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Index A Acidic aerosols, effects of, 18, 135-137 Additivity, 7, 54 assumptionsin cancer model, 193-198 in generalized model, 215-217 allow closes, 102-104, 195-198 and responses in interactions, 83, 100 and risks associated with individual components, 180-182 in simple model, 215 Aerosols acidic, effects of, 18, 135-137 collection procedures for, 72-73 Aflatoxin bioactivity of, 50 effects in animals, 29 Air, ambient benzo(a)pyrene in, 13 particulate matter in. See Particulate matter in air Air pollution, sulfur dioxide and particulate matter in, 31, 133-137 Alcohol intake, smoking with, and oral cancer, 6, 20, 32-33, 148-151 Aliphatic compounds, 79 Ambient exposure, variability in, 23 American Conference of Governmental Industrial Hygienists, 72 Ames assay, for mutagen content of tobacco smoke, 170-171 221 Analysis of mixtures, 78-89 requirements for, 80-81 separation methods for, 81, 82-87 spectroscopy and spectrometry in, 87-89 Animal studies, 6, 25-30 alcohol intake and cigarette smoking, 32-33 analysis of inhalation experiment, 211-215 asbestos exposure and smoking, 32, 144 chlorination byproducts in water, 33 coal-mine dust, 34, 160-161 coke-oven emissions, 33-34, 156- 157 complexity of agents affecting, 27-28 developmental toxicology, 202-207 fractional factorial design in, 57-58 hydrocarbon toxicity, 45 lead exposure, 31-32 limitations of, 28-30 in long-term exposures, 27 nonconcurrence with human experience, 30-34 radon daughters and cigarette smoke, 32, 141 screening for necrologic disorders, 45 in short-term exposures, 26-27 sulfur dioxide exposure, 27-28, 29, 31, 134-136 toxicokinetics in, 30 Antagonism, and interactions of components, 7, 83 Aquatic test systems, 56 Aqueous samples, collection of, 73-74

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222 Aromatic compounds, 79 Asbestos exposure, interaction with cigarette smoke, 20, 29-30, 32, 143-148 Case studies Ashford-Cobby model, 217, 218, 219 B Battery approach to testing, 46 Benzene exposure, and cancer risk, 22 Benzo(a)pyrene air temperature affecting, 67 in cigarette smoke, 146 asindicatorof exposure, 13 Bioassay directed fractionations, 49-51 preparation of materials for, 77-78 Bioavailability and exposure assessment, 14-16 physical state of substrate affecting, 15-16 Biologically effective dose, 7-8, 11 Blood pressure, lead exposure affecting, 31-32, 137-140 Bronchitis, from coal-mine dust, 34, 159 C Cancer models, 185-201 additivity assumptions in, 193-198 and background tumor rate, 195 dose-response relationshipin, 192-193 exposure to multiple agents in, 186-188 and prediction of risk at low doses, 198-199 synergism effect in, 183-192 Cancer risk assessment with comparative-potency method, 47 from chlorination byproducts in water, 151-155 and initiation-promotion studies, 117- 118 recommendations for research in, 119- 120 in rubber industry, 22 Carbon monoxide interaction with carbon dioxide, 174, 211-215 in tobacco smoke, 170 Carcinogens benzo(a)pyrene, 13 fish sensitivity to, 56 identification of, 28-29 initiation-promotion studies of, 117 INDEX and protective effect of micronutrients, 20 screening studies for, 44 cigarette-smoke toxicity, 168- 171 fire atmospheres, 172- 175 hexacarbonneuropathy, 176-178 Chemical characterization of mixtures, 66, 79 search for causative agents, 51-52 Chemotherapy for cancer, maximal tolerable doses in, 26 Chlorinated dibenzofurans, differential uptake of, 15 Chlorination byproducts in water, 151-155 evaluation of risks from, 33 long-term exposure to, 19 Chloroform, interaction with chlordecone, 54-55 Chromatography, 82, 84-87 column, 84 gas, 88, 89 gel-permeation, 85 high-performance, liquid, 85, 86 high-resolution techniques in, 85-86 supercritical-fluid, 87 thin-layer, 85 Cigarette smoking. See Smoking Classification of complex mixtures, 65-66 chemical, 66, 79 Cluster sampling, 69 Coal gasification, hazardous materials in, 128- 129 Coal-mine dust constituents in, 129- 130 toxic effects of, 34, 157-161 Coal tar exposure in animals, 33, 156 materials in, 127 Coke-oven emissions, 155-157 animal studies, 33-34 control of, 19 and lung cancer risk, 13 relative potency tests of, 47 Collection of samples, procedures in, 72-76 for aqueous materials, 73-74 for gases and aerosols, 72-73 for nonaqueous liquids, 74-75 for solids and sediments, 75-76 Combustion products, 127 129 Comparative-potency studies, 46-49, 106-108 Cox proportional hazards model, 210

