 329
chemical components and related botanicals, 178-179, 206-207
Framework review process, 11, 100, 106-108, 110-111
historical use of supplements, 61, 137-141
monographs, various, 54, 55, 57, 59, 63-64, 68-69, 71-78
plant family information, 322-351
review approaches, various, 49, 51-57, 59-61, 63-64, 68-69, 71-79
monographs, 54, 55, 57, 59, 63-64, 68-69, 71-78
pregnant women, 53, 56, 60, 64, 68-69
sales value of, 19
supplements defined, 20
teratogenicity, plant family information, 336, 340, 348-349
C
Carcinogenicity
animal studies, 163, 164, 172, 368
chemical components and botanicals, taxonomic relatedness, 187-197
saw palmetto, 376, 378, 451, 453, 455
shark cartilage, 381
supplements, various, 23, 75, 69, 290
Cardiovascular effects
chemical components and botanicals, taxonomic relatedness, 187-199, 381
saw palmetto, 279, 377, 378, 379, 432
Cartilage, see Shark cartilage
Case reports and case series, 72
see also Adverse events;
Prototype safety monographs
adverse event reporting and, 127, 128, 135, 283
Framework review process, 88, 90, 101, 135, 283, 388-389, 422
Cell studies, 115(n.10), 158, 211, 212
see also Genetic toxicology
chromium picolinate, 373
in vitro assays, 106, 112, 151, 219-220, 223, 225, 229
Center for Food Safety and Applied Nutrition, 97, 305
Chaparral, 264-265
adverse events, 388-403, 420, 436
animal studies, 390-391, 437-439
carcinogenicity, 394, 420, 432-433
cellular studies, 387, 399, 441-448
contaminants and adulterants, 357, 358, 359, 389, 393, 398, 399
dosage and administration, 357, 387-388, 390, 391, 394-395, 396, 397-398, 420
gender factors, 396
individual components, 386-387, 401, 411-419, 449
international perspectives, 276, 396
Internet marketing, 394-395
prototype monographs, 272-275, 284-285, 287-290, 356-449
hepatoxicity, 264-265, 356-362, 387-401 (passim), 428-431, 446
Chemical components and related botanicals, 20, 175-214, 263, 392
see also Chaparral;
Saw palmetto
age-related metabolism changes, 248
alcohol extraction, 139, 202, 203, 205, 207
alkaloids, 38, 179, 183, 186-204 (passim), 323-351 (passim)
animal studies, 187-200 (passim), 210, 211
cultivation and other conditional factors, 201-202, 205
endogenous substances, 108, 115, 175, 208-210, 214, 238, 363, 367, 372, 373
Framework review process, 11, 100, 106-108, 110-111, 377
functional relatedness, 92, 175, 208, 210-212, 279-280, 283, 299, 392, 453, 476-477
general classes and specific constituents of concern, 180-181
historical/traditional use, 203-204, 205, 376, 377, 386
immunotoxicity, 191, 199, 200, 201, 324, 331, 345
New Chemicals Program (EPA), 314-315
pharmacokinetics and pharmacodynamics, 179, 204, 396
structural relatedness, 48, 52, 80, 89, 92, 106, 118, 124, 158, 175, 179, 182, 183, 200, 205-208, 211, 212, 214, 218, 315, 391, 392-393
taxonomic relatedness, 92, 175, 178, 182-201, 213-214, 299, 322-351, 378, 381, 391
teratogenicity, 187-195 (passim), 199, 200, 207
Children, 48, 64, 248, 365, 369, 370, 376
Chromium picolinate
clinical research, 373-374
dosage and administration, 276, 372-373, 374
international perspectives, 373
prototype monograph, 275-276, 372-375
Clinical studies and trials, 141-145, 151-156
see also Case reports and case series
adverse event reporting and, 130, 133, 420, 466
chaparral, 388-389
chromium picolinate, 373-374
epidemiologic studies and, 87, 105, 146, 148-151
Framework review process, 105, 126, 127, 293
prototype safety monographs, 277, 283, 363-368 (passim), 370, 373-374, 377, 381, 384, 388-389, 420
glucosamine, 277, 363-366 (passim)
new drug evaluation, 312-313
review approaches, various, 45, 49, 67-68, 72, 312
Cohort studies, 67, 105, 147-148, 149-151
Commission E, 54-57, 71-73, 396, 456
Contaminants and adulterants
see also Good manufacturing processes
animal studies, 266
botanical supplements, various, 191, 195, 199, 201, 329
chaparral, 357, 358, 359, 389, 393, 398, 399
FDA’s general policy, history, 26, 27, 30, 37-39 (passim), 130, 297
glucosamine, 264
saw palmetto, 377
supplement review approaches, various, 44, 70, 78
Cosmetic, Toiletry, and Fragrance Association, 310-311
Cosmetics, FDA review approach, 310-312
Cost-effectiveness
adverse event reporting, 129
Framework approach, 301
in vitro studies, 218
regulatory environment and, 1, 21
Court decisions, See Litigation
D
Definitional issues
adverse event, 126(n.1)
dietary supplements, 2, 3, 6, 19-20, 36, 85
epidemiological studies, 146(n.6)
Framework for supplements, 3, 80-81, 88, 96-97, 106-108
risk, 168-169
serious health problem, 6(n.5), 88(n.3), 96-97, 106-108, 224
signal, Framework risk assessment, 88
Tolerable Upper Intake Level (UL), 70
vitamins and minerals, 28
vulnerable subpopulations, 112
xenobiotics, 235(n.2)
Demographic factors
see Age factors;
Epidemiological studies;
Gender factors;
Race/ethnicity;
