s9 index

A2-AAF. See 2-AcetylaminofluoreneAbalone poisoning, 1079Abamectin, 787, 788fAbciximab, thrombocytopenia and, 404, 404tAbietic acid, allergic contact dermatitis

from, 660tAbortifacients, from plants, 973–974Abortion, spontaneous, 703–704ABP. See Androgen-binding proteinAbrins, 968Absolute luminance threshold, 574Absorbed dose, radiation, 921–924Absorption, 14, 36–37, 38f, 107–108, 108f,

111, 230by gastrointestinal tract, 111–115, 112t,

115t, 874, 1052–1053, 1053tby lungs, 115–117, 116f, 874through skin, 117–119, 117f, 654–656, 874of solvents, 874after special routes of administration, 119transdermal drug delivery, 655–656

Acceptable daily intake (ADI), 91–93,1059, 1142

Accessory sex organsfemale, 686male, 683–684, 684f, 697

ACE. See Angiotensin converting enzymeAcebutolol, cardiotoxicity, 614t, 617Acentric fragment, 330, 340, 343Acephate, 779Acesulfame, in food, 1056tAcetaldehyde, 153–154, 282, 480, 484,

486, 893biotransformation, 41t, 154–156cardiotoxicity, 613, 629vasculotoxicity, 642

Acetaldehyde dehydrogenase, 893Acetaminophen, 44, 72

biotransformation, 135, 137, 164, 164f, 180,181f, 182, 184–185t, 188, 189t,191–192, 198, 199f, 201, 203t,204–205, 213–214, 481, 509, 1118

cellular dysregulation, 52hepatotoxicity, 476t, 479t, 481, 482, 482f,

1118–1119impairment of cellular maintenance, 60t, 63laboratory tests on stat basis, 1112tmetabolites as ultimate toxicants, 37tnephrotoxicity, 503, 509–510occupational disease, 1130poisoning, 1098, 1103, 1103t, 1118–1119

postmortem concentrations in blood, 1098Rumack-Mathew nomogram, 1112,

1112f, 1119Acetanilide

biotransformation, 183, 185toxidative hemolysis and, 397t

Acetazolamide, developmental effects, 367

Acetic acidin food, 1056t, 1062tocular toxicity, 575

Acetoacetamide, thyroid toxicity, 726fAcetochlor, 794Acetohexamide, biotransformation, 145Acetone, 196, 629

cardiotoxicity, 630tlaboratory tests on stat basis, 1112toccupational disease, 1127ttoxicokinetics, 875, 875f

Acetophenazine, cardiotoxicity, 622Acetostearin, in food, 1057t4-Acetoxy-androstene-3,17-dione, reproductive

system toxicity, 689t2-Acetylaminofluorene (2-AAF)

biotransformation, 40, 169f, 178, 189, 189t,205f, 210f

carcinogenicity, 244, 244f, 250–251, 257,299, 301f

developmental effects, 364genetic effects, 327Leydig cell tumor development and, 744mutagenicity, 256–257, 257tas promoting agent, 276

Acetylandromedol, 1083Acetylation, 135, 197, 197f, 208–211,

209–210f, 253fN-Acetylbenzidine nitrenium ion,

carcinogenicity, 252fN-Acetylbenzo-p-quinoneimine (NAPQI), 22,

164, 180, 182, 481biotransformation, 41t, 214nephrotoxicity, 503

Acetylcholine, 56, 632Acetylcholinesterase, 18, 18f, 56, 775

aged enzyme, 779, 783inhibition of, 779–781, 779–780f, 780tocular, 566t, 570snake venom, 957t, 959

Acetylcholinesterase agents, treatment ofpoisoning, 782–784, 783f, 783t

Acetyl-CoA, 208N-Acetylcysteine (NAC), 818

for acetaminophen poisoning, 1112, 1119biotransformation, 208

Acetylethyltetramethyl tetralin (AETT),neurotoxicity, 553t

N-Acetylglucosaminidase, 532, 825Acetylhydrazine, biotransformation, 169f, 210Acetylonitrile, 42

adrenal toxicity, 719N-Acetylprocainamide (NAPA), 1105t, 1106

laboratory tests on stat basis, 1112tN-Acetyltransferase, 208–211, 209–210f, 213,

217f, 218, 219f, 254f, 657ocular, 566t, 571

ACGIH. See American Conference ofGovernmental Industrial Hygienists

Acid(s), ocular toxicity, 575Acid anhydrides

hypersensitivity reaction to, 456–457occupational disease, 1128

Acid-base pair, 110Acidification, urinary, 1115Acidophils, 712, 713fAcid phosphatase, 532, 848

prostatic, 684Acid rain, 849, 994–995, 995fAcid volatile sulfides (AVS), 1016–1017Acne, 664–665

chloracne, 665, 665f, 666t, 792Aconitase, 40, 47Aconite, 3Aconitine, 55t, 56, 969Acquired immunity, 424–428, 433

cellular components, 425–428, 426fgeneral considerations, 424–425, 424t,

426–427tmemory, 424specificity, 424

Acridine, phototoxicity, 663tAcridine yellow, 45Acrinathrin, poisoning, 785tAcrolein, 47

air pollution, 999, 1005–1006biotransformation, 41thepatotoxicity, 480vasculotoxicity, 634, 642

Acrosome, 680Acrylamide

biotransformation, 690tneurotoxicity, 548t, 551occupational disease, 1127t, 1130ocular toxicity, 566t, 567, 584–585reproductive system toxicity, 690t

Acrylic monomer, allergic contact dermatitisfrom, 660t

Acrylonitrileadrenal toxicity, 717, 719biotransformation, 189tcarcinogenicity, 285t, 301f

ACTH, 678t, 712–713, 717immune effects, 431tvasculotoxicity, 636t

Actin, 46, 598Action potential, cardiac, 600, 600fActivated partial thromboplastin time, 406, 408Active transport, 110–111, 111t, 1052tActivin, 678tAcute dermal toxicity test, 27Acute exposure, 14Acute lethality study, 27Acute lymphoblastic leukemia (ALL), 402–403Acute myelogenous leukemia (AML),

402–403, 403f, 889Acute-phase proteins, 69f, 70–71, 421t,

423–424

INDEX

NOTE: Page numbers in boldface refer to major discussions. Page numbers followed by a t refer to tables; numbers followed by an f indicate figures.

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Acute-phase response, 423Acyclovir, nephrotoxicity, 496tAcylanilide, 791tAcylation, 136tAcyl-CoA:amino acid N-acyltransferase, 211, 212fAcyl-CoA:cholesterol acyl transferase, 718Acyl-CoA oxidase, 42Acyl-CoA synthetase, 211, 212fN-Acyltransferase, 211Adaptive immunity. See Acquired immunityADCC. See Antibody-dependent cellular

cytotoxicityAdders, 955, 956–957tAddison’s disease, 719Additive effect, 17Adenohypophysis, 712, 713fAdenosine, 120f, 607Adenosine diphosphate (ADP), vasculotoxicity,

636tAdenosine triphosphate. See ATPS-Adenosylmethionine (SAM), 206–208Adenyl kinase, 274Adenylyl cyclase, 611, 611f, 632, 634f, 742ADH. See Antidiuretic hormoneADI. See Acceptable daily intakeAdibendan, cardiotoxicity, 614t, 617–618Adipic acid, in food, 1056tAdrenal cortex

mechanisms of toxicity, 717–719, 718fpathologic alterations and proliferative

lesions, 719structure and function, 716–717

Adrenal medullamechanisms of toxicity, 720–721, 721–722fpathologic alterations and proliferative

lesions, 721–723, 722–723fstructure and function, 719–720

Adrenergic receptorsalpha, 55t, 56–57, 618, 632beta, 55t, 56, 611, 611f, 618–619, 632, 634f

Adrenocorticotropic hormone. See ACTHAdriamycin, reproductive system toxicity, 691tAdulterated food, 1054, 1143Advection, 1015Adverse health effect, 15

definition, 1007–1008, 1008fAerosol, in lungs, 116–117A-esterase, 137, 139Aflatoxin(s), 47

biotransformation, 164carcinogenicity, 89–90, 281tin food, 1054t, 1067t, 1076–1077, 1077thepatotoxicity, 478immunosuppression by, 446occupational disease, 1127t

Aflatoxin B1, 25, 1076biotransformation, 163, 163f, 189t, 191,

217, 1077carcinogenicity, 73, 75–76, 75f, 244f, 245,

250, 252f, 257, 262, 282, 283t, 290,299t, 301f, 1077

mutagenicity, 257tAflatoxin B1 2,3-epoxide, carcinogenicity, 252fAflatoxin B1 8,9-epoxide, biotransformation,

41t, 216–217Aflatoxin epoxide, 26Aflatoxin G1, 1076

biotransformation, 189tAflatoxin 8,9-oxide, 46–47Agaricus bisporus, 640Agency for Toxic Substances and Disease

Registry (ATSDR), 870Agent Orange, 9, 439, 792, 1092Age of Enlightenment, 4–5Aggregated detriment, 923, 923tAggregated model, 1031Aggressive behavior, 162Aging (enzyme), 779Agranulocytosis, 400Agricultural workers, asthma-like

syndrome, 1130AHR. See Aryl hydrocarbon receptorAIDS, 486AIDS therapeutics, immunosuppression by,

448–449AIHA. See American Industrial Hygiene

AssociationAir

air-water interphase, 1016single-phase chemical behavior, 1015soil-air interphase, 1016

Air pollution, 515, 979–1008, 1015. Seealso Smog

accidental versus fence-line exposure,1006–1007

acrolein, 1005–1006adverse health effect, 1007–1008, 1008faldehydes, 1005assessing risks associated with, 982–988,

983f, 985tcarbon monoxide, 1006carcinogenicity, 250, 991–992, 992fefforts to regulate, 980EPA standards for toxic pollutants, 1147epidemiologic evidence of health effects,

988–993formaldehyde, 1005history, 979–982hyperresponsive individuals, 986indoor, 988, 989f, 992–993, 1130lung effects, 526–529, 990metals, 997nitrogen dioxide, 1003–1005outdoor, 988–992, 989f, 993–1007oxidant-type, 987ozone, 1000–1003particulate matter. See Particulate matterphotochemical, 987, 999reducing-type, 987–988risk assessment

animal tests, 985animal-to-human extrapolation, 986–987clinical tests, 984–985exposure, 987–988qualitative, 985quantitative, 985sources, 987–988

sentinel plants, 986solvents, 873–874sulfates, 994–997sulfur dioxide, 993–994sulfuric acid, 994–997worldwide problem, 981, 982f

Air Pollution Control Act, 980

Air toxics. See Hazardous air pollutantsAirway reactivity, 522, 996Airway resistance, 522, 530Ajmalicine, 188Alachlor, 794–795

carcinogenicity, 794in well water, 794–795

ALA-D. See �-Aminolevulinic acid dehydrataseAlanine aminotransferase (ALT), 23, 477ALARA concept, 100Albendazole, biotransformation, 176Albumin, 71, 120–121, 120f, 815, 831, 847

secretion, 473fAlbuterol

biotransformation, 135cardiotoxicity, 614t, 618

Alclometasone, cardiotoxicity, 627–628Alcohol(s), 7, 893–895

biotransformation, 184tcardiotoxicity, 629ethanol. See Ethanolinduction of cytochrome P450, 192methanol, 894–895

Alcohol dehydrogenase, 37, 43, 136t, 145–146,146f, 152–154, 154–155f, 480, 582, 629,891, 893, 895–896f, 896–897, 1119

atypical, 154ocular, 566t, 570

Alcoholic cardiomyopathy, 604, 613, 894Alcoholic hepatitis, 483Alcoholism, 162, 353t, 355, 365, 450, 472,

478, 480–481, 894risk modifier for, 156

Alcohol sulfotransferase, 204, 206Alcohol-tobacco amblyopia, 584Aldehyde(s)

air pollution, 999, 1005cardiotoxicity, 629

Aldehyde dehydrogenase, 43, 136t, 137, 152,154–156, 154f, 155t, 193–194, 480,486, 629, 895–898, 1119

ocular, 566t, 570Aldehyde oxidase, 144, 152, 156, 157f,

159–160, 186, 844Aldehyde reductase, ocular, 566t, 570Aldicarb

biotransformation, 170fecotoxicology, 1024immunosuppression by, 442poisoning, 778

Aldo-keto reductase superfamily, 146, 156Aldose reductase, ocular, 566t, 570, 577Aldosterone

cardiotoxicity, 626tsynthesis, 717

Aldrinbiotransformation, 185t, 774immunosuppression by, 441poisoning, 771t, 772storage in body, 774structure, 770t

Alfentanil, biotransformation, 185tAlgae, toxic products, 971–972Aliphatic chlorocarboxylic acids, 791tAlkali disease, 846Alkaline phosphatase, 477, 501, 532Alkalinization, urinary, 1115

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Alkaloidshepatotoxicity, 478poisoning, 1093

Alkene epoxide, biotransformation, 141, 141fAlkoxyacetic acid, 8981-Alkyladenine, 259t3-Alkyladenine, 259t7-Alkyladenine, 259tAlkylamines

biotransformation, 177vasculotoxicity, 640–642

Alkyl N-arylcarbamates, 791tAlkylating agents, 47

carcinogenicity, 286, 286tdevelopmental effects, 352leukemia and, 402reproductive system toxicity, 691–692

3-Alkylcytosine, 259tO2-Alkylcytosine, 259tO6-Alkyldeoxyguanosine, 257, 525O4-Alkyldeoxythymidine, 2573-Alkylguanine, 259t7-Alkylguanine, 259t, 327O6-Alkylguanine, 257, 259tO6-Alkylguanine-DNA-alkyltransferase, 66, 71Alkylphosphate, 259tAlkyl thiocyanate, 764

biotransformation, 216f3-Alkylthymine, 259tO2-Alkylthymine, 259tO4-Alkylthymine, 257, 259tAlkyltin, impairment of cellular

maintenance, 60tAlkyltransferase, 265ALL. See Acute lymphoblastic leukemiaAllele-specific colony hybridization, 335Allergic asthma, 16Allergic contact dermatitis, 659–660, 660t

plants causing, 966Allergic reactions, 15–16Allergy, food. See Food allergyAllethrin

biotransformation, 787poisoning, 785t

Allopurinolaplastic anemia and, 394tbiotransformation, 157f, 158cardiotoxicity, 614t, 618neutropenia and, 402t

All-or-none response, quantal, 19–20Alloxan

biotransformation, 148impairment of cellular maintenance, 60tlung damage caused by, 522vasculotoxicity, 643t

Allyl alcoholbiotransformation, 156hepatotoxicity, 477f, 479t, 480

Allylaminebiotransformation, 162, 642, 644fvasculotoxicity, 634, 637, 640–642, 641t

Allyl isopropyl acetamide, biotransformation,47, 192

�1 acid glycoprotein, 120Alpha1-antiprotease, 71Alpha1-antitrypsin, 824

deficiency, 524

�2u-globulin, 279, 294, 902�2u-globulin nephropathy, 900–902, 1132Alpha2-macroglobulin, 70–71Alpha particles, 918, 922

interaction with matter, 919–920ALT. See Alanine aminotransferaseAluminosis, 527tAluminum, 848–850

Alzheimer’s disease, 850amyotrophic lateral sclerosis, 850dialysis dementia, 849–850lung and bone toxicity, 527t, 849neurotoxicity, 543t, 849parathyroid toxicity, 739Parkinsonism-dementia syndromes of

Guam, 850toxicity, 849toxicokinetics, 849

Aluminum calcium silicate, in food, 1062tAluminum phosphide, 801

in food, 1056tAlveolar cells, 518, 518fAlveolar duct, 517Alveolar macrophages, 423, 444, 522, 526, 996Alveolar sac, 517Alveolar ventilation rate, 233Alveoli, 117, 235, 516, 520Alzheimer’s disease, 546, 640, 848, 850Amacrine cells, 566tAmalgam dental filling. See Dental amalgamAmanita phalloides, 479�-Amanitin

distribution, 38impairment of cellular maintenance, 64presystemic elimination, 37

Amatoxins, 970Ambient toxicity test, 1029Amblyopia, toxic, 584Amcinonide, cardiotoxicity, 627–628American Academy of Forensic Sciences, 1093American Board of Forensic Toxicology, 1093American Conference of Governmental

Industrial Hygienists (ACGIH), 83,1125–1126

American Industrial Hygiene Association(AIHA), 1136

American Society for Testing Materials(ASTM), 1136

American Society of Toxicology, 9Ames, Bruce, 9, 322Ames test. See Salmonella/microsome testAMH. See Antimüllerian hormoneAmidochlor, 794Amiflamine, biotransformation, 185tAmikacin, cardiotoxicity, 615t, 621Amine oxidase, 637Amino acid(s)

excitatory, in plants, 971intestinal absorption, 1053t

Amino acid conjugation, 135, 136t, 197f,211–213, 212f

Amino acid oxidase, snake venom, 957t,959–960

Amino acid transporter, 506Aminoacyl-tRNA synthetase, 212f, 2132-Amino-anthracene, biotransformation, 656o-Aminoazotoluene, carcinogenicity, 244, 244f

Aminobenzene, methemoglobinemia and, 395tp-Aminobenzoic acid (PABA), 25

biotransformation, 209, 209fin photopatch test, 664tthyroid toxicity, 726

4-Aminobiphenyl, 210biotransformation, 164, 183, 189t, 191, 202carcinogenicity, 252, 262

�-Aminocaproic acid, 409vasculotoxicity, 636t

6-Aminochrysene, biotransformation, 189tp-Aminodiphenyl, carcinogenicity, 285t2-Aminofluorene, 66

biotransformation, 189t, 209co-oxidation, 254mutagenicity, 257

Aminoglutethimideadrenal toxicity, 718biotransformation, 209reproductive system toxicity, 689t

Aminoglycosidesallergic contact dermatitis from, 660tcardiotoxicity, 615t, 621developmental effects, 374distribution, 38nephrotoxicity, 496t, 500, 504, 505f, 510

Amino group, amino acid conjugation, 211Aminoguanidine, 10708-Aminoguanine, 257Aminohippuric acid, octanol/water partition

coefficient, 109t�-Aminolevulinic acid dehydratase (ALA-D),

46, 830, 831f, 1019�-Aminolevulinic acid synthetase, 830,

831f, 10192-Amino-6-methylimidazo[4,5-b] pyridine, 2102-Aminonaphthalene, 210

biotransformation, 164, 183, 202–203, 202f,203t, 205

6-Aminonicotinamide, neurotoxicity, 543t2-Amino-6-nitrobenzylalcohol,

biotransformation, 1892-Amino-4-(5-nitro-2-furyl)thiazole (ANFT),

biotransformation, 165Aminonitrotoluene, vasculotoxicity, 645Aminopeptidase, 140Aminopeptidase M, 215, 217f, 218p-Aminophenol (PAP)

biotransformation, 164, 218nephrotoxicity, 510

7�(4�-Amino)phenylthioandrostenedione,reproductive system toxicity, 689t

3-Aminopropionitrileadrenal toxicity, 717vasculotoxicity, 637, 641t

Aminopterin, developmental effects, 353t, 3744-Aminopyridine, cardiotoxicity, 606Aminopyrine, 48

biotransformation, 164, 166, 179, 185teffect on granulocytes, 401tneutropenia and, 402t

Aminorex fumarate, vasculotoxicity, 643tAminosalicylic acid

biotransformation, 209, 209fdistribution, 120fmegaloblastic anemia and, 393toxidative hemolysis and, 397t

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4-Aminostilbene, carcinogenicity, 260Aminotriazole

inhibition of cytochrome P450, 879thyroid toxicity, 726, 726f

Amiodarone, 72biotransformation, 185t, 690tcardiotoxicity, 614t, 617clinical uses, 606distribution, 38impairment of cellular maintenance, 59tlung damage caused by, 530neurotoxicity, 553tocular toxicity, 566tpigmentary disturbances from, 666treproductive system toxicity,

690t, 691Amitriptyline

biotransformation, 185t, 199fcardiotoxicity, 615t, 622poisoning, 1120therapeutic monitoring, 1105t

Amitrolebiotransformation, 44carcinogenicity, 89tcellular dysregulation, 52

AML. See Acute myelogenous leukemiaAmmodendrine, 973Ammonia

anhydrous, occupational disease, 1128lung damage caused by, 527tocular toxicity, 575skin burns, 658t

Ammonium carbonate, in food, 1056tAmmonium hydroxide

in food, 1057tocular toxicity, 575

Ammonium sulfate, in food, 1056tAmnesic shellfish poisoning, 1078–1079Amodiaquine, biotransformation, 166Amoxapine, poisoning, 1120Amoxicillin, hepatotoxicity, 476tAMPA receptor, 971Amphenone

adrenal toxicity, 718–719reproductive system toxicity, 698tthyroid toxicity, 726

Amphetaminesanalytic toxicology, 1096biotransformation, 161, 167, 178f, 179cardiotoxicity, 618cellular dysregulation, 56excretion, 39forensic urine drug testing, 1100tneurotoxicity, 556t, 557poisoning, 1103t, 1116treabsorption, 39vasculotoxicity, 643t

Amphotericin Baplastic anemia and, 394tcardiotoxicity, 615t, 621impairment of cellular maintenance, 60tnephrotoxicity, 494, 496t, 499–500, 503,

510–511Ampicillin

coagulation factor inhibitor developmentand, 406t

neutropenia and, 402tAmprenavir

biotransformation, 185tcardiotoxicity, 622

Amygdalin, 970biotransformation, 42metabolites as ultimate toxicants, 37t

�-Amylase, occupational disease, 1127t, 1128Amyl O-dimethylaminobenzoic acid,

phototoxicity, 663tAmyl nitrate, methemoglobinemia and, 395t�-Amyloid, 640, 848Amyloid A, 71, 423Amyloid P, 423Amyotrophic lateral sclerosis, 848, 850Amytal, impairment of cellular maintenance, 59tAnabasine, 972–973Anabolic steroids

cardiotoxicity, 627hepatotoxicity, 476t, 478

Anagyrine, 973Analgesic(s)

nephrotoxicity, 500vasculotoxicity, 639

Analgesic nephropathy, 499, 510Analytic toxicology, 1089–1107

anions, 1090biological monitoring and, 1106–1107,

1106f, 1107tclinical toxicology and, 1103–1104corrosives, 1090criminal poisoning, 1099–1100, 1099tdefinition, 1089forensic toxicology and, 1092–1093forensic urine drug testing, 1100–1102,

1100–1101tgases, 1090in general toxicology, 1092investigation of poison death, 1093–1099metals, 1090miscellaneous compounds, 1091nonmetals, 1090nonvolatile organic substances,

1090–1091, 1091fseparation of toxic agent, 1090–1091, 1091ftherapeutic drug monitoring, 1104–1106,

1104f, 1105tvolatile substances, 1090

Anaphylactic reaction, 961Anaphylactoid reaction, 961

to food, 1070–1071, 1070tAnatoxin A, 54t, 972Androgen(s), 675, 682, 684, 697–698

carcinogenicity, 248t, 286cardiotoxicity, 626t, 627developmental effects, 353t, 374factors affecting effectiveness, 698thepatotoxicity, 476timmunosuppression by, 447as promoting agent, 267, 275t

Androgen-binding protein (ABP), 681, 683,695, 698–699

Androgen receptor, 369, 676, 697–698, 1021Androstane-3,17-diol-3,17-disulfate, 203Androstane receptor, 49Androstanol, 193t, 1951,4,6-Androstatriene-3,17-dione, reproductive

system toxicity, 689tAndrostene-17-carboxylic acid, reproductive

system toxicity, 698t

Androstenedione, 180cardiotoxicity, 626t, 627

Androstenol, 195Anemia, 391. See also specific types of anemiaAnemonin, 966Anesthetics, cellular dysregulation, 56Aneuploidy, 290, 324, 330, 340

assay for, 331t, 340–341, 342ANFT. See 2-Amino-4-(5-nitro-2-furyl)

thiazoleAngina pectoris, 603Angiogenesis, 632, 635Angiotensin converting enzyme (ACE), 717Angiotensin-converting enzyme (ACE)

inhibitors, nephrotoxicity, 496t, 499Angiotensin I, 717, 1070Angiotensin II, 604, 610, 632, 635, 638,

717, 1070Angiotensinogen, 635Anhydroecgonine methylester, 1097Anilazine, 797tAniline(s), 1075

adrenal toxicity, 718–719biotransformation, 184t, 199f, 203, 203tcarcinogenicity, 242methemoglobinemia and, 395toccupational disease, 1127t

Aniline 4-hydroxylase, 196Animal and Plant Health Inspection Service

(APHIS), 1150–1151Animal drug, in human food, 1072–1073, 1144Animal feed, 973Animal models

hematologic risk assessment, 409–410, 410tin immunotoxicology, 436–437

Animal tests, 88–90, 89t. See also Bioassayacute lethality studies, 27air pollution risk assessment, 985animal-to-human extrapolation, 986–987animal welfare requirements, 1150–1151carcinogen identification, 293–296, 294tchronic toxicity study, 29–31, 29–30fcosts, 32tdescriptive, 26–32dose-response assessment, 92–94establishing acceptable levels of exposure,

1132–1133history, 7immunotoxicity, 462mutagenicity tests, 31–32occupational risk assessment, 1132occupational toxicology, 1135of reproductive toxicity, extrapolation of data

to humans, 704sensitization tests, 28skin and eye irritation tests, 27–28spontaneous tumor incidence, 295tsubacute toxicity studies, 28subchronic toxicity studies, 28–29using albino animals, 573

Animal toxinsabsorption, 946arachnid, 947–952arthropod, 947–952bioavailability, 946biotransformation, 946–947cardiotoxicity, 629centipedes, 952–953

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excretion, 947functions, 945insects, 953–954millipedes, 953properties, 945–947reptiles, 954–961site of action, 946

Animal Welfare Act (AWA), 1150–1151Anion(s), analytic toxicology, 1090Anion gap, 1113

calculation, 1113elevated, 1119

differential diagnosis, 1113tANIT. See �-Naphthyl-isothiocyanateAnkylosing spondylitis radiation therapy, 927,

931–932, 932tAnnatto, in food, 1055tANP. See Atrial natriuretic peptideAnt(s), 953–954Antacids, 850Antagonism, 17

chemical, 17dispositional, 17functional, 17receptor, 17

Anthracenephototoxicity, 663tpigmentary disturbances from, 666t

Anthracenones, 972Anthracyclines

biotransformation, 147–148cardiotoxicity, 615t, 619–620

Antiandrogens, 675developmental effects, 369reproductive system toxicity, 692

Antiarrhythmic agents, cardiotoxicity,613–619, 614t

Antibacterial agents, 7cardiotoxicity, 615t, 621nephrotoxicity, 499poisoning, 1116tvasculotoxicity, 643t

Antibody, 421t, 424Antibody-dependent cellular cytotoxicity

(ADCC), 428Antibody response

cellular interactions, 429fkinetics, 430f

Anticaking agents, 1055t, 1062tAnticholinergic syndrome, 1111, 1111tAnticholinesterase agents

biotransformation, distribution, and storage,781–782, 781f

mechanism of toxic action, 779–781,779–780f, 780t

poisoning, 775–779, 776tAnticoagulants

oral, toxicology, 407–408from plants, 970rodenticides, 801–802vasculotoxicity, 643t

Antidiuretic hormone (ADH), 494, 501,713, 852

Antidote, 1109, 1117Antiestrogens, 692Antifungal agents, cardiotoxicity, 615t, 621Antigen, 15, 424Antigen-antibody interaction, 15

Antigen-presenting cells (APC), 425–428,428–429, 459

Antihistamines, 15cardiotoxicity, 616t, 623–624

Antihypertensive agents, nephrotoxicity, 496tAntimalarials, 8Antimicrobial agents, in food, 1055t, 1062tAntimitotic effects, of plant toxins, 967Antimony, 853Antimony spots, 853Antimüllerian hormone (AMH), 675, 681Antimycin A

cardiotoxicity, 609, 609fimpairment of cellular maintenance, 59tnephrotoxicity, 506

Antineoplastic agentscardiotoxicity, 615t, 619–621vasculotoxicity, 639

Antioxidant(s), 43, 283in food, 1055t

Antioxidant-responsive element (ARE), 149,194, 217

Antiplatelet antibodies, 404Antipsychotic agents, cardiotoxicity, 622Antipyrine

biotransformation, 185tthyroid toxicity, 726, 731

Antiquity, 3–4Antithrombin III, 635Antitoxin, 17Antivenom, 961–962

bee, 954hypersensitivity reaction, 961–962preparation, 961scorpion, 948snake, 961spider, 950

Antiviral agents, cardiotoxicity, 615t, 621–622ANTU. See �-Naphthyl thioureaApamin, 954

cellular dysregulation, 55tAPC. See Antigen-presenting cellsAP endonuclease, 66APHIS. See Animal and Plant Health

Inspection ServiceApidae, 954Aplastic anemia, 393, 394t, 403Apomorphine, induction of emesis, 1114Apoptosis, 61–63, 62f, 64f, 71, 276

of cardiac myocytes, 610–611, 611f, 612t,619–620

apoptotic stimuli, 610signal transduction, 610–611

failure, 76–77inhibitors, 77–78, 78fof liver cell, 477of myocytes, 603in prenatal development, 360–361, 362fin preneoplastic lesion, 269in renal cell injury, 502–503, 503ftesticular, 676–677, 679ftissue repair, 67

Apoptotic protease activating factor (Apaf),62f, 63, 610, 611f

Apparent volume of distribution, 227–228, 228tAprindine

biotransformation, 185tneutropenia and, 402t

Aprotinin, 409vasculotoxicity, 636t

AP site, 47, 66, 262–263, 326f, 327Aquatic ecotoxicology, 1022, 1028–1030

acute and chronic toxicity testing, 1028–1029field studies, 1029–1030sublethal effects, 1029

Aquatic food chain, 834Aqueous humor, 568–569Arabic gum, 1056–1057tArachidonic acid, 166, 173, 254, 505, 570

biotransformation, 184t, 186, 656peroxidation, 255f

Arachnidsscorpions, 947–948, 948tspiders, 947–952, 949tticks, 952

Arc welder’s lung, 527tARE. See Antioxidant-responsive elementArene epoxide, biotransformation, 214Arene oxide, 174

biotransformation, 141, 141f, 214ARF, 74–75fArgentaffin reaction, 723Arginine ester hydrolase, snake venom,

955, 957tArgyria, 855Argyrophil reaction, 723ARNT. See Aromatic receptor nuclear

transporterAroclor

developmental effects, 369immunosuppression by, 438thyroid toxicity, 730

Aromatase, 689tAromatic amines, mutagenicity, 257Aromatic hydrocarbons, 889–893

benzene, 889–891ethylbenzene, 892immunosuppression by, 445leukemia and, 402styrene, 892–893toluene, 891–892vasculotoxicity, 645–646xylenes, 892

Aromatic receptor nuclear transporter (ARNT),48, 193–194, 438

Aromatization, 162, 162fArrhythmia, 602–603, 605–607Arsanilic acid, 818Arsenate, 818

cellular uptake, 816developmental effects, 361as insecticide, 764metabolites as ultimate toxicants, 37treabsorption, 39

Arsenic, 13, 46, 98f, 812–814, 818–820air pollution, 992fbiliary excretion, 475biomarkers, 820–821, 821tbiotransformation, 206, 819blood, 821, 821tcarcinogenicity, 245, 246t, 281t, 285t, 294,

820, 1135skin cancer, 668

in cosmetics, 4developmental effects, 367drinking water, 818–820

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Arsenic (continued)in food, 1073–1074hair, 821, 821thepatotoxicity, 476t, 478immunosuppression by, 443lung damage caused by, 525, 527tmechanisms of toxicity, 819neurotoxicity, 543toccupational disease, 1127t, 1135as pesticide, 763poisoning, 1093, 1096, 1098reproductive system toxicity, 820teratogenicity, 820toxicokinetics, 818–819toxicology, 819–820treatment of poisoning, 817, 821urine, 821, 821tvasculotoxicity, 645

Arsenic acid, 818Arsenicals, 7

aplastic anemia and, 394tcarcinogenicity, 286t

Arsenic hydride, hemolytic anemia and, 398Arsenic pentoxide, 818Arsenic salts, as promoting agent, 270tArsenic selenide, 818Arsenic trichloride, 818Arsenic trioxide, 818, 1092–1093, 1135Arsenious oxide, 801Arsenite

cellular dysregulation, 52impairment of cellular maintenance, 59t

Arsine, 820, 1093occupational disease, 1127t, 1138target organ, 108

Arson, 1092Artemisinin, 192Arthropods, venomous or poisonous, 947–952Art materials, 1148Arylacetamide deacetylase, 211N-Arylcarbamate, 791tArylesterase, 137, 782Aryl hydrocarbon hydroxylase, 645, 689, 1052tAryl hydrocarbon receptor (AHR), 45, 49, 50t,

86, 149, 192–194, 201, 275, 438, 665Arylnitrenium ion, biotransformation, 41tAryloxyalkylcarboxylic acids, 791t2-Arylpropionyl-CoA epimerase, 212Arylsulfotransferase, 204Asbestos, 306

air pollution, 992f, 1006biotransformation, 41carcinogenicity, 245–246, 284, 285tCPSC regulations, 1148EPA regulations, 1145immunosuppression by, 444lung damage caused by, 523, 525, 526, 527toccupational disease, 1127tas promoting agent, 270t

Asbestosis, 515, 526, 527t, 1126Ascorbic acid, 66f, 607L-Asparaginase

parathyroid toxicity, 739–740reproductive system toxicity, 691t

Asparagus odor, 1067t, 1069tAspartame, 1056tAspartate aminotransferase (AST), 23

Aspergillus flavus, 245, 282Aspirin, 154, 165, 195

effect on platelets, 405nephrotoxicity, 510octanol/water partition coefficient, 109turticaria from, 666vasculotoxicity, 643t

Assassin bug, 954AST. See Aspartate aminotransferaseAstemizole

biotransformation, 185tcardiotoxicity, 606, 616t, 621–624

Asthenic-vegetative syndrome, 835Asthma, 522, 525, 527t

allergic, 16occupational, 1126, 1128–1130, 1129t, 1134

Asthmatics, 989, 994, 996, 1004ASTM. See American Society for

Testing MaterialsAstrocytes, 122Atenolol

adrenal toxicity, 720cellular dysregulation, 55t

Atherogenesis, carcinogenesis and, 634, 635fAtheroma, 634Atherosclerosis, 632, 634–635, 642,

644–646, 894Atomic bomb survivors, 923, 927–929, 928fATP (adenosine triphosphate)

availability, determination of form of celldeath, 63, 64f

depletion, 57–58, 58f, 59t, 61, 504ATPase, microtubule-associated, 538ATP kinase, 204ATP sulfurylase, 204ATP synthase, 57–58, 58f, 60, 61fAtractyloside, impairment of cellular

maintenance, 59tAtrazine

cellular dysregulation, 49ecotoxicology, 1037

Atrial fibrillation, 602Atrial flutter, 602Atrial natriuretic peptide (ANP), 610Atrioventricular node, 600Atropine, 17, 46, 972, 1117

cellular dysregulation, 54t, 57neurotoxicity, 556toctanol/water partition coefficient, 109tocular toxicity, 570treatment of organophosphate poisoning,

782–783, 783tAtrotoxin, cellular dysregulation, 55tATSDR. See Agency for Toxic Substances and

Disease RegistryAuerbach, Charlotte, 322Autoantibody, drug-induced, 398Autoimmune response

assessment, 460to xenobiotics, 460–461

Autoimmunity, 451, 451f, 459–461mechanisms, 459–460multiple chemical sensitivity syndrome, 461

Automobile emissions, 981. See also Gasolinevasculotoxicity, 642t, 646

Autonomic agents, vasculotoxicity, 639Avermectin, 123

biotransformation, 787cellular dysregulation, 54tmechanism of action, 787–788structure, 788f

AVS. See Acid volatile sulfidesAWA. See Animal Welfare ActAxonal degeneration, 538–539, 539fAxonal regeneration, 67Axonal transport, 537–539, 537f

fast, 537–538, 537fslow, 538

Axonopathy, 539, 540f, 546–552, 548t5-Azacytidine, carcinogenicity, 281tAzapetine, biotransformation, 159Azastene, reproductive system toxicity, 689tAzathioprine

biotransformation, 208carcinogenicity, 286timmunosuppression by, 447–448leukemia and, 402pure red cell aplasia and, 394

Azideimpairment of cellular maintenance, 59tneurotoxicity, 543t

Azidothymidine, aplastic anemia and, 394tAzinophos methyl, biotransformation, 781Aziridinylbenzoquinone, biotransformation,

