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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

chaparral, 388-403, 420, 436

chromium picolinate, 275, 373

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)

labeling and, 130, 134

MedWatch, 16, 39, 129, 302-303, 313, 484

melatonin, 368, 370

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

elderly persons, 48, 248, 277

infants, 248-249, 311, 326, 368, 472

Tolerable Upper Intake Level (UL), 70

Agency for Healthcare Research and Quality, 49-51, 66-68



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Dietary Supplements: A Framework for Evaluating Safety 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 chaparral, 388-403, 420, 436 chromium picolinate, 275, 373 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) labeling and, 130, 134 MedWatch, 16, 39, 129, 302-303, 313, 484 melatonin, 368, 370 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 elderly persons, 48, 248, 277 infants, 248-249, 311, 326, 368, 472 Tolerable Upper Intake Level (UL), 70 Agency for Healthcare Research and Quality, 49-51, 66-68

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Dietary Supplements: A Framework for Evaluating Safety 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 Amino acids, 20, 34, 61, 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 chaparral, 390-391, 437-439 chemical components and botanicals, taxonomic relatedness, 187-200 (passim), 210, 211 chromium picolinate, 373, 374 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 Redbook, 157, 158 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 animal studies, 158, 159, 166 melatonin, 369, 370 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

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Dietary Supplements: A Framework for Evaluating Safety consumption, 22 contaminants and adulterants, 191, 195, 199, 201, 329 FDA, general, 2, 28, 30, 34 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 history of regulation, 2, 24 litigation, 2, 31 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 stevia, 30, 34 supplements defined, 20 teratogenicity, plant family information, 336, 340, 348-349 C Carcinogenicity animal studies, 163, 164, 172, 368 chaparral, 394, 420, 432-433 chemical components and botanicals, taxonomic relatedness, 187-197 human studies, 138, 146 melatonin, 368, 370 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 melatonin, 369, 379 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 chaparral, 387, 399, 441-448 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 immunotoxicity, 388, 394, 395 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

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Dietary Supplements: A Framework for Evaluating Safety 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 adverse events, 275, 373 animal studies, 373, 374 clinical research, 373-374 diabetics, 275-276, 373 dosage and administration, 276, 372-373, 374 in vitro assays, 283, 373 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 demographic factors, 143, 145 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) melatonin, 368, 369, 370 new drug evaluation, 312-313 review approaches, various, 45, 49, 67-68, 72, 312 saw palmetto, 377, 466 shark cartilage, 381, 384 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 shark cartilage, 380, 382 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 additives, 2, 29, 31, 36, 307 adverse event, 126(n.1) dietary supplements, 2, 3, 6, 19-20, 36, 85 drugs, 27, 28 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

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Dietary Supplements: A Framework for Evaluating Safety animal studies, 163-164 clinical trials, 143, 145 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 glucosamine, 276-278, 365 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 additives, 4-5, 32-33, 80 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 labeling, 22, 35, 38 litigation, 7, 25 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 stevia, 30, 34 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 glucosamine, 363, 364, 365 historical use of supplements, value as evidence, 138-140 melatonin, 279, 368, 369, 370 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

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Dietary Supplements: A Framework for Evaluating Safety review process, conflicts of interest, 46, 59, 65, 270 saw palmetto, annual sales, 455 supplement sales, annual, 1, 19 Elderly persons, 48, 248 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 botanicals, 2, 28, 30, 34 chemical components and related botanicals, 178-179, 206-207 Center for Food Safety and Applied Nutrition, 97, 305 chaparral, 275-276, 396 chromium picolinate, 276

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Dietary Supplements: A Framework for Evaluating Safety 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 in vitro assays, 223, 230-231 industry resistance to regulation, 2 labeling, 28-29, 31-35, 38 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 funding, 295, 301 health care professionals, 98, 99 historical use of supplements, 93, 101-104 (passim), 124 human studies, 100, 101-103 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

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Dietary Supplements: A Framework for Evaluating Safety 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 process, overview, 3, 6-11 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 signal detection, 6-9, 86-89 signal review, 9, 87, 89-91 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) diabetics, 276-278, 365 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 adverse event reporting, 16, 283, 303 Framework review process, 98, 99