Vulnerable groups
animal studies, 163-164
historical use of botanicals, particular groups, 140, 395, 397
socioeconomic status, consumption of supplements, 23
Department of Agriculture, 29
Department of Health and Human Services
see also Food and Drug Administration
Agency for Healthcare Research and Quality, 49-51, 66-68
Agency for Toxic Substances and Disease Registry, 374-375
Health Research and Health Services Administration, 31
imminent hazard, 37
National Center for Toxicological Research, 17
National Institutes of Health, 17, 66-67, 304-305
Office of Dietary Supplements, 99-100
Diabetics
chromium picolinate, 275-276, 373
Dietary Reference Intakes, 25, 31, 51, 70-71, 118, 119, 120, 254
Recommended Dietary Allowance (RDA), 60, 71
Tolerable Upper Intake Level (UL), 51, 70-71, 119, 254, 372
Dietary Supplement Health and Education Act (DSHEA), 1, 6, 19, 24, 30, 36-39, 78
adverse event reporting, 135-136, 301-303
barriers to FDA regulation, 18, 21, 297, 299, 300
committee recommendations, 15-16, 297, 300-301, 321
current status of foods, additives, drugs, and supplements regulated, 4-5, 32-33
definition of supplements, 2, 6, 20, 36, 85
Framework approach, 6, 86, 91, 95, 253, 294, 295, 299, 300-301
funding, 301
history of use, 299
monitoring, 300-301
postmarket surveillance, 80
premarket approval, 3, 16, 32-33, 38, 79-80, 295, 299
proof of harm, 267-268
safety standards, legislative text, 7, 25
signal detection, 86
unreasonable risk determination, 14, 268
Dietary Supplement Labels: Key Elements, 17, 304
Dosage and administration considerations
adverse event reporting, 134
animal studies, 158, 161-163, 170-173, 282, 364, 368
oral administration, 156, 457-458, 468
bioavailability, 114-115
chaparral, 357, 387-388, 390, 391, 394-395, 396, 397-398, 420
chemical components and related botanicals, general, 178, 205
chromium picolinate, 276, 372-373, 374
Framework review approach, 95, 96, 98, 114-115, 118-119
science-based principles applied, 318-319
prototype safety monographs, 276, 279, 282, 357, 363, 364-365, 368, 369, 370, 372-373, 374, 377, 387-388, 451-452
historical use of supplements, value as evidence, 138-140
non-oral exposure routes, 47, 50, 53, 56, 58, 60, 62, 64, 456
review approaches, various, 47, 50, 52-53, 55-56, 58, 60, 62, 64, 66, 67, 72
saw palmetto, 377, 451-452, 456, 457-458
shark cartilage, 282
vitamins and minerals, 118-121
weighing inconsistent evidence, 263, 267
E
Economic factors
see also Cost-effectiveness;
Funding
review approaches, various, 81
review process, conflicts of interest, 46, 59, 65, 270
saw palmetto, annual sales, 455
supplement sales, annual, 1, 19
glucosamine, 277
Endogenous substances, 108, 115, 175, 208-210, 214, 238, 363, 367, 372, 373
Environmental Protection Agency, 229
New Chemicals Program, 314-315
Enzyme activity, 167
functionally related substances, 211
in vitro studies, 106, 158, 211, 218, 220-221
Epidemiological studies, 67, 146-151, 156
see also Historical use of supplements;
Prevalence of use
adverse events reports and, 129, 148, 149
case-control studies, 87, 105, 146, 148-151
cohort studies, 67, 105, 147-148, 149-151
defined, 146(n.6)
Framework review process, 105, 126, 294
pharmacoepidemiology, 484
spontaneous adverse reporting, weaknesses, 129
European Scientific Cooperative on Phytotherapy, 73
Evidence-based Practice Centers, 66-67
Expertise
see also Advisory committees, external;
Monographs
Framework review process, 319, 320-321
committee members/consultants, 481-487
cosmetics ingredients evaluation, 311
FDA, 2, 3, 15, 21, 29, 295-296, 310
generally recognized as safe (GRAS) foods, 310
in vitro assays, 224
literature reviews, 45
over-the-counter drugs, 313
review approaches, various, 43, 44, 46, 51-66 (passim), 69, 71, 75, 77
signal identification, 88
External advisory committees, see Advisory committees, external
F
Federal Food and Drugs Act, 26
Federal Food, Drug, and Cosmetic Act, 2, 26-27, 78, 96, 307
Federal government
see also Department of Health and Human Services;
Food and Drug Administration;
Legislation;
Regulatory issues
Department of Agriculture, 29
Environmental Protection Agency, 229
New Chemicals Program, 314-315
Federal Hazardous Substances Act, 223
Federal Meat Inspection Act, 26
Fetal development, 112, 230, 248-249, 259
see also Pregnancy and lactation
prototype safety monographs, 274, 360, 378, 383, 452, 453, 457, 476
supplement review approaches, various, 48, 50, 53, 56, 58, 60, 62, 64, 68-69
teratogenicity, 69, 166, 230, 248-249, 259, 267, 282, 309, 312, 382, 383, 458, 477
chemical components and related botanicals, 187-195 (passim), 199, 200, 207
new drug applications, 312
plant family information, 336, 337, 340, 348-349
Food Additives Amendment, 2, 29-31, 307
Food and Drug Administration
see Framework for dietary supplements, general;