147–148Azithromycin, cardiotoxicity, 615t, 621Azobenzene, 193Azo dyes

absorption, 113urticaria from, 666

Azo-reduction, 144–145, 144fAzoxybenzene, 193Azoxymethane, carcinogenicity, 274tAZT. See ZidovudineAzulfidine, neutropenia and, 402t

BBAA. See Butoxyacetic acidBabesiosis, 396–397Baboon syndrome, 659Bacillus cereus, 1081Bacitracin

allergic contact dermatitis from, 660–661turticaria from, 667t

Background radiation, 938–940, 938f, 939tBacterial toxins, in food, 1080–1082BAL. See British anti-LewisiteBalkan nephropathy, 509Balsam of Peru

allergic contact dermatitis from, 660–661turticaria from, 667t

BALT. See Bronchial-associated lymphoid tissueBand of Bungner, 538–539Barban, hypersensitivity reaction, 458Barbie box, 195Barbital, elimination, 133Barbiturates, 192

cellular dysregulation, 54t, 56distribution, 120fmaggot analysis, 1094poisoning, 1096, 1103t

Baritosis, 854Barium, 45, 814, 848, 853–854

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cardiotoxicity, 629, 630tcellular dysregulation, 55tdistribution, 38

Barium carbonate, 801, 854Barium sulfate, 854Bartonellosis, 396–397Basal cell(s), 654Basal cell carcinoma, 663, 668, 929, 930tBase excision repair, 261, 262t, 327Base substitution, 328–329, 337Basophils, 399, 421f, 712, 713fBAT. See Best available technologyBateson, W., 352Batrachotoxin, cellular dysregulation, 55tBax protein, 62f, 63, 75, 361, 610, 611fBBDR model. See Biologically based dose-

response modelB cells, 420, 421–422t, 424, 425–428, 426f,

428, 712development and differentiation, 429f

bcl-2 gene, 272t, 277fBcl-2 protein, 62f, 63, 68, 75, 77, 361, 610, 611fBCNU. See 1,3-Bis-(2-chloroethyl)-

1-nitrosourea2-BE. See 2-ButoxyethanolBeaded lizard, 954–955Beclomethasone, cardiotoxicity, 627–628Bee(s), 954Beer drinker’s cardiomyopathy, 613Beetanuria, 1067t, 1069tBehavioral tests, 542

of visual function, 574Behavioral toxicity test, 32Behavioral toxicology, 32BEI. See Biological exposure indexBelladonna alkaloids, 3, 972

cellular dysregulation, 54–55tBenchmark dose, 24, 28, 94, 94f

assessment of developmental toxicity using,376–377

Benchmark response, 94Benomyl

acute toxicity, 797tgenetic effects, 330structure, 796f

Benoxaprofenbiotransformation, 199fphototoxicity, 663t

Bentazone, 791tBentonite, in food, 1065Benzadryl. See DiphenhydramineBenzaldehyde, biotransformation, 156, 159Benzalkonium chloride, 576

allergic contact dermatitis from, 660tBenz[a]anthracene, carcinogenicity, 281t, 847Benzene, 14, 870, 889–891

air pollution, 992f, 1006aplastic anemia and, 393, 394tbiological monitoring, 1106, 1107tbiomarkers, 891biotransformation, 43, 165, 165f, 184t, 189t,

191, 876, 889–890, 890f, 892carcinogenicity, 279t, 281t, 284, 285t, 889environmental contamination, 873hematopoietic toxicity, 889leukomogenesis, 402, 889–891myelosuppression by, 165

occupational disease, 1127toctanol/water partition coefficient, 109tOSHA standards, 1147partition coefficient, 233tphysiologic toxicokinetic model,

232, 234as promoting agent, 270treproductive system toxicity, 674site and mechanism of toxic actions, 773solvent abuse, 873target organ, 108

Benzene hexachloride, poisoning, 771tBenzene oxide, 889, 891Benzidine, 210

biotransformation, 164, 199fcarcinogenicity, 73, 242, 244f, 252, 252f,

285t, 299toccupational disease, 1127t

Benzisoxazolesbiotransformation, 160mechanism of action, 791t

Benzoates, urticaria from, 666Benzocaine

allergic contact dermatitis from, 660tcardiotoxicity, 623methemoglobinemia and, 395t

Benzodiazepinesanalytic toxicology, 1096cellular dysregulation, 54t, 56maggot analysis, 1094poisoning, 1103t, 1110–1111thyroid toxicity, 729

Benzoic acid, 891absorption, 112biotransformation, 203, 211, 212fmechanism of action, 791toctanol/water partition coefficient, 109turticaria from, 667t

Benzonitrile, impairment of cellularmaintenance, 59t

Benzophenone, allergic contact dermatitisfrom, 660t

Benzo[a]pyrene, 74f, 96, 127, 149, 194, 1052tbiotransformation, 40, 141, 142f, 163, 183,

189, 189t, 206, 254, 255fcarcinogenicity, 243, 243f, 250–252, 252f,

262, 847cooxidation, 254developmental effects, 361genetic effects, 327, 334immunosuppression by, 440–441in lymph, 1053metabolites as ultimate toxicants, 37tvasculotoxicity, 634, 645–646, 646f

Benzo[e]pyrene, carcinogenicity, 243fBenzo[a]pyrene 7,8-dihydrodiol,

biotransformation, 163, 165Benzo[a]pyrene 7,8-dihydrodiol-9,10-oxide,

41t, 142Benzo[a]pyrene 7,8-diol-9,10-epoxide

carcinogenicity, 252f, 253mutagenicity, 257t

Benzo[a]pyrene 4,5-oxide, 142fo-Benzoquinone, 889, 890fp-Benzoquinone, 889, 890f, 891

impairment of cellular maintenance, 59tBenzothiazolesulfenamide, allergic contact

dermatitis from, 660tBenzotriazoles, mechanism of action, 791tBenzoxazines, 791tBenzoylecgonine, 1095Benzoyl peroxide, as promoting agent, 270t, 669Benzoylpropethyl, 791tBenzphetamine, biotransformation, 184–185tBenzydamine, biotransformation, 167, 169Benzyl alcohol, 891

biotransformation, 877Benzylamine oxidase, 642O6-Benzylguanine, biotransformation, 159Benzylhydrazine, biotransformation, 169fBenzylic carbocation, biotransformation, 41t�-Benzyl-N-methylphenethylamine, 1099Benzyloxyresorufin, biotransformation, 184t, 186Bepridil

clinical uses, 606thyroid toxicity, 729

Beriberi heart disease, 613Berylliosis, 457, 527t, 821–822Beryllium, 821–822

carcinogenicity, 246t, 285t, 822granulomatous reactions to, 666hypersensitivity reaction to, 457immune reactions to, 815immunosuppression by, 444lung damage caused by, 525, 527toccupational disease, 1127tpulmonary effects, 821–822skin effects, 821toxicokinetics, 821

Beryllium disease, 457Beryllium oxide, immunosuppression by, 444Beryllium-specific lymphocyte proliferation

test, 457Best available technology (BAT), 306B-esterase, 137–139Best practicable technology (BPT), 306Beta blockers, cardiotoxicity, 617�-Glucuronidase, 140, 144, 145f, 198, 657�-Lactam, 113, 500Beta lyase, 44, 217f, 218, 219f, 500, 508Betamethasone, cardiotoxicity, 627–628�2-Microglobulin, 825–826, 831, 847, 857Beta particles, 918–919, 922

interaction with matter, 920Betel chewing, carcinogenicity, 283t, 284Bezafibrate, effect on hemoglobin, 395BHA. See Butylated hydroxyanisoleBhopal, India, 980–981, 988, 1007t-BHP, impairment of cellular maintenance, 60tBHT. See Butylated hydroxytolueneBicuculline, cellular dysregulation, 54tBid protein, 62f, 63Big Blue Mouse, 338Bile, formation, 474–476, 475fBile acid(s), 203t, 211Bile acid-CoA:amino acid N-acyltransferase, 211Bile duct, 475–476

damage, 476t, 477–478Bile salt(s), 474–475, 486

acinar gradient, 474fBile salt excretory protein, 126Bile salt sulfotransferase, 204Biliary excretion, 39, 126–128, 126t, 198, 203,

215, 475–476, 486, 729, 730f

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Bilirubin, 475–476, 663biotransformation, 198–202, 199fdistribution, 120fneurotoxicity, 536

Bioaccumulation, 1016Bioactivation, 876Bioassay

chronic 2-year, 293–294, 294f, 294–295t,297–298

extrapolation of data to human risk, 301–303history, 7medium-term, 295–296, 296fstatistical analysis, 303–304, 303–304ftissue specific, 294–295, 294t

Bioavailability, 230, 1016, 1018, 1092chemicals in sediment, 1016chemicals in soil, 1017–1018, 1018fchemicals in water column, 1016

Bioconcentration, 1016Biological exposure index (BEI), 871,

1126, 1134Biologically based dose-response (BBDR)

model, 96Biologically effective dose, 1018Biological monitoring, 1106–1107, 1106f,

1107t, 1136–1138, 1137tBiomagnification, 1016Biomarker, 85, 96, 97f, 463, 481

of cancer, 1019definition, 1018ecotoxicology, 1018–1020of effect, 1019effects-related, 23of exposure, 1018–1019integration with molecular biology, 1020interpretation, 1019–1020of sublethal effects, 1023of susceptibility, 1019

Biomonitoring, 1029–1030Bioreductive drugs, 147Biotransformation, 13–14, 17, 26, 40,

107–108, 114, 133–134, 1095. See alsoXenobiotic biotransforming enzymes

of carcinogens, 250–254, 252–253fhepatic, 480–482metabolism versus, 134in pregnancy, 363–365species differences, 134, 137stereochemical aspects, 134–135, 135f

Biphenyl(s), 39, 1934-Biphenylamine, occupational disease, 1127tBipolar cells, 566tBipyridyl herbicides, 793–795, 793fBird-egg syndrome, 1068Bird snake, 955, 956–957tBirth defects. See Developmental toxicityBirth weight, 3761,3-Bis-(2-chloroethyl)-1-nitrosourea (BCNU),

lung damage caused by, 530Bis(chloromethyl)ether

carcinogenicity, 244, 244f, 285tmutagenicity, 257occupational disease, 1127t

1,4-Bis[2-(3,5-dichloropyridyloxy)]-benzene, aspromoting agent, 270t

Bis-hydroxycoumarin, drug interactions, 407Bismuth, 848, 850–851

aplastic anemia and, 394thost factors influencing toxicity, 815neurotoxicity, 543tpigmentary disturbances from, 666ttoxicity, 850–851toxicokinetics, 850

Bismuth glycolyarsanilate, 850Bismuth sodium thioglycollate, 850Bismuth sodium triglycocollanate, 850Bismuth subcarbonate, 851Bismuth subgallate, 851Bismuth subnitrate, 851, 853Bismuth subsalicylate, 850Bisphenol A

allergic contact dermatitis from, 660tcardiotoxicity, 625cellular dysregulation, 49developmental effects, 368–369

2,3-Bisphosphoglycerate, 395Bisulfite, biotransformation, 165Bite cells, 397Bithionol, in photopatch test, 664tBitolterol, cardiotoxicity, 614t, 618Blackfoot disease, 645, 668Black lung, 515Black sore, 798Black widow spider, 949–950Blastocyst, 687Bleomycin, 41, 72

genetic effects, 329leukemia and, 402lung damage caused by, 523, 530pigmentary disturbances from, 666t

Bleomycin hydrolase, 530Blind staggers, 846Blister beetles, 954Blister cells, 397Blood. See also specific blood components

postmortem analysis, 1098as target organ, 389–390toxic effects of plants, 970–971

Blood-brain barrier, 38–39, 122–123, 133,535–536, 536f, 558, 571, 645, 830

Blood compartment, 236–237Blood flow, 233Blood gas analysis, 531Blood-retinal barrier, 569Blood-testis barrier, 39, 133, 681, 683, 688–689Blood-to-gas partition coefficient, 116Blood urea nitrogen (BUN), 502, 502fBlood vessels. See also Vascular system

of eye, 567–568vascular wall, 631, 631f

BMAA. See �-N-Methylamine-L-alanineBOAA. See �-N-Oxalylamino-L-alanineBody burden, 1137

of drug or poison, 1098Body fat, distribution of lipophilic solvents,

875–876Body packer, 1114Body surface area

exposed portions of casually dressedindividual, 768t

percent represented by body regions, 768tBoldenone, cardiotoxicity, 626t, 627Bone. See also Skeletal effects

as storage depot, 122

Bone marrow, 390–391, 390f, 420, 420tBone marrow assay, in hematologic risk

assessment, 410Boomslangs, 955, 956–957tBordeaux mixture, 763–764Borgia family, 4Boric acid, poisoning, 1116tBorneol, 198Boron, vasculotoxicity, 641tBotanical insecticides, 789–790Bottleneck, genetic, 1025Botulinum toxin, 1080–1081

cellular dysregulation, 56LD5, 13tin lymph, 1053

Botulism, 1080–1081Bovine spongiform encephalopathy

(BSE), 1082BPT. See Best practicable technologyBradycardia, 602Brassica seeds, thyroid toxicity, 725Bravo thermonuclear test, 931BRCA1 gene, 272tBreast implant, 450Breath holding, 523Breathing pattern, 521, 523, 531Breeding behavior, 1023Bretylium

cardiotoxicity, 614t, 617clinical uses, 606

Bridging necrosis, 477British anti-Lewisite (BAL), 17, 816–817, 821,

833, 837, 851Brodie, Bernard, 8Brodifacoum, effect on coagulation, 406tBrofaromine, biotransformation, 185tBromide, poisoning, 1116t6-Bromoandrostene-3,17-dione, reproductive

system toxicity, 689tBromobenzene

biotransformation, 509impairment of cellular maintenance, 60tnephrotoxicity, 509

Bromobenzene 3,4-oxide,biotransformation, 41t

Bromochloromethane, solubility, 873Bromodichloromethane, carcinogenicity, 301fBromohydroquinone

impairment of cellular maintenance, 59tnephrotoxicity, 506, 509

Bromonidine, biotransformation, 1592-Bromo-2-nitropropane, allergic contact

dermatitis from, 661tp-Bromophenylacetyl urea, neurotoxicity, 548t3-Bromopropionitrile, adrenal toxicity, 717Bronchi, 516, 517fBronchial-associated lymphoid tissue (BALT),

420t, 421Bronchial provocation test, 455Bronchial smooth muscle, 522Bronchioles, 516–517, 517fBronchiolitis obliterans, 528tBronchitis, 994

chronic, 521, 527–528tBronchoalveolar lavage, 516Bronchoconstriction, 522Bronchodilators, cardiotoxicity, 614t

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Bronchogenic cancer, 525Bronchoprovocation test, 522Bronchopulmonary dysplasia, 529Brown recluse spider, 949t, 950–951Brown widow spider, 950BSE. See Bovine spongiform encephalopathyBudesonide, biotransformation, 185tBuehler test, 28, 455, 661Building-related illness, 993, 1130Bulbourethral gland, 684Bumble bees, 954BUN. See Blood urea nitrogenBundle of His, 600�-Bungaratoxin

biotransformation, 43cellular dysregulation, 54t

�-Bungaratoxin, biotransformation, 43Bupivacaine, cardiotoxicity, 616t, 623Bupropion, biotransformation, 184t“Burden of proof,” 1142Burns, 118

chemical, 658, 658themolytic process associated with, 396

Burton’s lines, 833Buserelin

Leydig cell tumor development and, 748treproductive system toxicity, 693

Bushmasters, 955–957tBusulfan

developmental effects, 353tleukemia and, 402reproductive system toxicity, 691t, 693t

Butachlor, 794Butadiene

biotransformation, 184tvasculotoxicity, 634, 641t

1,3-Butadiene, 403, 870, 892air pollution, 992fbiotransformation, 186, 1135carcinogenicity, 1135lung damage caused by, 526occupational disease, 1135vasculotoxicity, 647

1,4-Butanedithiol, adrenal toxicity, 7171-Butanethiol, adrenal toxicity, 7172-Butanol, 893

biotransformation, 203tButhionine-S-sulfoximine, 213, 217–218Butoxyacetic acid (BAA), 898–9002-Butoxyethanol (2-BE), 898–900Butterflies, 953Butter yellow. See N,N-Dimethyl-

4-aminoazobenzenet-Butyl alcohol, 902Butylated hydroxyanisole (BHA), 142, 194,

216–217, 1052tbiotransformation, 165, 166fcarcinogenicity, 89t, 279t, 301fin food, 1055t, 1065as promoting agent, 275turticaria from, 667t

Butylated hydroxytoluene (BHT), 142, 194biotransformation, 165, 166f, 189in food, 1055tpigmentary disturbances from, 666tas promoting agent, 268f, 275turticaria from, 667t

p-(t-Butyl) catechols, pigmentary disturbancesfrom, 666t

p-(t-Butyl) formaldehyde resin, allergic contactdermatitis from, 660t

t-Butylhydroperoxide, nephrotoxicity, 498f, 506Butyl methoxydibenzoylmethane, in photopatch

test, 664tButyl nitrite, methemoglobinemia and, 395tButyrylcholinesterase, 16B vitamins, 585Byssinosis, 527t, 1126

CCadaveric alkaloids, 1096Cadaverine, 1070, 1096

biotransformation, 162Cadherin, 67, 77Cadmium, 17, 49, 812–813, 822–826

absorption, 113–114acute toxicity, 823biliary excretion, 475biomarkers

of effects, 825–826of exposure, 826

blood, 822, 826carcinogenicity of, 245, 246t, 285t, 825cardiovascular effects, 629, 630t, 825cellular dysregulation, 50tchronic pulmonary disease, 823–824chronic toxicity, 823–825developmental effects, 367dietary, 822distribution, 121ecotoxicology, 1016–1017, 1020excretion, 125exposure, 822in food, 1074hepatotoxicity, 480host factors influencing toxicity, 815hypertension and, 825immunosuppression by, 443impairment of cellular maintenance, 60t, 63intestinal absorption, 1053tLeydig cell tumor development and, 744lung damage caused by, 525nephrotoxicity, 499–500, 507, 824neurotoxicity, 825reproductive system toxicity, 683t, 690, 695,

695t, 698reversibility of renal effects, 826skeletal effects, 824–825toxicokinetics, 822–823, 823ftreatment of poisoning, 816–818, 826urine, 813, 822, 826

Cadmium chloride, 825Cadmium oxide, lung damage caused by, 527tCadmium sulfate, 825Caffeine, 1071t

biotransformation, 158, 178f, 179, 184–185t,186, 188, 209

cardiotoxicity, 608, 624pituitary toxicity, 714therapeutic monitoring, 1105t

Calcimycin, impairment of cellularmaintenance, 59t

Calcineurin, 604, 605f

Calcitonin, 734–737, 735f, 738fpituitary toxicity, 714

Calcium, 45absorption, 112blood, 734–737cardiac overload, 608distribution, 120fhomeostasis, 737, 738f

in kidney, 504–505lead impairment, 830perturbation by carbon tetrachloride, 887

intracellular, sustained rise, 58–59, 60f,60t, 61

metabolism, effect of cadmium, 824–825poisoning, 1116turine, 825in vascular smooth muscles cells, 632, 632f

Calcium acetate, in food, 1055–1057tCalcium-ATPase, 57

cardiac, 601f, 602Calcium bromate, in food, 1055tCalcium carbonate, in food, 1055–1056tCalcium channel, 46, 55t, 58, 632

cardiac, 600–601, 600–601feffect of pyrethroid esters, 786, 786f

Calcium channel blockers, 606biotransformation, 180cardiotoxicity, 617effect on platelets, 405Leydig cell tumor development and, 745

Calcium chloride, in food, 1055–1056tCalcium cycling, 58Calcium hydroxide, ocular toxicity, 575Calcium-magnesium ATPase, 773, 786Calcium oxalate, 966Calcium oxide, skin burns, 658tCalcium peroxide, in food, 1056tCalcium pump, 46Calcium-sensitizing agents, cardiotoxicity,

617–618Calcium stearate, in food, 1055tCalcium transporter, 113Calcium uncoupler, 58Calmodulin, 644, 773, 830, 849, 887Calomel, 836Caloric intake, 1051, 1065Calpain, 59, 506, 539Camphor, 971

poisoning, 1110cAMP-protein kinase, 743fCamptothecin, hematotoxicity, 410Canalicular cholestasis, 476t, 477Cancer, 242

biomarkers, 1019deaths attributed to environmental factors, 280ffamilial, 323risk assessment, 324–325sporadic, 323

Cancer prevention, 286–287, 287tactive, 287, 287tpassive, 287, 287t

Cancer slope factors, 870Cannabinoid, immunosuppression by, 449Capillary, 631–632Capillary endothelium, porosity, 38Caprolactam, carcinogenicity, 281tCaprylic acid, in food, 1062t

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Capsaicin, 60t, 968Capsaicin receptor, 56Captafol, 796f, 798–799Captan

acute toxicity, 797tstructure, 796f

Captopril, 48adrenal toxicity, 719biotransformation, 185t, 208developmental effects, 353texcretion, 125nephrotoxicity, 499–500

Carbamates, 774–784, 775fbiotransformation, distribution, and storage,

781–782, 781fcellular dysregulation, 56ecotoxicology, 1022–1023hypersensitivity reaction to, 458immunosuppression by, 442mechanism of toxic action, 779–781,

779–780f, 780tpoisoning, 775–779, 776tstructure, 775ftreatment of poisoning, 782–784, 783f, 783t

Carbamazepineaplastic anemia and, 394tbiotransformation, 142–143, 175, 176f,

184–185t, 186developmental effects, 374effect on granulocytes, 401tlaboratory tests on stat basis, 1112tmegaloblastic anemia and, 393tpoisoning, 1117treproductive system toxicity, 683ttherapeutic monitoring, 1105ttoxic epidermal necrolysis and, 667

Carba mix, allergic contact dermatitisfrom, 661t

Carbamylhydrazine, vasculotoxicity, 641tCarbaryl

immunosuppression by, 442mechanism of toxic action, 781poisoning, 778

Carbazeran, biotransformation, 159Carbimazole

aplastic anemia and, 394tthyroid toxicity, 726, 726f

Carbofuran, ecotoxicology, 1035–1036Carbohydrates, as promoting agents, 283Carbonaceous material, airborne particulate

matter, 998Carbonate anion radical, 40, 42Carbon dioxide, 48

in food, 1056tCarbon disulfide, 47, 903–905

biotransformation, 903–904, 904fcardiotoxicity, 905developmental effects, 374neurotoxicity, 547–550, 548t, 549f, 871,

904–905occupational disease, 1127t, 1130ocular toxicity, 566t, 567, 585vasculotoxicity, 641t, 647, 905

Carbonium cation, biotransformation, 41tCarbon monoxide, 44, 108, 115, 173,

885–886, 1052air pollution, 987–988, 1000, 1006binding to hemoglobin, 396

cardiotoxicity, 609in fire victim, 1092impairment of cellular maintenance, 59tNational Ambient Air Quality

Standards, 981tneurotoxicity, 536–537, 543toccupational disease, 1127t, 1138poisoning, 1111–1112, 1114as ultimate toxicant, 37tvasculotoxicity, 642t, 646

Carbon tetrachloride, 17, 44, 68–69, 71–72,887, 893

absorption, 117air pollution, 992faplastic anemia and, 394tbiotransformation, 40, 137, 151, 151f, 189,

189t, 481cardiotoxicity, 630tin food, 1074thepatotoxicity, 471, 476, 476t, 479t, 481,

482, 880, 887immunosuppression by, 445impairment of cellular maintenance, 59–60tmetabolites as ultimate toxicants, 37tneurotoxicity, 543toccupational disease, 1127t, 1130poisoning, 1114target organ, 108toxicokinetics, 875

Carbonyl reductase, 135, 135f, 145, 146f, 147,149, 152, 156

Carbonyl reduction, 145–146, 146fCarboxin, 797tCarboxyamidase, 782Carboxyamidotriazole, hematotoxicity, 410Carboxyhemoglobin, 646, 1006, 1111, 1112tCarboxylesterase, 18, 18f, 43, 137, 137–140,

138f, 140f, 143, 143f, 180, 782, 787ocular, 566t, 570

Carboxylic acid group, amino acidconjugate, 211

Carboxymethylcellulose, urticaria from, 667tCarboxypeptidase, 140Carbutamide, aplastic anemia and, 394tCarcinogen(s). See also specific compounds

airborne particulate matter, 998–999classification

“inadequate evidence,” 281, 281t“limited evidence of carcinogenicity,”

281, 281t“sufficient evidence of carcinogenicity,”

281, 281tcomplete, 278, 278t, 669definition, 242DNA-damaging, molecular genetic targets,

271–273, 272–274tin food, 1064–1066, 1064t

biological versus statistical significance,1065–1066

food additives, 1060–1061identification, 88–91, 89t, 287–297

epidemiologic studies, 280–281, 281–282textrapolation of bioassay data to human

risk, 301–303long-term tests, 288t, 293–296, 294tmedium-term tests, 288t, 293–296, 294tmouse skin tumor promotion, 668–669mutagenesis assay, 288–293, 288t, 290f

short-term tests, 288–293, 288t, 290f,297–298, 322

transformation in cell culture, 288t, 293using transgenic and knockout mice, 297

metabolism, 250–255, 252–255fnatural history of neoplastic development,

266–280nongenotoxic, 77–78, 78foccupation-associated, 284, 285tplant chemicals, 970potency, 300t, 301, 301fregulation, 304–305, 305t, 1143specific differences, 25–26threshold level, 303

Carcinogenesis, 72–78. See also specificcompounds

atherogenesis and, 634, 635fcell division and, 265–266definitions, 242–243by diet, 250, 251t, 282–283, 283tDNA repair and, 259–266failure of apoptosis, 76–77failure to terminate proliferation, 77film and fiber, 245–246, 526genetic and nongenetic mechanisms,

278–281historical aspects, 8–9, 242hormonal, 246–250, 247f, 248t, 249fin humans, 280–286, 280f, 281tincomplete, 271inorganic chemical, 245, 246tlifestyle, 282–284, 283tlog-probit model, 304lung, 525mechanisms

chemical structure and carcinogenesis,255, 256f

free radicals, 254–255, 254–255fmacromolecular adduct formation,

257–259, 258fmetabolism of carcinogens, 250–255,

252–255ffrom medical therapy and diagnosis,

285–286, 286tby mixtures of chemicals, 250models

knockout mice, 297multistage models, 296–297, 297f, 304,

304f, 743, 743fMVK model, 304, 304ftransgenic mice, 297

mutagenesis and, 255–257mutations and, 73, 73f, 271nongenotoxic carcinogens, 77–78, 78forganic chemical, 243–245, 243–244fovarian, 752–753skin, 667–669stages

cell and molecular mechanisms,271–276, 271t

initiation, 266, 267, 267t, 269f, 271, 271t,277–280, 278f, 278t, 287, 287t, 324

progression, 266, 267t, 269–271, 270f,270t, 276–280, 278f, 278t, 287,287t, 324

promotion, 266, 267–269, 267t, 268–269f,271t, 273–280, 274–275f, 275t,277–278f, 278t, 287, 287t, 324, 669

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Carcinogenic burden, 303Carcinogenic index, 300tCarcinogenicity test, 26, 29–30, 29f

background tumor incidence, 30–31, 30fCarcinogenic potential, evaluation, 297–301

dose-response problem, 298–301, 299f,299t, 325

problem of cross-species extrapolation,297–298, 298f

Carcinoma, 242Cardiac cycle, 600Cardiac glycosides, 604, 968, 1084

cardiotoxicity, 614t, 617Cardiac hypertrophy, 599, 602, 603–604

hypertrophic signal transduction, 604, 605fhypertrophic stimuli, 604

Cardiac muscle, 598, 599fCardiac nerves, toxic effects of plants,

968–969Cardiac output, 233, 235, 602, 631Cardiac remodeling, 599, 603Cardiomyopathy, 604

alcoholic, 604, 613, 894dilated, 604, 610hypertrophic, 604

Cardiotoxicityof alcohols, 629of aldehydes, 629of androgens, 626t, 627of animal and plant toxins, 629of anthracyclines, 615t, 619–620of antiarrhythmic agents, 613–619, 614tof antibacterial drugs, 615t, 621of antifungal agents, 615t, 621of antihistamines, 616t, 623–624of antineoplastic agents, 615t, 619–621of antiviral agents, 615t, 621–622of centrally acting drugs, 615–616t, 622of cisapride, 624of cytokines, 627t, 628–629of estrogens, 625, 626tof ethanol, 613, 614tof glucocorticoids, 626t, 627–628of halogenated alkanes, 629, 630tof immunosuppressants, 616t, 624of industrial agents, 629–631, 630tof inotropic agents, 613–619, 614–615tof ketones, 630tof local anesthetics, 616t, 622–623mechanisms

altered coronary blood flow, 606–607, 612tapoptosis and oncosis, 610–611, 611f,

612tinhibition of sodium, potassium-ATPase,

604–606interference with ion homeostasis, 604, 612torganellar dysfunction, 608–609, 612toxidative stress, 607–608, 607f, 612t

of metals, 629–631, 630tof methylxanthines, 624of mineralocorticoids, 626–627t, 627–628of miscellaneous drugs, 616tof naturally occurring substances, 625–629,

626–627tof pharmaceutical agents, 612–621,

614–616tof progestins, 625–627, 626tof radiocontrast agents, 616t, 625

of sildenafil, 624–625of solvents, 629, 630tof steroids, 625–628of thyroid hormones, 627t, 628

Cardiotrophin-1, 604, 628Cardiovascular system. See also Heart;

Vascular systemoccupational disease, 1130

�-Carotene, 283in food, 1055t

Carpenter bees, 954Carprofen, hepatotoxicity, 471, 477fCAR� receptor, 195Carson, Rachel, 9CASA. See Computer-aided sperm analysisCascara sagrada, 967Case-control study, 90, 90t, 1132, 1134Case reports, occupational disease, 1132, 1134CASMA. See Computer-aided sperm motion

analysisCaspase, 62f, 63, 77, 361–362, 506, 610, 611fCassava, 585, 971, 1071Catalase, 43, 43f, 154, 155f, 166, 397, 397f,

638, 893, 895, 895fcardiac, 607, 607focular, 566t, 570

Cataract, 576–577Catechol, 889, 890f, 891Catecholamines

cardiotoxicity, 606, 612, 614t, 617, 618–619demonstration in tissue sections, 723neurotoxicity, 544–545, 545fsynthesis and storage, 719–720vasculotoxicity, 632, 636t, 639

Catechol-O-methyltransferase, 207�-Catenin, 74fCaterpillars, 953Cationic amphophilic drugs, lung damage

caused by, 530Causal relationship, 22Caustic burn, 575CBG. See Corticosteroid binding globulinCDRH. See Center for Devices and

Radiological HealthC/EBP, 70Cefamandole, reproductive system toxicity, 691Cefbuperazone, reproductive system toxicity, 691Cefoperazone, reproductive system toxicity, 691Celecoxib, 192

biotransformation, 184–185tCeliac disease, 1067tCell cycle

embryonal, 361, 362fregulation, 276, 277f

Cell death. See also Apoptosisinduction by unknown mechanisms, 63–64toxic, 57–64

Cell differentiation, prenatal, 361Cell division, carcinogenesis and, 265–266Cell division cycle, 68, 68fCell-free corrosivity test, 88Cell-mediated cytotoxicity, 429–430, 430fCell-mediated immunity, 424, 428–430, 429f,

434–435Cell membrane, 109–111

model, 109, 109ftransport across, 38

Cell migration, 69

Cell nucleus, energy deposition, 924Cell proliferation, 67–69, 71–72

failure to terminate, 77in prenatal development, 361

Cellular dysfunction, 36f, 48–64, 48fCellular dysregulation, 53–57

electrically excitable cells, 53–57, 53f,54–55t

gene expression, 49–53ongoing cellular activity, 53–57signal transduction, 49–52, 51ftoxicant-induced, 48f, 49–57transcription, 49, 50t

Cellular maintenanceexternal, impaired, 48f, 64internal, impaired, 48f, 57–64

Cellular repair, in peripheral neurons, 67Center for Devices and Radiological Health

(CDRH), 436Centipedes, 952–953Centrally acting drugs, cardiotoxicity,

615–616t, 622Central nervous system, toxic responses, 692Central peripheral distal axonopathy, 546Central visual system

pharmacokinetics, 570f, 571toxic responses, 586–587

to lead, 586–587to methyl mercury, 587

Cephaeline, 1100Cephaloridine, 125

nephrotoxicity, 500Cephalosporin, 25

biotransformation, 690tcoagulation factor inhibitor development

and, 406themolytic anemia and, 399nephrotoxicity, 500octanol/water partition coefficient, 109treproductive system toxicity, 690t, 691urticaria from, 667t

CEQ. See Council for Environmental QualityCeramide, 62f, 118, 610–611, 611f, 620, 655CERCLA. See Comprehensive Environmental

Response, Compensation andLiability Act

Cerebrospinal fluid, removal of toxic agents,128–129

Cerulide, 1081Ceruloplasmin, 120, 120f, 816, 840, 841fCervix, 686C-esterase, 137CF. See Consumption factorChamber Scarification Test, 658Chaperone, molecular, 65Charcoal, 17

activated, 1114–1115, 1118–1120multiple-dose, 1116–1117, 1117t

antidotal properties, 1109Cheiracanthium species, 949t, 951Chelation, 816Chelation therapy, 816–818, 1117

with hemodialysis, 818Chelonitoxin, 1080Chemical(s)

environmental. See Environmentalchemical/contaminant

interactions, 17

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Chemical allergy, 15Chemical antagonism, 17Chemical burn, 658, 658tChemical carcinogenesis. See CarcinogenesisChemical Carcinogenesis Research Information

System, 99Chemical idiosyncrasy, 16Chemical transport, in environment,

1014–1015Chemodynamics, 1014–1015Chemotherapy, 286

bone marrow effects, 393Chernobyl accident, 929–931, 931f, 1025

“liquidators,” 930Chernoff/Kavlock assay, 372, 373tChewing tobacco, carcinogenicity, 284Chick embryo neural retina cell culture, 373tChicken, models in immunotoxicology, 436–437Chief cell(s), parathyroid

proliferative lesions, 740–741structure and function, 737–739, 738f

Chief cell adenoma, 740–741Child, solvent sensitivity, 877–878Child abuse, poisoning as form of, 1099–1100Childhood exposure, 370–372Chilopoda, 952–953China white, 1092Chinese hamster cells, cytogenetic assays,

338, 339fChinese hamster ovary assay, 288, 289t, 291fChinese restaurant syndrome, 558Chinomethionate, 797tChip arrangement test, 574Chiral xenobiotics, 134–135Chloracne, 665, 665f, 666t, 792Chloral hydrate, 1099

biotransformation, 146, 146fpoisoning, 1116t

Chlorambucilgenetic effects, 341leukemia and, 402reproductive system toxicity, 691t, 693t

Chloramine, allergic contact dermatitisfrom, 660t

Chloramphenicolaplastic anemia and, 394tbiotransformation, 144, 144f, 199–201, 199f,

203t, 877carcinogenicity, 286tcardiotoxicity, 621coagulation factor inhibitor development

and, 406tdistribution, 120feffect on granulocytes, 401tneurotoxicity, 543tsideroblastic anemia and, 392t

Chlorate, oxidative hemolysis and, 397tChlorbenzylate, poisoning, 771tChlorcyclizine, 1052tChlordane, 96, 194, 774

aplastic anemia and, 394tcarcinogenicity, 285tcellular dysregulation, 50tdistribution, 121ecotoxicology, 1016immunosuppression by, 441–442poisoning, 771t

storage in body, 774structure, 770tthyroid toxicity, 729

Chlordecone, 72cellular dysregulation, 53, 55t, 56hepatotoxicity, 772impairment of cellular maintenance, 59–60tneurotoxicity, 548toccupational disease, 1127tpoisoning, 771t, 772reabsorption, 39reproductive system toxicity, 674, 676

Chlordiazepoxide, aplastic anemia and, 394tChlorfenvinphos

biotransformation, 782poisoning, 777

Chlorhexidineallergic contact dermatitis from, 660tin photopatch test, 664t

Chloride, in food, 1056tChloride channel, effect

of avermectins, 788of pyrethroid esters, 786of scorpion venom, 948

Chlorinated benzenes, 770tChlorinated cyclodienes

poisoning, 772toxic actions, 773

Chlorinated hydrocarbons, 880–889carbon tetrachloride, 887chloroform, 887–889, 888fdistribution, 39methylene chloride, 885–887tetrachloroethylene, 884–885, 885ftrichloroethylene, 880–884

Chlorinated organics, in food, 1074–1075, 1074tChlorine, 16

absorption, 115lung damage caused by, 527toccupational disease, 1127tskin burns, 658t