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INDEX D Developmental toxicology, 202-207 dose-response models in, 204-206 statistical methods in, 202-204 trend test in, 206 Diethylnitrosamine exposure, and responses in fish, 56 Diethylstilbestrol effects in animals, 29 Dinitropyrenes, bioactivity of, 50 Dioxins, in liquid or semisolid media, and bioavailability, 15-16 Distillation products, 127-129 Dosage biologically effective, 7-8, 11 for inhaled materials, 16-18 estimation with sampling, 12 exposure related to, 8, 11 - 18 maximal tolerated doses, 26, 112 prediction of low-dose risks, 115- 117 surrogates for, 12 and synergism, 7 Dose-response relationships, 11 in cancer model, 192-193 in developmental effects, 204-206 in interaction studies, 54-55, 100 Dump sites, hazardous chemicals in, 130 Duration of sampling, importance of, 67-68 E Effect-search strategies, 52-53 Effects of complex mixtures questions related to, 40-41 strategies related to, 42-49 Emphysema, from coal-mine dust, 34, 157-158 Empirical models, 121, 209-219 requirements for, 55-56 Experimental design for mixtures, 110- 119 and developmental-effects studies, 120- 121 empirical modeling in, 209-219 identification of toxic agents in, 111 - 113 for initiation-promotion studies, 117- 118 for predicting low-dose risks, 115- 117 response-surface analysis in, 113-115 for screening and low-dose extrapolation, 118-119 Exposure assessment of cost of, 25 and misclassifications, 12 223 complexity of, 18- 19 direct measurements of, 23 history of, 24 indicators of, 13-14 indirect measurements of, 23 inexact and incorrect measurements of, 25 multiple carcinogenic agents in, 186- 188 interactive effects of, 20-22 relationship to dose, 8, 11 - 18 routes of, 66-67 and analysis of mixtures, 80 end bioavailability, 15 statistical issues in, 24-25 F Fires, toxic agents in, 53 case study of, 172-175 Fish species, toxicity testing with, 56 Formaldehyde, and clearance rates for particles in respiratory tract, 18 Fractional factorial design, for assessment of substances, 57-58, 107-108, 119 Fractionations bioassay-directed, 49-51 general considerations in, 79-82 methods in, 82-87 Fuels, hazardous chemicals in, 127-129 G Gases, collection procedures for, 72-73 Gasification of coal, hazardous materials in, 128-129 Gasworkers, exposure to benzo(a)pyrene in, 13 Generalized linear models, 210-219 Global approach in testing of mixtures, 107-108 Grid patterns for sampling, 71 H Haloalkanes, interaction with ketones, 54, 55 Hewlett-Plackett model, 217-219 Hexacarbon-neuropathy case, 44, 176-178 Hexobarbital activity, interspecies variations in, 30 Hydrocarbons boiling range and aromaticity of, 45 . chemical search for components in, 52