Legislation;
Monitoring;
Notification requirements;
Regulatory issues
additives, 4-5, 32-33, 80, 307-309, 311
adverse event reporting, 16, 127-131 (passim), 133, 294, 301-303
animal studies, 157, 158, 167-168
barriers to supplement regulation, 17-18, 21, 28-29, 287, 299, 300
chemical components and related botanicals, 178-179, 206-207
Center for Food Safety and Applied Nutrition, 97, 305
chromium picolinate, 276
committee charge/methodology, 1-2, 13, 21, 43-48, 269, 270, 292, 316-321
committee recommendations, 15-18, 300-305, 321
contaminants and adulterants, general policy, 26, 27, 30, 37-39 (passim), 130, 297
content uniformity standards, 17
cosmetics, FDA review approach, 310-312
current status of foods, additives, drugs, and supplements regulated, 4-5, 6, 32-33
generally recognized as safe (GRAS) foods, 2, 5, 29-30, 32-33, 80, 307-308, 309-310
glucosamine, 277-278
good manufacturing practices, 17, 30, 39, 78(n.7), 130, 303-304
historical perspectives, 2-3, 22-39
historical use of supplements, 136, 152
Human Services National Toxicology Program, 17, 305
industry resistance to regulation, 2
monitoring, 300-301
National Center for Toxicological Research, 17, 305
new drug applications (NDAs), 23, 27
over-the-counter drugs, 23, 24, 313-314
premarket approval, 3, 16, 32-33, 36, 79-80, 295, 299, 307-309
Dietary Supplement Health and Education Act (DSHEA), 3, 16, 32-33, 38, 79-80, 295, 299
prevalence of use interests, 7, 25, 251
public education, 302-303
Framework review process, 14, 16, 98-99, 123, 269, 293, 394, 455
Redbook, 80, 157, 158, 206, 223, 308
research methodology, general, 21
safety monographs, 10
safety standards, legislative text, 7, 25
saw palmetto, 280
serious health problem, 6, 88, 224
unreasonable risk determination, 2, 3, 14
vitamins and minerals, 28, 31, 34, 36
Foreign countries, see International perspectives
Framework for dietary supplements, general, 6-15
see also Advisory committees, external;
Prototype safety monographs
animal studies, 11, 94, 100, 101, 102, 103, 105, 106, 293
approaches by others and existing Frameworks, 43-81
barriers to supplement regulation, 17-18, 21, 28-29, 299
botanicals, 11, 100, 106-108, 110-111
case reports and case series, 88, 90, 101, 135, 283, 388-389, 422
committee charge/methodology, 1-2, 21, 43, 316-321
committee recommendations, 2, 3, 15-18, 21, 85-124
cost of, 301
chemical components and related botanicals, 11, 100, 106-108, 110-111, 377
definitional issues, 3, 80-81, 88, 96-97, 106-108
Dietary Supplement Health and Education Act (DSHEA), 6, 86, 91, 95, 253, 294, 295, 299, 300-301
dosage and administration considerations, 95, 96, 98, 114-115, 118-119
science-based principles applied, 318-319
prototype safety monographs, 276, 279, 282, 357, 363, 364-365, 368, 369, 370, 372-373, 374, 377, 387-388, 451-452
epidemiological studies and, 105, 126, 294
health care professionals, 98, 99
historical use of supplements, 93, 101-104 (passim), 124
initial review procedure, 8, 9, 89-91, 119-120
integrative evaluation, 3, 8, 9, 11, 91-100, 102, 120-121, 293, 319
focused vs broad-based, 10, 14, 92, 93, 98, 117, 123, 264, 269, 273, 277, 278, 279, 282, 285-286
interactions with other substances, 11, 100, 109, 113, 294-295
prototype safety monographs, 279-280, 281, 359-360, 368, 369, 370, 379, 400
Internet reporting, 10
literature reviews, 91, 92-93, 94
prototype safety monographs, 287, 368, 370, 401-403
pharmacokinetics and pharmacodynamics, 109, 113, 364
proof of risk/harm, 86, 95, 97, 100, 101, 109, 115
prototype safety monographs, 267-268, 274, 278, 284
unreasonable risk determination, 2, 3, 10, 13, 14, 15, 18, 298-299
public education, 14, 16, 98-99, 123, 269, 293, 394, 455
reproductive toxicity, 106, 274, 275, 279, 280, 281, 287, 312
prototype safety monographs,, 280, 284, 358, 360, 376, 378, 451, 452, 453, 455, 457
science-based principles applied, 11-13, 44-45, 95, 97, 100-116, 293
advisory committees, external, 318-319
methodology for study, 318-319
prototype safety monographs, 283-291
toxicology, general, 11, 17, 100, 103, 104, 106-108, 110-111, 299
unreasonable risk determination, 10, 13, 14, 15, 18, 85, 86, 93, 95, 99, 100, 101, 103, 115, 298
utilization of the Framework, 14, 117, 292-296, 301
vitamins and minerals, 118-121
vulnerable groups, 109, 112-113, 118-119, 318
xenobiotics, 11, 100, 109, 359-360, 400
Funding
content uniformity standards, 17
cosmetics ingredients review, 311
Dietary Supplement Health and Education Act (DSHEA), 301
Framework approach utilization, 295, 301
good manufacturing practices, 17, 303-304
research, incorporation of ingredient safety, 305
G
Gastrointestinal effects
chaparral, 391
chemical components and botanicals, taxonomic relatedness, 187-199
shark cartilage, 382
Gender factors
see also Pregnancy and lactation;