Chlornaphazine, carcinogenicity, 286t, 299tChloroacetanilides, 794–795, 794fChlorobenzene, 193

biotransformation, 174, 176f, 214fChlorobenzilate, carcinogenicity, 279t2-Chloro-1,1-difluoroethylene, 152, 152fChlorodifluoromethane, 8871-Chloro-2,4-dinitrobenzene, biotransformation,

213, 216Chloroform, 870

absorption, 116biotransformation, 189, 189t, 191–192,

508, 876carcinogenicity, 77, 279t, 888–889cardiotoxicity, 630tdevelopmental toxicity, 887drinking water, 873, 887excretion, 128in food, 1074timpairment of cellular maintenance, 60tnephrotoxicity, 503, 508poisoning, 1114

p-Chloromercuribenzoate (PCMB), 137Chloromethyl ether, lung damage

caused by, 5254-Chloro-2-methyloxyacetic acid (MCPA),

764, 791fChloromethylperoxy radical, 887Chloronicotinyl insecticides, 788, 789, 789f2-Chlorooxirane, biotransformation, 41tChloropentafluoroethane, cardiotoxicity, 630tChlorophenoxy compounds, 791–793, 791f

vasculotoxicity, 641tChlorophentermine, adrenal toxicity, 719Chloroquine

adrenal toxicity, 718distribution, 38neurotoxicity, 548tocular toxicity, 566t, 570pigmentary disturbances from, 666tretinotoxicity, 578–579vasculotoxicity, 643tvolume of distribution, 228t

Chlorothalonil, 797tChloro-1,2,2-trichlorovinylthioketene,

biotransformation, 41tChloroxylenol, allergic contact dermatitis

from, 660tChlorphenothane, aplastic anemia and, 394tChlorphentermine

adrenal toxicity, 718lung damage caused by, 530

Chlorplatinate salt, hypersensitivity reactionto, 457

Chlorpromazine, 193–194, 1052taplastic anemia and, 394tbiotransformation, 167, 169, 169f, 171–172,

176–177, 185tcardiotoxicity, 616t, 622cellular dysregulation, 50tdistribution, 38effect on granulocytes, 401thepatotoxicity, 476t, 486lupus anticoagulant and, 407tocular toxicity, 566t, 577in photopatch test, 664tphototoxicity, 663treproductive system toxicity, 685t, 688vasculotoxicity, 639

Chlorpromazine free radical, 44fChlorpropaine, biotransformation, 139Chlorpropamide

aplastic anemia and, 394tdrug interactions, 407neutropenia and, 402t

Chlorprothixene, cardiotoxicity, 622Chlorpyrifos

dose-response relationship, 18, 18fecotoxicology, 1037–1038mechanism of toxic action, 780

Chlortetracycline, aplastic anemia and, 394tChlorthiamid, 791tChlorzoxazone, biotransformation, 175f,

184t, 188Chlorzoxazone 6-hydroxylase, 196Cholangiodestructive cholestasis, 477Cholecalciferol, 737, 738fCholera toxin, 46Cholestasis, 485–486, 486f

canalicular, 476t, 477cholangiodestructive, 477

Cholesterol, 717, 718fbiotransformation, 203t

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vasculotoxicity, 643tCholesterol epoxide hydrolase, 141Cholesterol ester, 118Cholesteryl ester hydroxylase, neutral, 718Cholestyramine, 108

effect on coagulation, 406texcretion, 126megaloblastic anemia and, 393t

Cholic acid, as promoting agent, 267, 268fCholine acetyltransferase, 830Cholinergic crisis, 56Cholinergic syndrome, 1111, 1111tCholinesterase, 23, 137, 1019Cholinesterase inhibitors, 1023Cholyl-CoA synthetase, 211Choriocapillaris, 569, 578Chromaffin cells, 719–723Chromaffin reaction, 723Chromate, 826

biotransformation, 40carcinogenicity, 285tcellular uptake, 816reabsorption, 39respiratory tract damage caused by, 525

Chromatid alteration, 290Chromic acid, ocular toxicity, 575Chromium, 37t, 814, 826–827

absorption, 113air pollution, 992fallergic contact dermatitis from, 659, 660tbiomarker, 813biotransformation, 42carcinogenicity, 245, 246t, 285t, 827granulomatous reactions to, 666hemolytic anemia and, 398human body burden, 826hypersensitivity reaction to, 457immune reactions to, 815immunosuppression by, 444lung damage caused by, 525, 527toccupational disease, 1128reproductive system toxicity, 695ttoxicity, 827vasculotoxicity, 644

Chromium(III), 839–840essentiality, 839–840

Chromogranin A. See Parathyroidsecretory protein

Chromophobes, 712, 713fChromosomal aberrations, 324, 692, 692t

assay for, 331t, 338–339, 339fhuman population monitoring, 343–344structural, 330technological advances in detection,

344–345Chromosomal alterations

carcinogen identification from, 290–292formation

in germ cells, 330–331in somatic cells, 330

germ cell mutagenesis, 341–342in vitro, 289t, 290–292in vivo, 289t, 290–291in tumors, 345

Chromosome banding, 344Chromosome counting, 340Chromosome number, changes, 330

Chromosome painting, 339Chronic beryllium disease, 821–822Chronic exposure, 14Chronicity index, 24Chronic lymphocytic leukemia (CLL), 402Chronic myelogenous leukemia (CML),

402–403Chronic organophosphate-induced

neuropsychiatric disorder (COPIND), 776Chronic pulmonary disease, cadmium and,

823–824Chronic solvent encephalopathy, 871–872, 872tChronic toxicity study, 29–31, 29–30fChronic 2-year bioassay, 293–294, 294f,

294–295t, 297–298Chrysanthemic acid, 784Chrysene, carcinogenicity, 243, 243fChymotrypsin inhibitors, 1051Ciclopiroxolamine, biotransformation, 199fCicutoxin, 971Cigarette smoking, 201, 211, 218, 261, 343.

See also Nicotineair pollution, 990, 992carcinogenicity, 250, 283–284, 283t, 299tdevelopmental effects, 353t, 355, 367immunosuppression by, 444interaction with atom bomb radiation, 928lung damage caused by, 519, 523–525, 529metals in smoke, 815occupational disease, 1127tpassive smoking, 990in pregnancy, 557

Cigar smoking, 585Ciguatera poisoning, 1079Ciguatoxin, 1079

cellular dysregulation, 55tCiliary epithelium, 568Cimetidine, 154

aplastic anemia and, 394tbiotransformation, 167, 169–171, 170f, 176Leydig cell tumor development and, 746, 748treproductive system toxicity, 682, 683t

Cineole, 971Cinerin, 784Cinerolol, 784Cinnamic aldehyde

allergic contact dermatitis from, 660turticaria from, 667t

Cinnamon, 1055tCinnamyl alcohol, biotransformation, 153Cinnamyl anthranilate, in food, 1065Cinnarizine, biotransformation, 185tCinoxate, in photopatch test, 664tCiprofibrate, 195Ciprofloxacin

cardiotoxicity, 621coagulation factor inhibitor development

and, 406tCircadian rhythm, 880Circumventricular organ, 536, 558Cirrhosis, 72, 472, 476t, 478, 880Cisapride

biotransformation, 185tcardiotoxicity, 606, 616t, 621–622, 624

Cismethrin, poisoning, 785tCisplatin, 852–853

effect on granulocytes, 400

hemolytic anemia and, 399nephrotoxicity, 496t, 500, 503, 506,

511, 853neurotoxicity, 548treproductive system toxicity, 695

Citalopram, biotransformation, 184–185tCitral, in food, 1055tCitral dimethyl acetal, immunosuppression

by, 450Citreoviridin, in food, 1077tCitric acid, in prostatic secretions, 684Citric acid cycle, 60Citrinin, nephrotoxicity, 509Citrus Red No. 2, 1054, 1057tClara cells, 518, 884Clarithromycin, cardiotoxicity, 615t, 621Clastogenicity, 290–291Clavulanate, hemolytic anemia and, 399Clean Air Act, 12, 83, 86t, 99, 304–305, 305t,

901, 980–981, 1147Clean Water Act, 304, 305tClearance, 228, 229f

total body, 228Cleavage, 357Clinical toxicology, 3, 13, 1109–1120. See also

Poisoned patientanalytic toxicology and, 1103–1104case examples, 1118–1120

acetaminophen poisoning, 1118–1119methanol poisoning, 1119tricyclic antidepressant poisoning,

1119–1120historical treatment of poisoning, 1109history, 1109–1110poison control center, 1109–1110strategy for treatment of poisoned patient,

1110–1120Clinical trial

hematologic risk assessment, 410–411, 411tphase I, 411phase II, 411phase III, 411risks of air pollution, 984–985

Clioquinol, neurotoxicity, 548tCLL. See Chronic lymphocytic leukemiaClobetasol, cardiotoxicity, 627–628Clofibrate, 26, 46

carcinogenicity, 279tcellular dysregulation, 50tLeydig cell tumor development and, 748tas promoting agent, 275t

Clofibric acid, 193, 195, 200distribution, 121, 121teffect on hemoglobin, 395

Clomiphenedevelopmental effects, 368pituitary toxicity, 714reproductive system toxicity, 683t

Clonazepam, biotransformation, 209Clonidine

reproductive system toxicity, 685ttransdermal delivery, 656

Clonipramine, biotransformation, 185tClopidogrel

effect on platelets, 405thrombocytopenia and, 405

Clorgyline, 160–161

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Clostridial infection, 396–397Clostridium botulinum, 306, 1080–1081Clostridium butyricum, 1080–1081Clostridium perfringens, 1081Clotrimazole, 188, 193–196Clozapine, 48

agranulocytosis and, 411biotransformation, 166–167, 169, 185tcardiotoxicity, 616t, 622effect on granulocytes, 401neutropenia and, 402t

CML. See Chronic myelogenous leukemiaCoagulation, 405–406Coagulation factor(s), 405–406, 472, 473f, 637

decreased synthesis, 406increased clearance, 406, 406tvitamin K-dependent, 406–407, 406t

Coagulation factor II, 406Coagulation factor V, 406tCoagulation factor VII, 406Coagulation factor VIII, 406tCoagulation factor IX, 406Coagulation factor X, 406Coagulation factor XIII, 406tCoal dust

lung damage caused by, 527toccupational disease, 1127t

Coal tarcarcinogenicity, 242–243, 668pigmentary disturbances from, 666t

Coal workers’ pneumoconiosis, 1126Cobalamin, 839Cobalt, 839

allergic contact dermatitis from, 659, 660tcarcinogenicity, 246tcardiotoxicity, 629, 630tgranulomatous reactions, 666hypersensitivity reaction, 457immunosuppression by, 444intestinal absorption, 1053toccupational disease, 1128reproductive system toxicity, 695, 695ttoxicity, 839toxicokinetics, 839vasculotoxicity, 644

Cobalt caprylate, in food, 1055tCobalt chloride


Cobalt tallate, in food, 1055tCobras, 955, 956–957t, 961�-Cobrotoxin, cellular dysregulation, 54tCobweb spider, 949t, 951Cocaine, 1094

analytic toxicology, 1097biotransformation, 137, 138f, 139, 169, 169f,

206, 1095, 1095–1096fbody packer, 1114cardiotoxicity, 610, 616t, 622, 623cellular dysregulation, 56developmental effects, 353t, 355, 365,

367, 374forensic urine drug testing, 1100timmunosuppression by, 449impairment of cellular maintenance, 59tnephrotoxicity, 496tneurotoxicity, 556t, 557

poisoning, 1094f, 1103tthrombocytopenia and, 405use in pregnancy, 557, 639, 687vasculotoxicity, 639

Cocarcinogen, 282Codeine

biotransformation, 135, 185t, 188, 199fforensic urine drug testing, 1100t

Code of Federal Regulations, 1150Cohort study, 90, 90t, 990, 1132

prospective, 1132retrospective, 1132, 1134

Colchicine, 46, 967absorption, 113genetic effects, 330impairment of cellular maintenance, 64megaloblastic anemia and, 393tneurotoxicity, 548t, 552, 552foctanol/water partition coefficient, 109tpoisoning, 1093

Cold stress, to wildlife, 1024Colecemid, genetic effects, 330Collagen, in lungs, 524Collagenase, snake venom, 957t, 958Collecting duct, 492f, 494

toxic injury, 500Colloidal tripotassium dicitrato bismuthate, 850Colony-stimulating factors, 423Color additives, 1050, 1054–1058, 1054t,

1057t, 1144daily intake, 1058safety evaluation, 1058–1061

Color vision, 574assessment, 574deficit, 574

Colostomy, 851Comedogenic chemicals, 664Comet assay, 334–335Comfrey tea, 969, 1075Common normal distribution pattern, 95Community, 982

diversity, 1024trophic structure, 1024

Community effects, 1023–1024Community risk profile, 101Community tolerance, pollution-induced, 1024Comparative genomic hybridization, 345Comparative risk analysis, 100Compartments, 232Complement system, 399, 421t, 423–424

alternative pathway, 423–424, 423fclassical pathway, 423–424, 423f

Complete carcinogen, 278, 278t, 669Complexation, 816Complexation therapy, 816–818Compliance, lung, 531Comprehensive Environmental Response,

Compensation and Liability Act(CERCLA), 12, 86t

Compton effect, 921Computational toxicology, 463Computer-aided sperm analysis (CASA), 703Computer-aided sperm motion analysis

(CASMA), 697Computer software, toxicokinetics, 230Concern level, 1059–1061, 1060tConcern level tests, 1058, 1058t

Conducting airways, 516, 517fConduction system, cardiac, 600–601Cone(s), 569, 578

effects of cardiac glycosides, 579Conenose bug, 954Configuration, inversion, 135Congenital malformations. See Developmental

toxicityCongo Red, vasculotoxicity, 636tConiine, 973, 1083

poisoning, 1093Conjugation, 197

amino acid, 135, 136t, 197f, 211–213, 212fglucuronide, 136tglutathione, 135, 136t, 197f, 213–218,

214–217f, 219f, 254, 571sulfate, 136t

Conjunctiva, 567Connexin, 67Conotoxins, cellular dysregulation, 54–55tConstitutive androstane receptor, 50tConsumer Product Safety Act, 86tConsumer Product Safety Commission (CPSC),

12, 86t, 304, 1142regulatory programs, 1147–1148

Consumption factor (CF), 1061, 1061tContact dermatitis, 657–662

allergic, 659–660, 660tchemical burns, 658, 658tirritant, 657–658plants causing, 966–967testing methods

diagnostic, 661–662predictive, 660–661

Contact herbicides, 790Contact hypersensitivity

in experimental animals, 455–456, 456fin humans, 456

Contact sensitizers, 661Contact urticaria, 666Contraceptive steroid, biotransformation, 192Contrast sensitivity, 574Convallarin, 1084Convallatoxin, 968Cooking, substances produced in food,

1082–1083, 1083tCooxidation, peroxidase-dependent,

162–166, 163fCopeland bill, 7COPIND. See Chronic organophosphate-

induced neuropsychiatric disorderCopper, 840–841

absorption, transport, and excretion,114, 841f

biliary excretion, 475cellular uptake, 816deficiency, 840distribution, 120fin drinking water, 840essentiality, 840hemolytic anemia and, 398hepatotoxicity, 476thost factors influencing toxicity, 815occupational disease, 1127treproductive system toxicity, 698sideroblastic anemia and, 392ttoxicity, 840–841

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toxicokinetics, 840treatment of poisoning, 818vasculotoxicity, 644

Copperheads, 955, 956–957tCopper sulfate, 791tCoproporphyrinogen oxidase, 830, 831fCoral snakes, 955, 956–957tCornea, 567, 568f, 569

clouding, 575damage, 566t

evaluation, 572functions, 575toxic responses, 575–576

Corneal endothelium, 567Corneal epithelium, 567Corneal stroma, 567Corneocytes, 654–655Corona radiata, 687Coronary artery disease, 603Coronary blood flow, altered, 606–607, 612tCoronary vasoconstriction, 606Coronary vasospasm, 606Coroner, 1092–1093Corrositex assay, 572Corrosives, analytic toxicology, 1090Cortexolone, adrenal toxicity, 718Corticosteroid(s), 216

allergic contact dermatitis from, 660timmunosuppression by, 447ocular toxicity, 566t, 577reproductive system toxicity, 693tteratogenicity, 719vasculotoxicity, 636t

Corticosteroid binding globulin (CBG), 1020Corticosterone, 717

cardiotoxicity, 626t, 627–628Corticotropin-releasing hormone (CRH),

678t, 717Cortisol. See HydrocortisoneCortisone, cardiotoxicity, 626t, 627–628Corundum smelter’s lung, 527tCosmetics

hypersensitivity reaction to, 458ocular toxicity, 576regulation, 1144

Cotinine, 159, 186, 355Cotton dust

lung damage caused by, 527toccupational disease, 1127t

Coughing, 117Cough reflex, plant chemicals affecting, 968Coulston, Fredrick, 8Coumadin, 801–802Coumarin

biotransformation, 175, 175–176f, 182, 184t,186, 198, 217

developmental effects, 353t, 374impairment of cellular maintenance, 64

Coumarin 7-hydroxylase, 186Coumestans, 674Coumestrol, developmental effects, 368Council for Environmental Quality (CEQ),

86tCount median diameter, 521Courtroom testimony, 1102–1103Covalent binding, of toxicant to target

molecule, 45–46, 45t

CPSC. See Consumer Product SafetyCommission

CPT-11, biotransformation, 139C-reactive protein, 70–71, 423Creatine, urine, 692Creatine kinase, cardiac, 603Creatinine, serum, 502, 502fCreatinine clearance, 502CREB, 274Creosote, carcinogenicity, 668o-Cresol, biotransformation, 876p-Cresol, in food, 1055tCreutzfeldt-Jakob disease, 1082CRH. See Corticotropin-releasing hormoneCrigler-Najjar syndrome, 201Criteria pollutants, 980–981Critical adverse effect, 92Critical flicker fusion frequency, 574CroFab, 962Crohn’s disease, 704Crops, worldwide harvest losses, 765, 765tCross-examination, 1102Crossing over, 686Cross-reacting chemicals, 659, 662f, 662tCross-sectional study, 90, 90t, 1132, 1134Cross-sensitization, 152Cross-species extrapolation, 297–298, 298fCrotalids, 956t, 960–961cis-Crotonalide fungicides, impairment of

cellular maintenance, 59tCrotoxin, 960Cryptogenic fibrosing alveolitis. See

Pulmonary fibrosisCryptorchidism, 744Crystallin, 576–577CS syndrome, 784–786, 785tCTL assay. See Cytotoxic T-lymphocyte assayCuban epidemic of optic neuropathy, 585–586Cumulative exposure, 98–99Cumulative risk, 98–99Cuprizone, neurotoxicity, 553tCurare, 46, 972

urticaria from, 666Curative fungicides, 797Curing agents, 1054tCyanide, 396

absorption, 115biotransformation, 43, 218–219cardiotoxicity, 609, 609fcellular dysregulation, 57impairment of cellular maintenance, 57–58,

59t, 61neurotoxicity, 536–537, 543tpoisoning, 1117as ultimate toxicant, 37t

Cyanoacrylateallergic contact dermatitis from, 660tvasculotoxicity, 640, 643t

2-Cyanoethyl-N-hydroxythioacetamide,biotransformation, 203t

Cyanogenic chemicals, in plants, 970–971Cyanoketone, reproductive system toxicity, 689tCyanomethemoglobin, 396Cycad, 558, 1071Cycasin, 115, 1051, 1067t, 1071, 1072tCyclamate, carcinogenicity, 1065Cyclic AMP, 274, 522, 632, 634f, 742

Cyclic GMP, 522, 685Cyclin, 49, 52, 68f, 74–75fCyclin-dependent protein kinase, 49, 52, 68f,

74f, 75, 75f, 276Cyclobenzaprine, biotransformation, 198, 199fCyclodienes, 770t

cellular dysregulation, 54t, 56Cyclohexane(s), 770t

site and mechanism of toxic actions, 773Cyclohexane carboxylic acid,

biotransformation, 162, 162fCyclohexene oxide, 143Cycloheximide, hepatotoxicity, 476Cyclohexylmethyl phosphorofluoridate

structure, 775ftreatment of poisoning, 784

Cyclooxygenase, 162, 163f, 173, 254, 255f, 639Cyclopamine, developmental effects, 378Cyclopentenyl cytosine, hematotoxicity, 410Cyclopentolate hydrochloride, urticaria

from, 667tCyclophosphamide

biotransformation, 159, 184–185t, 189t, 190,190f, 877

cardiotoxicity, 615t, 620–621developmental effects, 353t, 360–361,

360f, 362feffect on granulocytes, 400hepatotoxicity, 476t, 478, 479timmunosuppression by, 447leukemia and, 402lung damage caused by, 530reproductive system toxicity, 683t, 691t, 693tvasculotoxicity, 634, 639, 643t

Cyclopiazonic acid, 1076, 1077tCycloprothrin, poisoning, 785tCycloserine, sideroblastic anemia and, 392tCyclosporine, 63

absorption, 113biotransformation, 136, 182, 185t, 191–192cardiotoxicity, 624hepatotoxicity, 476t, 486immunosuppression by, 448nephrotoxicity, 496t, 498–499, 503, 511presystemic elimination, 37as promoting agent, 275, 275treproductive system toxicity, 691therapeutic monitoring, 1105tthrombocytopenia and, 405

Cyfluthrin, poisoning, 785tCyhalothrin, poisoning, 785tCyhexatin, impairment of cellular

maintenance, 59tCypermethrin

biotransformation, 787immunosuppression by, 442poisoning, 785tsite and mechanism of toxicity, 786

Cyphenothrinbiotransformation, 787poisoning, 785t

Cyproheptadine, biotransformation, 199fCyproterone

cellular dysregulation, 50tdevelopmental effects, 357reproductive system toxicity, 685t, 698t

Cysteamine, biotransformation, 169, 170f, 171

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Cysteine, 481octanol/water partition coefficient, 109t

Cysteine conjugate, 207, 254Cystine, octanol/water partition coefficient, 109tCytisine, cellular dysregulation, 54tCytochalasin, 46, 340, 340f

in food, 1077timpairment of cellular maintenance, 60t, 64

Cytochrome b, 609Cytochrome b5, 173–174, 194Cytochrome b5 methemoglobin reductase,

394–395, 397Cytochrome b5 reductase, 16, 65Cytochrome c, 61–63, 62f, 609–610, 611fCytochrome c oxidase, 44, 646, 840Cytochrome oxidase, 61, 486, 608–609Cytochrome P450, 40, 43, 47, 49, 71, 89,

134–135, 136t, 137, 139, 141–147, 145f,151, 154, 155f, 159, 163–165f, 167,172–196, 210, 251, 360, 480–481, 781

activation of xenobiotics, 189–191, 189t, 190fadrenal, 717–718age-related differences, 877Bacillus megaterium, 195catalytic cycle, 174, 174fCYP1, 181CYP1A, 193t, 196CYP1A1, 189t, 192–194, 516, 523, 529,

566t, 570, 638, 656, 668, 876,878, 1019

CYP1A2, 86–87, 96, 178f, 181f, 182,183–184, 183t, 185t, 189t, 191–194,201, 211, 407, 566t, 570, 880

CYP1B1, 645, 668CYP1E1, 876CYP2, 181CYP2A, 182CYP2A1, 194, 196CYP2A2, 196CYP2A6, 175f, 181f, 182, 183–184t, 186,

189t, 192CYP2B, 193t, 196, 1019CYP2B1, 180, 181f, 194–195, 516, 523, 880CYP2B1/2, 196, 876, 879CYP2B2, 194–195CYP2B6, 183–184t, 186, 190f, 191–192CYP2B12, 656CYP2B19, 656CYP2C, 187, 192CYP2C6, 194CYP2C7, 196CYP2C8, 183–184t, 186–187, 189tCYP2C9, 175f, 181f, 183–184t, 187, 189t,

190, 192, 407CYP2C10, 181CYP2C11, 194, 196, 891CYP2C12, 196, 203CYP2C13, 196CYP2C18, 183t, 187, 189tCYP2C19, 175f, 178f, 182–183, 183–184t,

187, 189f, 192–193CYP2D6, 178f, 181f, 182, 183t, 185t,

187–188, 189t, 192, 878CYP2E1, 165, 175f, 178f, 181f, 182,

183–184t, 188, 189t, 190–192, 190f,196, 480–481, 508–509, 876–880,883–885, 886f, 887–891, 893, 1118

CYP2F1, 523CYP2F2, 529CYP3, 181CYP3A, 180–181, 188–189, 192, 193t, 481,

529, 887CYP3A1, 195–196CYP3A2, 194–196CYP3A4, 175f, 176, 178–179f, 180, 181f,

182–183, 183t, 185t, 189t, 190–192,190f, 407, 523, 613, 617, 621–622, 624

CYP3A5, 183tCYP3A7, 203CYP4A, 175f, 181, 193t, 196CYP4A1, 195, 566t, 570, 883CYP4A2, 195–196CYP4A3, 195CYP4A6, 195CYP4A9/11, 189, 189tCYP4B1, 516, 523, 570CYP4B2, 566tCYP11A1, 174CYP19, 162, 174dealkylation reaction, 177–178, 178fdeamination reaction, 179deficiency, 182dehalogenation reaction, 179–180dehydrogenation reaction, 180, 181fdemethylation reaction, 179desulfuration reaction, 179–180embryonal, 364environmental factors effecting, 182epoxidation reaction, 175ester cleavage, 179fethnic differences, 878gender differences, 878hydroxylation reaction, 174–175, 175finduction, 182, 184–185t, 192–196, 193t,

879inhibition, 182, 184–185t, 191–192, 879knockout mice, 191in lung, 523, 529ocular, 570oxidative group transfer, 178f, 179–180oxygenation reaction, 174, 177–178, 177fpolymorphisms, 99reaction catalyzed by, 173reaction phenotyping, 183renal, 500in skin, 656solvent metabolism, 876substrate specificity, 183sulfoxidation reaction, 176testicular, 689vascular, 637–638, 645

Cytogenetic assay, 331–333t, 334,338–341, 342

advances, 344–345aneuploidy, 340–341human population monitoring, 343–344micronucleus assay, 339–340, 340fsister chromatid exchange, 340, 341f

Cytokines, 425, 426–428tcardioprotective, 628cardiotoxicity, 627t, 628–629

Cytomegalovirus infection, 353t, 365Cytosine arabinoside

effect on granulocytes, 400

reproductive system toxicity, 691t, 693tCytoskeleton, renal cell, 504Cytotoxic T-lymphocyte (CTL) assay, 434Cytotrophoblast, 687

D2,4-D, 195, 764, 1092

hypersensitivity reaction to, 458neurotoxicity, 548toctanol/water partition coefficient, 109tpoisoning, 792structure, 791ftoxicity, 792

d4t. See StavudineDABA. See 2,4-Diaminobutyric acidDactinomycin, leukemia and, 403Daffodil itch, 966Danazol

cardiotoxicity, 626t, 627hepatotoxicity, 478reproductive system toxicity, 689t

Dapsonebiotransformation, 42, 166, 184–185t,

209–210, 209fmethemoglobinemia and, 395tneurotoxicity, 548toxidative hemolysis and, 397tpoisoning, 1117t

Dareste, Camille, 352Darkling beetles, 954Daunorubicin

biotransformation, 145, 148cardiotoxicity, 610, 615t, 619

DBCP. See DibromochloropropaneDCA. See Dichloroacetic acidDCVC. See Dichlorovinyl-L-cysteineddC. See ZalcitabineDDD

adrenal toxicity, 718–719poisoning, 771tstructure, 770t

DDEdevelopmental effects, 369ecotoxicology, 1017t, 1019reproductive system toxicity, 698

ddI. See VidexDDT, 7, 12, 46, 113, 194, 764, 769–770,

775, 801absorption, 109, 114, 119biotransformation, 152, 154f, 774carcinogenicity, 77, 301fcardiotoxicity, 625cellular dysregulation, 49, 50t, 55t, 56developmental effects, 357, 368distribution, 38, 108, 121ecotoxicology, 1019, 1026in food, 1074–1075immunosuppression by, 441–442impairment of cellular maintenance, 59tin milk, 129octanol/water partition coefficient, 109tpoisoning, 770–771, 771treproductive system toxicity, 674, 676,

698, 701site and mechanism of toxic actions,

772–773, 773f

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storage in body, 774structure, 770ttarget organs, 16thyroid toxicity, 729vasculotoxicity, 639

DDT-dehydrochlorinase, 152Death. See also Poison death

classified in relation to specific activities,302, 302t

determining cause of, 1092–1093Death angel, 970Death cap, 970DEBQI. See 2,6-DiethylbenzoquinonimineDe Brinvillers, Marchioness, 4Debrisoquine

biotransformation, 182, 185t, 187–188vasculotoxicity, 636t

Decalin, nephrotoxicity, 507–508Decamethylcyclotetrasiloxane,

immunosuppression by, 451Decarboxylase, 45Deep vein thrombosis, 639DEF. See S,S,S,S-Tributyl phosphorotrithioateDeficiency, 20Deformations, 359DEG. See Diethylene glycolDehalogenation, 144, 150–152, 151–153f,

179–180oxidative, 150–151, 152f

DEHP. See Diethylhexyl phthalateDehydroepiandrosterone

biotransformation, 203tcardiotoxicity, 626t, 627

Dehydroepiandrosterone sulfate, 195biotransformation, 203

17�-Dehydrogenase, 1020Dehydrohalogenation, 1516-Dehydrotestosterone, 180Delaney clause, 8–9, 83, 304–306, 766,

1064–1065, 1072, 1143DES proviso, 1064

Delavirdinebiotransformation, 185tcardiotoxicity, 622

Delayed hypersensitivity response (DHR),429–430, 434

Delayed toxicity, 16Deleterious effects, 15Deletion, 328–330, 337, 341Delivery, 36–44, 38fDeltamethrin

biotransformation, 787poisoning, 785, 785ttoxicity, 786

De Medici, Catherine, 4Dementia, aluminum and, 849–850Demethylchlortetracycline, phototoxicity, 663tDemyelination, 541, 552DEN. See DiethylnitrosamineDendritic cells

follicular, 425Langerhans, 425, 453

Dendrotoxin, cellular dysregulation, 55tDental amalgam, 817, 834–835, 85511-Deoxojervine, 9736-Deoxyacyclovir, biotransformation, 157f, 158Deoxyguanine prodrugs, biotransformation, 159

3-(Deoxyguanosine)-N2-ylacetylaminofluorene, 266

Department of Transportation (DOT), 12, 86tDeprenyl, 160–162

biotransformation, 185tDepurination, 47Dermal exposure, 14Dermatitis

allergic, 659–660, 660tplants causing, 966

contact. See Contact dermatitisnickel, 838–839photocontact, 664

Dermis, 118, 653–654, 655fDerris powder, 790DES. See DiethylstilbestrolDescriptive toxicology, 12, 12fDesferrioxamine, 817, 843, 850, 1117Desflurane, cardiotoxicity, 616t, 622Desglucouzarin, 968Deshayes, Catherine, 4Designer drugs, 1092Desipramine

biotransformation, 169f, 185t, 203tcardiotoxicity, 616t, 622therapeutic monitoring, 1105t

Desmethylcitalopram, biotransformation, 185tDesmethylimipramine, volume of

distribution, 228t17,20-Desmolase, 689tDesmopressin, thrombocytopenia and, 405Desogestrel, cardiotoxicity, 625, 626tDesonide, cardiotoxicity, 627–628Desoximetasone, cardiotoxicity, 627–628Detergent, 64

impairment of cellular maintenance, 60tocular toxicity, 576

Deterministic model, 1031Detoxication, 8, 38f. See also

Biotransformationof electrophiles, 43failure, 43–44of free radicals, 43, 43fof nucleophiles, 43of protein toxins, 43of toxicants with no functional groups, 43

Detoxification, 480–482, 876Development, 356

signal transduction, 377t, 378, 378ftiming of key events, 357, 357t

Developmental arrest, 352Developmental immunotoxicity, 462Developmental toxicity, 88. See also Pregnancy

assessmentalternative testing strategies, 372, 373tbenchmark-dose approach, 376–377concordance of data, 374–375, 375tdose-response modeling, 376f, 377elements of risk analysis, 375–376epidemiologic studies, 372–374multigeneration tests, 370regulatory guidelines for in vivo testing,

370, 371tchildhood exposures, 370–372critical periods of susceptibility, 356–359direct, 365dose-response patterns, 359–360

of endocrine-disrupting chemicals, 368–370endpoints of toxicity, 356–359of environmental chemicals, 1021–1022of glycol ethers, 899indirect, 365of lead, 829–830mechanisms and pathogenesis, 360–363,

360–363fmolecular basis of dysmorphogenesis,

362–363relationship to maternal toxicity,

365–368, 366fthreshold concept, 359–360

Developmental toxicology, 31, 351–378, 578definition, 351future, 377–378history, 351–352principles, 356–360, 356tscope of problem, 352–356

Dexamethasone, 180, 195cardiotoxicity, 626t, 627–628cellular dysregulation, 50tdevelopmental effects, 358

Dextromethorphan, biotransformation, 178f,185t, 188, 192

Dextropropoxyphene, poisoning, 1103tDextrorphan, biotransformation, 199fDFP. See O,O-Diisopropyl phosphorofluoridateDHR. See Delayed hypersensitivity responseDiabetes mellitus, 353t, 365, 880, 1113tDiacylglycerol, 604, 605f, 632, 633fDiagnostic procedures, carcinogenesis from,

285–286, 286tDialkyltin, immunosuppression by, 443Diallyl sulfide, inhibition of cytochrome

P450, 879Dialuric acid, biotransformation, 148Dialysis, treatment of poisoned patient,

1115–1116Dialysis dementia, 546, 849–850Diamide


Diamine, biotransformation, 216fDiamine oxidase, 136t, 160–162, 160f,

162, 10702,4-Diaminobutyric acid (DABA), 971

in food, 1072tDiaminotoluene, 870

vasculotoxicity, 645Diaquo-diamino platinate, biotransformation, 41tDiarrhetic shellfish poisoning, 52Diatrizoate meglumine, cardiotoxicity, 616t, 625Diazepam

biotransformation, 178f, 182–184, 185t, 187,192

for carbamate poisoning, 784carcinogenicity, 281tinduction of cytochrome P450, 879for organochlorine poisoning, 774reproductive system toxicity, 685t

Diazinon, poisoning, 777Diazolidinyl urea, allergic contact dermatitis

from, 660–661tDiazoxide, cellular dysregulation, 57Dibenz[a,c]anthracene, carcinogenicity, 243fDibenz[a,h]anthracene, carcinogenicity, 243, 243f

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Dibenzo[c,q]carbazole, carcinogenicity, 243, 243fDibenzo-p-dioxin, 193, 1132

in milk, 129Dibenzofuran, 193Dibromochloropropane (DBCP), 799, 800

biotransformation, 690tcarcinogenicity, 301foccupational disease, 1127t, 1133reproductive system toxicity, 674, 681, 690t,

692–693, 703Dibromoethane, biotransformation, 218, 219f4,5-Dibromosalicylanide, in photopatch test, 664t1,2-Dibromotetrafluoromethane,

cardiotoxicity, 630tDibutylphthalate, developmental effects, 369Dicentric chromosome, 330, 343Dichlobenil, 791tDichloroacetic acid (DCA), 870, 881–884, 882f1,4-Dichlorobenzene

carcinogenicity, 89tnephrotoxicity, 507–508occupational disease, 1127t

Dichlorodifluoromethane, cardiotoxicity, 630tp,p�-Dichlorodiphenyldichloroethylene,

carcinogenicity, 279tDichlorodiphenylethanes, 770tDichlorodiphenyltrichloroethane. See DDTDichloroethane

biotransformation, 218immunosuppression by, 446

Dichloroethylene, 72cardiotoxicity, 630thepatotoxicity, 476t, 486, 880immunosuppression by, 445impairment of cellular maintenance, 63inhibition of cytochrome P450, 879

Dichloromethane. See Methylene chloride1,2-Dichloro-4-nitrobenzene, biotransformation,

213, 214f2,6-Dichloro-4-nitrophenol, 203, 205–206Dichlorophen (dichlorophene)

allergic contact dermatitis from, 660tin photopatch test, 664t

2,4-Dichlorophenoxyacetic acid. See 2,4-D1,2-Dichloropropane, biotransformation, 189tDichloropropene, 797tDichlorovinyl-L-cysteine (DCVC), 882–883

impairment of cellular maintenance, 59tnephrotoxicity, 496

Dichlortetrafluorethane, cardiotoxicity, 630tDichlorvos, 779Diclofenac

aplastic anemia and, 394tin bile, 476biotransformation, 184t, 187, 199f, 202,

202f, 207hepatotoxicity, 476t, 483–484

Dicloxacillin, neutropenia and, 402tDicofol

poisoning, 771–772, 771tstructure, 770t

Dicumarol, 970drug interactions, 407

Dicyclohexylmethane-4,4�-diisocyanate (HMDI),hypersensitivity reaction to, 455

Didanosine, impairment of cellularmaintenance, 59t

Dideoxynucleoside, 58Di-n-dibutyltin dichloride, immunosuppression

by, 443Dieldrin, 194

absorption, 114carcinogenicity, 279t, 285timmunosuppression by, 441poisoning, 771treproductive system toxicity, 772site and mechanism of toxic actions, 773storage in body, 774structure, 770t