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224 in cigarette-smoke condensate, 49 in coal tar, 127 comparative potency of, 48 in petroleum, 128 Hydrocyanic acid, interaction with carbon monoxide, 174 Hypertension, and lead exposure, 31-32, 137-140 I Identification of toxic agents, 111 - 113 Indicators of exposure, 13- 14 Inhaled materials and estimation of effective dose, 16- 18 and particulate clearance affected by sulfur dioxide, 133- 137 repetitive exposure to, 23 Initiation-promotion studies, designs for, 117-118 Interactions of components in mixtures, 6-7, 20-22 and dose-response curves, 54-55, 100 and generalized additive model, 215-217 mechanistic principles in, 55 and synergism effect in cancer model, 183-192 testing for, 109 International Agency for Research on Cancer (IARC), 21, 28-29 International Commission on Radiological Protection, 16, 24-25 International Standards Organization, 72 Interpretation of results, and comparative evaluation, 106-108 Interspecies variability in susceptibility to toxicants, 25-30 K Ketones, interaction with haloalkanes, 54, 55 L Lead exposure and hypertension, 31-32, 137- 140 and interspecies variations in absorption, 30 Liquid-liquid partitioning, 81, 82, 83-84 Liquids, nonaqueous, collection of samples, 74-75 Litter effect, in developmental toxicology, 202 INDEX Long-term exposures, 18- 19 animal studies of, 27 Low-dose exposure and additivity of excess risks, 195-198 prediction of risk in, 115-117, 198-200 Lungs cancer of and asbestos exposure in smokers, 20, 29-30, 32, 143-148 and exposure to benzo(a)pyrene, 13 and radon exposure in smokers, 20, 29-30, 32, 140-143 risk assessment with comparative-potency method, 47 smoking associated with, 13, 32 in uranium miners, 142-143 deposition of airborne particles in, 16-18 disease from coal dust, 34, 157-161 M Mathematical models, 102- 105 in comparative-potency testing, 47 for estimation of exposure, 24-25 Matrix testing, 45-46 Meteorologic considerations in sampling, 67 Micronutrients, protective effects of, 20 Miners coal dust exposure in, 34, 157-161 radon exposure and smoking in, 32, 142- 143 Model-driven strategies, 53-56 Models in toxicology, 100- 101 animal. See Animal studies cancer, 185-201 dose-extrapolation, 105-106 dose-response, 102-105 empirical, 121, 209-219 requirements for, 55-56 mathematical, 24-25, 47, 102-105 multistage, 180 for cancer risk, 186-201 for two materiels, 104 pharmacokinetic, 108-110, 121-122 quasibiologic, 217-219 Mortality data from surveys of occupations and industries, 21 Multiple exposures, interactive effects of, 20-22 Multistage models, 180 for cancer risk, 186-201 for two materiels, 104

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INDEX Multistage sampling, 69 Mutagens in tobacco smoke, 170-171 N National Cancer Institute, 44 National Research Council, 19, 20, 23, 28, 29 Neuropathy, hexacarbon, 44-45, 176- 178 Newark soil samples, 14- 15 Nitrogen dioxide asindicatorofexposure, 14 toxic effects of, 27 Nitroparaffins, chemical search for components in, 52 Nitrosamines, in tobacco smoke, 170 Nutrition and ingestion exposures from food, 23 and lead exposure, 137-140 and protective effects of micronutrients, 20 o Oil shale, constituents in, 128, 130 Oral cancer risk, alcohol intake and smoking in, 6, 20, 32-33, 148-151 Organometallic compounds, 79 Origins of complex mixtures, 127-131 Ozone and clearance rates for particles in respiratory tract, 18 as indicator of exposure, 14 p Pairing of data bases, 51 Particulate matter in air active agents in, 134 collection procedures for, 72-73 and estimation of effective dose, 16- 18 as indicator of exposure, 14 and sulfur dioxide, 31, 133- 137 temperature affecting, 67 Petroleum fractions, biologic activity of, 128 Pharmacokinetic models, 108- 110, 121 - 122 Physical characteristics of mixtures, 66 Pneumoconiosis, coal-workers, 34, 157- 158 Polychlorinated biphenyls bioactivity of, 50 in liquid or semisolid media, and bioavailability, 15-16 soil binding of, 15 225 Polyurethane foam, thermal degradation products of, 51, 129, 173 Population groups, complexity of, 20 Potency of compounds, comparative studies of, 46-49, 106-108 Predictions and approach in testing mixtures, 39-40, 41-42 and comparative potencies of similar substances, 106-107 and designs for low-dose extrapolation 115-117 in interaction studies, 58-59 in low-dose exposure, 198-200 and nonconcurrence between human and animal responses, 30-34 and risks associated with individual components, 180- 182 strategies related to, 53-56 unexpected results in, 109 and value of animal studies, 25-30 Pregnancy, and developmental toxicology, 202-207 Probability sampling, 68-69 Q Quality assurance, and sample integrity, 24, 78 Quasibiologic models, 217-219 Questions in testing related to causative agents, 41 related to effects, 40-41 related to predictability, 39-40, 41-42 related to strategies, 58-59 R Radiation exposure and skin cancer in smokers, 143 variations in, 19 Radon exposure, interaction with cigarette smoke, 20, 29-30, 32, 140-143 Random sampling, 68-71 Recommendations for research, 119-123 Respiratory tract, deposition of airborne particles in, 16- 18 Response-surface designs, 113- 115 Roofers, exposure to benzo(a)pyrene in, 13 Roofing tar, relative potency tests of, 47 Rubber industry, cancer risk in, 22