Reproductive toxicity
chaparral, 396
saw palmetto, 280, 284, 376, 378, 451, 452, 453, 455, 457, 458, 468-470
Generally recognized as safe (GRAS), 2, 5, 29-30, 32-33, 80, 307-308, 309-310
Genetic toxicology
see also Teratogenicity
adverse events, birth defects, 126(n.1)
chromium picolinate, 373
in vitro studies, 218, 221, 225-231
new drug applications, 312
Glucosamine
adverse events, 366
animal data, 276-277, 283, 364, 365
clinical research, 277, 363-366 (passim)
dosage and administration considerations, 363, 364, 365
elderly persons, 277
in vitro data, 276-277
prototype safety monograph, 276-278, 363-366
Good manufacturing practices, 17, 30, 39, 78(n.7), 130, 303-304
H
Health care professionals
see also Prescription drugs
marketing to, 26
Natural Medicines Comprehensive Database, 74
professional education, 16, 98, 99, 302
saw palmetto, prevalence of use, 283
Health Research and Health Services Amendments, 31
Hepatic system
alcohol use and abuse, 23, 129, 358, 359, 399
chemical components and botanicals, taxonomic relatedness, 187-199, 391
hepatotoxic substances, general, 248
prototype monographs,
chaparral, 264-265, 356-362, 387-401 (passim), 428-431, 446
chromium picolinate, 372
glucosamine, 365
melatonin, 369
Herbals, see Botanicals
Historical perspectives, 2, 19, 22-39
see also Historical use of supplements;
Legislation
botanicals, regulation of, 2, 24
consumption of supplements, 19, 22
labeling, 22, 28, 31-35, 78-79, 223
number/sales of dietary supplements, 1, 19
vitamin and minerals, regulatory history, 28, 31, 34, 36
Historical use of supplements, 22, 299
chemical components and related botanicals, 203-204, 205, 376, 377, 386
dosage and administration considerations, evidence value, 138-140
evidence value, general, 61, 126, 127, 136-141, 152, 299
Framework review process, acceptable evidence, 102, 103, 104
science-based principles applied, 318-319
specific supplements, 93, 101-104 (passim), 124, 299, 376, 377, 386, 387-388, 452, 455
racial/ethnic groups, 140, 395, 397
vitamin and mineral supplement consumption, 19
Homeopathic Pharmacopoeia of the United States, 27
Hormones
see also Androgens
endogenous, 210
in vitro assays, 230
melatonin, 369
saw palmetto, prototype monograph for antiandrogenic risks, 95, 286, 450-477
supplements defined, 20
Human Services National Toxicology Program, 17, 305
Human studies and data, 126-153
see also Adverse events;
Clinical studies and trials;
Epidemiological studies;
Historical use of supplements;
Signal detection
Framework review process, 100, 101-103
historical use of supplements, 93, 101-104 (passim), 124
interactions, supplement-induced, 241-242
prototype monographs, 285, 287, 358, 363-368 (passim)
chromium picolinate, 373-374
glucosamine, 277, 363-364, 365
review approaches, various, 45, 49, 266
I
Immunotoxicity
allergic reactions, 69-70, 191, 201, 324, 345, 350, 365, 388
animal studies, 159
chemical components and related botanicals, 191, 199, 200, 201, 324, 331, 345
interactions with other substances, 236, 239, 240, 241
melatonin, 369
In vitro assays, 217-232
animal studies and, 224
cell studies, 106, 112, 151, 219-220, 223, 225, 229
cost of, 218
enzymes, 106, 158, 211, 218, 220-221
FDA policy, general, 223, 230-231
Framework for dietary supplements, 11, 94, 100, 101, 102, 108-109, 127, 293
prototype safety monographs, 283, 287, 373, 378, 381, 382, 384, 391, 440
functionally related substances, 210, 211
genetic toxicology, 218, 221, 225-231
glucosamine, 276-277
historical use data on supplements and 137
integration of data, 258-259, 267
interactions, supplement-induced, 240-241
review approaches, various, 45, 49, 57, 59, 61, 299
serious adverse effects, 224-225
shark cartilage, 381, 382, 384
types of, by effect observed, 219-221, 240-243
types of, by experimental system, 221-222
validated studies, 222-224
Infants, 248-249, 311, 326, 368, 472
see also Lactating women
Integration of data, 9-10
see also Advisory committees, external
biological activity/mechanism of action, 256-259
cross-design synthesis, 262-265
focused integrative evaluation, 9, 10, 11, 86
Framework process, 3, 8, 9, 11, 91-100, 102, 120-121, 293, 319
focused vs broad-based, 10, 14, 92, 93, 98, 117, 123, 264, 269, 279, 273, 277, 278, 279, 282, 285-286
glucosamine, 278
inconsistent data, 262-267, 287-290
science-based principles for, 253-268, 285-291
causal models, 256-262
proof of harm, 267-268
weighing inconsistent evidence, 262-267, 319
Interactions, 235-244
see also Side effects
biological activity/mechanism of action, 236-244
Framework review process, 11, 100, 109, 113, 294-295
prototype safety monographs, 279-280, 281, 359-360, 368, 369, 370, 379, 400
immunotoxicity, 236, 239, 240, 241
other formal review approaches, 48, 51, 53, 56, 58, 62, 63, 69, 72, 76