Diesel exhaust, 998Diet. See also Food

carcinogenesis by dietary components, 250,251t, 282–283, 283t

solvent sensitivity and, 880Dietary supplements, 1062t, 1063–10642,6-Diethylbenzoquinonimine (DEBQI), 794Diethyldithiocarbamate, biotransformation,

180, 199fDiethyldithiocarbamate methyl ester,

biotransformation, 146Diethylene glycol (DEG), 897Diethyl ether, 198

excretion, 128Diethylhexyl phthalate (DEHP)

biotransformation, 690tcarcinogenicity, 279tin food, 1065reproductive system toxicity, 690–691, 690t

Diethyl maleate, 217biotransformation, 213, 214f

Diethylnitrosamine (DEN)carcinogenicity, 260, 260t, 274t, 281t, 301fimmunosuppression by, 441

Diethylpyrocarbonate, in food, 1065Diethylstilbestrol (DES), 7, 16, 714, 716

binding to alpha-fetoprotein, 1021biotransformation, 199fcarcinogenicity, 249f, 254, 285–286, 286t,

299t, 301cardiotoxicity, 625, 626tcellular dysregulation, 50tdevelopmental effects, 353t, 354,

368–369, 374immunosuppression by, 446reabsorption, 39reproductive system toxicity, 674, 676,

682, 683tthrombocytopenia and, 404

Diffusion, 233, 1015eddy, 1015through epidermis, 655facilitated, 111tin lungs, 519particle deposition in respiratory tract, 521simple, 109–110

Diffusion-limited compartment, 234–235, 234fDiffusion-limited transport, 233Diflorasone, cardiotoxicity, 627–628Diflunisal

biotransformation, 199f, 202developmental effects, 367

Difluoroethane, cardiotoxicity, 630tDigitalis, 3, 968Digitonin, distribution, 120f

Digitoxigenin monodigitoxoside,biotransformation, 199

Digitoxin, 604, 1084biotransformation, 180, 181fcardiotoxicity, 614t, 617distribution, 120excretion, 128octanol/water partition coefficient, 109tocular toxicity, 566tretinotoxicity, 579–580volume of distribution, 228t

Diglycerides, in food, 1055t, 1057tDigoxin, 604

cardiotoxicity, 614t, 617laboratory tests on stat basis, 1112toctanol/water partition coefficient, 109tocular toxicity, 566tpoisoning, action level, 1113postmortem blood, 1098retinotoxicity, 579–580therapeutic monitoring, 1105t

1,2-Dihaloethane, biotransformation, 153fDihydrocapsaicin, 968

inhibition of cytochrome P450, 879Dihydrodiol dehydrogenase, 149, 152, 156,

889, 890fDihydroergotamine, vasculotoxicity, 643tDihydrolipoic acid, 819Dihydromandelaldehyde, biotransformation, 159Dihydroprogesterone, reproductive system

toxicity, 698tDihydropyrimidine dehydrogenase,

149–150, 150fDihydrotestosterone, 676

cardiotoxicity, 626t, 627immunosuppression by, 447

2,4-Dihydroxybenzoic acid, thyroid toxicity, 7261,25-Dihydroxyvitamin D, 739, 825, 831Diisocyanate, occupational disease, 1128O,O-Diisopropyl phosphorofluoridate (DFP)

biotransformation, 138f, 139mechanism of toxic action, 779–780poisoning, 778structure, 777f

�-Diketones, neurotoxicity, 547, 549f, 550Dilated cardiomyopathy, 604, 610Diltiazem, 619

biotransformation, 185tcardiotoxicity, 614t, 617clinical uses, 606

2,3-Dimercaptopropanol. See British anti-Lewisite

Dimethoatebiotransformation, 782poisoning, 777

6,7-Dimethoxy-4-(4�-chlorobenzyl)isoquinoline,biotransformation, 177, 177f

4-Dimethylaminoazobenzenebiotransformation, 160carcinogenicity, 244, 244f, 250, 255

4-Dimethylaminophenol, 218impairment of cellular maintenance, 59t

Dimethylaminopropionitrile, neurotoxicity, 548tDimethylaminostilbene

carcinogenicity, 299fin lymph, 1053

Dimethylaniline, biotransformation, 146, 169f

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Dimethyl arsenic (DMA), 819Dimethylarsinic acid, 11357,12-Dimethylbenz[a]anthracene (DMBA), 7

biotransformation, 40, 191, 205fcarcinogenicity, 243, 243f, 248, 274timmunosuppression by, 440ovarian tumor development and, 749vasculotoxicity, 645

Dimethyl-bisdithiocarbamate, 799Dimethylformamide

hepatotoxicity, 476t, 477, 477foccupational disease, 1127treproductive system toxicity, 683t

Dimethyl hexanedione (DMHD), neurotoxicity,550f, 551

Dimethylhydrazinebiotransformation, 169fcarcinogenicity, 260, 260t

Dimethyl mercury, 814distribution, 124

Dimethyl-methylphosphonate,carcinogenicity, 89t

Dimethylnitrosaminecarcinogenicity, 244, 244f, 252fgenetic effects, 334vasculotoxicity, 641t

1,3-Dimethyl-3-phenyl-1-nitrosourea,biotransformation, 140f

Dimethyl selenide, 845Dimethylsulfoxide (DMSO), enhancement of

skin permeability, 118Dimethyl telluride, 855Dimethylvinphos, biotransformation, 213Dinitroaniline

impairment of cellular maintenance, 59tmechanism of action, 791t

Dinitrobenzamide, excretion, 128Dinitrobenzene, reproductive system toxicity,

690, 693Dinitrochlorobenzene, 47, 661fDinitrocresol, 764Dinitrophenol, 48

aplastic anemia and, 394tcardiotoxicity, 609impairment of cellular maintenance, 58, 59tmechanism of action, 791t

Dinitrotolueneoccupational disease, 1127treproductive system toxicity, 693vasculotoxicity, 634, 641t

2,4-Dinitrotolueneimmunosuppression by, 445vasculotoxicity, 645

2,6-Dinitrotoluenebiotransformation, 144–145, 145fvasculotoxicity, 645

Dinocap, 797tDinoflagellate poisoning, 1078Di-n-octyltin dichloride, immunosuppression

by, 443Dioscorides, 3–41,4-Dioxane, carcinogenicity, 279tDioxin, 96, 193, 1092

air pollution, 992fcarcinogenicity, 284chloracne, 665developmental toxicity, 1020

ecotoxicology, 1017t, 1019LD5, 13t

Dioxin receptor, 193Dioxin-responsive element (DRE), 193, 438Dipeptidase, 41tDiphacinone, 800fDiphenhydramine, 15

in photopatch test, 664tpoisoning, 1103t

Diphenylacetic acid, biotransformation, 211Diphenyl ethers

impairment of cellular maintenance, 59tmechanism of action, 791t

Diphenylguanidineallergic contact dermatitis from, 660turticaria from, 667t

Diphenylhydantoinbiotransformation, 184t, 187developmental effects, 353tdistribution, 124

Diphenylmethane-4,4�-diisocyanate (MDI)hypersensitivity reaction to, 455urticaria from, 667t

Diphenylmethylane, reproductive systemtoxicity, 698t

Diphenylmethylphosphine,biotransformation, 170f

Diphtheria toxin, 46Diploda, 953Dippers’ flu, 777Dipropylnitrosamine (DPN), immunosuppression

by, 441Diquat, 793–795

impairment of cellular maintenance, 60tpoisoning, 794structure, 793fultimate toxicant, 37t

Direct testimony, 1102Dirithromycin, cardiotoxicity, 615t, 621Discharge limits, 1146Disease vectors, control, 765Dismutase, 254fDisopyramide

cardiotoxicity, 613, 614tclinical uses, 605

Disposition, 107–108Dispositional antagonism, 17Dispositional tolerance, 17Dissolved organic carbon (DOC), 1016Distal tubule, 492f, 494

toxic injury, 500Distribution, 107, 108f

absorption versus presystemic elimination,36–37

blood-brain barrier, 122–123excretion versus reabsorption, 39–40mechanisms facilitating distribution to

target, 38mechanisms opposing distribution to target,

38–39passage of toxicants across placenta,

123–124, 123tstorage of toxicants in tissues, 120–122to and from target, 37–38, 38ftoxication versus detoxication, 40–44volume. See Volume of distribution

Distribution coefficient, 233

Disulfide, 46Disulfide reduction, 146, 146fDisulfiram, 156, 893, 1067t

biotransformation, 146, 146f, 208inhibition of cytochrome P450, 879neurotoxicity, 553t

Dithiocarbamate (DTC), 799, 817–818allergic contact dermatitis from, 660tneurotoxicity, 545

Dithioisocarbamate, 764Dithiol dihydrolipoic acid, 65f2,6-Dithiopurine, biotransformation, 158Diuretics, 124

nephrotoxicity, 496tDivalent-metal ion transporter, 111tDMA. See Dimethyl arsenicDMBA. See 7,12-Dimethylbenz[a]anthraceneDMC, poisoning, 771tDMDM hydantoin, allergic contact dermatitis

from, 660tDMHD. See Dimethyl hexanedioneDMN. See N-NitrosodimethylamineDMNM, adrenal toxicity, 718–719DMPS, 817DMSA, 817, 821, 833DMSO. See DimethylsulfoxideDNA. See also Genetic toxicology

cross-linking, 261, 262fdamage, 262f, 326–327, 326f

carcinogen identification from, 292–293from carcinogens, 271–273, 272–274tby chemicals, 326f, 327developmental effects, 360–361by endogenous agents, 327by ionizing radiation, 326–327, 326fprimary, 289t, 292–293by radiation, 924–925in renal cell injury, 505–506by ultraviolet light, 326f, 327

double-strand breaks, 261–262, 262f,326–327, 326f

endogenous damage, 265t, 266ethylation, 257fragmentation, 47human, polymorphisms, 99hydroxylation, 257methylation, 77, 257–259, 259treplication, 329–330single-strand breaks, 326–327, 326fsynthesis, 68, 74f, 77as target for carcinogenesis, 255–256template function, 46–47unscheduled DNA synthesis, 293, 334–335,

691–692DNA adduct, 255–257, 259, 266, 271, 327,

329, 334, 1019persistence, 259–261, 260t

DNA damage assay, 332t, 333–334DNA-dependent protein kinase, 328DNA fragmentation factor, 62fDNA-glycosylase, 66DNA methyltransferase, 258–259DNA photolyase, 65DNA polymerase, 327DNA repair, 65–67, 257, 293, 327–328,

329–330base excision repair, 262, 262t, 327

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DNA repair (continued)carcinogenesis and, 259–266direct reversal of DNA damage, 262tdouble-strand-break repair, 262–263, 262t,

264f, 328excision repair, 66extent, 265t, 266failure, 73, 73fhomologous recombination, 262–263, 262t,

264f, 328mechanisms, 261–265, 262–265f, 262tO6-methylguanine-DNA methyltransferase

repair, 328mismatch repair, 262t, 263, 265f, 266,

277, 328nonhomologous end-joining, 262t, 263,

264f, 328nucleotide excision repair, 261–262, 262t,

263f, 264t, 327recombinational repair, 67in reproductive system, 691–692single-strand annealing pathway, 263

DNA repair assay, 332t, 334–335DNase, snake venom, 957t, 959Dobutamine, cardiotoxicity, 614t, 618DOC. See Dissolved organic carbonDodds, E.C., 7Dodecylaminoethyl glycine hydrochloride,

allergic contact dermatitis from, 660tDodine, 797tDofetilide

cardiotoxicity, 614t, 617clinical uses, 606

Dolasetron, biotransformation, 185tDominant lethal mutation, 342Dominant lethal test, 32, 288, 331tDominant mutation, 324Domoate

cellular dysregulation, 54timpairment of cellular maintenance, 60t

Domoic acid, 971, 1067t, 1078–1079neurotoxicity, 556t, 558

Done nomogram, salicylate poisoning,1112, 1112f

Dopa, 720Dopa carboxylase, 720Dopamine, 56, 247, 713, 720

biotransformation, 160, 162, 203t, 205, 207neurotoxicity, 544–545, 545fvasculotoxicity, 639

Dopamine beta-hydroxylase, 720Dopamine reuptake transporter, 557Dosage

by surface area, 20, 20tby weight, 20, 20t

Dose-effect relationships, for metals,813–814, 814f

Dose rate-reduction factor (DREF), 923–924Dose-response curve, shape, 20–22, 21–22fDose-response problem, in evaluation of

carcinogenic potential, 298–301, 299f,299t, 325

Dose-response relationship, 17–24, 106assumptions in deriving, 22–23developmental toxicity, 359–360, 376f, 377for essential nutrients, 20, 21fevaluation

comparison of dose responses, 23, 24fmargins of safety and exposure, 24potency versus efficacy, 24, 25ftherapeutic index, 23–24

history, 5hormesis, 20–22, 21findividual, 18, 18finflections in curve, 22quantal, 18–20, 19–20f, 20t, 26risk characterization, 92–94, 92f

Dosimetry, 520Dosing interval, 14, 15fDOT. See Department of TransportationDoxaminol, biotransformation, 203tDoxepin

cardiotoxicity, 616t, 622poisoning, 1120

Doxorubicin, 45, 47, 72biotransformation, 40, 42f, 148cardiotoxicity, 604, 608, 610, 615t, 619, 620fhematotoxicity, 410impairment of cellular maintenance, 59tleukemia and, 402–403nephrotoxicity, 499neurotoxicity, 536, 542–544, 543treproductive system toxicity, 693tultimate toxicant, 37tvasculotoxicity, 639

Doxylamine, 194biotransformation, 160, 176

DPN. See DipropylnitrosamineDraize test, 27–28, 118, 571–572DRE. See Dioxin-responsive elementDREF. See Dose rate-reduction factorDressing fungicides, 797Drinking water

arsenic, 818–820chlorination, 887chloroform, 887copper, 840EPA standards, 1146–1147, 1177–1180lead, 827solvents, 870, 873

Drinking water intake, 98tDriving performance, 1102Driving under the influence of drugs, 1102Driving under the influence of ethanol, 1102Drosophila assay, for developmental

toxicity, 373tDrosophila sex-linked recessive lethal assay, 331tDrug(s)

FDA regulation, 1144FDA testing requirements, 1149hypersensitivity reaction to, 457–458vasculotoxicity, 639–640, 643–644t

Drug-induced autoantibody, 398Drug-membrane component, 398Drying agents, in food, 1054tDTC. See DithiocarbamateDT-diaphorase, 43, 144–149, 158,

193–194, 1052tinducible, 149

DTPA, 817Dubois, Kenneth, 8Dusts, respiratory, 529Dye industry, 284Dying-back neuropathy, 546

Dynein, 538Dysmorphogenesis, 362–363Dysregulation

cellular. See Cellular dysregulationof extracellular signal production, 52–53

Dysrepair, 71carcinogenesis, 72–78fibrosis, 72tissue necrosis, 71–72toxicity from, 71–78

EEAAR. See Excitatory amino acid receptorEBDC. See Ethylene-bisdithiocarbamateEbselen, biotransformation, 206ECG. See ElectrocardiogramEclampsia, 365Ecogenetics, 99Ecologic risk assessment, 1035–1037,

1035f, 1036tprobabilistic, 1036–1037

Economic form, 25Ecosystem, 1022Ecotoxicology, 13, 1013–1038. See also

Environmental chemical/contaminantaquatic, 1022, 1028–1030biomarkers, 1018–1020chemical interactions and natural

stressors, 1024chemical movement, fate, and exposure,

1014–1018definition, 1013endocrine and developmental disruptors,

1020–1022extrapolation of wildlife data to humans,

1037–1038genotoxicity, 1025Good Laboratory Practices, 1030methods used, 1014modeling, 1030–1034

effects of toxicant, 1032exposure, 1031–1032, 1032findividual-based versus aggregated

models, 1031input, 1030linking models to GIS, 1032, 1033–1034foutput, 1030spatially distributed versus lumped

models, 1031steps, 1030–1031stochastic versus deterministic

models, 1031population and community effects,

1023–1024risk assessment, 1023, 1035–1038,

1035f, 1036toverlapping distributions, 1036–1037, 1036fstochastic simulations, 1037, 1037f

sublethal effects, 1022–1023terrestrial, 1022, 1026–1027toxicity tests, 1022trophic-level transfer of contaminants,

1024–1025wildlife sentinels, 1014, 1018, 1025, 1038

Ecstasy, 1092hepatotoxicity, 476t, 478

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Ectoderm, 358ED10, 92ED50, 24Eddy diffusion, 1015Edema

intramyelinic, 552, 554pulmonary. See Pulmonary edema

Edetic acid, 113–114, 817, 833in food, 1056toctanol/water partition coefficient, 109t

EDS. See Ethane dimethane sulfonateEDSTAC. See Endocrine Disruptor Screening

and Testing Advisory CommitteeEDTA. See Edetic acidEEC. See Estimated environmental

concentrationEffective dose, 23, 24fEffects-related biomarker, 23Efficacy, 24, 25fEffluents, 1028Effluent standards, 1146Egasyn, 140EGF. See Epidermal growth factorEggshell thinning, 1019, 1026EGME. See Ethylene glycol monomethyl etherEhrlich, Paul, 23Ejaculate, 684Ejaculation, 684–685Elapids, 956t

Australian, 957tElastase, in lung, 524–525Elderly, solvent sensitivity, 878Electrically excitable cells, dysregulation,

53–57, 53f, 54–55tElectrocardiogram (ECG), 602Electromagnetic radiation

adverse responses to, 662–663immunosuppression by, 450

Electron capture, 918–919Electron transfer reactions, 46Electron transport chain, 40, 57, 58f, 59t, 60

in cardiac myocytes, 609, 609fElectron volt, 918Electrooculogram (EOG), 572–573Electrophile

detoxication, 43formation, 40, 41thard, 45, 45tsoft, 45, 45t

Electrophysiologic techniques, for visualfunction testing, 572–574

Electrophysiology, of heart, 600–602Elimination, 233

classic toxicokinetics, 226–227, 227tpresystemic, 37, 38f, 114

Elimination rate, 14, 15fELISA. See Enzyme-linked immunosorbent

assayEllagic acid, biotransformation, 203tEllipticine, 186Elongation factor 2, 46Embalming fluid, 1094Embolus, 635Embryo, 358. See also Developmental toxicityEmbryo lethality, 359Emergency toxicology, 1103, 1103tEmergent effect, 1025

Emesis, induction in poisoned patient,1109–1110, 1114–1115

Emetine, 1100Emission, 685Emissions Standards for Mobile Sources, 981Emodin, 967Emphysema, 519, 524–525, 527tEmulsifiers, 1054tEnalapril

developmental effects, 353tvasculotoxicity, 639

Encainidebiotransformation, 185tcardiotoxicity, 613, 614t

Encephalopathychronic, solvent-induced, 871–872, 872tlead, 829

Enclosure study, 1027Endangered Species Act, 1036Endocrine disruptors, 368–370, 674

developmental effectshuman evidence, 369impact on screening and testing programs,

369–370laboratory animal evidence, 368–369

effect on hormone secretion andtransport, 1020

effect on hormone synthesis andmetabolism, 1020

receptor-mediated effects, 1020sensitive life stages, 1020timing of exposure, 1020in wildlife species, 1017t, 1020–1022

Endocrine Disruptor Screening and TestingAdvisory Committee (EDSTAC),370, 1021

Endocrine system. See also specific organstoxic responses, 712–753

Endoderm, 358Endogenous compounds, as ultimate

toxicants, 37tEndometrium, 686Endonuclease, in renal cell injury, 505–506Endopeptidase, 140Endorphins, 678t

immune effects, 431tEndosulfan

poisoning, 771tstructure, 770t

Endothelial cells, vascular, 631–632, 632f, 634,637t, 638, 640

Endothelin, 511, 604, 632Endotheliochorial placenta, 123, 123t, 687Endotoxin, 880, 894, 1080, 1130

developmental effects, 367hepatotoxicity, 479toccupational disease, 1127tvasculotoxicity, 636t, 640

Endrin, poisoning, 771tEnergy, 918Energy requirements, of nervous system,

536–537Enflurane

biotransformation, 151–152, 184t, 188cardiotoxicity, 616t, 622, 629

Engine exhaust, carcinogenicity, 250Enhanced species study, 1027

Enkephalins, 720immune effects, 431t

5-Enolpyruvyl-shikimate-3-phosphatesynthetase (EPSPS), 795

Enoxicin, cardiotoxicity, 621Enteque seco, 973Enteral administration, 111Enterohepatic circulation, 198, 203, 476Enterotoxin, 1080Environmental chemical/contaminant. See also

Ecotoxicologybioavailability, 1016–1018chemical behavior, 1016–1018chemical interactions, 1024diffusivity, 1015movement, fate, and exposure, 1014–1018single-phase chemical behavior, 1015transformations, 1017transport

in air, 1015between phases, 1015–1016in soil, 1015in water, 1015

trophic-level transfer, 1024–1025Environmental factors, neurodegenerative

diseases and, 545–546Environmental justice, 100Environmental monitoring, 1136Environmental Protection Agency (EPA), 9, 12,

85, 86t, 91, 304, 324, 980, 1142air pollution standards, 1147control over toxicology, 1148drinking water standards, 1146–1147,

1177–1180guidelines for immunotoxicity testing,

435–436guidelines for reproductive toxicity testing,

701, 702thazard evaluation of pesticides, 85, 87thazardous waste regulations, 1146industrial chemicals regulation, 1145–1146locating testing guidelines, 1150pesticide regulations, 1145testing of industrial chemicals, 1149–1150toxicology requirements for pesticides,

1149water pollution standards, 1146

Environmental sex determination, 1021Environmental toxicology, 3, 13, 1013–1014Enzyme(s)

in food, 1054thypersensitivity reaction to, 458occupational disease, 1134toxins acting as, 46

Enzyme-linked immunosorbent assay (ELISA),433, 434f

Enzymuria, 501–502EOG. See ElectrooculogramEosin, phototoxicity, 663tEosinophil(s), 399, 421fEosinophilia-myalgia syndrome, 399EPA. See Environmental Protection AgencyEPA Exposure Factors Handbook, 97Ephedra alkaloids, cardiotoxicity, 618Ephedrine, cardiotoxicity, 614t, 618Ephemeroptera-Plecoptera-Trichoptera (EPT)

index, 1029–1030

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Epichlorohydrinallergic contact dermatitis from, 660treproductive system toxicity, 691

Epicutaneous Maximization Test, 661Epidemiologic study

carcinogen identification by, 280–281,281–282t

of developmental toxicity, 372–374evaluation of carcinogenic potential,

297, 299evaluation of reproductive toxicity, 704occupational disease, 1132, 1134–1135

Epidemiologymolecular, 1020in risk assessment, 90–91, 90t

Epidermal growth factor (EGF), 497–498, 677tas promoting agent, 275t

Epidermal growth factor (EGF) receptor, 52,86–87, 96

Epidermis, 117–118, 653–654, 655fEpididymis, 680, 682f, 683, 697Epigenetic carcinogens, 77–78Epileptiform seizures, toxic effect of plants, 971Epinephrine, 604, 606, 720, 723

biotransformation, 160, 205, 207cardiotoxicity, 614t, 618–619cellular dysregulation, 55timmune effects, 431tvasculotoxicity, 636t, 639, 643t

Epipodophyllotoxincarcinogenicity, 286leukemia and, 402

Epirubicin, cardiotoxicity, 615t, 619Episodic observation, 280Episulfonium ion, biotransformation, 41tEpitheliochorial placenta, 123, 123tEPN

inhibition of carboxylesterase, 782neurotoxicity, 551structure, 777f

Epoxide hydratase, 889, 890f, 892Epoxide hydrolase, 43, 136t, 141–144,

141–143f, 174, 194, 656, 667Epoxy resin


Epping jaundice, 478EPSPS. See 5-Enolpyruvyl-shikimate-

3-phosphate synthetaseEPT index. See Ephemeroptera-Plecoptera-

Trichoptera indexEquilin, cardiotoxicity, 625, 626tEquol, 1021Erabutoxin, 960

biotransformation, 43cellular dysregulation, 54t

Eradicative fungicides, 797Erectile dysfunction, 685, 685tErection, 684–685Ergonovine

cellular dysregulation, 55tvasculotoxicity, 643t

Ergot alkaloids, 969in food, 1077timpairment of cellular maintenance, 59t

Ergotaminecellular dysregulation, 55t

vasculotoxicity, 636t, 643tErythrocytes. See Red blood cellsErythrocytosis, 391Erythromycin, 188, 191, 195–196

biotransformation, 179, 185tcardiotoxicity, 615t, 621

Erythron, toxicology, 391–399Erythropoietin, 428t

immunosuppression by, 449Escherichia coli

in food, 1081lac operon, 289, 292f, 335, 338strain O157:H7, 1081verocytotoxin-producing, 405

Esculin, 967Esfenvalerate, poisoning, 785tEsmolol, cardiotoxicity, 614t, 617Essential nutrient, dose-response relationship,

20, 21fEsterase, 136t, 137–144, 657Estimated daily intake, 1058–1059Estimated environmental concentration

(EEC), 1026Estradiol, 676, 688f, 1020–1021

biotransformation, 185tcarcinogenicity, 248, 249fcardiotoxicity, 625, 626tdevelopmental effects, 368–369hepatotoxicity, 477fimmunosuppression by, 446Leydig cell tumor development and,

745, 748tas promoting agent, 267, 268ftransdermal delivery, 656

Estriol, cardiotoxicity, 625, 626tEstrogen(s), 247, 687

assessment, 699–701biotransformation, 207carcinogenicity, 248, 254, 281t, 286, 286tcardiotoxicity, 625, 626tdevelopmental effects, 368–369dose-response curve, 20hepatotoxicity, 476t, 486immunosuppression by, 446–447nephrotoxicity, 496tpituitary toxicity, 714as promoting agent, 267, 275treproductive system toxicity, 683t, 685t,

689t, 698tEstrogen receptor, 49, 50t, 368, 447, 699–701,

750–751, 771, 1021knockout mice, 752

Estrogen sulfotransferase, 204Estrone

biotransformation, 199f, 203tcardiotoxicity, 625, 626t

Ethacrynic acid, biotransformation, 145,213, 216

Ethambutolneutropenia and, 402tocular toxicity, 566t, 586

Ethane dimethane sulfonate (EDS),reproductive system toxicity, 691

Ethanol, 72, 196, 870, 893–894absorption, 109biotransformation, 43, 139, 153–156, 158,

188, 203t, 480, 486, 613, 893

blood alcohol level, 894carcinogenicity, 282, 283t, 294, 894, 894tcardiotoxicity, 608, 613, 614tcellular dysregulation, 54tdevelopmental effects, 353t, 354–355, 359,

361, 365, 367, 372, 374dose-response curve, 21effect on granulocytes, 400, 401telimination, 229, 230tgender differences in response, 893hepatotoxicity, 472, 476, 476t, 478, 479t,

480, 482–484, 486–487, 880, 894immunosuppression by, 450impairment of cellular maintenance, 59tinduction of cytochrome P450, 876, 879laboratory tests on stat basis, 1112tLD5, 13tmegaloblastic anemia and, 393tneurotoxicity, 542, 543tpoisoning, 113t, 1103, 1103tpresystemic elimination, 37reproductive system toxicity, 685t, 691sideroblastic anemia and, 392tuse in pregnancy, 893

Ethidium bromide, neurotoxicity, 553tEthinylestradiol

biotransformation, 182, 185t, 192, 203t, 206carcinogenicity, 249fcardiotoxicity, 625, 626t

Ethioninecarcinogenicity, 244f, 245, 250hepatotoxicity, 476

Ethosuximide, aplastic anemia and, 394tEthoxycoumarin, 1052tEthoxycoumarin-O-deethylase, 6562-Ethoxyethanol, reproductive system

toxicity, 690Ethoxyquin, 142, 216–2177-Ethoxyresorufin, 1052t

biotransformation, 178f, 183, 185t, 186, 1967-Ethoxyresorufin O-deethylase, 1052t7-Ethoxy-4-trifluoromethylcoumarin,

biotransformation, 184t, 186Ethyl acrylate, carcinogenicity, 89, 89tEthylation, of DNA, 257Ethylbenzene, 892

environmental contamination, 873Ethyl bromide, cardiotoxicity, 630tEthyl carbamate. See UrethaneEthyl chloride, cardiotoxicity, 630tEthyldibromide, carcinogenicity, 253fEthylene

absorption, 116excretion, 128

Ethylene-bisdithiocarbamate (EBDC), 799carcinogenicity, 89t

Ethylenediamineallergic contact dermatitis from, 660timmunosuppression by, 444

Ethylene diamine tetraacetic acid. See Editic acidEthylene dibromide, 764, 799, 800

air pollution, 992fbiotransformation, 189tcarcinogenicity, 254

Ethylene dichlorideair pollution, 992fbiotransformation, 189t

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Ethylene glycol, 7, 48, 896–897biotransformation, 156, 896, 896fdevelopmental toxicity, 897metabolites as ultimate toxicants, 37tnephrotoxicity, 496t, 897occupational disease, 1127toctanol/water partition coefficient, 109tpoisoning, 113t, 1103–1104, 1104f, 1117

Ethylene glycol dimethyl ether, 898Ethylene glycol monoethyl ether (EGME)

biotransformation, 690, 690timmunosuppression by, 446reproductive system toxicity, 690, 690t

Ethylene oxide, 764, 799carcinogenicity, 285tdevelopmental effects, 353t, 357genetic effects, 342neurotoxicity, 548toccupational disease, 1127tskin burns, 658t

Ethylene thiourea (ETU), 799cellular dysregulation, 52

Ethyleniminecarcinogenicity, 244fmutagenicity, 257

Ethylenurea melamine formaldehyde resin,allergic contact dermatitis from, 661t

O6-Ethylguanine, 260Ethylmethane sulfonate, developmental

effects, 357Ethylnitrosourea

carcinogenicity, 260, 260tdevelopmental effects, 357genetic effects, 341

Ethylphenyl propriolate, irritant dermatitisfrom, 657

5-Ethyl-2(1H )-pyrimidone,biotransformation, 159

O4-Ethylthymidine, 526O4-Ethylthymine, 261Ethynylestradiol, 1021

cellular dysregulation, 50tdevelopmental effects, 368

9-Ethynylphenanthrene, 186, 1925-Ethynyluracil, biotransformation, 1598-Ethyoxycaffeine, genetic effects, 329Etidocaine, cardiotoxicity, 616t, 623Etodolac, biotransformation, 199f, 202Etoposide, biotransformation, 185t, 186Etretinate, developmental effects, 353tEtridiazole, 797tETU. See Ethylene thioureaEudolex 8020, in photopatch test, 664tEukaryotes, nonmammalian, mutagenicity

assays, 332t, 335–337European Common Market, 305Evans blue, vasculotoxicity, 636tExchange transfusion, treatment of poisoned

patient, 1116Excision repair, 66, 71Excitation-contraction coupling,

601–602, 601fExcitatory amino acid(s)

neurotoxicity, 557–558in plants, 971

Excitatory amino acid receptor (EAAR),557–558, 557f

Excitotoxin, 557–558Excretion, 38f, 39, 107–108, 108f

biliary, 39, 126–128, 126t, 198, 203, 215,475–476, 486, 729–730f

in cerebrospinal fluid, 128–129exhalation, 128, 133fecal, 125–128intestinal, 128in saliva, 129in sweat, 129urinary, 124–125, 125f, 198, 203, 211, 215

Exculetin, 158Exercise-induced food allergy, 1068Exhalation, 128, 133, 235, 518, 875Exotoxin, 1080Experimental pathology, 8Experimental toxicology, 5Expert witness, 1102–1103Exposure, 24

assessment, 96–99, 98f, 98tcumulative, 98–99duration, 14frequency, 14, 15froute, 14, 32site, 14

Exposure chamber, 530Exposure monitoring

biological monitoring, 1136–1138, 1137tenvironmental monitoring, 1136

Extensive metabolizer, 134External dose, 1018Extracellular matrix

fibrosis, 72replacement, 69

Extracellular space, 234Extracellular water, 119–120Extramedullary hematopoiesis, 390Extravascular hemolysis, 399Eye. See also Ocular system; Visual function

anatomy, 568ftoxic responses, 566–587

Eye irritation test, 27–28

FFacilitated diffusion, 111t, 1052tFADD protein, 62fFamciclovir, biotransformation, 159FANFT, biotransformation, 165Farnsworth D-15 test, 574Farnsworth-Munson 100 Hue test, 574Fas ligand, 62f, 63, 610Fas receptor, 75Fast acetylator, 209, 211Fat

as promoting agents, 283as storage depot, 121–122

Fatty acid(s)co-oxygenation, 254distribution, 120ffree, 58, 59–60t� oxidation, 189, 196vasculotoxicity, 636t

Fatty acid hydroperoxide, impairment ofcellular maintenance, 60t

Fatty acyl-CoA oxidase, 195Fatty liver, 472, 476–477, 476t

Favism, 1067t, 1069tFDA. See Food and Drug AdministrationFDCA. See Food, Drug, and Cosmetic ActFD&C Blue No. 1, 1054, 1057, 1057tFD&C Blue No. 2, 1054, 1057, 1057tFD&C Green No. 1, 301fFD&C Green No. 3, 1054, 1057, 1057tFD&C Red No. 3, 1054, 1057t

thyroid toxicity, 725, 731–733, 732–733fFD&C Red No. 4, 1055tFD&C Red No. 40, 1054, 1057FD&C Yellow No. 5, 1055t, 1057, 1057tFD&C Yellow No. 6, 1054, 1057, 1057t,

1066Fecal excretion, 125–128Federal Hazardous Substances Act (FHSA),

1147–1148Federal Insecticide, Fungicide, and Rodenticide

Act (FIFRA), 8, 12, 86–87t, 305, 305t,1027, 1143, 1145, 1149–1150

pesticide regulation, 766Federal Register, 1063, 1150Federal Water Pollution Control Act, 86t, 1146Felbamate, aplastic anemia and, 394tFemale reproductive capacity, testing

estrogens and their receptors, 699–701general considerations, 699, 700toogenesis/folliculogenesis, 699ovulation/fertilization/implantation, 701

Fenarimolacute toxicity, 797treproductive system toxicity, 689t

Fenfluramine, cardiotoxicity, 618Fenitrothion, 767

biotransformation, 781Fenoterol, cardiotoxicity, 614t, 618Fentanyl, transdermal delivery, 656Fenthion

poisoning, 777retinotoxicity, 584

Fenton reaction, 40, 42f, 70, 544, 545fFenvalerate

biotransformation, 787poisoning, 785, 785t

Feprazone, biotransformation, 198Ferbam, 799Fer-de-lances, 955, 956–957tFerredoxin, 173, 1081Ferredoxin reductase, 173Ferritin, 112, 480, 815, 815, 822, 842Ferrochetalase, 392f, 830, 831fFerrohemoglobin, 40Ferrous sulfate, 842

LD5, 13tFerroxidase I, 842Fertility Assessment by Continuous Breeding

protocol, 703Fertilization, 357, 679f, 686, 687

evaluation, 701Fescue toxicosis, 969Fetal alcohol effects, 355Fetal alcohol syndrome, 354–355, 365, 542,

893Fetal gasoline syndrome, 900Fetal period, 358–359FETAX, 373t�-Fetoprotein, 1020–1021

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Fetus, 358. See also Developmental toxicitypassage of toxicants across placenta,

123–124, 123t, 364FEV1, 531FGF. See Fibroblast growth factorfgf gene, 272tFHSA. See Federal Hazardous Substances ActFialuridine

biotransformation, 40hepatotoxicity, 471, 476, 476t, 486impairment of cellular maintenance, 59t

Fiber, deposition in respiratory tract, 521Fiber carcinogenesis, 245–246, 526Fiberglass, carcinogenicity, 284, 285tFibrin clot formation, 405–406Fibrin glue, coagulation factor inhibitor

development and, 406tFibrinolysis, 635

inhibitors, 409Fibrinolytic agents, toxicity, 408–409Fibroblast(s), 518

cardiac, 599–600Fibroblast growth factor (FGF), adrenal

toxicity, 723, 723fFibrosis, 72

pulmonary. See Pulmonary fibrosisField fungi, 1076Field study

aquatic ecotoxicology, 1029–1030terrestrial ecotoxicology, 1026–1027

FIFRA. See Federal Insecticide, Fungicide, andRodenticide Act

Film carcinogenesis, 245–246Filtration (passive transport), 110Finasteride

developmental effects, 369Leydig cell tumor development and, 748treproductive system toxicity, 682, 683t