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Dietary Supplements: A Framework for Evaluating Safety 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 shark cartilage, 281, 381 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 FDA regulation, 2-3, 22-39 labeling, 22, 28, 31-35, 78-79, 223 litigation, 28, 31 number/sales of dietary supplements, 1, 19 vitamin and minerals, regulatory history, 28, 31, 34, 36 Historical use of supplements, 22, 299 botanicals, 61, 137-141 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 FDA policy, general, 136, 152 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 carcinogenicity, 138, 146 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 melatonin, 368, 369, 370 review approaches, various, 45, 49, 266 I Immunotoxicity allergic reactions, 69-70, 191, 201, 324, 345, 350, 365, 388 animal studies, 159 chaparral, 388, 394, 395 chemical components and related botanicals, 191, 199, 200, 201, 324, 331, 345 interactions with other substances, 236, 239, 240, 241 melatonin, 369 saw palmetto, 455, 465, 471 In vitro assays, 217-232 adverse event reporting and, 132, 135, 224

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Dietary Supplements: A Framework for Evaluating Safety animal studies and, 224 cell studies, 106, 112, 151, 219-220, 223, 225, 229 chaparral, 287, 391, 440 chromium picolinate, 283, 373 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 saw palmetto, 378, 471-475 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 definition, 3, 8 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 metabolic, 238-239, 360 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) chaparral, 276, 396 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

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Dietary Supplements: A Framework for Evaluating Safety 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 risks, general, 16, 264 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 botanicals regulated, 2, 31 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 adverse events, 368, 370 androgens, 377 animal studies, 368 behavioral toxicity, 369, 370 carcinogenicity, 368, 370 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

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Dietary Supplements: A Framework for Evaluating Safety 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 in vitro studies, 106, 109 interactions, supplement-induced, 238-239, 360 saw palmetto, 456, 471-475 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 melatonin, 279, 284-285, 368 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 Natural Standard, 59-61, 75 NDGA, see Chaparral Nephrotoxicity, see Renal system Nervous system effects chemical components and botanicals, taxonomic relatedness, 187-199 melatonin, 369, 370 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 PDR for Herbal Medicines, 59-61, 75-76 PDR for Nutritional Supplements, 61-63, 76-77

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Dietary Supplements: A Framework for Evaluating Safety 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 lactation, 314, 347 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, chaparral, 284, 395 chromium pincolate, 275 glucosamine, 363 saw palmetto, 280, 283, 284 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 Proof of risk/harm, 5, 295 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

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Dietary Supplements: A Framework for Evaluating Safety 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 shark cartilage, 281, 381 human studies, 285, 287, 358, 363-368 (passim) chromium picolinate, 373-374 glucosamine, 277, 363-364, 365 melatonin, 368, 369, 370 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 glucosamine, 276-278, 363-366 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 botanicals, historical perspectives, 2, 24

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Dietary Supplements: A Framework for Evaluating Safety committee work, comments received, 321 cost factors, 1, 21 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 monitoring, 15-16, 300 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 chaparral, 280, 284, 358, 360 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 causal models, 256-262, 288 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 chaparral, 361-362, 401 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

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Dietary Supplements: A Framework for Evaluating Safety definition of risk, 168-169 FDA, historical perspectives, 29-30, 33 interactions, supplement-induced, 243 New Chemicals Program (EPA), 314-315 new drugs, 23, 312-314 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 clinical trials, 143, 145 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 causal models, 256-262, 288 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 androgens, 95, 286, 450-477 animal studies, 453, 456, 457-458, 468-470, 476-477 carcinogenicity, 376, 378, 451, 453, 455 clinical research, 143, 145 dosage and administration, 377, 451-452, 456, 457-458 gender factors, 280, 284, 376, 378, 451, 452, 453, 455, 457, 458, 468-470 immunotoxicity, 455, 465, 471 in vitro data, 378, 471-475 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

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Dietary Supplements: A Framework for Evaluating Safety 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 Stevia, 30, 34 Surveys consumer beliefs, 22-24, 36 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

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Dietary Supplements: A Framework for Evaluating Safety 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 elderly persons, 48, 248, 277 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 glucosamine, 276-278, 365 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) Framework review process, 11, 100, 109, 359-360, 400