other xenobiotics and supplements, 11, 100, 109, 145, 221, 236-237, 238-240, 241-243, 249, 279-280, 281, 359-360, 400
pharmacokinetics and pharmacodynamics, 236-243, 244
types of, 236-238
International perspectives, 157
adverse event reporting, European Union regulation, 131(n.3)
chromium picolinate, 373
European Scientific Cooperative on Phytotherapy, 57-61, 73
German Commission E, 54-57, 71-73, 396, 456
melatonin, 283
review approaches, various, 49, 52, 68
saw palmetto, 279-280, 283, 456
unreasonable risk determination, 15, 298
World Health Organization, 63-64, 70, 77
Internet
chaparral marketing, 394-395
Framework integrative evaluation results, 10
monographs, various review approaches, 59
MedWatch, 39
Natural Medicines Comprehensive Database, 74-75
prototype safety monographs, 14, 269, 394, 455
Investigational New Drug application, 312
K
Kidneys, see Renal system
L
Labeling and packaging
adverse event reporting and, 130, 134
chaparral, safety monograph, 394
committee recommendations, 16, 304
Dietary Supplement Health and Education Act (DSHEA), 22, 35, 38
Dietary Supplement Labels: Key Elements (Inspector General), 17, 304
FDA policies, general, 28-29, 31-35, 38
good manufacturing practices, 130
historical perspectives, 22, 28, 31-35, 78-79, 223
Labeling of Hazardous Materials Act, 223
Nutrition Labeling and Education Act, 31-35
resources on dietary supplements, various, 44
saw palmetto, safety monograph, 454-455
Labeling of Hazardous Materials Act, 223
Lactating women
prototype safety monographs, 314, 347, 364, 365, 368, 369, 454
supplement review approaches, various, 56, 58, 60, 62, 64, 68-69, 70, 75
Legislation
see also Dietary Supplement Health and Education Act;
Regulatory issues
committee recommendations, 15-16, 297, 300-301, 321
Constitutional law, 29
Federal Food and Drugs Act, 26
Federal Food, Drug, and Cosmetic Act, 2, 26-27, 78, 96, 307
Food Additives Amendment, 2, 29-31, 307
Federal Hazardous Substances Act, 223
Federal Meat Inspection Act, 26
Food and Drug Act, 26
Health Research and Health Services Amendments, 31
historical review, 22-39
in vitro assays, related legislation, 223
Labeling of Hazardous Materials Act, 223
Nutrition Labeling and Education Act, 31, 33-35
Prescription Drug User Fee Act, 35
Toxic Substances Act, 314
Literature reviews, 46
cosmetics ingredients evaluation, 311
Framework for dietary supplements, 91, 92-93, 94
prototype monographs, 287, 368, 370, 401-403
review approaches, various, 45, 50, 52, 57-63 (passim), 67, 68-69, 72, 74
Litigation
DSHEA safety standards, legislative text, 7, 25
historical perspectives, 28, 31
vitamins and minerals, 31
Liver, see Hepatic system
L-tryptophan, 34-35
M
Mechanism of action, see Biological activity/mechanism of action
MedWatch, 16, 39, 129, 302-303, 313, 484
Melatonin
androgens, 377
animal studies, 368
clinical trials, 368, 369, 370
dosage and administration considerations, 279, 368, 369, 370
international perspectives, 283
prototype safety monograph, 278-279, 284-285, 290, 367-371
Men, see Gender factors
Mental health, see Behavioral toxicity
Metabolism and metabolites, 16, 76, 77(n.6), 114, 122, 130, 177
see also Enzyme activity
age-related changes, 248
animal studies, 158, 161-162, 360
chaparral, 396
glucosamine, 277
interactions, supplement-induced, 238-239, 360
Minerals, see Vitamins and minerals
Minority groups, see Race/ethnicity
Monitoring
see also Adverse events;
Signal detection
committee recommendations, 15-16, 300
FDA policy, general, 300-301
Framework review process, 11, 96, 97, 99-100, 293, 295, 300-301
new drugs, 312
postmarket surveillance, 79-80, 309
prototype monographs, 11
chaparral and melatonin, 272, 284-285
Special Nutritional Adverse Event Monitoring System (SN/AEMS), 272, 275, 279, 281, 389, 402, 436
Special Nutritional Event Monitoring System (SN/AEMS), general, 300
Monographs, various
see also Prototype monographs
botanicals, 54, 55, 57, 59, 63-64, 68-69, 71-78
Internet review approaches, 59
N
National Center for Complementary and Alternative Medicine, 66-67
National Center for Toxicological Research, 17, 305
National Health Interview Surveys, 22
National Institute of Environmental Health Sciences, 91, 99-100
National Institutes of Health, 17, 66-67, 304-305
National Institute of Environmental Health Sciences, 91, 99-100
National Center for Complementary and Alternative Medicine, 66-67
Natural Medicines Comprehensive Database, 74-75
Natural chemistry, see Botanicals;
Chemical components and related botanicals
NDGA, see Chaparral
Nephrotoxicity, see Renal system
Nervous system effects
chemical components and botanicals, taxonomic relatedness, 187-199
shark cartilage, 383
New Chemicals Program (EPA), 314-315
New drug applications (NDAs), 23, 27
Nordihydroguaiaretic acid (NDGA), see Chaparral
Notification requirements, 27, 80