Fipronil, 789, 789fFire ants, 953–954Firemaster BP-6, 439Firemaster FF-1, 439Firming agents, 1054tFirst-pass elimination (first-pass effect), 37,

114, 119, 136, 230, 874–875, 1053FISH. See Fluorescence in situ hybridizationFish. See also Aquatic ecotoxicology

models in immunotoxicology, 436–437toxins, 1078–1080

Fish liver poisoning, 1079Fish-odor syndrome, 171, 1067t, 1069tFish roe poisoning, 1079Fish tapeworm, 393tFK506

biotransformation, 185tcardiotoxicity, 608, 624immunosuppression by, 448nephrotoxicity, 496t, 511

FK506–binding protein, 608, 624Flame retardant, 439, 665Flash-evoked electroretinogram, 572Flavin monooxygenase, 41t, 43, 136t, 137, 139,

146, 166–172, 169–170f, 178catalytic cycle, 168, 171ftissue levels, 172t

Flavor agents, 1054tFlavor enhancers, 1054t

Flecainidebiotransformation, 185tcardiotoxicity, 613, 614tclinical uses, 605

Flectol H, 1065Flour-treating agents, 1054tFlow cytometry

in immunotoxicology, 431–432, 432ftesting of male reproductive capacity, 697

Flucinolone, cardiotoxicity, 627–628Fluconazole, developmental effects, 353tFlucynthrate, poisoning, 785tFlucytosine, cardiotoxicity, 615t, 621Fludrocortisone, cardiotoxicity, 627–628Flunarizine, biotransformation, 185tFlunisolide, cardiotoxicity, 627–628Fluocinonide, cardiotoxicity, 627–628Fluoranthene, phototoxicity, 663tFluorescence in situ hybridization (FISH), 324,

330, 338, 343–345Fluoride

absorption, 114distribution, 122nephrotoxicity, 499poisoning, 1116t

Fluoroacetamide, 800f, 801Fluoroacetate, 801

biotransformation, 40impairment of cellular maintenance, 57, 59tmetabolites as ultimate toxicants, 37tpoisoning, 801structure, 800f

2�-Fluoroarabino-dideoxypurine,biotransformation, 158

Fluorocarbons, cardiotoxicity, 629, 630tFluorocitrate, 801Fluorodecanoic acid, 1955-Fluorodeoxyuridine, vasculotoxicity, 639, 643tFluorometholone, cardiotoxicity, 627–6284-Fluoro-10-methyl-12-benzanthracene,

vasculotoxicity, 641tFluoroquinolones, cardiotoxicity, 615t, 6215-Fluorouracil

absorption, 113allergic contact dermatitis from, 660tbiotransformation, 150, 150fcardiotoxicity, 615t, 620developmental effects, 359, 359f, 376f, 377reproductive system toxicity, 691tvasculotoxicity, 639

Fluoxetine, 188biotransformation, 185tcardiotoxicity, 616t, 622poisoning, 1103t

Fluoxymesterone, cardiotoxicity, 626t, 627Fluphenazine

biotransformation, 169f, 185tcardiotoxicity, 622

Flurazepam, neutropenia and, 402tFlushing syndrome, 155, 480, 893Flutamide

biotransformation, 185tdevelopmental effects, 369immunosuppression by, 447Leydig cell tumor development and,

746, 748tmethemoglobinemia and, 395t

reproductive system toxicity, 682, 683t,692, 698t

Fluvalinate, poisoning, 785tFluvoxamine, cardiotoxicity, 622Flux, 233Fly agaric, 971FOB. See Functional observational batteryFocal adhesion kinase, 62f, 63Folate deficiency, 393, 393f, 393t, 585Foliar fungicides, 796Follicle, ovarian, 685Follicle-stimulating hormone (FSH), 676,

687–688, 693, 701, 712–714, 713f,742, 742–743f, 746

Folliculogenesis, 699Folpet, 796f, 798–799Fomepazole, 1117Food

adulterated, 1054, 1143aflatoxins in, 1054tanaphylactoid reaction, 1070–1071, 1070tanimal drugs in, 1072–1073, 1144arsenic in, 1073–1074bacterial toxins in, 1080–1082bovine spongiform encephalopathy, 1082cadmium in, 1074carcinogens in, 1064–1066, 1064t

biological versus statistical significance,1065–1066

chlorinated organics in, 1074–1075, 1074tdigestion and absorption, 1052–1053FDA regulations, 1143–1144from genetically altered crops,

1062–1063, 1063thealth-enhancing properties, 1051lead in, 1073metals in, 1073–1074methods to evaluate safety, 1058–1062miscellaneous contaminants in, 1083–1084molds and mycotoxins in, 1075–1078, 1077tnature and complexity, 1051–1052,

1051–1052tnitrate in, 1075, 1076t, 1081nitrite in, 1075, 1076tnitrosamides in, 1075, 1075tnitrosamines in, 1075, 1075tN-nitroso substance in, 1075, 1075tnovel, 1063organic, 1082pesticides in, 1144presumption of safety, 1050safety, 1066–1071safety standards, 1053–1066seafood toxins in, 1078–1080substances produced by cooking,

1082–1083, 1083tunavoidable contaminants, 1054, 1073–1078urticaria from, 667t

Food additives, 1050–1052, 1054–1058,1055–1057t. See also Color additives

assignment of concern level and requiredtesting, 1059–1061, 1060t

carcinogenicity, 1060–1061estimated daily intake, 1058–1059FDA regulations, 1143–1144FDA testing requirements, 1149immunosuppression by, 450

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postmarketing surveillance, 1063“reasonable certainty of no harm,” 1050regulation, 1054“safe for intended conditions of use,” 1050safety evaluation

direct additives, 1058–1061indirect additives, 1061, 1061t, 1144

Food allergy, 1062–1063chemistry of food allergens, 1068–1069, 1068tdemographics, 1069description, 1068, 1068texercise-induced, 1068false, 1071

Food anaphylaxis, 1067tFood and Drug Administration (FDA), 12, 83,

86t, 304, 1142control over toxicology, 1148cosmetics regulations, 1144food safety regulations, 1143–1144guidelines for testing reproductive toxicity,

701, 702thuman drug regulations, 1144medical device regulations, 1144pesticide regulations, 766testing requirements for food additives, 1149toxicologic testing requirements for human

drugs, 1149Food-borne disease, 1080Food categories, 1059, 1059tFood chain, 1024–1025Food colors. See Color additivesFood contaminants, 1050

methods to evaluate safety, 1058–1062Food, Drug, and Cosmetic Act (FDCA), 8–9,

12, 304, 305t, 1050, 1053, 1143, 1148GRAS (“generally recognized as safe”)

substances, 1053–1054tpesticide amendments, 1071pesticide regulation, 766use of tolerance, 1054, 1054t

“Food-grade purity,” 1050Food hypersensitivity, 1067tFood idiosyncrasy, 1067t, 1069–1070, 1069tFood infection, 1080Food intake, estimation, 1059, 1060tFood intolerance, 1067, 1067tFood labeling, 1071Food poisoning, 1067t, 1069, 1080–1082Food Quality Protection Act (FQPA), 86t, 93, 98,

100, 370–372, 462, 1014, 1021, 1072pesticide regulation, 766

Food reaction, 1066–1071Food recall, 1054Food restriction, 1024

Leydig cell tumor development and, 745,746–747f

Food sensitivity, 1066, 1067tFood toxicology, 1049–1084

introduction, 1050–1053safety of food, 1066–1071safety standards for foods, food ingredients,

and contaminants, 1053–1066substances for which tolerances may not be

set, 1078–1084tolerance setting for substances in food,

1071–1078uniqueness, 1051

Foraging behavior, 1023, 1025Foreign body, in gastrointestinal tract, 1114Foreign-body tumorigenesis, 245–246Forensic toxicology, 5, 12, 1089, 1089–1107

analytic toxicology and, 1092–1093courtroom testimony, 1102–1103criminal poisoning, 1099–1100, 1099tforensic urine drug testing, 1100–1102,

1100–1101thuman performance testing, 1102investigation of poison death, 1093–1099

Forensic urine drug testing (FUDT),1100–1102, 1100–1101t

confidentiality, 1101cutoff values, 1101false positives, 1101–1102reporting results, 1101urine adulterants, 1101, 1101t

Formaldehyde, 26, 218, 799, 895, 895f, 902absorption, 115air pollution, 992f, 999, 1005allergic contact dermatitis from, 660–661tbiotransformation, 153carcinogenicity, 284, 285t, 1005CPSC regulations, 1148in food, 1065hypersensitivity reaction to, 458–459immunosuppression by, 444respiratory tract damage caused by, 523, 525vasculotoxicity, 642

Formaldehyde dehydrogenase, 153–154, 895fFormestane, reproductive system toxicity, 682Formic acid, 895, 895f, 1119

in ant venom, 953impairment of cellular maintenance, 59tretinotoxicity, 582

Formicidae, 953–954Formulation aids, 1054tFormyl-THF dehydrogenase, 895, 895fForskolin, adrenal toxicity, 723, 723fForward mutation assay, 331, 331t, 335Fosetyl-A1, carcinogenicity, 89tfos gene, 272t, 276, 888Fos protein, 49, 274Fostriecin, hematotoxicity, 410Fowler’s solution, 668Foxglove, cardiotoxicity, 629FPN color test, 1096FQPA. See Food Quality Protection ActFrameshift mutation, 328–329Free radicals

in carcinogenesis, 254–255, 254–255fdetoxication, 43, 43fformation, 40–42, 42f

Freon, solvent abuse, 873Freund’s complete adjuvant test, 28Frog embryo teratogenicity assay, 88Fructose

in seminal vesicle secretions, 684vasculotoxicity, 643t

Fructose intolerance, 1069tFSH. See Follicle-stimulating hormoneFUDT. See Forensic urine drug testingFuel(s), 900–903

automotive gasoline, 900–901jet fuel, 902–903kerosene, 903

Fuel additives, 900–903methemoglobinemia and, 395tmethyl tertiary-butyl ether, 901–902

Fumigants, 799–800, 1056tdibromochloropropane, 800ethylene dibromide, 800phosphine, 799–800

Fumonisins, 50, 970, 1077in food, 1078nephrotoxicity, 496, 503, 509

Functional antagonism, 17Functional observational battery (FOB), 542, 573Functional residual volume, 530, 531fFundoscopic examination, 572Fungicides, 796–799

curative, 797dithiocarbamates, 799dressing, 797eradicative, 797foliar, 796hexachlorobenzene, 798pentachlorophenol, 798phthalimides, 798–799protective, 797soil, 797

Furafylline, 186, 192Furan, in milk, 129Furazolidone, oxidative hemolysis and, 397tFurfural, carcinogenicity, 279tFurosemide, reproductive system toxicity, 689tFutile cycle, 167

GGABA, 46, 773Gabapentin, therapeutic monitoring, 1105tGABA receptor, 54t, 56, 542, 773, 788–789, 892Galactosamine, 198Galen, 1109Gallium, 848, 851

toxicity, 851toxicokinetics, 851

Gallium arsenide, 818, 851immune effects, 435, 443

GALT. See Gut-associated lymphoid tissueGambiertoxin, 1079Gametogenesis, 357Gamma-aminobutyric acid. See GABAGamma globulin, 120Gamma rays, 918, 922

interaction with matter, 920–921, 921tleukemia and, 403lung damage caused by, 519

Gamma-ray emission, 919Ganglion cells, 720GAP. See GTPase-activating proteinGap junction, 77, 578, 689, 727Garlic breath, 855Gases

absorption in lungs, 115–116analytic toxicology, 1090toxic, 520

Gasolineair pollution, 992, 992fautomotive, 900–901carcinogenicity, 901hepatotoxicity, 901

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Gasoline (continued)nephrotoxicity, 900–901reproductive system toxicity, 900short-term exposure limit, 900threshold limit value, 900

Gasoline additives. See Fuel additivesGastric juice, 111Gastric lavage, 1114–1115, 1119–1120Gastrin, 736Gastrointestinal contents, pH, 115tGastrointestinal tract

absorption by, 111–115, 112t, 115tbiotransformations in, 136–137, 1052, 1052body packer, 1114digestion and absorption, 1052–1053solvent absorption, 874toxic effects of plants, 967–968

Gastrulation, 358Gatifloxacin, cardiotoxicity, 621GATT. See General Agreement on Trade

and TariffsGeiling, Eugene Maximillian, 7Gelleborein, 1084Gemfibrozil

Leydig cell tumor development and, 746, 748treproductive system toxicity, 683t

Gemifloxacin, cardiotoxicity, 621Gene expression

analysis, 345dysregulation, 49–53

Gene expression array. See Microarray analysisGene mutation. See MutationGene mutation assay, 331, 331t

in vivo, 289tGeneral Agreement on Trade and Tariffs

(GATT), 91General anesthetics, cardiotoxicity, 616t, 622“Generally recognized as safe” substances. See

GRAS substancesGenetic alterations

detection, 331–342, 331–333tassay design, 331–334, 333–334fcytogenetic assays, 332–333t, 338–341development of testing strategies, 342DNA damage and repair assays, 332t,

334–335germ cell mutagenesis, 333t, 341–342in mammals, 332t, 337–338in nonmammalian eukaryotes, 332t,

335–337in prokaryotes, 332t, 335, 336ttransgenic assays, 337–338

in germ cells, 324health impact, 323–324induction, 326–331in somatic cells, 323–324

Genetic disease, 324Genetic polymorphism, 26Genetic risk assessment, 325, 325fGenetic toxicity tests, on food additives,

1060–1061Genetic toxicology, 99, 321–346

cancer risk assessment, 324–325definition, 321detection of genetic alterations, 331–342,

331–333tgenetic risk assessment, 325, 325fhealth impact of genetic alterations, 323–324

history, 321–323human population monitoring, 343–344induction of genetic alterations, 326–331new approaches for, 344–345

Gene-Tox database, 99Genistein, 1020

developmental effects, 368Genomics, 462Genotoxicity

ecogenotoxicology, 1025mutagenicity versus, 321

Genotypic sex, 675Gentamicin

cardiotoxicity, 615t, 621coagulation factor inhibitor development

and, 406tlaboratory tests on stat basis, 1112tnephrotoxicity, 498–499, 503vasculotoxicity, 643t

Geographic information systems (GIS),1031–1032, 1032–1033f

mapping exposure and effects, 1032Geometric mean, 520–521Geometric standard deviation, 520–521Germander, hepatotoxicity, 481Germane, 854Germanium, 854Germanium dioxide, 854Germ cell(s), 674

apoptosis, 677formation of chromosomal alterations,

330–331formation of gene mutations, 329–330, 329fgenetic alterations, health impact, 324

Germ cell micronucleus assay, 342Germ cell mutagenesis, 333t, 341–342

chromosomal alterations, 341–342dominant lethal mutations, 342gene mutations, 341

Germinal mutation, 32Gestodene, 188

biotransformation, 192GFR. See Glomerular filtration rateGH. See Growth hormoneGila monster, 954–955Gilbert’s disease, 201Ginger-jake walk, 7, 551, 777gip-2 gene, 272tGIS. See Geographic information systemsGlafenin, nephrotoxicity, 499Glibenclamide, cardiotoxicity, 607Gliotoxin


�2u-Globulin, 38, 64, 88, 89t, 125in proximal tubule, 504

�2u-Globulin nephropathy, 507–508Glomerular filtration, 124Glomerular filtration rate (GFR), 493–495,

495–496f, 496–498, 502, 502f, 506Glomerulonephritis, 500Glomerulosclerosis, 498Glomerulus, 492, 492–493f

toxic injury, 499–500GLP. See Good Laboratory PracticesGlucagon, 736

as promoting agent, 275tGlucitol, in food, 1055t

Glucocorticoid(s), 49, 52, 716–717cardiotoxicity, 626t, 627–628effect on granulocytes, 400immunosuppression by, 447

Glucocorticoid receptor, 50tGlucocorticoid-responsive element (GRE),

194, 217Gluconic acid, octanol/water partition

coefficient, 109tGlucose, octanol/water partition coefficient, 109tGlucose-6-phosphatase, 608Glucose-6-phosphate dehydrogenase, 65, 398,

398f, 698Glucose-regulated proteins, 498

grp78, 498Glucose tolerance factor, 839–840�-Glucosidase, 42Glucosuria, 5013-O-Glucosyl-11-deoxojervine, 973Glucuronidation, 126, 135, 136t, 197–203,

197–199f, 202f, 729, 782Glucuronyl transferase, 253fGlufosinate, 795–796

mechanism of action, 791tpoisoning, 796structure, 795f

Glutamate, 586impairment of cellular maintenance, 60tneurotoxicity, 557

Glutamate receptor, 54t, 56, 542, 558Glutamine synthetase, 509, 795�-Glutamylcysteine synthetase, 213�-Glutamyltransferase, 41t, 501�-Glutamyltranspeptidase, 215, 217f, 218, 494,

506, 508–510Glutaraldehyde

allergic contact dermatitis from, 660turine adulterant, 1101t

Glutaredoxin, 65, 65–66f3,3�,4,4�-Glutathio-5,5�-hexachlorobiphenyl,

193–194Glutathione, 22, 43, 44f, 65–66f, 398, 481,

494, 607, 607foctanol/water partition coefficient, 109tsynthesis, 213

Glutathione conjugation, 135, 136t, 197f,213–218, 214–217f, 219f, 254, 571

addition reactions, 213displacement reactions, 213of electrophilic heteroatoms, 216fof xenobiotics with electrophilic carbon, 214f

Glutathione disulfide, 44, 44fGlutathione S-ethylbromide, carcinogenicity, 254Glutathione peroxidase, 43, 43f, 65, 66f, 166,

214, 217, 397, 397f, 523, 544–545,545f, 638, 845–846, 846f

cardiac, 607, 607focular, 566t, 571

Glutathione reductase, 43, 44f, 65, 65–66f,638

ocular, 566t, 571Glutathione thiyl radical, 44, 44fGlutathione S-transferase, 26, 41t, 43, 48, 71,

89, 137, 139, 146, 149–152, 174,193–194, 213–218, 217f, 253f, 254,523, 642, 644f, 656, 667, 878, 883, 885,886f, 887, 892, 1052t

ocular, 566t, 571

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Glutethimideneurotoxicity, 548treproductive system toxicity, 698t

Glyceraldehyde-3-phosphate dehydrogenase,46, 61, 698

Glycerol, vasculotoxicity, 641t�-Glycerophosphate dehydrogenase, 698Glycine, octanol/water partition coefficient, 109tGlycine conjugation, 212Glycine N-methyltransferase, 194Glycine receptor, 45, 54t, 56–57Glycol(s), 896–898

diethylene glycol, 897ethylene glycol, 896–897immunosuppression by, 446poisoning, 1103propylene glycol, 897–898

Glycol ethers, 86biotransformation, 898, 898fcarcinogenicity, 900developmental toxicity, 899hematotoxicity, 899–900immunotoxicity, 446, 900occupational disease, 1133reproductive system toxicity, 899

Glycolic acid, 896Glycolic acid oxidase, 896Glycylsarcosine, absorption, 113Glycyrrhizic acid, 1071, 1072tGlycyrrhizin, vasculotoxicity, 635Glyoxylic acid, 896Glyoxylic acid oxidase, 896Glyphosate, 767, 795

mechanism of action, 791tpoisoning, 795structure, 795f

GnRH. See Gonadotropin-releasing hormoneGoiter, 196, 734, 839, 852Goitrin, 726, 1072tGoitrogen, 247, 725, 1051, 1067tGold, 848, 851

aplastic anemia and, 394tbiliary excretion, 475effect on granulocytes, 401timmune reactions to, 815immunosuppression by, 444nephrotoxicity, 496t, 500neurotoxicity, 548tneutropenia and, 402ttoxicity, 851toxicokinetics, 851

Gonadal dysgenesis, 675Gonadal function

central modulation, 676ovarian, 685–686, 685fpostovarian processes, 686–687posttesticular processes, 682–685testicular, 676–682

Gonadal sex, 675Gonadectomy, parathyroid adenoma and, 740Gonadotrophs, 712, 713fGonadotropin(s), carcinogenicity, 247, 248tGonadotropin-releasing hormone (GnRH), 76,

688f, 742, 742f, 751Good Laboratory Practices (GLP), 27

applied to ecotoxicology, 1030Goodpasture’s disease, 459Gout, lead and, 832

G protein(s), 46, 50, 73, 273–275, 558,632, 634f

G-protein receptor kinase, 274gpt delta mouse, 338Grain dust, occupational disease, 1127tGramicidin, impairment of cellular

maintenance, 59tGranulocyte(s), 399

evaluation, 399–400toxic effects, 400–401

effects on function, 400effects on proliferation, 400idiosyncratic toxic neutropenia, 400–401

Granulocyte-colony stimulating factor,400, 423

Granulocyte-macrophage-colony stimulatingfactor, 423, 659

Granulocyte-monocyte colony-formingcells, 400

Granulocyte-monocyte-colony stimulatingfactor, 427t, 449

Granulocytopoiesis, 400, 401fGranulomatous disease, 666Granulosa cells, 685, 701Granulosa cell tumor, 747Grapefruit juice, 188GRAS (“generally recognized as safe”)

concept, 1144dietary supplements, 1063–1064importance, 1062–1064for novel foods, 1063transgenic plant policy, 1062–1063, 1063t

Grass spiders, 949Grass staggers, 843GRAS (“generally recognized as safe”)

substances, 1053–1054tsafety requirements, 1061–1062, 1062t

Graves’ disease, 734Gray, 921Grayanotoxins, 969, 1083

cellular dysregulation, 55tGray baby syndrome, 202Grb2-Sos complex, 273GRE. See Glucocorticoid-responsive elementGrepafloxacin, cardiotoxicity, 606, 615t, 621GRF. See Glucocorticoid-responsive elementGriseofulvin, 194


excretion, 125, 126tgenetic effects, 330

Growth factor(s), 51f, 69fGrowth factor receptors, 49Growth hormone (GH), 712–713, 713f

immune effects, 431tGs�, 619GTPase-activating protein (GAP), 52Guamanian neurodegenerative complex, 558Guanethidine

biotransformation, 167, 169reproductive system toxicity, 685tvasculotoxicity, 636t

Guanine-nucleotide exchange factors (GEF),273–274

Guanosine triphosphatase, 273Guanoxan, biotransformation, 185tGuinea pig maximization test, 28, 455,

660–661

Gunn rat, 200–201Gut-associated lymphoid tissue (GALT),

420t, 421

HHaff disease, 1080Hair analysis, 1094

arsenic, 1098metals, 813–814zinc, 848

Halcinonide, cardiotoxicity, 627–628Half-life, 228–229, 229fHaloalkanes

cardiotoxicity, 629, 630timmunosuppression by, 445–446nephrotoxicity, 496t

Haloalkenesimmunosuppression by, 445–446nephrotoxicity, 500

Halogenated hydrocarbonschloracne, 665immunosuppression by, 438–440nephrotoxicity, 508–509

Halogenated salicylanilides, photoallergy, 664Halogenation, reductive, 150–151, 151–152fHalon, cardiotoxicity, 629Haloperidol

biotransformation, 145, 146f, 160–161, 185tcardiotoxicity, 622

Halophenol, 791tHalothane, 47, 71

autoimmune reaction to, 460, 460tbiotransformation, 151–152, 152f, 180,

189t, 190cardiotoxicity, 616t, 622, 629cellular dysregulation, 54texcretion, 128hepatotoxicity, 151, 180, 190, 460, 476t, 483

HAP. See Hazardous air pollutantsHapten, 15, 398, 424, 500, 520, 659Haptoglobin, 71Hard metal disease, 527tHard metal pneumoconiosis, 839Harvard Six Cities Study, 990, 991fHarvester ants, 953–954Harvey, William, 352Hawk, Philip B., 7Hay fever, 966Hazard, 84Hazard identification, 85–91, 985

animal tests, 88–90, 89tintegrating qualitative aspects of risk

assessment, 91in vitro and short-term tests, 87–88structure/activity relationships, 86–87use of epidemiologic data, 90–91, 90t

Hazardous air pollutants (HAP), 981, 991,999, 1006

Hazardous Substances Data Bank, 99Hazardous waste, EPA regulation, 1146HCB. See HexachlorobenzenehCG. See Human chorionic gonadotropinHCH. See HexachlorocyclohexaneHCTZ, neutropenia and, 402tHDL. See High-density lipoproteinsHealth effects test guidelines, 435–436Health Hazard Evaluation (HHE) program, 1132

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Heart. See also Cardiac entries; Cardiotoxicityanatomy, 598–599, 599fcellular phenotypes within, 599–600, 599fdisturbances in function

abnormal rhythms, 602–603cardiac hypertrophy, 603–604cardiomyopathy, 604heart failure, 603–604ischemic heart disease, 603

electrophysiology, 600–602action potential, 600–602, 600felectrical conduction, 600–601excitation-contraction coupling,

601–602, 601ffunctions, 598, 602ftoxic effects of plants, 968–969toxic responses, 597–631

Heart block, 603Heart failure, 603–604, 610, 628Heart rate, 602Heat-shock proteins. See Stress proteinsHedgehog signaling pathway, 378, 378fHeinz body, 397Helium, in food, 1062tHelodermin, 955Helothermine, 955Hemangiosarcoma, cardiac, 647Hematite miner’s lung, 527tHematologic monitoring, 409–411, 410tHematopoiesis, 390–391, 390f

extramedullary, 390Hematopoietic inductive microenvironment, 391Hematoporphyrin, phototoxicity, 663tHematotoxicity, 389

of glycol ethers, 899–900primary, 390risk assessment, 409–411

animal models and hematologicmonitoring, 409–410, 410t

bone marrow assay, 410clinical trials, 410–411, 411tpreclinical, 409–410, 410t

secondary, 390Hematotoxicology, 389Heme, synthesis, 392, 392f, 830Heme oxygenase, 71, 813, 830, 856Hemicholinium-3, LD5, 13tHemlock, 3–4, 973, 1083Hemochorial placenta, 123, 123t, 687Hemochromatosis, 480, 842–843Hemodialysis, 393t

with chelation, 818treatment of poisoned patient, 1115–1116,

1116t, 1119Hemoendothelial placenta, 123, 123t, 687Hemofiltration, treatment of poisoned

patient, 1116Hemoglobin, 392, 815, 842

alterations in respiratory function, 394–396,395f, 395t

heterotopic effects, 395–396homotropic effects, 394–395

oxidation, 397–398oxygen dissociation curve, 394, 395fsynthesis, 392

Hemolysisextravascular, 399

intravascular, 399nonoxidative chemical-induced, 398oxidative, 397–398, 397f, 397t

Hemolytic anemia, 396–399immune, 398–399nonimmune, 396–398

Hemolytic uremic syndrome, 405Hemoperfusion, treatment of poisoned

patient, 1116Hemosiderin, 665, 815, 842Hemosiderosis, 817Hemostasis, 632

toxicology, 403–409toxicology of agents used to modulate,

407–409Henderson-Hasselbalch equation, 110–112Heparin, 17

toxicity, 408Heparin-induced thrombocytopenia (HIT),

404–405, 404t, 408Hepatitis, 483, 880

alcoholic, 483halothane, 151, 180, 190, 460, 483

Hepatitis B infection, 478, 486Hepatocyte growth factor (HGF), 68–69, 69f,

497–498Hepatolenticular degeneration, 840Hepatotoxicity, 471–487

of 1,1,2-trichloroethylene, 882–883Hepoxilin epoxide hydrolase, 141Hepsulfan, hematotoxicity, 410Heptachlor

biotransformation, 774poisoning, 771t, 772structure, 770t

Heptafluoro-1-iodopropane, cardiotoxicity,629, 630t

Herbicides, 790–796bipyridyl derivatives, 793–795, 793fchloroacetanilides, 794–795, 794fchlorophenoxy compounds, 791–793, 791fcontact, 790mechanism of action, 791tphosphonomethyl amino acids,

795–796, 795fpostemergent, 790preemergent, 790preplanting, 790selective, 790translocated, 790

Hermaphrodite, 675Heroin

biotransformation, 135, 139cellular dysregulation, 54teffect on granulocytes, 400immunosuppression by, 449–450

Herpes simplex infection, 353tHETE, ocular toxicity, 570Heterocyclic amines

carcinogenicity, 282, 1082–1083, 1083tin food, 1082–1083, 1083tmutagenicity, 1083, 1083t

Heteroptera, 954Hevein, 966Hexachlorobenzene (HCB), 7, 770t, 798

acute toxicity, 797tbiotransformation, 877

excretion, 128in food, 1074timmunosuppression by, 441phototoxicity, 663poisoning, 798vasculotoxicity, 639

Hexachlorobutadienebiotransformation, 218, 219freabsorption, 39

Hexachlorocyclohexane (HCH), 7, 769,770t, 774

Hexachlorodibenzo-p-dioxin, chloracne, 665tHexachloroethane, carcinogenicity, 89tHexachlorophene

allergic contact dermatitis from, 660tneurotoxicity, 553t, 554ocular toxicity, 566tpercutaneous absorption, 655in photopatch test, 664t

1,2-Hexafluoroethane, cardiotoxicity, 630tHexahydrophthalic anhydride, urticaria

from, 667tHexane

metabolites as ultimate toxicants, 37tneurotoxicity, 548t

n-Hexane, 870, 1135biotransformation, 175, 689–690, 690tneurotoxicity, 547, 871occupational disease, 1127tocular toxicity, 566treproductive system toxicity, 689–690, 690tretinotoxicity, 583–584solubility, 873

2,5-Hexanedione, 47, 62, 870, 1135biotransformation, 41timpairment of cellular maintenance, 64neurotoxicity, 547, 549–550f

2-Hexanone, 870Hexobarbital, 1052t

biotransformation, 137, 187, 199felimination, 133

Hexose monophosphate shunt, 398, 398fHGF. See Hepatocyte growth factorHGPRT. See Hypoxanthine-guanine

phosphoribosyltransferaseHHE program. See Health Hazard Evaluation

programHI-6, treatment of organochlorine poisoning, 784High-density lipoproteins (HDL), 717High linear-energy-transfer particle (LET),

920, 922High mountain disease, 972High-production-volume chemical, 85Hippocrates, 3Histamine, 632, 666, 720

biotransformation, 162, 206f, 207distribution, 120fpoisoning, 1067t, 1070, 1070tvasculotoxicity, 635, 643t

Histamine N-methyltransferase, 207HIT. See Heparin-induced thrombocytopeniaHit model, 95Hives. See UrticariaHMDI. See Dicyclohexylmethane-4,4�-

diisocyanatehMLH1 gene, 272tHomeobox gene, 352

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Homicide, 1092Homing behavior, 1023Homocysteine, vasculotoxicity, 634, 636t, 637,

640, 643tHomologous recombination, 67, 262–263,

262t, 264f, 328Homolytic fission, 40Homosalate, in photopatch test, 664tHomovanillyl aldehyde, biotransformation, 159Honey bees, 954Honey poisoning, 969, 1083–1084Hormesis, 20–22, 21f, 276Hormonal carcinogenesis, 246–250, 247f,

248t, 249fHormones. See also specific hormones

hepatic metabolism, 473fimmune effects, 430immunosuppression by, 446–447regulation and feedback control, 1020–1021

Hornets, 954Host resistance assay, 435, 435tHouse dust mites, 11305-HT2 receptor, 55tHuman challenge study, 1132, 1134–1135Human chorionic gonadotropin (hCG), immune

effects, 431tHuman embryonic palatal mesenchyme test, 373tHuman performance testing, 1102Human population monitoring

confounders, 343genetic toxicity, 343–344study group for, 343

Human repeat insult patch test, 456Humectants, 1056tHumoral immunity, 424, 428–430, 429f,

433–435Hyacinth itch, 966Hyaluronidase, 698, 955

snake venom, 957t, 958Hydantoin, developmental effects, 374Hydra assay, for developmental toxicity, 373tHydralazine, 48, 160

autoimmune reaction to, 460, 460tbiotransformation, 209–210lupus anticoagulant and, 407tneurotoxicity, 548treproductive system toxicity, 683t

Hydrazides, cellular dysregulation, 56Hydrazine

biotransformation, 167reproductive system toxicity, 698tvasculotoxicity, 634

Hydrazinobenzoic acid, vasculotoxicity,640, 641t

Hydrochloric acidocular toxicity, 575respiratory tract damage caused by, 523

Hydrocodone, biotransformation, 185tHydrocortisone, 716–717

absorption, 1124cardiotoxicity, 626t, 627–628

Hydrocyanic acid, 1007Hydrofluoric acid, ocular toxicity, 575Hydrogen abstraction, 46, 47Hydrogenated starch hydrolysate, 1056tHydrogen chloride

occupational disease, 1127t

skin burns, 658tHydrogen cyanide, 799, 1072t

occupational disease, 1127tHydrogen fluoride

lung damage caused by, 527toccupational disease, 1127tskin burns, 658tvasculotoxicity, 641t

Hydrogen peroxide, 40–42, 42f, 148, 148f,174, 254, 254f, 397, 503, 520, 525,544, 545f, 607f, 893

in food, 1056timpairment of cellular maintenance, 59tskin burns, 658tultimate toxicant, 37t

Hydrogen sulfide, impairment of cellularmaintenance, 59t

Hydrolysis, 135, 136t, 137–144Hydroperoxide, 16415-Hydroperoxy-PGF2�, biotransformation, 216fHydrophobicity, percutaneous absorption

and, 655Hydroquinone, 149

allergic contact dermatitis from, 660tbiotransformation, 165pigmentary disturbances from, 666f, 666t

N-Hydroxy-2-Acetylaminofluorenebiotransformation, 160, 203, 203t, 206,

210f, 255fcarcinogenicity, 251, 253f

8-Hydroxyadenine, 47N-Hydroxy-2-aminofluorene,

biotransformation, 210, 210fN-Hydroxy-2-aminonaphthalene,

biotransformation, 203, 203tN-Hydroxy-4-aminoquinoline-1-oxide,

biotransformation, 212f, 2134-Hydroxy-androstene-3,17-dione, reproductive

system toxicity, 689tHydroxyarginine, biotransformation, 185tN-Hydroxyaromatic amines, 202, 202f

biotransformation, 210N-Hydroxyarylamine, biotransformation, 199f4-Hydroxybenzonitrile, 791t4-Hydroxybiphenyl, biotransformation, 199Hydroxychloroquine, retinotoxicity, 578–5796-Hydroxydopamine

biotransformation, 148neurotoxicity, 544–545, 545f

4-Hydroxyestradiol, biotransformation, 207Hydroxyethyl starch, coagulation factor

inhibitor development and, 406tHydroxyflutamide, reproductive system

toxicity, 6988-Hydroxyguanine, 47, 66, 255, 2575-Hydroxy-6-hydrothymine, 2555-Hydroxy-3-indoleacetaldehyde,

biotransformation, 159Hydroxylamine, oxidative hemolysis and, 397t11-Hydroxylase, 689t17-Hydroxylase, 689t21-Hydroxylase, 689t, 7191�-Hydroxylase, 73811�-Hydroxylase, 71917�-Hydroxylase, 717, 719Hydroxylation, 250–25112-Hydroxylauric acid, biotransformation, 189

Hydroxyl radical, 40, 42–43, 42f, 45, 47, 47f,60t, 70, 254–255, 254f, 503, 519, 525,529, 544, 545f, 607f

Hydroxymethyl polycyclic aromatichydrocarbons, biotransformation, 203t

5-Hydroxymethylthymine, 2574-Hydroxynonenal, 47, 259

biotransformation, 41tHydroxyprogesterone, cardiotoxicity, 625,

626tHydroxy radical, 8931�-Hydroxysafrole, biotransformation, 206Hydroxysteroid dehydrogenase, 146, 6573-Hydroxysteroid dehydrogenase, 689t17-Hydroxysteroid dehydrogenase, 689t18-Hydroxysteroid dehydrogenase, 7175-Hydroxytryptamine, 56Hydroxyurea

effect on hemoglobin synthesis, 392as promoting agent, 270t

25-Hydroxyvitamin D, 831Hyoscyamine, 972Hypercalcemia, 740–741Hypericin, 967Hyperlipoproteinemia, 634Hyperprolinemia, 156Hypersensitivity pneumonitis, 1126Hypersensitivity reaction, 15, 451, 451f

assessmentcontact hypersensitivity in animals,

455–456, 456fcontact hypersensitivity in humans, 456IgE-mediated hypersensitivity, 455respiratory hypersensitivity in animals,