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226 S Sampling, 66-78 cluster, 69 collection procedure in 72-76 9 collection strategy in, 66-71 for close estimation, 12 grid patterns, 71 meteorologic considerations in, 67 multistage, 69 and preparation of materials for assay, 77-78 probability, 68-69 quality assurance in, 24, 78 random, 68-71 and routes of exposure, 66-67 spatial considerations in, 68-71 and storage of samples, 76-77 stratified, 69 systematic, 69-71 temporal factors in, 67-68 Screening studies, 44-45 and designs for low-dose extrapolation, 118-119 Seasonal considerations in sampling, 67 Sediments, collection of samples from, 75-76 Separation of mixture constituents, 81, 82-87 chromatography in, 82, 84-87 liquid-liquid partitioning in, 81, 82, 83-84 Short-term exposures, 18 animal studies, 26-27 Silica dust, and clearance rates for particles in respiratory tract, 18 Simplex-centroid design, in surface analysis, 114 Simplex-lattice design, in surface analysis, 114 Skin absorption of materials in repetitive exposures, 23 cancer of, and effects of smoking and radiation, 143 Smoking alcohol intake with, and oral cancer, 6, 20, 32-33, 148-151 animal studies of, 27 and asbestos exposure, 20, 29-30, 32, 143- 148 and benzo(a)pyrene exposure, 13 and biologically active compounds in smoke, 28, 129, 170 INDEX case study of, 168-171 and clearance rates for particles in respiratory tract, 18 and exposure to toxic ingredients, 19 fractionation of smoke condensate, 49 and radon exposure, 20, 29-30, 32, 140- 143 relative potency tests of, 47 and skin cancer from radiation, 143 Soil samples collection of, 75 2,3,7,8-tetrachlorodibenzo-p-dioxin in, 14-15 Solid materials, collection of samples in, 75-76 Solvents for elusion of substances from water, 74 for extraction of materials from samples, 75, 82 in preparation of materials for assay, 77 Soots, comparative-potency studies of, 47 Spatial considerations in sampling, 68-71 Spectroscopy and spectrometry, 87-89 Statistical methods in developmental toxicology, 202-204 in quantitation of exposure, 24-25 Storage of collected samples, 76-77 Stratified random sampling, 69 Sulfur dioxide in animal studies, 27-28, 29, 31, 134-136 as indicator of exposure, 14 and particulate matter in air, 31, 133-137 Sulfuric acid, and clearance rates for particles in respiratory tract, 18 Surface analysis, designs used in, 114 Surveys of occupations and industries, mortality data in, 21 Synergism, 7 in cancer model, 183- 192 Systematic sampling, 69-71 T Temporal considerations in sampling, 67-68 Teratologic effects of chemical mixtures, 202-207 Testing aquatic systems in, 56 battery approach in, 46 bioassay-directed fractionation in, 49-51 bioassay identification in, 53

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INDEX chemical search in, 51-52 choice of end points in, 41, lot in developmental toxicology, 206-207 comparative-potency approach in, 46-49 complexity of mixture affecting, 57-58 driving forces in, 58 effect search in, 52-53 empirical models in, 55-56 fractional factorial design in, 57-58, 107-108, 119 global approach in, 107-108 interaction studies in, 54-55 matrix, 45-46 mechanistic studies in, 55 pairing of data bases in, 51 recommendations for, 122- 123 screening studies in, 44-45 strategies in, 42-56 formulation of, 59 integration of, 56-60 related to causative agents, 49-53 related to effects, 42-49 related to predictability and models, 53-56 related to questions and problems, 58-59 structuring of questions in, 40-42 summing of component toxicities in, 53-55 tier, 43 44 2,3,7,8-Tetrachlorodibenzo-p-dioxin in soil samples, 14-15 Tier testing programs, 43 44 Time course in sampling, importance of, 67 Times Beach soil samples, 14-15 227 Tobacco smoke. See Smoking Toxicokinetics, interspecies variations in, 30 Trend test, in developmental toxicology, 206 Trihalomethanes, in water, 33, 151-155 U United States Environmental Protection Agency, 14, 17, 72, 76 Uranium miners, and lung cancer in smokers, 142 V Vegetable materials, pyrolysis products of, 129 Vinyl chloride effects in animals, 29 thermal degradation products of, 129 in tobacco smoke, 170 W Wastes, hazardous, 130 Water activated-carbon filtration of, 19 chlorination byproducts in, 151 - 155 evaluation of risks from, 33 long-term exposure to, 19 collection of samples, 73-74 extraction from samples, 74, 75 hazardous chemicals in, 130-131

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