adverse event reporting, 16, 104, 126, 294, 301-303, 366
spontaneously reported, 16, 127-136, 293, 373, 432
Evidence-based Practice Centers, 66, 67
federally supported research, results publication, 17
generally recognized as safe (GRAS), 2, 5, 29-30, 32-33, 80, 307-308, 309-310
intent to market, 3, 16, 38, 303
new chemicals, 314-315
new drugs, 311-314
Nutrition Labeling and Education Act, 31-35
O
Office of Dietary Supplements, 99-100
Over-the-counter drugs, 23, 302(n.2), 313-314, 456
P
Packaging and labeling, see Labeling and packaging
Peer review, 44, 46, 50, 52, 55-66 (passim), 69
Pharmacoepidemiology
Framework review process, 484
Pharmacokinetics and pharmacodynamics, 312
animal studies, 159, 161-162, 163, 172, 241-242
chemical components and related botanicals, 179, 204, 396
Framework review process, 109, 113, 364
glucosamine, 364
integration of data, 267
interactions, supplement-induced, 236-243, 244
Plant-based supplements, see Botanicals
Poison Control Centers, 16
Postmarket surveillance, 79-80, 309
Pregnancy and lactation, 48, 50, 53, 56, 58, 60, 62, 64, 248-249, 365, 369, 458, 476
see also Fetal development
abortifacients, 189, 193, 197, 199
botanicals, various review approaches, 53, 56, 60, 64, 68-69
fetus, impacts on, 48, 50, 53, 56, 58, 60, 62, 64, 68-69, 112, 230, 248-249, 259, 274, 337, 360, 378, 383, 452, 453, 457, 476
glucosamine, prototype monograph, 364, 365
melatonin, prototype monograph, 368, 369
saw palmetto, prototype monograph, 454
supplement review approaches, various, 56, 58, 60, 62, 64, 68-69, 70, 75
review approaches, various, 48, 50, 53, 56, 58, 60, 62, 64, 68-69, 112, 230, 248-249, 259, 274, 337, 360, 378, 383, 452, 453, 457, 476
Premarket approval, 3, 16, 32-33, 36, 79-80, 295, 299, 303, 307-309
Dietary Supplement Health and Education Act (DSHEA), 3, 16, 32-33, 38, 79-80, 295, 299
Prescription Drug User Fee Act, 35
Prescription drugs, 302(n.2)
see also Over-the-counter drugs
adverse event reports and, 130
consumer expectations, 23
Framework, application of, 118
in vitro data and, 231
PDR for Herbal Medicines, 75-76
saw palmetto, 280, 379, 455, 456
Prevalence of use, 250-251
FDA authority to undertake civil proceedings, 7, 25, 251
Framework review process, 109, 112, 114, 318-319
glucosamine, 277
prototype safety monographs,
chromium pincolate, 275
glucosamine, 363
shark cartilage, 284
Processing of supplements
alcohol extraction, 139, 202, 203, 205, 207, 393
good manufacturing practices, 17, 30, 39, 78(n.7), 130, 303-304
manufacturers, Framework review approach, 295
preparation methods, individuals, 202, 205, 451-452
Professional education, 302
see also Monographs
adverse event reporting, 16
Framework review process, 16, 98, 99
committee’s summary findings and recommendations, 297-299
categories of scientific evidence,
animal data, 156-157, 161, 172
human information and data, 127, 134, 136, 141, 142, 151
in vitro data, 218, 222-224, 229
integrating and evaluation data, scientific principles, 253, 264, 266, 267-268
Dietary Supplement Health and Education Act (DSHEA), 267-268
Framework review approach, 86, 95, 97, 100, 101, 109, 115
unreasonable risk determination, 2, 3, 10, 13, 14, 15, 18, 298-299
prototype monographs, 267-268, 274, 278, 284
review approaches, various, 48, 75, 76
Prototype monographs, 10, 13-14, 89, 91, 92, 93-95, 98, 121-123, 269-271, 304
adverse events, 272, 275, 279, 281, 283, 366, 368, 373, 377, 388-389, 432, 466
advisory committees, external, 290
animal studies, 283, 285, 287, 358, 360, 364, 365, 368, 373, 381, 437-439, 453, 456, 457-458, 468-470, 476-477
behavioral toxicity, 278, 279, 369, 370
committee charge/methodology, 2, 13, 21, 269, 270, 316, 317, 320
external advisory committees, 271
fetal development, 274, 360, 378, 383, 452, 453, 457, 476
hepatic system
chaparral, 264-265, 356-362, 387-401 (passim), 428-431, 446
chromium picolinate, 372
glucosamine, 365
melatonin, 369
human studies, 285, 287, 358, 363-368 (passim)
chromium picolinate, 373-374
glucosamine, 277, 363-364, 365
initial reviews, 54, 272-278 (passim), 281-282, 284
integrative evaluation, 10, 271, 276, 277, 281, 282-283, 285-291
data gathering strategies, 286-287
focused vs broad-based monograph, 10, 14, 269, 279, 273, 277, 278, 279, 282, 285-286
inconsistent data, 287-290
Internet publication, 14, 269, 394, 455
lactating women, 314, 347, 364, 365, 368, 369, 454
literature reviews, 287, 368, 370, 401-403
monitoring, 11, 272, 279, 284-285, 368
Special Nutritional Event Monitoring System (SN/AEMS), 272, 275, 279, 281, 389, 402, 436
prevalence of use, 275, 283, 284, 291, 363, 395
proof of risk/harm, 267-268, 274, 278, 284
review and updating of, 291
science-based principles applied, 283-291
signal detection, 270-271, 272, 275-278 (passim), 281, 283-284
specific case studies using, 269-291, 356-477