454–455to beryllium, 821classification, 451–454, 452fto drugs, 457–458to enzymes, 458to formaldehyde, 458–459to metals, 457, 815to pesticides, 458to snake venom, 961–962systemic, 462–463type I, 451–452, 452f, 961type II (antibody-dependent cytotoxic

hypersensitivity), 452type III, 452, 453f, 962type IV, 452–454, 453–454f, 659–660,

664, 815to xenobiotics, 456–459

Hypersusceptibility, 19Hypertension, 603, 628, 632, 635, 638–639,

644–645cadmium and, 825lead and, 832

Hyperthermia, developmental effects, 365–366Hypertrophic cardiomyopathy, 604Hypoaconitine, 969Hypochlorous acid, 70Hypoglycemia, 57Hypoglycin, 1072t

impairment of cellular maintenance, 59tHypophyseal portal system, 713Hypospadias, 676Hypotension, 634–635

postural, 634–635

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Hypothalamic-hypophyseal portal system,712

Hypothalamic-pituitary-gonadal axis, 687–688,688f, 742, 742f

Hypothalamic-pituitary-testis axis, 745fHypothalamic-pituitary-thyroid axis, 729, 734fHypothyroidism, 704Hypoxanthine, biotransformation, 157f, 158Hypoxanthine-guanine phosphoribosyltransferase

(HGPRT), 288, 291fhuman population monitoring, 343–344

Hypoxanthine-guaninephosphoribosyltransferase (HGPRT)forward mutation assay, 331t, 337

Hypoxia, 536

IIACUC. See Institutional Animal Care and

Use CommitteeIAP. See Inhibitor of apoptosis proteinIARC. See International Agency for Research

on CancerIball index, 300t, 301IBI. See Index of Biotic IntegrityIbopamine, biotransformation, 207Ibotenic acid, 971–972Ibuprofen

biotransformation, 212nephrotoxicity, 510poisoning, 1103t

Ibutilidecardiotoxicity, 614t, 617clinical uses, 606

ICAM. See Intercellular adhesion moleculeICH. See International Commission on

HarmonizationIchthyohemotoxin, 1078Ichthyohepatotoxin, 1078–1079Ichthyootoxin, 1078–1079Ichthyosarcotoxin, 1078–1079I-compounds, 259ICRP. See International Commission on

Radiation ProtectionIdiopathic copper toxicosis, 841Idiosyncratic reactions, 16, 26, 411

chemical, 16Idoxuridine, allergic contact dermatitis

from, 660tIDPN. See �,��-IminodipropionitrileIfosphamide, biotransformation, 185t, 189t,

190IGF. See Insulin-like growth factorIB, 52ILCR. See Incremental lifetime cancer riskIleostomy, 851Illicit drugs, 1092. See also specific drugs

forensic urine drug testing, 1100–1102,1100–1101t

impurities, 1098–1099Imazalil, 797tImidacloprid, 789, 789fImidazolidinyl urea, allergic contact dermatitis

from, 660–661tImidazolines, 791t�,��-Iminodipropionitrile (IDPN),

neurotoxicity, 548t, 550–551, 550f

Imipraminebiotransformation, 146, 167, 169, 171–172,

184t, 187, 198, 199f, 201cardiotoxicity, 616t, 622distribution, 120poisoning, 1120

Immature double-positive cells, 428Immediate hypersensitivity, 451–452, 452fImmediate toxicity, 16Immune complex, 500Immune-mediated disease, 451–461

autoimmunity, 459–461hypersensitivity, 451–459

Immune-mediated thrombocytopenia, 404tImmune response, in hepatotoxicity,

483–484, 484fImmune system, 420–430

cellular components, 421fin lung, 520toxic responses, 419–463

Immunityacquired, 424–428, 433cell-mediated, 424, 428–430, 429f, 434–435definition, 419humoral, 424, 428–430, 429f, 433–435innate, 421–424, 421t, 432–433

Immunocompetence, 419assessment

acquired immunity, 433fcell-mediated immunity, 434–435functional, 432–433general, 431–432, 432fhost resistance assays, 435, 435thumoral immunity, 433–435innate immunity, 432–433

Immunoenhancement, 419, 420fImmunoglobulin, 424–425, 459

structure, 424, 425fImmunoglobulin A, 424, 424tImmunoglobulin D, 424–425, 424tImmunoglobulin E, 424, 424t, 451, 452f

IgE-mediated hypersensitivity, 455Immunoglobulin G, 424, 424t, 428, 451, 452fImmunoglobulin M, 424–425, 424t, 428,

451, 452fImmunology, neuroendocrine, 430, 430f, 431tImmunosuppression, 286, 419, 420f

by drugs of abuse, 449–450by electromagnetic fields, 450by food additives, 450by glycols and glycol ethers, 446by halogenated aromatic hydrocarbons,

438–440by hormones, 446–447by inhaled substances, 444–445by metals, 442–444by mycotoxins, 446by nitrosamines, 441by organic solvents, 445–446by pesticides, 441–442by polycyclic aromatic hydrocarbons,

440–441by silicon-based materials, 450–451by therapeutic agents, 447–449by ultraviolet radiation, 450

Immunosuppressive drugs, 447–448cardiotoxicity, 616t, 624

Immunotoxicityanimal models, 436–437assessment

health effects test guidelines, 435–436medical device testing, 436NTP tier approach, 435, 436tregulatory approaches to, 435–436transgenic and SCID mice, 462

developmental, 462evaluation of mechanisms of action,

437, 438tof glycol ethers, 900of lead, 832relation between animal and human data,

437, 437fImmunotoxicology

molecular biology methods, 462new frontiers and challenges, 461–463risk assessment, 463

Impaction, particle deposition in respiratorytract, 521

Implantation, 687evaluation, 701

Imprinting (during gametogenesis), 357Inactivation, 17Incomplete carcinogenesis, 271Incremental lifetime cancer risk (ILCR),

97, 98fIND. See Investigational New DrugIndex of Biotic Integrity (IBI), 1029Indian childhood cirrhosis, 841Indicator species, 1030Indicator tissue, 813Indicine, biotransformation, 146Indinavir


Indium, 854Indium chloride, 854Indium phosphide, 854Individual-based model, 1031Individual dose-response relationship, 18, 18fIndocyanine green, excretion, 126Indole-3-carbinol, 172, 1052tIndolinones, 791tIndomethacin, 165

aplastic anemia and, 394texcretion, 127–128, 128tLeydig cell tumor development and,

746, 748tnephrotoxicity, 510ocular toxicity, 566tretinotoxicity, 580

Indoor air pollution, 988, 989f,992–993, 1130

building-related illnesses, 993, 1130sick-building syndromes, 993, 993t, 1130

Indoramin, biotransformation, 185tIndustrial chemicals

cardiotoxicity, 629–631, 630tEPA regulation, 1145–1146EPA testing requirements, 1149–1150vasculotoxicity, 640–647, 641t

Industrial revolution, 980Infectious disease

hemolysis associated with, 396–397occupational, 1126, 1128t, 1130

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Inflammation, 69f, 254cells and mediators, 70production of reactive oxygen and

nitrogen species, 70Inflammatory response

in hepatotoxicity, 483–484vascular, 637

Ingestion, 14Inhalant. See also Lung(s); Respiratory tract

toxic, 520Inhalation, 14, 115–117, 235, 518, 874–875.

See also SolventsInhalation exposure system, 530Inhalation study, 27Inhalation toxicity test, 32Inhalation toxicology, 7–8, 515Inhibin, 676, 677–678t, 681, 683, 742, 742fInhibitor of apoptosis protein (IAP), 77Initiating agent, 278, 278tInitiation index, 300tInitiation stage, of carcinogenesis, 266, 267,

267t, 269f, 271, 271t, 277–280, 278f,278t, 287, 287t, 324

Innate immunity, 421–424, 421t, 432–433cellular components, 422–423, 422tgeneral considerations, 421–422soluble factors, 423–424

Inner cell mass, 357Inorganic chemical carcinogenesis, 245, 246tInositol, in food, 1055tInositol triphosphate, 60t, 604, 605f, 632, 633fInotropic agents, cardiotoxicity, 613–619,

614–615tInsect(s)

ants, 953–954bees, 954caterpillars, moths and butterflies, 953disease vectors, 1130true bugs, 954

Insecticides, 769–789absorption, 117anticholinesterase inhibitors, 774–784avermectins, 787–788botanical, 789–790chloronicotinyl, 789nicotine, 789–790nitromethylenes, 788–789organochlorine compounds, 769–774phenylpyrazoles, 789, 789fpyrethroid esters, 784–787rotenoids, 790selective toxicity, 25

Instant Clean ADD-IT-ive, 1101Institutional Animal Care and Use Committee

(IACUC), 1151Insulin-like growth factor-1 (IGF-1), 497–498,

677–678tInsulin-like growth factor-1 (IGF-1) receptor,

75, 75fInsulin-like growth factor-2 (IGF-2), 677t

carcinogenicity, 248Insulin receptor, 883Integrated risk information system (IRIS),

95, 99, 870Integrin, 67, 70, 72, 497f, 642Interagency Regulatory Liaison Group

(IRLG), 1150

Interagency Testing Committee (ITC),1149–1150

Intercellular adhesion molecule (ICAM),70, 657, 659

Interception, particle deposition in respiratorytract, 521

Interferon, cardiotoxicity, 628–629Interferon-�, 421t, 427t

immunosuppression by, 449Interferon-�, 421t, 427tInterferon-�, 427t, 430, 456, 456f, 459, 659

cardiotoxicity, 627timmunosuppression by, 449

Interleukin, 69fInterleukin-1, 70–71, 423, 426t, 428, 429f,

523, 538, 610, 659, 662, 677–678t,847, 890

Interleukin-1�, 523, 604, 611, 611fcardiotoxicity, 627t, 628–629

Interleukin-2, 11, 426t, 428, 429f, 456, 456f,523, 610, 659

cardiotoxicity, 627t, 628nephrotoxicity, 496t

Interleukin-3, 361, 423, 426t, 659Interleukin-4, 426t, 428, 429f, 456, 456fInterleukin-5, 426t, 456, 456f, 523Interleukin-6, 68, 70–71, 361, 423, 426t, 428,

429f, 456, 456f, 847cardiotoxicity, 627t, 628

Interleukin-7, 426tInterleukin-8, 70, 426t, 523Interleukin-9, 426tInterleukin-10, 426t, 456, 456fInterleukin-11, 426tInterleukin-12, 427t, 449, 659Interleukin-13, 427t, 456, 456fInterleukin-14, 427tInterleukin-15, 427tInterleukin-16, 427tInterleukin-17, 427tInterleukin-18, 427tIntermediate syndrome, 777Internal dose, 1018, 1136–1137International Agency for Research on Cancer

(IARC), 91, 99International Commission on Harmonization

(ICH), 31, 370, 371t, 1149guidelines for testing reproductive toxicity,

701, 702tInternational Commission on Radiation

Protection (ICRP), lifetimeenvironmental lung cancer risk fromradon, 935

International normalized ratio, 407International Organization for Standardization

(ISO), 1136International pollution, 981International Programme on Chemical Safety

(IPCS), 96, 99, 324Interplexiform cells, 566tInterstitial cell-stimulating hormone. See

Luteinizing hormoneInterstitial fluid, 122Interstitial nephritis, 510Interstitial space, 232Interstitial water, 119–120Intestinal excretion, 128

Intestinal microflora, 113, 115, 115t, 128,136, 144–145, 145f, 198, 245,645, 839

Intestinal motility, 113Intestinal wall, 128Intracellular binding, reversible, 38Intracellular binding proteins, 39Intracellular space, 232Intracellular water, 119–120Intradermal test, 455Intramuscular administration, 119Intramyelinic edema, 552, 554Intraocular pressure, 575Intraperitoneal administration, 119Intrauterine growth retardation, 359, 376Intravascular hemolysis, 399Intravenous administration, 119Inulin clearance, 502Inverse dose rate effect, 933Inversion, 330Inversion of configuration, 135Investigational drug, 1149Investigational New Drug (IND), 29In vitro tests, for hazard identification, 87–88Iodide

biotransformation, 167developmental effects, 353texcess, 728poisoning, 1116t

Iodineblockage of uptake, 725–726, 726fdeficiency, 725, 734excess, 726fmedical administration of I-131, 931radioactive, selective toxicity, 25

Iodoacetamide, cellular dysregulation, 52Iodoacetate

impairment of cellular maintenance, 58,59t, 61

vasculotoxicity, 643tIodopyrine, thyroid toxicity, 726Iodothyronine deiodinase, 845, 846fIohexol

cardiotoxicity, 616t, 625effect on granulocytes, 400

Ion channel, 38Ionization constant, 110, 110fIonizing radiation. See also Radiation

DNA damage due to, 326–327, 326fskin cancer and, 668

Ionomycin, nephrotoxicity, 506Ion trapping, 1115Iopamidol, nephrotoxicity, 512Iotrol, nephrotoxicity, 512Ioxaglate, effect on granulocytes, 400IPCS. See International Programme on

Chemical SafetyIPDI. See Isophorone diisocyanateIprodione, 797tIridium, 852Irinotecan, 201IRIS. See Integrated risk information systemIris, 568, 568fIRLG. See Interagency Regulatory

Liaison GroupIron, 37t, 842–843

absorption, 112–113, 842

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Iron (continued)air pollution, 997carcinogenicity, 246tchelation therapy, 817–818deficiency, 842dietary, 842dietary restriction, 1052distribution, 120fhepatotoxicity, 479t, 480laboratory tests on stat basis, 1112toverload, 842poisoning, 113t

action level, 1113presystemic elimination, 37reproductive system toxicity, 695toxicity, 842–843toxicokinetics, 842treatment of poisoning, 843

Iron-deficiency anemia, 392, 842Iron oxide

in food, 1062tlung damage caused by, 527t

Irradiation. See RadiationIrreversible inhibitor, 783Irreversible toxic effects, 16Irritant dermatitis, 657–658Ischemia-reperfusion injury, 606–607, 608fIschemic heart disease, 602, 603, 610

ischemia-reperfusion injury, 606–607, 608fIschemic preconditioning, 607Ishihara color plates, 574ISO. See International Organization for

StandardizationIsobutyl nitrate, methemoglobinemia

and, 395tIsocitrate dehydrogenase, 698Isocyanate

biotransformation, 44lung damage caused by, 527t

Isodrin, poisoning, 771tIsoflavenoids, 674Isoflavones, 1051Isoflurane

biotransformation, 151–152, 184t, 188cardiotoxicity, 616t, 622

Isolated perfused lung method, 532Isomalathion, 1133Isoniazid, 48, 193, 196, 1070

autoimmune reaction to, 460, 460tbiotransformation, 209–210, 209fcoagulation factor inhibitor development

and, 406tinduction of cytochrome P450, 192neurotoxicity, 548tneutropenia and, 402tpoisoning, 113t, 1116tpure red cell aplasia and, 394, 394tsideroblastic anemia and, 392t

Isophorone, carcinogenicity, 89tIsophorone diisocyante (IPDI), hypersensitivity

reaction to, 455Isoprene, partition coefficient, 233tIsopropyl alcohol

cardiotoxicity, 629poisoning, 1113trespiratory tract damage caused by, 525

Isopropyl chloride, cardiotoxicity, 630t

Isopropylfluorophosphatase, 137Isopropyl methylphosphonic acid, 775Isoproterenol

cardiotoxicity, 610, 614t, 618–619vasculotoxicity, 639

Isoretinoin, adrenal toxicity, 720Isosafrole, 193, 196Isothiazolins, occupational disease, 1127tIsothiocyanate, in food, 1072tIsotope effect, 174Isotretinoin. See Retinoic acidIsradine, reproductive system toxicity, 683tItai itai, 824, 1074ITC. See Interagency Testing CommitteeIto cells, 69, 473–474, 475f, 480, 482,

483f, 713Itraconazole, 191

cardiotoxicity, 621Ivermectin, 787

distribution, 123mechanism of action, 787–788structure, 788ftreatment of pyrethroid poisoning, 787

JJacobine, 970Jake leg. See Ginger-jake walkJasmolin, 784Jasmolol, 784Jervine, 968, 973

developmental effects, 378Jet fuel, 902–903

immunotoxicity, 902pulmonary effect, 903

JNK, 69Joule, 918Jumping spiders, 949, 949t, 952jun gene, 272t, 276Jun protein, 49, 52, 274

KKainate, 971

cellular dysregulation, 54timpairment of cellular maintenance, 60tneurotoxicity, 556t, 558

Kainate receptor, 558, 971Kanamycin, cardiotoxicity, 615t, 621Kaolin, lung damage caused by, 528tKaolinosis, 528tKaryotypic instability, 270, 277Kepone, developmental effects, 368

shakes, 772Keratin, 654Keratinocytes, 653–654Kerma, 921Kernicterus, 121Kerosene, 903Keshan disease, 845–847Ketamine, cellular dysregulation, 54tKetanserine, cellular dysregulation, 55tKetoconazole, 188, 191, 193–196

cardiotoxicity, 621Leydig cell tumor development and, 746reproductive system toxicity, 689t

Ketoprofen, biotransformation, 199f

Kidnaping, involving poisoning, 1099Kidney. See also Nephrotoxicity; Renal entries

anatomy, 491–494, 492–493fdistal tubule and collecting duct, 492f, 494loop of Henle, 492f, 494proximal tubule, 492f, 493–494renal vasculature and glomerulus, 492,

492–493fassessment, 501–502, 501–502fexcretion of toxicants, 39, 124–125, 125fmechanisms of toxic injury

calcium homeostasis, 504–505cell death, 502–503, 503fcell volume and homeostasis, 504cytoskeleton and cell polarity, 504endonucleases, 505–506lysosomes, 504, 505fmitochondria, 504molecular targets, 504phospholipases, 505proteinases, 506

mediators of toxicity, 503, 503fpathophysiologic responses, 494–499.

See also Renal failureadaptation after toxic insult, 496–498,

497–498fas storage depot, 121toxic effects of plants, 970toxic injury to

collecting duct, 500distal tubule, 500glomerulus, 499–500incidence and severity of toxic

nephropathy, 499loop of Henle, 500papillary injury, 500–501proximal tubular injury, 500site-selective injury, 499susceptibility to, 499–501

toxic responses, 491–512Killer cells, 421fKinesin, 538Kissing bugs, 954Klear, 1101Klinefelter’s syndrome, 675, 695Knockout mice, 294t

cytochrome P450, 191models of carcinogenesis, 297

Kojic acid, in food, 1077tKonzo, 971Kraits, 955, 956–957tKupffer cells, 423, 473, 475f, 478, 482, 483f,

887, 894

LLabeling index, 68, 68fLabeling of Hazardous Art Materials Act

(LHAMA), 1148lac operon, Escherichia coli, 289, 292f,

335, 338Lactate dehydrogenase, 501, 532, 613, 896

cardiac, 603LDH-X, 698snake venom, 957t, 960

Lactic acid, 1113tvasculotoxicity, 636t

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Lactitol, 1056tLeydig cell tumor development and,

746, 748tLactoperoxidase, 162Lactose intolerance, 1066, 1067t,

1069–1070, 1069tLADD. See Lifetime average daily doseLafarge, Marie, 1093Laminar flow, 1015Laminin, 456, 461Lamotrigine

biotransformation, 199ftherapeutic monitoring, 1105t

Landscape, 1022Lange, Willy, 8Langerhans cells, 654, 659, 663Lanolin, allergic contact dermatitis from,

660–661tLansoprazole

biotransformation, 176, 177f, 184t, 185t, 187inhibition of testosterone synthesis, 745–746Leydig cell tumor development and, 746

Lantadene, 970Lanthanum, cardiotoxicity, 629, 630tLanthony Desaturated Panel D-15 test, 574Lateral geniculate nucleus (LGN), 566t, 584Latex, 967Latex allergy, 458, 666–667, 667t, 1127t, 1129Latex-fruit syndrome, 966Latex particles, absorption, 113Lathyrism, 637, 971Lathyrogen, vasculotoxicity, 635Latrodectus species, 949–950, 949tLatrotoxin, 950

cellular dysregulation, 55tLauric acid, biotransformation, 175, 175fLay witness, 1102Lazaroid, 511LC50, 27, 92LD50, 13, 18, 24, 92, 95

determination, 19, 27L-dopa

autoimmune reaction to, 461tbiotransformation, 205, 206f, 207

Lead, 5, 7, 46, 812–813, 827–834absorption, 113–114, 828airborne, 828, 997birth outcomes, 832blood, 828f, 829, 1104bone, 829, 832carcinogenicity, 245, 246t, 832–833cardiotoxicity, 629, 630tcardiovascular effects, 832cellular dysregulation, 52, 55t, 56cellular uptake, 816central visual system toxicity, 586–587developmental effects, 353t, 829–830dietary, 827–828distribution, 38–39, 120–124dose response, 833, 833tdrinking water, 827ecotoxicology, 1017–1018, 1025effects on developing nervous system,

830, 830telimination, 108excretion, 829exposure, 827–829, 828f

in food, 1073gout and, 832hematologic effects, 398, 830–831, 831fhost factors influencing toxicity, 815immunosuppression by, 442–443immunotoxicity, 832intestinal absorption, 1053tin milk, 129National Ambient Air Quality Standards, 981tnephrotoxicity, 499, 831–832, 833tneurotoxicity, 543t, 554–555, 829–830, 833toccupational disease, 1127t, 1130, 1133ocular toxicity, 566t, 567, 570peripheral neuropathy, 830pigmentary disturbances from, 666tpoisoning, 1113–1114reproductive system toxicity, 674, 692,

692–693t, 695, 695t, 832, 833tretinotoxicity, 580–582

animal studies, 581–582occupationally exposed workers, 580–581

sideroblastic anemia and, 392tskeletal effects, 832soft tissue, 829target organs, 16, 108toxicity, 829toxicokinetics, 828–829treatment of poisoning, 817–818, 833as ultimate toxicant, 37tvasculotoxicity, 644–645

Lead acetate, octanol/water partitioncoefficient, 109t

Lead arsenide, 818Lead arsenite, 1135Leaded gasoline, 813Lead lines, 833Lead paint, 554, 827

ingestion, 1113–1114Leavening agents, 1056tLectins, 967–968, 973–974Leflunomide, immunosuppression by, 448Legislation, 6–7, 85, 86t. See also Regulation;

Regulatory programsLehman, Arnold, 7–8Lens, 568f, 569, 571

damage, 566tfunction, 576toxic responses, 576–577

Leptophosmechanism of toxic action, 779neurotoxicity, 551poisoning, 777–778

LET. See High linear-energy-transfer particleLethal concentration. See LCLethal dose, 23–24, 24fLethality study, 23Lethal time. See LTLeukemia, 401–402. See also specific

types of leukemiafrom ankylosing spondylitis radiation

therapy, 931–932, 932tLeukemia inhibitor factor (LIF), 604, 628Leukemogenesis, 401–403Leukemogenic agent, 402–403Leukocytes, 399Leukon, toxicology, 399–401Leukotriene A4, 141

Leukotriene A4 hydrolase, 141Leukotriene B4, 69f, 70, 657, 662Leukotriene C4, 69f, 214–216Leuprolide, reproductive system toxicity,

682Levamisole, neutropenia and, 402tLevofloxacin, cardiotoxicity, 621Levosimendan, cardiotoxicity, 614t, 617–618Lewin, Louis, 5Leydig cells, 675, 680, 681–682, 682f, 683t,

688–689, 688f, 692–693, 695, 699structure and endocrinologic regulation,

742, 742–743fLeydig cell tumor, 741–746

incidence, 741–742, 741fmechanisms of development, 744–746, 744t,

745–746f, 746t, 749tNational Toxicology Program classification,

743–744LFA. See Lymphocyte function-

associated antigenLGN. See Lateral geniculate nucleusLH. See Luteinizing hormoneLHAMA. See Labeling of Hazardous Art

Materials ActLHRH. See Luteinizing hormone-

releasing hormoneLibido, 688Licorice, 1071, 1072t

vasculotoxicity, 635Lidocaine

biotransformation, 185t, 1104cardiotoxicity, 613, 614t, 616t, 622–623cellular dysregulation, 56clinical uses, 605first-pass effect, 119methemoglobinemia and, 395tneutropenia and, 402tpostmortem blood, 1098

LIF. See Leukemia inhibitor factorLifestyle carcinogenesis, 282–284, 283tLifetime average daily dose (LADD), 97Ligand, 816Ligandin, 121Light, skin cancer and, 667–668Limbic-cerebellar syndrome, 544Limiting conditions, 233d-Limonene, 26, 125

carcinogenicity, 77, 89t, 279nephrotoxicity, 500, 504, 507

Linamarin, 971Lindane

carcinogenicity, 279teffect on granulocytes, 400hepatotoxicity, 772impairment of cellular maintenance, 60tnephrotoxicity, 507–508poisoning, 771t, 772site and mechanism of toxic actions, 773structure, 770t

Linearized multistage (LMS) model, 95Linoleic acid, in food, 1062tLinuron, reproductive system toxicity, 683tLipid(s), molecular repair, 65, 66fLipid alkoxyl radical, 47Lipid body, 712Lipid-lowering drugs, 49

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Lipid peroxidation, 46–47, 47f, 66f, 71, 151f,254, 259, 398, 481, 503, 505, 607, 887,893–894

Lipoproteins, 38, 120, 637–638Lipoxygenase, 163Lisofylline, 135, 135f, 145Lithium, 45, 813–814, 848, 852

cellular dysregulation, 56–57developmental effects, 353t, 374laboratory tests on stat basis, 1112tnephrotoxicity, 498–499neurotoxicity, 548tpoisoning, action level, 1113thyroid toxicity, 728toxicokinetics, 852

Lithium carbonate, 852autoimmune reaction to, 461t

Lithium hydride, 852Little fire ants, 953–954Liver

acinar zonation, 472–473, 474fbile formation, 474–476, 475fbiotransformations, 136–137excretion of toxicants by, 39fatty, 472, 476–477, 476tfunctions, 471–472, 472tmicrosomal enzyme induction, 729–731,

729–731fsinusoids, 473, 475fas storage depot, 121structural organization, 472–474, 474ftoxic effects of plants, 969–970toxic responses, 471–487tumors, 476t, 478

Liver compartment, 235–236, 236fLiver function tests, 126Liver injury

bile duct damage, 476t, 477–478canalicular cholestasis, 476t, 477cell death, 476t, 477cirrhosis, 476t, 478dysfunction without cell damage, 472, 473fexperimental systems, 479, 480ffactors, 479–484, 479f

activation of sinusoidal cells, 482–483, 483fbioactivation and detoxification, 480–482inflammatory and immune responses,

483–484, 484fuptake and concentration, 479–480

mechanismscholestasis, 485–486, 486fcytoskeletal disruption, 484–485, 485fmitochondrial damage, 486–487

sinusoidal damage, 476t, 478types, 476–478

Liver specific transporter, 126Lizards, 954–955LMS model. See Linearized multistage modelLOAEL, 28, 92, 92f, 94Local anesthetics, cardiotoxicity, 616t, 622–623Local toxicity, 16Locoweed, 971–972LOEC, 1028LOEL, 1026Log logistic model, 95Log-probit model, 95, 304Lomefloxacin, cardiotoxicity, 621

London smog, 988–989Long-term tests, for carcinogen identification,

288t, 293–296, 294tLoop of Henle, 492f, 494

toxic injury, 500Lopanoic acid, biotransformation, 199fLophotoxin, cellular dysregulation, 54tLoratidine, 194

biotransformation, 179f, 185tLosartan, biotransformation, 185tLovastatin, biotransformation, 139Love Canal, 9Low-density lipoproteins (LDL), 647, 894, 905

oxidation, 638, 638freceptor-mediated internalization, 639

“Lowest observed adverse effect level.”See LOAEL

“Lowest observed effect concentration.”See LOEC

Loxapine, cardiotoxicity, 622Loxosceles species, 949t, 950–951LT50, 24Lubricants, in food, 1056tLumped model, 1031Lung(s). See also Pulmonary entries;

Respiratory tractabsorption, 115–117, 116facute response to injury

airway reactivity, 522cell proliferation, 523–524mediators of toxicity, 523pulmonary edema, 522

airborne agents that injury, 526–529,990–992, 992f

assessment of lung injuryinhalation exposure systems, 530in vitro, 532isolated lung cell population, 532–533isolated perfused lung, 532lung explants and slices, 532microdissection, 532morphologic techniques, 531–532organotypic cell culture system, 532pulmonary function tests, 530–531, 531fpulmonary lavage, 532

blood-borne agents that injure, 529–530chronic response to injury

asthma, 525emphysema, 524–525fibrosis, 524lung cancer, 525–526

clearance of particles from, 522effect of aluminum, 849gas exchange

diffusion, 519evaluation, 531ventilation, 518–519

gas-exchange region, 516–518mechanism of injury to, 522–523occupational respiratory diseases,

1126–1130, 1127–1128tpathogenesis of toxic response, 519–522

oxidative burden, 519–520toxic inhalants, 520

solvent absorption, 874structure, 516, 517ftoxic effects of plants, 968

toxic responses, 515–533Lung cancer, 523, 525–526, 527–528t,

991–992, 992famong uranium miners, 932–935

Lung cell preparation, 532–533Lung compartment, 235, 235fLung compliance, 531Lung explants/slices, 532Lupus anticoagulant, 406, 407tLupus erythematosus, 663Luteinizing hormone (LH), 676, 687–688,

688f, 701, 712–714, 713f, 742,742–743f, 746

Leydig cell tumor development and, 746mouse models of ovarian tumors, 751–752

Luteinizing hormone-releasing hormone(LHRH), 687–688

Luteotrophs, 712, 713f20-Lyase, 689tLycorin, 966Lymphatic circulation, 1053

venom transport, 946Lymph nodes, 420, 420tLymphocyte(s), 399, 518Lymphocyte function-associated antigen

(LFA), 659Lymphoid organs, 420Lymphoid tissue, 420tLymphokines, 428Lymphopoiesis, 391Lysolecithin, neurotoxicity, 553tLysophosphatide fatty acyl-CoA transferase,

66fLysosomal accumulation, 38Lysosomes, renal cell, 504, 505fLysozyme, 421tLysyl oxidase, 840

MMAA. See Methoxyacetic acidMAAD. See MethoxyacetaldehydeMacrolides, cardiotoxicity, 615t, 621Macronutrient, 1051Macrophage(s), 420, 421f, 421–422t, 422–423,

425, 430Macrophage assay, 433Macrophage-colony stimulating factor, 423MACT. See Maximal achievable control

technologyMad honey poisoning, 969Magendie, 5Maggot analysis, 1094Magnesium, 843

air pollution, 997deficiency, 843occupational disease, 1127ttoxicity, 843toxicokinetics, 843vasculotoxicity, 644

Magnesium hydroxide, ocular toxicity, 575Magnesium tetany, 843Ma huang, cardiotoxicity, 615t, 618Maimonides, 4Maitotoxin, 1079

cellular dysregulation, 55timpairment of cellular maintenance, 60t

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Major histocompatibility complex (MHC),425, 426f, 428, 459

Malabsorption, 406tMalabsorption syndrome, 393tMalaria, 396–397Malate dehydrogenase, 698Malathion

assessment of toxicity, 1133biotransformation, 139, 781–782hypersensitivity reaction to, 458immunosuppression by, 441impurities in, 1133maggot analysis, 1094

MALD. See MethoxyacetaldehydeMaleic anhydride, urticaria from, 667tMale reproductive capacity, testing

androgens and their receptors, 697–698flow cytometry, 697general considerations, 693–697secretory biomarkers, 698–699semen analysis, 697sex accessory organs, 697sperm counts and motility, 697

Malformation, 359. See also Developmentaltoxicity

Malignant, definition, 242Malling, Heinrich, 322Malonate, impairment of cellular

maintenance, 59tMalondialdehyde, 47MALT. See Mucosa-associated lymphoid tissueMambas, 955, 956–957tMammals, mutagenicity assays, 332t, 337–338Mancozeb


Maneb, 796fManganese, 37t, 843–844

absorption, 113biliary excretion, 475cardiotoxicity, 629, 630tdeficiency, 844hepatotoxicity, 476t, 486intestinal absorption, 1053tneurotoxicity, 543tpresystemic elimination, 37reproductive system toxicity, 528t, 695ttoxicity, 844toxicokinetics, 844vasculotoxicity, 644

Manganese dioxide, 844Manganese pneumonia, 528tManganese pneumonitis, 844Manganism, 844Mannosidase, inhibitors in plants, 971–972MAO. See Monoamine oxidaseMAPK. See Mitogen-activated protein kinaseMarch hemoglobinuria, 396Marginal irritant, 657Margin of exposure (MOE), 24, 93Margin of safety (MOS), 24, 93Marijuana, forensic urine drug testing,

1100t, 1101Marine Protection Research, Sanctuaries

Act, 86tMasonin, 966Mass balance differential equations, 234–235

Mass median aerodynamic diameter (MMAD),521, 990

Mast cells, 421fMATC. See Maximum allowable toxicant

concentrationMaternal toxicity, relationship to developmental

toxicity, 365–368, 366fMaximal achievable control technology

(MACT), 981Maximally exposed individual (MEI), 97Maximum allowable toxicant concentration

(MATC), 1028Maximum contaminant level (MCL), 1146–1147Maximum contaminant level goal (MCLG),

1146–1147Maximum likelihood estimate (MLE), 95Maximum tolerated dose (MTD), 29, 293,

299, 1064–1065MBC. See Methyl-benzimidazol-2-yl-carbamateMBK. See Methyl butyl ketoneMCL. See Maximum contaminant levelMCLG. See Maximum contaminant level goalMCPA. See 4-Chloro-2-methyloxyacetic acidMCT. See MonocrotalineMDI. See Diphenylmethane-4,4�-diisocyanateMdm2 protein, 75f2-ME. See 2-MethoxyethanolMechanism-based inhibition, 175Mechanistic toxicology, 11–12, 12fMechlorethamine, carcinogenicity, 244f, 285tMDR. See Multidrug-resistant proteinMED. See Minimal erythema doseMedian, 520–521Median dose, 24Median lethal dose. See LD50

Medical devicesimmunotoxicity testing, 436regulation, 1144

Medical examiner, 1092–1093Medical therapy, carcinogenesis from,

285–286, 286tMedium-term bioassay, 295–296, 296fMedium-term tests, for carcinogen

identification, 288t, 293–296, 294tMedroxyprogesterone

cardiotoxicity, 625, 626tdevelopmental effects, 357

Medrysone, cardiotoxicity, 627–628Med Watch, 411Mees’ lines, 819Mefloquine, aplastic anemia and, 394tMegaloblastic anemia, 393, 393f, 393tMEGX. See MonoethylglycinexylidideMEHP. See Mono-2-ethylhexyl phthalateMEI. See Maximally exposed individualMeiosis, 679, 686Melamine

carcinogenicity, 89tin food, 1065

Melanin, 38, 573, 577–578, 653–654,662–663, 665

intraocular, 569–570Melanocytes, 653, 662–663Melanocyte-stimulating hormone (MSH),

712, 713fMelanoma, malignant, 663Melphalan, leukemia and, 402

Membrane carrier proteins, metal transport, 816Membrane fluidity, 109Membrane-limited compartment. See Diffusion-

limited compartmentMenab, 797tMenadione, 160

biotransformation, 145, 148fimpairment of cellular maintenance, 59–60t

Meningeal surface, 536Menke’s disease, 816, 841Menstruation, 686Menthyl anthranilate, in photopatch test, 664tMepazine, aplastic anemia and, 394tMeperidine, cellular dysregulation, 54tMephenytoin

biotransformation, 134, 175f, 182,184t, 186–187

effect on granulocytes, 401tMephobarbital, biotransformation, 184t, 187Mepivacaine, cardiotoxicity, 622–623Meprobamate

aplastic anemia and, 394tbiotransformation, 199fpoisoning, 1116t

Mercaptobenzothiazide, allergic contactdermatitis from, 660t

2-Mercaptobenzthiazole, 661f2-Mercaptoethanol, biotransformation, 2082-Mercaptoimidazole, biotransformation, 171Mercaptoimidazoline, in food, 10656-Mercaptopurine, 12

biotransformation, 158, 206f, 208reproductive system toxicity, 691t

Mercapturic acid, 215, 217fMercurials, allergic contact dermatitis

from, 660tMercuric chloride, 814, 835–836

autoimmune reaction to, 461nephrotoxicity, 496, 500, 504, 506occupational disease, 1127tvasculotoxicity, 636t