chaparral, 272-275, 284-285, 287-290, 356-449
chromium picolinate, 275-276, 283, 372-375
melatonin, 278-279, 284-285, 290, 367-371
saw palmetto, 95, 279-281, 286, 376-379, 450-477
shark cartilage, 281-283, 380-384
Proxmire Amendments, see Health Research and Health Services Amendments
Psychological factors, see Behavioral toxicity
Public education
see also Internet;
Labeling and packaging
adverse event reporting, 16
FDA, committee recommendations, 302-303
Framework review process, 14, 16, 98-99, 123, 269, 293, 394, 455
Pure Food and Drug Act, 26
R
Race/ethnicity
historical use of botanicals, particular groups, 140, 395, 397
supplement consumption, 23
Recommended Dietary Allowance (RDA), 60, 71
Redbook, 80, 157, 158, 206, 223, 308
Regulatory issues
see also Definitional issues;
Food and Drug Administration;
Framework for dietary supplements, general;
Labeling and packaging;
Legislation;
Litigation;
Notification requirements
adverse event reporting, 136
committee work, comments received, 321
current status of foods, additives, drugs, and supplements regulated by FDA, 4-5, 32-33
generally recognized as safe (GRAS) additives, 2, 5, 29-30, 80, 307-308, 309-310
historical perspectives, 24-39
in vitro tests, 229-231
information on safety, 1
international perspectives, 131(n.3)
melatonin, 283
review approaches, various, 49, 52, 68
saw palmetto, 279-280, 283, 456
investigative new drug applications, 311-312
New Chemicals Program (EPA), 314-315
over-the-counter drugs, 23, 302(n.2), 313-314, 456
safety monographs, 94
vitamin and minerals, regulatory history, 28, 31, 34, 36
Renal system, 130, 133, 163, 200, 238, 239, 240, 248, 249
chaparral, 274-275, 356, 358, 360
chromium picolinate, 275-276
melatonin, 369
Report of the Commission on Dietary Supplement Labels, 38
Reporting requirements, see Adverse events;
Premarket approval
Reproductive toxicity, 159, 166, 169, 200
see also Gender factors;
Pregnancy and lactation
Framework review process, 106, 274, 275, 279, 280, 281, 287, 312
prototype monographs
saw palmetto, 280, 284, 376, 378, 451, 452, 453, 455, 457
plant family information, 338
Research methodology
see also Adverse events;
Animal studies;
Chemical components and related botanicals;
Clinical studies and trials;
Definitional issues;
Epidemiological studies;
Framework for dietary supplements;
Genetic toxicology;
Historical use of supplements;
Human studies and data;
In vitro assays;
Integration of data;
Literature reviews;
Risk assessment strategies;
Surveys;
Toxicology
committee charge/methodology, 1-2, 21, 43-48, 269, 292, 316-321
FDA review, general, 21
integration of data, 253-268, 285-291, 319
peer review, 44, 46, 50, 52, 55-66 (passim), 69
science-based principles applied, 126, 156, 217, 235
adverse events, 104, 112, 126, 127-136, 141, 152
advisory committees, external, 318-319
chemical components and related botanicals, 176-177, 182, 205, 208, 210
integration of data, 253-268, 285-291, 319
vulnerable subpopulations, 247
Research recommendations, 15-18, 304-305
chromium picolinate, 375
glucosamine, 365-366
melatonin, 370
shark cartilage, 384
Respiratory effects
chemical components and botanicals, taxonomic relatedness, 187-199
Risk assessment strategies, 3, 11-13
see Animal studies;
Epidemiological studies;
Expertise;
Framework for dietary supplements, general;
Human studies and data;
In vitro assays;
Integration of data;
Monographs;
Proof of risk/harm;
Prototype monographs;
Safety monographs
cosmetics, FDA review approach, 310-312
current status of foods, additives, drugs, and supplements regulated, 4-5, 6, 32-33
definition of risk, 168-169
FDA, historical perspectives, 29-30, 33
interactions, supplement-induced, 243
New Chemicals Program (EPA), 314-315
review approaches, various existing, 43-81 (passim), 307-315
animal studies, 45, 49, 52, 55, 57, 59, 61, 63, 266-267, 312
biological activity/mechanism of action, 48, 49, 53, 58, 60, 64
botanicals, 49, 51-57, 59-61, 63-64, 68-69, 71-79
contaminants and adulterants, 44, 70, 78
currency of research, 45-65 (passim), 75
dosage and administration considerations, 47, 50, 52-53, 55-56, 58, 60, 62, 64, 66, 67, 72
expertise, general, 43, 44, 46, 51-66 (passim), 69, 71, 75, 77
in vitro assays, 45, 49, 57, 59, 61, 299
interactions with other substances, 48, 51, 53, 56, 58, 62, 63, 69, 72, 76
lactating, 56, 58, 60, 62, 64, 68-69, 70, 75
literature reviews, 45, 50, 52, 57-63 (passim), 67, 68-69, 72, 74
peer review, 44, 46, 50, 52, 55-66 (passim), 69
proof of risk/harm, 48, 75, 76
science-based principles applied, 126, 156, 217, 235
adverse events, 104, 112, 126, 127-136, 141, 152
advisory committees, external, 318-319
chemical components and related botanicals, 176-177, 182, 205, 208, 210
Framework approach proposed, 11-13, 44-45, 95, 97, 100-116