Mercuric ion, distribution, 38Mercuric salts, 835–836Mercurous mercury, 836Mercury, 5, 45, 812–813, 834–837

allergic contact dermatitis from, 660taplastic anemia and, 394tautoimmune reaction to, 460t, 461biological indicators

inorganic mercury, 836, 836t, 837fmethyl mercury, 837

biotransformation, 40, 41t, 206, 835cellular metabolism, 835developmental effects, 353t, 367dietary, 834disposition, 834–835ecotoxicology, 1016excretion, 126, 835exposure, 834

in pregnancy, 835granulomatous reactions to, 666host factors influencing toxicity, 815immune reactions to, 815immunosuppression by, 443metallic, 114nephrotoxicity, 500, 506–507, 507fneurotoxicity, 543t, 836

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Mercury (continued)occupational disease, 1127tocular toxicity, 566tpigmentary disturbances from, 666tpoisoning, 1096reproductive system toxicity, 695, 698target organ, 108toxicokinetics, 834–835toxicology

mercuric salts, 835–836mercurous mercury, 836mercury vapor, 835methyl mercury, 836

treatment of poisoning, 817–818, 837vasculotoxicity, 644–645

Mercury vapor, 834, 835Merphos, poisoning, 778Mesaconitine, 969Mescimol, cellular dysregulation, 56Mesocosm, 1029Mesoderm, 358Mesoridazine, cardiotoxicity, 622Mesothelioma, malignant, 526, 527tMestranol, cardiotoxicity, 625, 626tMesulergine, reproductive system toxicity,

682, 683tMetabolic activation, 40, 876Metabolic food reaction, 1067t, 1071, 1071tMetabolic inactivation, 876Metabolism

biotransformation versus, 134saturable, 236

Metabolism-dependent inhibition, 175Metabolite, 134Metalaxyl, 795, 797tMetal-binding proteins, 815–816

membrane carrier proteins, 816specific, 815–816

Metalloprotein complex, 815Metallothionein, 38, 71, 121, 125, 367–368,

368f, 480, 498, 507, 644, 684,813–814, 815, 819, 822, 823f, 835,847–851, 855, 987

biomarker for cadmium, 825cadmium complex with, 824, 826

Metal-responsive element-binding transcriptionfactor (MTF), 49, 50t

Metals. See also specific metalsair pollution, 997analytic toxicology, 1090in bile, 475biological cycles, 812–813, 813fbiological half-time, 813biomarkers, 813cardiotoxicity, 629–631, 630tcellular targets for toxicity, 814complexation and chelation therapy,

816–818detoxication, 43dose-effect relationships, 813–814, 814fecotoxicology, 1016, 1019–1020, 1024, 1030essential metals with potential for toxicity,

839–848in food, 1073–1074geologic cycles, 812–813, 813fhair analysis, 813–814hepatotoxicity, 480

host factors influencing toxicity,814–815, 814t

hypersensitivity reaction to, 457immunosuppression by, 442–444indicator tissue, 813intestinal absorption, 1053tlong-term effects, 813minor toxic, 853–858nephrotoxicity, 496t, 506–507related to medical therapy, 848–853reproductive system toxicity, 674, 690,

695, 698simultaneously extracted, 1017toxic effects, 811–858toxic metals with multiple effects, 818–839treatment of poisoning, 816–818urine, 1104vasculotoxicity, 634, 644–645

Metal transporter, 816Metaphase analysis, 331tMetaproterenol, cardiotoxicity, 614t, 618Metastasis, 242met gene, 272tMethadone, 160, 1104Methamidophos, poisoning, 777–778Methamphetamine

biotransformation, 167, 169clandestine synthesis, 1098–1099forensic urine drug testing, 1100t, 1101neurotoxicity, 556t

Methandrostenolone, cardiotoxicity, 626t, 627Methanol, 7, 48, 894–895

biotransformation, 153, 156, 582, 895,895f, 1119

cardiotoxicity, 629developmental effects, 358neurotoxicity, 543tocular toxicity, 566t, 894–895partition coefficient, 233tpoisoning, 113t, 894, 1103–1104,

1104f, 1119retinotoxicity, 582–583treatment of poisoning, 895

Methapyrilenebiotransformation, 176carcinogenicity, 244f, 245, 279t

Methaqualone, biotransformation, 176Methazolamide, aplastic anemia and, 394tMethemoglobin, 16, 40, 42, 46, 65, 71, 113,

218, 394, 396–397, 397f, 1067t, 1117poisoned patient, 1111, 1112t

Methemoglobinemia, 394–395, 395tMethemoglobin reductase, 71Methenolone, cardiotoxicity, 626t, 627Methicillin, aplastic anemia and, 394tMethimazole, 48, 167

biotransformation, 169, 170fdevelopmental effects, 353tneutropenia and, 402tthyroid toxicity, 726, 726f

Methiochlor, poisoning, 771tMethionine sulfoxide reductase, 65fMethomyl, poisoning, 778Methotrexate

biotransformation, 159developmental effects, 375effect on granulocytes, 400

nephrotoxicity, 496treproductive system toxicity, 691t, 693t

Methoxamine, vasculotoxicity, 645Methoxyacetaldehyde (MAAD; MALD)

immunosuppression by, 446reproductive system toxicity, 690

Methoxyacetic acid (MAA), 898–900immunosuppression by, 446reproductive system toxicity, 690–691

Methoxyamphetamine, biotransformation, 185t3-Methoxybenzidine, reproductive system

toxicity, 689tMethoxychlor

cardiotoxicity, 625developmental effects, 368poisoning, 771treproductive system toxicity, 683t, 771structure, 770t

2-Methoxyethanol (2-ME), 898–900developmental effects, 364–365immunosuppression by, 446reproductive system toxicity, 690–691

Methoxyfluranebiotransformation, 151–152cardiotoxicity, 616t, 622, 629excretion, 128nephrotoxicity, 500

Methoxyphenamine, biotransformation, 185tMethoxypsoralen, 186, 192

carcinogenicity, 286, 286tphototoxicity, 663t

7-Methoxyresorufin, biotransformation, 183,186, 196

�-N-Methylamino-L-alanine (BMAA),neurotoxicity, 556t, 558

N-Methyl-4-aminoazobenzene, 45carcinogenicity, 257

Methylaminopterin, developmental effects,353t

N-Methyl-D-aspartate, cellulardysregulation, 54t

Methylation, 135, 136t, 197, 197f,206–208, 206f

of DNA, 77, 257–259, 259tMethylazoxymethanol acetate,

neurotoxicity, 543tMethyl-benzimidazol-2-yl-carbamate (MBC),

reproductive system toxicity, 697Methyl bromide, 764, 799

cardiotoxicity, 630tneurotoxicity, 543tskin burns, 658t

Methyl butyl ketone (MBK)biotransformation, 1135neurotoxicity, 547, 548toccupational disease, 1135

Methyl carbonium ion, carcinogenicity, 252fMethyl chloride, cardiotoxicity, 630tMethylchloroisothiazolone, allergic contact

dermatitis from, 660t3-Methylcholanthrene, 127, 149, 172,

193–194, 199–200, 216carcinogenicity, 243, 243f, 251developmental effects, 364in lymph, 1053reproductive system toxicity, 683tthyroid toxicity, 729–730

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vasculotoxicity, 6456-Methylcoumarin, in photopatch test, 664tMethyl-2-cyanoacrylate, vasculotoxicity, 643tMethylcyclopentadienyl manganese tricarbonyl

(MMT), 981Methylcytisine, 969Methyldibromoglutaronitrile, allergic contact

dermatitis from, 661tMethyldithiocarbamate, immunosuppression

by, 442Methyldopa

autoimmune reaction to, 460, 460tbiotransformation, 203t, 207coagulation factor inhibitor development

and, 406themolytic anemia and, 398reproductive system toxicity, 685t

Methylene bluedevelopmental effects, 353tmethemoglobinemia and, 395toxidative hemolysis and, 397t

Methylene chloride, 885–887biotransformation, 189t, 218, 219f,

885–886, 886fcarcinogenicity, 886–887cardiotoxicity, 630tin food, 1065immunosuppression by, 446occupational disease, 1127t

Methylene dianiline, hepatotoxicity, 476t,477f, 478, 479t

3,4-Methylenedioxymethamphetamine,biotransformation, 207

Methyl ethyl ketone, 1135cardiotoxicity, 630t

Methylfentanyl, 1092Methylformamide, biotransformation, 184t7-Methylguanine, 257O6-Methylguanine, 260, 328, 526O6-Methylguanine-DNA methylase, 328Methylhexahydrophthalic anhydride,

urticaria from, 667t3-Methylindole, biotransformation, 165Methyl isobutyl ketone, 1135Methyl isocyanate

air pollution, 980–981, 988, 1007as ultimate toxicant, 37t

Methyllycaconitine, 972–973Methylmercaptoimidazole, aplastic anemia

and, 394t6-Methylmercaptopurine, biotransformation, 178fMethyl mercury, 813–814, 834

biological indicators, 837biotransformation, 835central visual system toxicity, 587developmental effects, 374distribution, 122–123ecotoxicology, 1016elimination, 835excretion, 127impairment of cellular maintenance, 60tneurotoxicity, 543t, 544occupational disease, 1127tocular toxicity, 566treabsorption from gallbladder, 476reproductive system toxicity, 674toxicology, 836

treatment of poisoning, 818Methylmethacrylate, effect on granulocytes, 400Methylmethane sulfonate

carcinogenicity, 257cellular dysregulation, 52developmental effects, 357

N-Methylnitrosoureacarcinogenicity, 73, 274tdevelopmental effects, 357pituitary toxicity, 714thyroid toxicity, 725, 725f

Methylochlor, 770tMethyl orange, 8Methyl parathion

biotransformation, 781immunosuppression by, 441

Methylphenylcarbinol, biotransformation, 199fMethylphenylethylhydantoin, aplastic anemia

and, 394t1-Methyl-4-phenylpyridine (MPP), 38, 161, 161f

impairment of cellular maintenance, 59–60t1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

(MPTP), 35biotransformation, 161–162, 176neurotoxicity, 543t, 545, 546f

Methylprednisolone, cardiotoxicity, 626t,627–628

8-Methylpsoralen, phototoxicity, 663t4-Methylpyrazole, 896Methyl salicylate, 657

octanol/water partition coefficient, 109tMethylsergide, vasculotoxicity, 643tMethyl tertiary-butyl ether (MTBE), 901–902,

981, 1006biotransformation, 902carcinogenicity, 901–902, 902tgroundwater contamination, 981

Methyltestosteronecardiotoxicity, 626t, 627reproductive system toxicity, 698t

N-Methyl-thiotetrazole cephalosporins, effecton coagulation, 406t

4-Methylumbelliferone, biotransformation, 1991-Methyluric acid, 158Methylxanthines, 158

cardiotoxicity, 616t, 624Metiamide, neutropenia and, 402tMetiram, 797tMetoclopramide, methemoglobinemia and, 395tMetolachlor, 795Metolazone, aplastic anemia and, 394tMetoprolol

biotransformation, 185tcellular dysregulation, 55t

Metrizamide, vasculotoxicity, 643tMetrizoate, vasculotoxicity, 643tMetronidazole

biotransformation, 176Leydig cell tumor development and, 748tneurotoxicity, 548treproductive system toxicity, 682, 683t

Metyrapone, reproductive system toxicity, 689tMexiletine

biotransformation, 185tcardiotoxicity, 613, 614tclinical uses, 605

MHC. See Major histocompatibility complex

Mianserin, biotransformation, 185tMichaelis-Menten expression, 236“Mickey Finn,” 1099Miconazole, 193–196Microangiopathic anemia, 396Microarray analysis, 96, 345Microbubule-associated neurotoxicity, 552, 552fMicrocosm, 1029Microcystin

distribution, 38hepatotoxicity, 476t, 478–480, 484–485, 485fimpairment of cellular maintenance, 64

Microcystin-LG, cellular dysregulation, 52Microcystis aeruginosa, 479Microfilamental dissociation, 58Microfilamental toxin, 64Microglia, 423Micromass assay, rat embryo limb bud,

372, 373tMicromercurialism, 835Micronucleus assay, 291, 331t, 339–340, 340f

germ cell, 342human population monitoring, 343

Micronutrient, 1051, 1073Microphallus, 676Microsomal enzyme induction, hepatic,

729–731, 729–731fMicrosomal ethanol oxidizing system, 154Microsomes, 32Microtubular toxin, 64Midazolam, biotransformation, 182, 185tMiddle Ages, 4MIF. See Müllerian inhibiting factorMifepristone. See RU-486Migraine, 205, 1069tMigration inhibitory factor, 428tMigratory behavior, 1023Milacemide, biotransformation, 160, 160f, 162Milk, secretion of toxic compounds into, 129Miller, Elizabeth, 8–9, 251, 322Miller, James, 8–9, 251, 322Millipedes, 953Mimosine, 973Minamata Bay, 587Mineralocorticoids, 716–717

cardiotoxicity, 626–627t, 627–628vasculotoxicity, 635

Mineral oil, in food, 1056tMiners’ disease, 5Miniaprine, biotransformation, 185tMinimal administered dose, 1098Minimal erythema dose (MED), 662Minimal risk level (MRL), 870Minocycline

pigmentary disturbances from, 666tthyroid toxicity, 728, 734, 734f

Minoxidil, biotransformation, 203, 203t, 205Mipafox

mechanism of toxic action, 779poisoning, 777–778structure, 777f

Mirexcarcinogenicity, 301fecotoxicology, 1026hepatotoxicity, 772immunosuppression by, 441–442poisoning, 771t, 772

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Mismatch repair, 262t, 263, 265f, 266,277, 328

Misonidazole, neurotoxicity, 548tMistletoe, 969Mithridates VI (King of Pontus), 4, 1109Mitochondria

in cardiac myocytes, injury to, 608–609, 609fhepatic, 486–487renal cell, 504

Mitochondrial accumulation, 38Mitochondrial permeability transition (MPT),

63, 504apoptosis, 61–63, 62fnecrosis, 61

Mitogen-activated protein kinase (MAPK),49–50, 52, 276, 604, 605f, 607, 620

Mitomycinbiotransformation, 147–148thrombocytopenia and, 404t, 405vasculotoxicity, 639

Mitomycin Cbiotransformation, 158carcinogenicity, 301fnephrotoxicity, 496treproductive system toxicity, 677

Mitosispromoters, 77–78, 78freplacement of lost cells by, 68–69, 68f

Mitotic index, 68, 68fMitotic recombination assay, 331tMivacurium, biotransformation, 139Mixed lymphocyte response (MLR), 435MK-0571, 195MLE. See Maximum likelihood estimateMLR. See Mixed lymphocyte responseMMA. See Monomethyl arsenicMMAD. See Mass median aerodynamic

diameterMMT. See Methylcyclopentadienyl

manganese tricarbonylMNNG, impairment of cellular

maintenance, 59tMOAT. See Multiple organic anion transporterModeling, ecotoxicology, 1030–1034Mode of action information, 96MOE. See Margin of exposureMolds

food-borne, 1075–1078, 1077toccupational disease, 1127t

Moldy corn poisoning, 970Molecular epidemiology, 91, 1020Molecular repair, 64–67, 64f

of DNA, 65–67of lipids, 65, 66fof proteins, 65, 65f

Molecular toxicology, 3Molindone, cardiotoxicity, 622Molybdate

cellular uptake, 816reabsorption, 39

Molybdenum, 844–845deficiency, 844–845reproductive system toxicity, 695toxicity, 845toxicokinetics, 844

Molybdenum hydroxylase, 156–160, 157fMolybdozyme. See Molybdenum hydroxylase

Mometasone, cardiotoxicity, 627–628Momorcharins, 973–974Monkshood, 56

cardiotoxicity, 6296-Monoacetylmorphine, 1101

forensic urine drug testing, 1100tMonoamine oxidase (MAO), 41, 136t,

159, 160–161, 160f, 179, 544,545f, 840, 1066

MAO-A, 160–162MAO-B, 160–162, 161f, 545, 546focular, 566t, 570

Monoamine oxidase inhibitors, 56reproductive system toxicity, 685t, 688

Monochlorodifluoromethane,cardiotoxicity, 630t

Monocrotaline (MCT), 968biotransformation, 172hepatotoxicity, 478, 479tlung damage caused by, 529–530

Monocrotophos, poisoning, 777Monocyte(s), 391, 399, 421f, 421t, 422,

422t, 518Monocyte chemotactic protein, 69f, 705�-Monodeiodinase, inhibition, 731–733,

732–733fMonoethylglycinexylidide (MEGX), 1104Mono-2-ethylhexyl phthalate (MEHP), 63

reproductive system toxicity, 677, 681,689t, 693

Monoglycerides, in food, 1055–1057tMonomethyl arsenic (MMA), 819Monomethylarsenic acid, 1135Mononuclear phagocyte system, 391Monooxygenase, 364Monosodium glutamate, 558

in food, 1055tMoray eel poisoning, 1079Moricizine

cardiotoxicity, 613, 614tclinical uses, 605

Morphine, 46, 1094biotransformation, 135–136, 176,

199–201, 199fcellular dysregulation, 54tdistribution, 123excretion, 39forensic urine drug testing, 1100timmunosuppression by, 449–450maggot analysis, 1094poisoning, 1093presystemic elimination, 37reproductive system toxicity, 685t

Morphine sulfate, LD5, 13tMOS. See Margin of safetyMoths, 953Motor activity tests, 542Motor neuron demyelination, 972Motor Vehicle Air Pollution Control Act, 980Mouse ear-swelling test, 455Mouse embryonic stem cell test, 372, 373tMouse heritable translocation assay, 331t, 342Mouse local lymph node assay, 88, 455Mouse lymphoma L5178Y assay, 288,

289t, 291fMouse model, ovarian tumors in mutant

strains, 751

Mouse ovarian tumor test, 373tMouse sex-chromosome loss test, 342Mouse skin tumor promotion, 668–669Mouse specific-locus test, 331t, 337, 341Mouse spot test, 337Moxifloxacin, cardiotoxicity, 615t, 621MPP. See 1-Methyl-4-phenylpyridineMPT. See Mitochondrial permeability transitionMPTP. See 1-Methyl-4-phenyl-1,2,3,

6-tetrahydropyridineMRL. See Minimal risk levelMSH. See Melanocyte-stimulating hormoneMTBE. See Methyl tertiary-butyl etherMTD. See Maximum tolerated doseMTF. See Metal-responsive element-binding

transcription factorMucinain, 966Mucociliary clearance, respiratory tract, 117,

516, 521–522, 999effect of sulfuric acid, 996

Muconaldehyde, 889, 890ft,t-Muconic acid, 891Muconic aldehyde, biotransformation, 41tMucosa-associated lymphoid tissue (MALT),

420t, 421Muller, H.J., 321Mullerian duct, 675Müllerian inhibiting factor (MIF), 675Multidrug-resistant protein (MDR), 110, 111t,

122–124, 125f, 126, 127f, 475, 475f,486, 536. See also P-glycoprotein

Multigeneration test, 31, 370, 701, 703, 1021Multihit model, 95Multiple chemical sensitivity syndrome, 461Multiple-dose activated charcoal,

1116–1117, 1117tMultiple organic anion transporter (MOAT),

475–476, 475fMultistage models

of carcinogenesis, 296–297, 297f, 304,304f, 743, 743f

of neoplastic development, 294tMumps, 704Munchausen syndrome by proxy, 1100Murphy, Sheldon, 8Muscarine, 972

neurotoxicity, 556tMuscarinic acetylcholine receptor, 54–55t,

56–57, 775, 779–780, 972Muscimol, 971

cellular dysregulation, 54tMuselergine, Leydig cell tumor development

and, 746, 748tMushroom, poisonous, 970, 972Musk ambrette, in photopatch test, 664tMusk xylene, 196

biotransformation, 145Mussel Watch, 1030Mustard gas, 5

absorption, 115genetic effects, 336respiratory tract damage caused by, 525

Mutagen(s), environmental, 1025Mutagenesis

carcinogenesis and, 255–257mechanisms, 257process, 256

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radiation and, 924–925Mutagenesis assay, 256, 288–293, 288t, 290f

in vivo, 288–290, 289tMutagenicity. See also specific compounds

determination, 31–32, 87, 342genotoxicity versus, 321

MutaMouse, 338Mutation, 32, 73, 73f, 323

background, 329carcinogenesis and, 271dominant, 324fixation, 266formation

in germ cells, 329–330, 329fin somatic cells, 328–329

in germ cells, 324, 341induction in transgenes in vivo, 289–290,

289t, 292fmolecular analysis, 345point, 9in proto-oncogenes, 73–75, 74f, 272, 323recessive, 324spontaneous, 77in tumor-suppressor genes, 75, 75f, 323

Mutation rate, 1025MVK model, 304, 304fmyc gene, 75, 272t, 276, 277f, 888Mycotoxins

in food, 1075–1078, 1077timmunosuppression by, 446nephrotoxicity, 509

Myc protein, 49, 52, 74f, 274Myelin, formation and maintenance,

539–541, 541fMyelin basic protein, 540Myelinopathy, 540f, 541, 552–555, 553tMyelin sheath, 538Myelodysplastic syndrome, 402Myeloid body, 510Myeloperoxidase, 48, 70, 162, 165–166,

165f, 168f, 891Myocardial infarction, 599, 603, 610Myocardial ischemia, 606–607, 608fMyocardial stunning, 606–607Myocytes, cardiac, 598–603, 599f

apoptosis, 603, 610–611, 611f,612t, 619–620

death, 607Myoglobin, 646Myosin, cardiac, 598Myristicin, 1071tMyxothiazole, impairment of cellular

maintenance, 59t

NNAAQS. See National Ambient Air

Quality StandardsNabam, 797t, 799NAC. See N-AcetylcysteineNADH dehydrogenase, 693NADH-diaphorase. See Cytochrome b5

methemoglobin reductaseNAD(P)H oxidase, 40, 70NAD-nucleotidase, snake venom, 957t, 959Nadolol

absorption, 114, 114t

excretion, 114NADPH-cytochrome P450 reductase, 147–148,

148f, 173–174, 194, 519, 523, 554NADPH-quinone oxidoreductase, 149Nafarelin, adrenal toxicity, 720Nafcillin, neutropenia and, 402tNafenopin, as promoting agent, 268, 268f, 275tNalidixic acid

oxidative hemolysis and, 397tphototoxicity, 663t

Naloxone, 17biotransformation, 199fcellular dysregulation, 54t

Nandrolone, cardiotoxicity, 626t, 627NAPA. See N-AcetylprocainamideNAPBQI, impairment of cellular

maintenance, 60tNaphthalene, 193

biotransformation, 159, 215fimmunosuppression by, 442lung damage caused by, 529ocular toxicity, 566t, 577oxidative hemolysis and, 397tvasculotoxicity, 639

Naphthalene dihydrodiol, ocular toxicity, 577Naphthalene 1,2-oxide, biotransformation, 141f�-Naphthoflavone, 149, 193–194, 193tNaphthoic acid, biotransformation, 203Naphthol, biotransformation, 199–201,

199f, 203tNaphthoquinone, biotransformation, 187Naphthylacetic acid, biotransformation, 2032-Naphthylamine

biotransformation, 44, 189tcarcinogenicity, 242, 244, 244f, 252, 254,

260, 260t, 284, 285toccupational disease, 1127t

�-Naphthyl-isothiocyanate (ANIT), 70hepatotoxicity, 476t, 483, 486impairment of cellular maintenance, 64

�-Naphthyl thiourea (ANTU), 800f, 801NAPQI. See N-Acetylbenzo-p-quinoneimineNaproxen

biotransformation, 199fnephrotoxicity, 510

Nararelin, Leydig cell tumor developmentand, 748t

Narcotine, poisoning, 1093Naringenin, 1066Nasal decongestants, 1101–1102

cardiotoxicity, 614tNasal passages, 516, 517f

cancer, 525formaldehyde and, 1005

clearance of particle from, 521–522Nasopharyngeal region, 116, 116fNational Academy of Sciences, lifetime

environmental lung cancer risk fromradon, 935

National Ambient Air Quality Standards(NAAQS), 981t

areas not in compliance with, 979, 980fNational Center for Toxicologic Research

(NCTR), 9National Council on Radiation Protection and

Measurements (NCRP), lifetime lungcancer risk from radon, 925

National Environmental Policy Act (NEPA),86t

National Institute for Occupational Safety andHealth (NIOSH), 653

recommended exposure limits, 1125National Institute of Environmental Health

Sciences (NIEHS), 9, 99National Institute of Health (NIH), lifetime

environmental lung cancer risk fromradon, 935

National Pollutant Discharge and EliminationSystem (NPDES) permit, 1028

National Research Council (NRC), 83National Safety Council, 7National Toxicology Program (NTP),

91, 1061, 1150classification of Leydig cell tumors,

743–744fertility assessment, 703

National Toxicology Program (NTP) test, 434National Toxicology Program (NTP) tier

approach, 435, 436tNatural killer cells, 421f, 421t, 422, 422t,

433Natural rubber latex, hypersensitivity

reaction to, 458NCRP. See National Council on Radiation

Protection and MeasurementsNCTR. See National Center for

Toxicologic ResearchNecessary risk, 306Necrosis, 61, 63, 64f, 67, 676, 679f

cardiac myocytes, 610liver cell, 477tissue, 71–72

NED. See Normal equivalent deviationNegative selection, 883Nelfinavir


Neoantigen, formation, 47–48, 202Neocarzinostatin, genetic effects, 329Neomycin

allergic contact dermatitis from, 660–661tmegaloblastic anemia and, 393t

Neonicotinoids, 788Neoplasia, 242

pathogenesis, 266–271Neostigmine, 781NEP. See Neutral endopeptidaseNEPA. See National Environmental Policy ActNephropathy

�2u-globulin, 900–902, 1132toxic, incidence and severity, 499

Nephrotoxicity, 491–512of cadmium, 824of chromium, 827of cisplatin, 853of halogenated hydrocarbons, 508–509of heavy metals, 506–507of lead, 831–832, 833tof mycotoxins, 509of therapeutic agents, 509–512of 1,1,2-trichloroethylene, 883

Nerium, 968Nerve gas, 774. See also Anticholinesterase

agents

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Nerve growth factor (NGF), 677–678tadrenal toxicity, 723, 723f

Nervous systemaxonal transport, 537–539, 537fblood-brain barrier, 535–536, 536fdevelopment, 541–542, 541fenergy requirements, 536–537myelin formation and maintenance,

539–541, 541fneurotransmission, 541occupational disease, 1130overview, 535–542toxic effects of plants, 971–972toxic responses, 535–558

Netilmicin, cardiotoxicity, 615t, 621neu gene, 272tNeural crest, 358, 735, 737Neural plate, 358Neural tube, 541fNeuritis

optic, 584retrobulbar, 584

Neuroasthenic syndrome, 871Neurobehavioral effects, of lead, 829–830Neurodegenerative disease, 545–546Neuroendocrine immunology, 430, 430f, 431tNeurofibrillary tangles, 849–850Neurofilaments, 538Neurohypophyseal system, 712Neurohypophysis, 713Neurokinin receptor, 903Neuromuscular junction, plant chemicals

blocking, 972Neuron, peripheral, cellular repair, 67Neuronopathy, 539, 540f, 542–546, 543tNeuropathic target esterase (NTE), 16, 551,

778aged enzyme, 779

Neuropeptides, immune effects, 430Neuropeptide Y, 720Neurophysin, 713Neuropsychological evaluation, 871–872, 872tNeurotensin, 720Neurotoxicants, retinotoxicity, 580–583Neurotoxicity, 535–558

of aluminum, 849assessment, 542axonopathy, 546–552, 548tof cadmium, 825functional manifestations, 542of lead, 829–830, 833tof mercury, 836myelinopathy, 552–555, 553tneuronopathy, 542–546, 543tneurotransmission-associated,

555–558, 556tNeurotransmission, 541Neurotransmission-associated neurotoxicity,

555–558, 556tNeurotransmitter(s), 541

alterations in levels, 56immune effects, 430

Neurotransmitter receptor, toxicant-receptorinteractions, 56

Neutraceuticals, 618, 627Neutral endopeptidase (NEP), 903Neutropenia, 400

idiosyncratic toxic, 400–401toxic

immune-mediated, 401, 402tmechanisms, 401, 402tnonimmune-mediated, 401, 402t

Neutrophil(s), 399, 421fcirculating, 400marginated pools, 400

Neutrophil count, 399Newborn, withdrawal symptoms, 1104Newborn mouse model, of chemical

carcinogenesis, 296NF1 gene, 272tNF-B, 52, 70, 610, 611f, 642NGF. See Nerve growth factorNicardipine

biotransformation, 185tthyroid toxicity, 729, 734, 734f

Nickel, 37t, 47, 837–839allergic contact dermatitis from, 659, 660tcarcinogenicity, 245, 246t, 285t, 838cardiotoxicity, 629, 630tessentiality, 838exposure, 837hypersensitivity reaction to, 457immune reactions to, 815immunosuppression by, 444indicators of toxicity, 839occupational disease, 1127t, 1128respiratory tract damage caused by,

525, 528ttoxicity, 838–839toxicokinetics, 837–838vasculotoxicity, 644

Nickel carbonyl, 838carcinogenicity, 244f, 245poisoning, 838treatment of poisoning, 817–818

Nickel chloride, 837Nickel dermatitis, 838–839Nickeloplasmin, 838Nickel oxide, 837Nickel subsulfide, 837Nickel sulfate, 837

allergic contact dermatitis from, 661thypersensitivity reaction to, 457

Nicotinamide, biotransformation, 207Nicotinamide N-methyltransferase, 207Nicotine, 972

adrenal toxicity, 720biotransformation, 159, 169–172, 169f,

176–177, 180, 181f, 184t, 186,206–207, 206f

cellular dysregulation, 54tdevelopmental effects, 355, 357as insecticide, 789–790LD5, 13tneurotoxicity, 555–557, 556tas pesticide, 763poisoning, 790transdermal delivery, 656vasculotoxicity, 636t, 639, 643t

Nicotine-1�-N-oxide, biotransformation, 160Nicotinic acetylcholine receptor, 54t, 56, 555,

557, 720, 779–780, 789, 972Nicotinic acid, 195, 207NIEHS. See National Institute of

Environmental Health SciencesNifedipine, biotransformation, 180, 181f, 185tNigrosine, allergic contact dermatitis from, 660tNIH. See National Institutes of HealthNIH shift, 175NIOSH. See National Institute for Occupational

Safety and HealthNIOSH Manual of Analytical Methods, 1136Nisin, 1081

in food, 1055tNissl substance, 537Nitrate, 113, 305

biotransformation, 42in food, 1075, 1076t, 1081methemoglobinemia and, 395tvasculotoxicity, 643t

Nitrazepam, biotransformation, 209Nitric acid, ocular toxicity, 575Nitric oxide, 42, 69f, 70, 503, 607f, 610–611,

611f, 667, 685air pollution, 999binding to heme, 396lung damage caused by, 519–520methemoglobinemia and, 395tvasculotoxicity, 640, 642t

Nitric oxide synthase, 42, 60, 61f, 70, 173,611, 611f

Nitriloacetic acid, carcinogenicity, 89Nitrilotriacetic acid, 41

carcinogenicity, 89tin food, 1065

Nitrite, 113, 305–306carcinogenicity, 282in food, 1075, 1076tmethemoglobinemia and, 394, 395turine adulterant, 1101, 1101tvasculotoxicity, 643t

4-Nitroacetophenone, biotransformation, 145Nitroaromatics, vasculotoxicity, 645Nitrobenzaldehyde, biotransformation, 154Nitrobenzene

biotransformation, 144fimmunosuppression by, 445methemoglobinemia and, 395toxidative hemolysis and, 397t

Nitro compounds, carcinogenicity, 254Nitroethane, methemoglobinemia and, 395t5-Nitrofuran, biotransformation, 165Nitrofurantoin

biotransformation, 40, 42f, 148lung damage caused by, 519neurotoxicity, 548tovarian tumor development and, 749–750,

750f, 750t, 752oxidative hemolysis and, 397tultimate toxicant, 37t

Nitrofurazone, coagulation factor inhibitordevelopment and, 406t

Nitrogen dioxide, 40, 42, 46fair pollution, 993, 1003–1005chronic effects, 1004general toxicology, 1003–1004immunosuppression by, 445inflammation of lung and host defense, 1004National Ambient Air Quality Standards,

981tpulmonary function effects, 1004

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respiratory tract damage caused by,522–523, 525

Nitrogen mustard, 47biotransformation, 190, 190fcarcinogenicity, 244, 244f, 262developmental effects, 352mutagenicity, 257reproductive system toxicity, 691t, 693t

Nitrogen oxidesair pollution, 987, 987f, 1000lung damage caused by, 528toccupational disease, 1127tskin burns, 658t

Nitroglycerinabsorption, 111biotransformation, 214methemoglobinemia and, 395toccupational disease, 1127ttransdermal delivery, 656

Nitromethylenes, 788–789, 789f2(Nitromethylene) tetrahydro-1,3-thiazine,

789, 789f4-Nitrophenol, biotransformation, 184t, 188,

199, 199f, 2054-Nitrophenol hydroxylase, 1963-Nitropropionic acid (3-NP)

in food, 1077timpairment of cellular maintenance, 59tneurotoxicity, 537, 543t

Nitroprusside, 421-Nitropyrene, biotransformation, 160, 189t4-Nitroquinoline 1-oxide

biotransformation, 214fcarcinogenicity, 73

Nitroreductase, 144, 145fNitro-reduction, 144–145, 144–145fNitrosamides, in food, 1075, 1075tNitrosamines, 113, 305

biotransformation, 184t, 190fcarcinogenicity, 250, 254, 282in food, 1075, 1075timmunosuppression by, 441lung damage caused by, 525–526percutaneous absorption, 655reproductive system toxicity, 683t

Nitrosation, 282N-Nitroso-bis-2-oxopropylamine,

carcinogenicity, 274tN-Nitrosodiethanolamine, percutaneous

absorption, 655N-Nitrosodimethylamine (DMN)

biotransformation, 189t, 190immunosuppression by, 441lung damage caused by, 526

N-Nitrosomorpholine, 77, 96Nitrosonitrotoluene, vasculotoxicity, 645Nitrosoperoxycarbonate, 42N-Nitrosoproline, 1075N-Nitroso substances, in food, 1075, 1075tNitroso-sulfamethoxazole, biotransformation, 41tNitrosourea

effect on granulocytes, 400leukemia and, 402

Nitrotolueneimmunosuppression by, 445methemoglobinemia and, 395t

3-Nitrotyrosine, 46f

Nitrous oxide, in food, 1056tNMDA receptor, 893, 971NNK

biotransformation, 177, 177f, 188, 189tcarcinogenicity, 244f, 245lung damage caused by, 526

NOAEL, 22, 24, 28, 91–94, 92f, 376–377Nocodazole, genetic effects, 330NOEC, 1028NOEL, 1142

for food additives, 1059Nonabsorbed ingesta, 126Nonanoic acid, irritant dermatitis from, 657Noncovalent binding, of toxicant to target

molecule, 45Nondisjunction, 675Nonenal, vasculotoxicity, 639Nongenotoxic carcinogen, 278–280,

279t, 322Nonhomologous end-joining, 262t, 263,

264f, 328Non-Indian childhood cirrhosis, 841Nonmetals, analytic toxicology, 1090Nonnucleoside reverse transcriptase inhibitors,

cardiotoxicity, 622Nonnutrient substances, in food, 1051, 1052tNonnutritive sweeteners, 1056tNonradiomimetic chemicals, 330Nonsteroidal anti-inflammatory drugs

(NSAIDs)nephrotoxicity, 496t, 499, 510phototoxicity, 663tvasculotoxicity, 639

Nonthreshold response, 94–95Nonvolatile organic substances, analytic

toxicology, 1090–1091, 1091f“No observed adverse effect level.”