advisory committees, external, 318-319
methodology for study, 318-319
prototype monographs, 283-291
integration of data, 253-268, 285-291, 319
vulnerable subpopulations, 247
unreasonable risk determination, 2, 3, 10, 13, 14, 15, 18, 298-299
S
Safety monographs
see also Prototype monographs
American Herbal Pharmacopoeia, 68-69
European Scientific Cooperative on Phytotherapy, 57, 59
German Commission E, 54, 55, 72
integration of data, 264(n.6)
PDR for Herbal Medicines, 59-61, 75-76
PDR for Nutritional Supplements, 61-63, 76-77
U.S. Pharmacopeia-National Formulary (USP-NF), 27, 28, 78-79
World Health Organization, 63-64, 77
Saw palmetto
adverse events, 279, 377, 379, 432, 466
animal studies, 453, 456, 457-458, 468-470, 476-477
carcinogenicity, 376, 378, 451, 453, 455
dosage and administration, 377, 451-452, 456, 457-458
gender factors, 280, 284, 376, 378, 451, 452, 453, 455, 457, 458, 468-470
individual components, 451, 463
international perspectives, 279-280, 283, 456
prescription drug status, 280, 379, 455, 456
prototype monographs, 95, 279-281, 286, 376-379, 450-477
Shark cartilage, 176(n.2)
adverse events, 281
angiogenesis inhibitor, 281, 282, 381-384
carcinogenicity, 381
dosage and administration, 282
in vitro studies, 281-282
prototype monographs, 281-283, 380-384
teratogenic effects, 282
Side effects, 378, 379, 381-384 (passim)
see also Interactions
supplement review approaches, various, 58, 63, 68, 69-70, 72, 76
Signal detection, 3, 6-9, 86-89, 119, 172
see also Adverse events;
Animal studies
defined, 88
expertise, 88
Socioeconomic status, consumption of supplements, 23
Special Nutritional Adverse Event Monitoring System (SN/AEMS), 272, 275, 279, 281, 300, 373, 389, 402, 436
Surveys
consumption of supplements, 22
National Health and Nutrition Examination Survey, 22
National Health Interview Surveys, 22
prevalence of use, 250-251
T
Telephone
adverse events reporting, 16, 303
consumer surveys, 24
MedWatch, 303
Teratogenicity, 69, 166, 230, 248, 259, 267, 282, 309, 312, 382, 383, 458, 477
animal studies, 248-249
chemical components and related botanicals, 187-195 (passim), 199, 200, 207
new drug applications, 312
plant family information, 336, 340, 348-349
Third National Health and Nutrition Examination Survey, 22
Time factors
see also Historical perspectives
adverse event reporting, 132, 133, 134, 135, 301-302
chaparral dose-response, 357
glucosamine, clinical trials, 363-364, 366
historical use of supplements, value as evidence, 138, 140-141, 152-153
investigational new drug application, 312
melatonin, length of use, 369, 370
notification of intent to market, 3, 38
premarketing review period, 16, 24, 38, 303
review frameworks, currency of research, 45-65 (passim), 75
Tolerable Upper Intake Level (UL), 51, 70-71, 119, 120, 372
Total dietary intake, 20
Toxic Substances Act, 314
Toxicological Principles for Safety of Food Ingredients, see Redbook
Toxicology
see also Animal studies;
Behavioral toxicity;
Chemical components and related botanicals;
Clinical studies and trials;
Genetic toxicology;
Immunotoxicity;
Reproductive toxicity
alcohol use and abuse, 23, 129, 358, 359, 399
botanicals, various review approaches, 68-69, 72
committee recommendations, 17
cosmetics ingredients evaluation, 311-312
Framework review process, 11, 17, 100, 103, 104, 106-108, 110-111, 299
U
Unreasonable risk determination, 2, 3, 24, 30, 32, 118, 119, 121, 131
Framework review process, 10, 13, 14, 15, 18, 85, 86, 93, 95, 99, 100, 101, 103, 115, 298
other review approaches, 48
U.S. Pharmacopeia-National Formulary (USP-NF), 27, 28, 78-79, 454
U.S. Recommended Daily Allowance (U.S. RDA), 31
V
Veterinary medicine, 159-161, 164, 187-200 (passim)
see also Animal studies
Vitamins and minerals, 20
see also Chromium picolinate
consumption, 19
defined, 28
FDA regulatory history, 28, 31, 34, 36
Framework review process, 118-121
historical perspectives, 19, 22, 28, 31, 34
litigation, 31
Recommended Daily Allowance (RDA), 118-121
review approaches, various, 61, 78
teratogenicity, Vitamin A-related, 248-249
Vulnerable groups, general, 247-250
see also Fetal development;
Pregnancy and lactation
adverse events, 112
children, 48, 64, 248, 365, 369, 370, 376
defined, 112
Framework review process, 109, 112-113, 118-119, 318
infants, 248-249, 311, 326, 368, 472
interactions, supplement-induced, 242
other supplement reviews, 48, 64, 70, 163-164
pre-existing disease conditions, 249
diabetics
chromium picolinate, 275-276, 373
hepatic system, chaparral, 358
insomnia, melatonin, 367
interactions with other xenobiotics, shark cartilage, 282
W
Women, see Gender factors;
Pregnancy and lactation
World Health Organization, 63-64, 70, 77
World Wide Web, see Internet
X
Xenobotics, 145, 221, 236-237, 238-240, 241-243, 249, 282
see also Interactions
defined, 235(n.2)