See NOAEL“No observed effect concentration” (NOEC),

1028“No observed effect level.” See NOELNorepinephrine, 56, 604, 720, 723

biotransformation, 160, 207cardiotoxicity, 614t, 618–619immune effects, 431tvasculotoxicity, 639, 643t

Norethindrone, cardiotoxicity, 625, 626tNorethynodrel, cardiotoxicity, 625, 626tNorfloxacin, cardiotoxicity, 621Norgestimate, cardiotoxicity, 625, 626tNorgestrel, cardiotoxicity, 625, 626tNormal equivalent deviation (NED), 19Normal frequency distribution, 18–19Norrie disease, 16119-Nortestosterone, 692Nortriptyline

biotransformation, 185ttherapeutic monitoring, 1105t

Nose breather, 516Novel foods, 10633-NP. See 3-Nitropropionic acidNPDES. See National Pollutant Discharge and

Elimination SystemNRC. See National Research CouncilNSAIDs. See Nonsteroidal anti-inflammatory

drugsNTE. See Neuropathic target esterase

NTP. See National Toxicology ProgramNuclear weapons testing, 931Nucleic acids, carcinogens bound to,

257, 258fNucleophile

detoxication, 43formation, 42hard, 45, 45tsoft, 45, 45t

5�-Nucleotidase, snake venom, 957t, 959Nucleotide excision repair, 66, 261–262,

262t, 263f, 264t, 327Nucleotide transporter, 111tNuisance dusts, 529Numerical chromosome changes, 330Nutrient, 1051

essential, dose-response relationship, 20, 21fNutrition, in pregnancy, 366, 366fNutritive sweeteners, 1056tNux vomica, 763

OObidoxime, treatment of organophosphate

poisoning, 783Objective testimony, 1102Obstructive airway disease, 531fOccupational disease, 1127–1128t

cardiovascular, 1130historical aspects, 5, 7nervous system, 1130respiratory, 1126–1130, 1127–1128troutes of exposure, 1126

Occupational exposure, 515EPA regulation of industrial chemicals,

1145–1146, 1149–1150recommended limits, 1155–1176

Occupational exposure limit (OEL),1125–1126, 1134

Occupational risk assessment, 1131–1132animal tests, 1132case reports, 1132, 1134epidemiology study, 1132, 1134–1135establishing causality, 1131–1132, 1131fhuman challenge studies, 1132, 1134–1135in vitro assays, 1132

Occupational Safety and Health Administration(OSHA), 12, 86t, 99, 304–305, 305t,1126, 1142

permissible exposure limits, 1125regulatory programs, 1147

Occupational toxicology, 1089, 1123–1138animal tests, 1135

for establishing acceptable levels ofexposure, 1132–1133

dermal exposure, 1124–1126determinants of dose, 1124–1125,

1125f, 1125tevaluation of occupational agents,

1131–1135exposure limits, 1125–1126exposure monitoring

biological monitoring, 1136–1138, 1137tenvironmental monitoring, 1136

ingestion, 1126inhalation exposure, 1124, 1126, 1133nature of work force, 1123–1124

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Occupational toxicology (continued)worker health surveillance, 1133–1135

Occupation-associated carcinogens, 284, 285tOcean Radioactive Dumping Ban Act, 86tOchratoxin

carcinogenicity, 301fdistribution, 38excretion, 128in food, 1077timmunosuppression by, 446impairment of cellular maintenance, 63nephrotoxicity, 500, 509

Octafluorocyclobutane, cardiotoxicity, 630tOctamethylcyclotetrasiloxane, 194

biotransformation, 178, 178fimmunosuppression by, 451

Octanol/water partition coefficient, 109,109t, 655

n-Octylamine, biotransformation, 171Octyl dimethyl p-aminobenzoic acid,

in photopatch test, 664tOctyl methoxycinnamate, in photopatch

test, 664tOctyl salicylate, in photopatch test, 664tOcular fundus, 572Ocular irritants, 575

testing of irritancy, 571–572Ocular system. See also Visual function

drug metabolism, 570–571pharmacodynamics, 567–570, 569–570fpharmacokinetics, 567–570, 569–570ftarget sites

cornea, 575–576lens, 576–577optic nerve and tract, 584–586retina, 577–584

toxic responses, 565–587xenobiotic transforming enzymes, 566t,

570–571Ocular toxicity. See also Retinotoxicity

of acids, 575of acrylamide, 584–585of bases, 575–576of carbon disulfide, 585of corticosteroids, 577of ethambutol, 586of light, 577of methanol, 894–895of naphthalene, 577of organic solvents, 576of phenothiazines, 577of surfactants, 576

OECD. See Organization for EconomicCooperation and Development

OEL. See Occupational exposure limitOflaxacin

biotransformation, 176cardiotoxicity, 621

Oil acne, 665Okadaic acid, 1079

cellular dysregulation, 52as promoting agent, 275, 275t, 669

Olanzapine, biotransformation, 167, 169Oleander, 1084

cardiotoxicity, 629Oleandrin, 968

cellular dysregulation, 55t

Olfactory epithelium, 516Oligodendrocytes, 539Oligomycin

cardiotoxicity, 609fimpairment of cellular maintenance, 59t

Olsalazine, 208Oltipraz, 216–217Omeprazole, 183, 186, 193

biotransformation, 176, 177f, 182–183,184–185t, 187, 192

megaloblastic anemia and, 393tOmethoate, poisoning, 777–778Oncogenes, 73, 271–273, 272t, 323

activation, 323–324functions, 272, 272t

Oncosisof cardiac myocytes, 610–611, 611f, 612tin renal cell injury, 502–504, 503f

Ondansetron, biotransformation, 185tOne-compartment model, 225–226, 226–227fOne-hit linear model, 95Oocytes, 685–686Oogenesis, 329–330, 329f, 679f, 685–686, 685f

evaluation, 699Open epicutaneous test, 28Ophthalmologic evaluation, 572Opiate(s)

analytic toxicology, 1096forensic urine drug testing, 1100t, 1101poisoning, 1103t

Opiate receptor, 46OPIDN. See Organophosphate-induced

delayed neurotoxicityOpinion (courtroom testimony), 1102Opioid(s), immunosuppression by, 449–450Opioid agonists, poisoning, 1114Opioid receptor, 54t, 449Opioid syndrome, 1111, 1111tOpium, 3OPPTS 870.7800, 436Opsonins, 71Opsonization, 399, 423Optic nerve, 568f, 569

toxic responses, 584–586Optic neuritis, 584Optic neuropathy, 584

Cuban epidemic, 585–586Optic tract, toxic responses, 584–586Optimization test, 28Oral contraceptives

carcinogenicity, 285–286cardiotoxicity, 625vasculotoxicity, 635, 636t, 639–640, 644t

Orange B, 1054, 1057tOrb spinners, 949Orellanin, 41Orfila, Mathieiv J.B., 5, 1093Organelles, toxicant accumulation, 38Organic-anion transporter, 110, 111t, 124,

125f, 126, 506Organic-anion transporting peptide family,

110, 111t, 126, 127fOrganic-cation transporter, 111, 111t, 124,

125f, 126, 127fOrganic chemical carcinogenesis, 243–245,

243–244fOrganic food, 1082

Organic lead, 833–834toxicity of, 833–834toxicokinetics, 833

Organic solvents. See SolventsOrganic solvent syndrome, 871–872Organization for Economic Cooperation and

Development (OECD), 91guidelines for testing reproductive toxicity,

701, 702tOrganochlorines, 769–774

biotransformation, distribution, andstorage, 774

classification, 770tecotoxicology, 1017t, 1024immunosuppression by, 441–442poisoning, 770–772, 771treproductive system toxicity, 693, 701site and mechanism of toxic actions,

772–774, 773–774ftreatment of poisoning, 774

Organogenesis, 358, 364Organomercury, occupational disease, 1130Organometallic compounds, 814Organophosphatase, 137, 138f, 139Organophosphate(s), 8, 11, 16–17, 23, 44,

774–784, 775fbiotransformation, distribution, and storage,

781–782, 781fcellular dysregulation, 56–57ecotoxicology, 1022–1023, 1026immunosuppression by, 441mechanism of toxic action, 779–781,

779–780f, 780tneurotoxicity, 548t, 551occupational disease, 1127t, 1130percutaneous absorption, 655poisoning, 775–779, 776treproductive system toxicity, 685, 693retinotoxicity, 584structure, 775ftreatment of poisoning, 782–784, 783f, 783tvasculotoxicity, 641t

Organophosphate-induced delayedneurotoxicity (OPIDN), 777–778, 777f

Organotin, immunosuppression by, 442, 443Organotypic cell culture system, 532Ornithine transcarbamylase, 1072tOronasal breather, 516Orphan Drug Act, 1117Oser, Bernard L., 7OSHA. See Occupational Safety and

Health AdministrationOsmium, 852Osmium tetroxide, 852Osmol gap, 1113

calculation, 1113elevated, 1119

differential diagnosis, 1113tOsteocalcin, 408Osteogenic sarcoma, 926Osteopontin, 642Osteoporosis, 829

heparin and, 408Ouabain, 1084

octanol/water partition coefficient, 109tretinotoxicity, 579–580

Ouabain resistance, 337

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Outdoor air pollution, 988–992, 989f,993–1007

accidental versus fence-line exposures,1006–1007

acute and episodic exposures, 988–990long-term exposures, 990–992, 991–992f

Outer-ring deiodinase, 729“Outrage factor,” 85Ovarian atrophy, 749Ovarian cycle, 686, 686fOvarian function

drugs that interfere with, 688, 689toogenesis, 685–686, 685fovarian cycle, 686, 686f

Ovarian tumor, 746–753associated with xenobiotics, 749–751mechanisms of tumorigenesis in rodents,

747–748in mutant strains of mice, 751–752tumorigenesis in rodents, 752–753,

752–753fOvary

biotransformations, 691, 691tdevelopment, 675endocrine functions, 746–753

Overnutrition, carcinogenicity, 283Overweight, carcinogenicity, 283Oviducts, 686Ovulation, 686, 692

evaluation, 701Ovum, 687�-N-Oxalylamino-L-alanine (BOAA), 971

neurotoxicity, 556tOxandrolone, cardiotoxicity, 626t, 627Oxazepam

biotransformation, 199f, 201thyroid toxicity, 734, 734f

Oxidant gases, immunosuppression by, 445Oxidation, 135, 136t, 152–196Oxidative burden, lung injury and, 519–520Oxidative dehalogenation, 150–151, 152fOxidative group transfer, 171Oxidative hemolysis, 397–398, 397f, 397tOxidative phosphorylation, 57–58, 58f, 71

in cardiac myocytes, 609, 609fOxidative stress, 266, 503, 503f, 511

mechanisms of cardiotoxicity, 607–608,607f, 612t

N-Oxide reduction, 146–147, 147fOxidizing agents, in food, 1056tOximes

biotransformation, 160treatment of organophosphate poisoning,

783, 783f, 783t8-Oxoguanine, 327Oxolinic acid, reproductive system

toxicity, 683tOxotremorine, cellular dysregulation, 55tOxybenzone, in photopatch test, 664tOxycarboxin, 797tOxygen

lung damage caused by, 529vasculotoxicity, 642t, 647

Oxyhemoglobin, 40, 46, 394Oxymetholone

carcinogenicity, 248, 249f, 286tcardiotoxicity, 626t, 627

immunosuppression by, 447Oxypurinol, cardiotoxicity, 614t, 618Oxytocin, 678t, 713Ozone, 68

air pollution, 987, 989, 999–1000,1000–1003

chronic effects, 1002–1003general toxicology, 1000–1001immunosuppression by, 445inflammation of lung and host defense, 1002interactions with copollutants, 1003lung damage caused by, 519–520, 522–523,

525, 528tNational Ambient Air Quality Standards,

981tparathyroid toxicity, 739pulmonary function effects, 1001–1002reactions with lipids in lung, 1001, 1001frespiratory system effects, 1001tolerance, 1003vasculotoxicity, 642t, 647

Pp16 protein, 74f, 75p21 protein, 68, 74f, 75, 75fp27 protein, 74f, 75p38 reactivating kinase, 604, 605fp53 gene, 26, 47, 68f, 272t, 276, 277f,

323, 361, 668p53 protein, 62f, 63, 68, 74–75f, 75–76,

610, 611fPABA. See p-Aminobenzoic acidPacemaker cells, 600Packaging materials, for food, 1061,

1061t, 1144Paclitaxel, 46, 965

absorption, 113biotransformation, 184t, 186genetic effects, 330neurotoxicity, 548t, 552, 552f

PAH. See Polycyclic aromatic hydrocarbonsPainter’s syndrome, 871–872Pair production, 920–921, 921tPalladium, 852Palladium chloride, 852Palm kernel oil, 1055tPalytoxin, 1079Pamidronate, adrenal toxicity, 720PAN. See Peroxyacetyl nitratesPancreastatin, 739Pancreozymin, 736Panel study, 982, 990Panic value, drug monitoring, 1106PAP. See p-AminophenolPapain, hypersensitivity reaction to, 458PAPS. See 3�-Phosphoadenosine-

5�-phosphosulfatePap test, 686Paré, Ambrois, 351Parabens, 1081Paracelsus, 4–5, 13Paragyline, 162Paraldehyde, poisoning, 113t, 1116tParallelogram approach, to risk assessment,

325, 325fParalytic shellfish poisoning, 1078

Paramethasone, cardiotoxicity, 627–628Paraoxon, 775

biotransformation, 41t, 137, 138fpoisoning, 778

Paraoxonase, 137–144Paraquat, 161, 161f, 793–795

biotransformation, 40, 42f, 148, 793distribution, 38excretion, 126immunosuppression by, 442impairment of cellular maintenance, 59tlung damage caused by, 519, 522–523, 529occupational disease, 1127toctanol/water partition coefficient, 109tpoisoning, 793presystemic elimination, 37structure, 793ftreatment of poisoning, 794ultimate toxicant, 37tvasculotoxicity, 641t

Parasympathetic nervesblockade by plant chemicals, 972stimulation by plant chemicals, 972

Parathion, 17, 775aplastic anemia and, 394tbiotransformation, 40, 139, 178–179f,

179–180, 189, 781immunosuppression by, 441octanol/water partition coefficient, 109tpoisoning, 777–778

Parathyroid glandage-related changes, 741chemical-induced toxic injury, 739–740proliferative lesions of chief cells, 740–741structure and function of chief cells,

737–739, 738fParathyroid hormone (PTH), 737–741, 738f

biosynthesis, 737–738, 738fcontrol of secretion, 738–739, 739f

Parathyroid secretory protein, 723,738–739f, 739

Parenteral administration, 14, 111, 140Pargyline, 161

biotransformation, 176Paris Green, 764Parkinsonism-dementia syndrome of Guam, 850Parkinson’s disease, 161–162, 207,

545–546, 844Paroxetine


Paroxysmal nocturnal hemoglobinuria, 399PARP. See Poly(ADP-ribose)polymerasePars intermedia, 712Particulate matter

air pollution, 987, 989–991, 997–999, 1000chronic effects and cancer, 998–999clearance from respiratory tract, 521–522

nasal passages, 521–522pulmonary clearance, 522tracheobronchial clearance, 522

deposition in respiratory tract, 520–521, 520fdeposition mechanisms, 521particle size and, 520–521

gas-particle interactions, 997–998lung overload caused by, 529in lungs, 116–117

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Particulate matter (continued)metals, 997National Ambient Air Quality Standards, 981tsize of particles

count median diameter, 521mass median aerodynamic diameter, 521

ultrafine carbonaceous matter, 998Partition coefficient, 233Parvovirus B-19 infection, 353tPassive diffusion, 1052tPassive smoking, 990Passive transport, 109–110Patch test, 456, 661, 662tPatent medicine, 6Pathogenesis, 360Patulin, in food, 1077tPBB. See Polybrominated biphenylsPBRE. See Phenobarbital-responsive elementPBTK model. See Physiologically based

toxicokinetic modelPCB. See Polychlorinated biphenylsPCBD-cys, impairment of cellular

maintenance, 59tPCDD. See Polychlorinated dioxinPCDF. See Polychlorinated dibenzofuranPCMB. See p-ChloromercuribenzoatePCN. See Pregnenolone 16�-carbonitrilePCNA. See Proliferating cell nuclear antigenPCP. See Pentachlorophenol; PhencyclidinePDGF. See Platelet-derived growth factorPEL. See Permissible exposure limitPeliosis hepatis, 478Penicillamine, 818, 821, 841

aplastic anemia and, 394tautoimmune reaction to, 461tbiotransformation, 208developmental effects, 353t, 374nephrotoxicity, 496t, 500vasculotoxicity, 643t

Penicillin, 25, 47aplastic anemia and, 394tcoagulation factor inhibitor development

and, 406tdistribution, 120fexcretion, 124–125hypersensitivity reaction to, 457–458thrombocytopenia and, 404turticaria from, 667t

Penicillinic acid, in food, 1077tPenis, 684–685Pentachlorobutadienyl-L-cysteine,

nephrotoxicity, 504Pentachloroethane, in food, 1074tPentachloroethylene, carcinogenicity, 89tPentachlorophenol (PCP), 48, 203, 796f, 798

biotransformation, 203timmunosuppression by, 441impairment of cellular maintenance, 58, 59tpoisoning, 798

Pentadecylcatechol, 661fallergic contact dermatitis from, 660t

Pentaerythritol triacrylate, 661fPentamidine

biotransformation, 184tnephrotoxicity, 496t

Pentanol, biotransformation, 153Pentazocine, poisoning, 1097f

4-Pentenoic acid, impairment of cellularmaintenance, 59t

Pentobarbitone, treatment of pyrethroidpoisoning, 787

Pentoxifylline, biotransformation, 135, 135f, 145Pentoxyresorufin, 1052tPentylenetetrazole, cellular dysregulation, 54tPeppermint oil, immunosuppression by, 450Peptidase, 136t, 140–141Peptide transporter, 111t, 124, 125fPeptidoglycan, occupational disease, 1127tPERC. See TetrachloroethylenePerchlorate, thyroid toxicity, 726, 726f, 1020Perchloroethylene. See TetrachloroethylenePercutaneous absorption, 654–656

measurements of penetration, 656transdermal drug delivery, 655–656

Percutaneous exposure, 14Perfluoroctanoate, reproductive system

toxicity, 683tPerfusion-limited compartment, 233–234, 234fPerfusion-limited transport, 233Perhexiline

biotransformation, 185timpairment of cellular maintenance, 59tneurotoxicity, 553t

Perhydroperoxy radical, 529Pericytes, 518, 632Perinatal toxicity, 31Perineural cells, 536Peripheral neuropathy, lead-related, 830Peritoneal dialysis, treatment of poisoned

patient, 1115–1116Permeability-area cross-product, 233Permethrin, 786Permissible exposure limit (PEL),

870–871, 1125data for specific chemicals, 1155–1176

Peroxidase, 40, 44f, 162–166Peroxidase-dependent co-oxidation,

162–166, 163fPeroxide ion, 254f, 893Peroxide shunt, 174, 174fPeroxisome proliferation, 883Peroxisome proliferator(s), 77, 193t, 275t,

279, 294Peroxisome proliferator-activated receptor

(PPAR), 46, 49, 50t, 195–196Peroxisomicine A2, 972Peroxyacetyl nitrates (PAN), air pollution, 999Peroxyl radical, 165, 167fPeroxynitrate, 519Peroxynitrite, 43, 47, 59t, 60, 70, 254, 503,

529, 607f, 610, 611fPerphenazine, cardiotoxicity, 622Personal hygiene products, hypersensitivity

reaction to, 458Personal protective equipment,

1124–1125, 1137Personal sampler, 1136Pertechnetate, thyroid toxicity, 726Perthane, 770tPerylene, carcinogenicity, 243fPesticides

botanical insecticides, 789–790carcinogenicity, 1145coagulation factor inhibitor development

and, 406tdefinition, 763dose-effect curve, 767, 768fecotoxicological assessment criteria, 1036tecotoxicology, 1017t, 1026EPA regulation, 1145EPA toxicology requirements, 1149exposure, 767–769, 767f

accidental or suicidal, 767bystander, 767, 769general public, 767occupational, 767–768, 768tprotection of hands, 769

in food, 1144frequency of poisoning, 764–765, 764ffumigants, 799–800fungicides, 796–799hazard evaluation, 85, 87therbicides, 790–796historical development, 763–766hypersensitivity reaction to, 458immunosuppression by, 441–442insecticides, 769–789quantities used in representative countries,

764, 765fregulatory mandates, 766–769, 766trodenticides, 800–802toxic effects, 763–802WHO classification, 802, 802t

P-glycoprotein, 37, 39, 110, 111t, 113pH, effect on ionization, 110Phagocytic activity, evaluation, 433Phagocytosis, 111, 117Phalloidin, 46, 970

hepatotoxicity, 476t, 479–480, 484–485impairment of cellular maintenance, 60t, 64

Pharmacodynamics, ocular, 567–570,569–570f

Pharmacogenetics, 134, 139Pharmacokinetics, 108, 225

in central visual system, 570f, 571ocular, 567–570, 569–570fin pregnancy, 363–365

Pharmacologic food reaction, 1067t,1071, 1071t

pH control agents, in food, 1056fPhenacetin, 1052t

biotransformation, 135, 164, 182–183,184–185t

carcinogenicity, 286t, 301fmethemoglobinemia and, 395toxidative hemolysis and, 397tvasculotoxicity, 639

Phenanthrene, phototoxicity, 663tPhenazopyridine

methemoglobinemia and, 395toxidative hemolysis and, 397t

Phencyclidine (PCP), 1094cellular dysregulation, 54tforensic urine drug testing, 1100tpoisoning, 1103t

Phenelzine, 161biotransformation, 160f

Phenobarbital, 17, 77, 151, 172, 182, 186, 188,193–195, 193t, 200–201, 216–217, 364

biotransformation, 184t, 207carcinogenicity, 247

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cellular dysregulation, 49, 50t, 52effect on bile flow, 127excretion, 124induction of cytochrome P450, 879inhibition of apoptosis, 77LD5, 13tmegaloblastic anemia and, 393tfor organochlorine poisoning, 774poisoning, 1115–1116, 1116–1117t

action level, 1113as promoting agent, 267, 268f, 275t, 276reabsorption, 39therapeutic monitoring, 1105tthyroid toxicity, 729–731

Phenobarbital-responsive element (PBRE),195, 217

Phenolbiotransformation, 165, 203t, 205oxidative hemolysis and, 397tskin burns, 658t

Phenol O-methyltransferase, 207Phenolphthalein, biotransformation, 199fPhenol red, distribution, 120fPhenolsulfotransferase, 164f, 204–206Phenothiazines, 193

autoimmune reaction to, 461tbiotransformation, 176cardiotoxicity, 616teffect on granulocytes, 401tmaggot analysis, 1094neurotoxicity, 555neutropenia and, 402tocular toxicity, 577

Phenothrinbiotransformation, 787poisoning, 785t

Phenotypic sex, 675–676Phenoxyacetic acid, carcinogenicity, 284, 285tPhenoxyl radical, 165, 166fPhentermine, cardiotoxicity, 618Phenylacetic acid, biotransformation, 211Phenylarsine oxide, impairment of cellular

maintenance, 60tPhenylbutazone

aplastic anemia and, 394tbiotransformation, 165, 167f, 198, 199fcoagulation factor inhibitor development

and, 406tdistribution, 120effect on granulocytes, 401t

p-Phenylenediamine, 661fallergic contact dermatitis from, 660–661t

Phenylephrine, 604cardiotoxicity, 615t, 618

Phenylethanolamine-N-methyltransferase(PNMT), 207, 720, 830

�-Phenylethylamine, biotransformation,160–161

Phenylethyl isothiocyanate, inhibition ofcytochrome P450, 879

Phenylhydrazine, oxidative hemolysis and, 397tS-Phenylmercapturic acid, 891Phenylmercuric acetate, urticaria from, 667tPhenylpropanolamine, cardiotoxicity, 615t, 618Phenylpyrazole insecticides, 788, 789, 789fPhenytoin, 186, 188, 194

biotransformation, 184t, 187, 210

carcinogenicity, 286tcardiotoxicity, 613, 614tcellular dysregulation, 55tclinical uses, 605coagulation factor inhibitor development

and, 406tdevelopmental effects, 367drug interactions, 407effect on granulocytes, 401tinduction of cytochrome P450, 879laboratory tests on stat basis, 1112tlupus anticoagulant and, 407tmegaloblastic anemia and, 393tneurotoxicity, 543tneutropenia and, 402tpure red cell aplasia and, 394therapeutic monitoring, 1105t

Pheochromocytoma, 721–723, 722–723f, 900Phidippus species, 949t, 952Phlebotomy, 843Phloroglucinol, thyroid toxicity, 726Phocomelia, 353–354Phorate, biotransformation, 170fPhoratoxin, 969Phorbol ester, 45–46, 77

cellular dysregulation, 50Phorbol myristate, adrenal toxicity, 723, 723fPhosgene, 5, 888

absorption, 115air pollution, 1007biotransformation, 41timmunosuppression by, 445nephrotoxicity, 503occupational disease, 1127trespiratory tract damage caused by, 523, 528t

Phosphatase, 52Phosphate transporter, 816Phosphatidylethanolamine, 888Phosphatidylinositol, 633fPhosphatidylinositol-4,5-bisphosphate, 632Phosphatidylinositol kinase, 274, 274f, 633fPhosphine, 799–800

biotransformation, 170fimpairment of cellular maintenance, 59toccupational disease, 1127tpoisoning, 799–800

3�-Phosphoadenosine-5�-phosphosulfate(PAPS), 203–206, 219

Phosphodiesterase, snake venom, 957t, 959Phosphodiesterase inhibitors,

vasculotoxicity, 6406-Phosphogluconate dehydrogenase, 65Phospholipase, 43, 58, 66f

in renal cell injury, 505Phospholipase A, 530Phospholipase A1, 604, 605fPhospholipase A2, 60t, 65, 505

snake venom, 957t, 958–959Phospholipase B, 530

snake venom, 957t, 958–959Phospholipase C, 274, 274f, 604, 605f,

607, 633fsnake venom, 957t, 958–959

Phospholipase D, 604, 605f, 608Phospholipid hydroperoxide, 66fPhospholipid peroxyl radical, 66fPhosphomonoesterase, snake venom, 957t, 959

Phosphonomethyl amino acids, 795–796, 795fPhosphorus, skin burns, 658tPhosphorylase, 887Phosphorylation, 219Phosphorylphosphatase, 782Phosphotriesterase, 782Photoallergy, 664, 664tPhotochemical air pollution, 987, 999Photocontact dermatitis, 664Photoelectric effect, 920Photopatch test, 664, 664tPhotosensitivity, 663–664

plants causing, 967Phototoxicity, 663–664, 663tPhototoxicology, 662–664

adverse responses to electromagneticradiation, 662–663

photosensitivity, 663–664pH paradox, 606–607Phthalate esters, 195

cellular dysregulation, 50treproductive system toxicity, 690–691

Phthalazine, biotransformation, 157fPhthalimides, 798–799Physiologically based toxicokinetic (PBTK)

model, solvents, 877Physiologic toxicokinetics. See Toxicokinetics,

physiologicPhysostigmine, 775, 781Phytates, 1051Phytoestrogens, 674, 1020

cardiotoxicity, 625developmental effects, 368

Phytophotodermatitis, 664Phytosterols, 1051PIC, air pollution, 992fPicenadol, biotransformation, 203tPickling agents, 1054tPicric acid, pigmentary disturbances from, 666tPicrotoxin, cellular dysregulation, 54t

LD5, 13tPICT. See Pollution-induced community

tolerancePig-bel, 1081Pigmentary disturbances, cutaneous,

665–666, 666f, 666tPilosebaceous duct, 119pim-1 gene, 272tPimobendan, cardiotoxicity, 614t, 617–618Pimozide, cardiotoxicity, 622Ping-pong Bi-Bi mechanism, 208, 211Pink disease, 836Pinocytosis, 111, 113, 1052tPiperonyl butoxide, 787, 789Pirbuterol, cardiotoxicity, 614t, 618Piroxicam, biotransformation, 184t, 187Pit cells, 473–474Pitch, carcinogenicity, 668Pitressin, vasculotoxicity, 636tPituicytes, 713Pituitary gland, 247

mechanisms of toxicity, 713–714morphologic alterations and proliferative

lesions of pituitary cells, 714–716,714–715f

structure and function, 712–713, 713fpKa, 110

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Placenta, 364, 687–688passage of toxicants across, 123–124,

123t, 364permeability, 687

Placental toxicity, 366f, 367Placentation, 687Plants, genetic and cytogenetic assays, 337Plant toxicity, 965–974

abortifacients, 973–974to blood, 970–971to bone, 973to cardiovascular system, 629, 968–969to gastrointestinal system, 967–968human food, 1083–1084to kidney, 970to liver, 969–970to lungs, 968to nervous system, 971–972at neuromuscular junction, 972to reproductive system, 973to skeletal muscles, 973to skin, 966–967teratogenesis, 973

Plaque-forming cell assay, 431, 432f, 433, 434fPlasma exchange, treatment of poisoned

patient, 1116Plasma proteins

as storage depots, 120–121, 120f, 121ttoxicant binding, 38

Plasma transminogen activator, 409Plasma water, 119–120Plasmin, 408Plasminogen, 408Platelet(s), 421f

toxic effects, 403–405toxin effects on function, 405

Platelet-activating factor, 69f, 70, 139Platelet-derived growth factor (PDGR),

69, 69f, 72Platinosis, 852Platinum, 848, 852–853

allergenic effects of platinum salts, 852antitumor effects of platinum

complexes, 852–853carcinogenicity, 853hypersensitivity reaction to, 457immune reactions to, 815immunosuppression by, 444mutagenicity, 853nephrotoxicity, 853occupational disease, 1128–1129reproductive system toxicity, 695t

Plicatic acid, 1129Plume event, 1031Plutonium, treatment of poisoning, 817PMN cells. See Polymorphonuclear cellsPNMT. See Phenylethanolamine-

N-methyltransferasePneumoconiosis, 527–528tPneumonitis, acute chemical, from

beryllium, 821Podophyllotoxin, 967POEA. See PolyoxyethyleneaminePoinsetta, 967Point mutation, 341Poison, definition, 13Poison control center, 1109–1110

Poison deathbody burden of drug or poison, 1098case history and specimens, 1093–1094,

1094f, 1094tinterpretation of analytic results, 1097–1099,

1097f, 1099fpostmortem blood tests, 1098toxicologic analysis, 1094–1097

Poisoned patient, 4–5, 13. See alsospecific chemicals

action levels, 1113, 1117clinical history, 1110–1118clinical stabilization, 1110criminal act, 1099–1100, 1099tenhancement of poison elimination,

1115–1117historical treatment of poisoning, 1109laboratory evaluation, 1111–1113,

1112f, 1112tstat basis, 1111, 1111t

physical examination, 1111, 1111tprevention of poison absorption, 1114–1115prognostic indicators of severity, 1117radiographic examination, 1113–1114strategy for treatment, 1110–1120supportive care, 1117–1118use of antidotes, 1117

Poison ivy, 661f, 966, 1127tPoison oak, 661f, 966Poison sumac, 661f, 966Polar body, 686Pollution-induced community tolerance

(PICT), 1024Poly(ADP-ribose)glycohydrolase, 67Poly(ADP-ribose)polymerase (PARP), 61,

61–62f, 63, 66–67, 71, 73, 361,610, 611f

Polyamine oxidase, 160–162, 160f, 162Polyaromatic hydrocarbons, 13Polybrominated biphenyls (PBB)

chloracne, 665tdistribution, 121immunosuppression by, 438–439in milk, 129thyroid toxicity, 729

Polybromodibenzofurans, chloracne, 665tPolychlorinated biphenyls (PCBs)

absorption, 114carcinogenicity, 279t, 281t, 285tcardiotoxicity, 625cellular dysregulation, 49, 50tchloracne, 665, 665tdevelopmental toxicity, 369, 374, 1020distribution, 121ecotoxicology, 1017t, 1019, 1026in food, 1075immunosuppression by, 438–439in milk, 129occupational disease, 1127treproductive system toxicity, 676, 691thyroid toxicity, 729toxicity equivalence factor, 86

Polychlorinated dibenzo-p-dioxin (PCDD)chloracne, 665timmunosuppression by, 438–440toxicity equivalence factor, 86vasculotoxicity, 645

Polychlorinated dibenzofuran (PCDF)chloracne, 665, 665timmunosuppression by, 438, 440toxicity equivalence factor, 86

Polychlorinated quaterphenyls, chloracne, 665Polychloronaphthalene, chloracne, 665tPolycyclic aromatic hydrocarbons (PAHs)

biotransformation, 141–142, 156, 192, 206carcinogenicity, 73, 192, 243, 243f,

252–254, 262, 285tskin cancer, 668

cellular dysregulation, 50tco-oxygenation, 254ecotoxicology, 1019, 1029genetic effects, 337immunosuppression by, 440–441induction of cytochrome P450, 193mutagenicity, 257occupational disease, 1127tphototoxicity, 663treabsorption, 39vasculotoxicity, 641t, 645

Polyethylene glycol, biotransformation, 203tPolyisocyanate, hypersensitivity reaction to, 456Polymorphism, genetic, 26Polymorphonuclear (PMN) cells, 420,

421t, 422–423Polymyxin, allergic contact dermatitis

from, 660tPolyols, adrenal toxicity, 722fPolyoxyethyleneamine (POEA), 795Polypeptide hormones, 712Polyphosphates, 1081Polysorbate 60, in food, 1057tPolyurethane, vasculotoxicity, 640Poor metabolizer, 134Poppy seeds, 1101Population, 982

age structure, 1023dose-response relationships, 18sex ratios, 1023

Population effects, 1023–1024Porphyria cutanea tarda, 193Porphyrins, 664Positron(s), 918–919Positron emission, 919Postemergent herbicides, 790Postmarketing surveillance, 411Postmortem investigation, 1092–1093Postnatal toxicity, 31Postovarian processes, 686–687

cervix, 686fertilization, 687implantation, 687oviducts, 686placentation, 687uterus, 686, 686fvagina, 686–687

Postreplication repair, 77Posttesticular processes, 682–685

accessory sex organs, 683–684, 684fefferent ducts, 683epididymis, 683erection and ejaculation, 684–685

Postural hypotension, 634–635Potassium, poisoning, 1116tPotassium bromide, in food, 1056t

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Potassium channel, 55t, 56–57cardiac, 600, 600–601f, 607effect of scorpion venom, 948

Potassium channel blockade, 605Potassium chlorate, methemoglobinemia

and, 395tPotassium dichromate, allergic contact

dermatitis from, 660tPotassium hydroxide, ocular toxicity, 575Potassium perchlorate, aplastic anemia and, 394tPotassium tellurate, 855Potency, 24, 25f

of carcinogen, 300t, 301, 301frelative, 300t, 301

Potentiation, 17Pott, Percivall, 5, 242, 668PPAR. See Peroxisome proliferator-activated

receptorP1 protein, 540Practolol, coagulation factor inhibitor

development and, 406tPralidoxime

absorption, 113distribution, 122treatment of organophosphate poisoning,

783, 783f, 783tPramoxine, cardiotoxicity, 623Prazosin

cellular dysregulation, 55tvasculotoxicity, 639

Predator/prey interactions, 1023–1025Predictive value, 409Prednisolone, cardiotoxicity, 626t, 627–628Prednisone

cardiotoxicity, 626t, 627–628reproductive system toxicity, 691t

Preeclampsia, 365Preemergent herbicides, 790Pregnancy. See also Developmental toxicity

cigarette smoking, 557cocaine use, 557, 639, 687ethanol use, 893maternal factors affecting development

disease, 365–366, 366fgenetics, 365, 366maternal toxicity, 366f, 367–368nutrition, 366, 366fplacental toxicity, 366, 367stress, 366, 366f

mercury exposure, 835metabolism, 363–365pharmacokinetics, 363–365use-in-pregnancy rating, 375

Pregnane X receptor, 50t, 195Pregnenolone, 717Pregnenolone 16�-carbonitrile (PCN), 127,

151, 180, 189, 193, 193t, 195, 200cellular dysregulation, 49, 50tthyroid toxicity, 729–730

Prehistoric humans, 3Preimplantation period, 357–358Premanufacturing notice, 86Prenatal development. See Developmental

toxicityPreneoplastic lesion, 267, 276

regression, 269Preplanting herbicides, 790

Presystemic elimination, 37, 38f, 114Prick-puncture test, 455Prilocaine

cardiotoxicity, 623methemoglobinemia and, 395t

Primaquinebiotransformation, 42, 160methemoglobinemia and, 395toxidative hemolysis and, 397t

Primidonedevelopmental effects, 374megaloblastic anemia and, 393t

Primitive streak, 358, 361Prion protein, 1082Proadifen, 160Probabilistic risk assessment, 1036–1037

overlapping distributions, 1036–1037,1036f

stochastic simulation, 1037, 1037fProbenicid, 125Probit units, 19, 27Procainamide, 48

autoimmune reaction to, 460, 460tbiotransformation, 137, 138f, 166, 209–210cardiotoxicity, 613, 614t, 616t, 622–623clinical uses, 605coagulation factor inhibitor development

and, 406tlaboratory tests on stat basis, 1112tlupus anticoagulant and, 407tneutropenia and, 402treabsorption, 39therapeutic drug monitoring, 1105t, 1106

Procainebiotransformation, 137, 138f, 139cardiotoxicity, 623cellular dysregulation, 56

Procarbazinebiotransformation, 169fleukemia and, 402reproductive system toxicity, 692, 693tthrombocytopenia and, 404

Procarcinogen, 26, 251, 252f, 334Procaspase, 62f, 63Procaterol, cardiotoxicity, 614t, 618Processing aids, food, 1056t, 1062tProfens, biotransformation, 212Profilin, 966Progabide, 143Progesterone, 676, 686–687, 717

biotransformation, 199fcardiotoxicity, 625, 626treproductive system toxicity, 698tvasculotoxicity, 636t

Progestinscardiotoxicity, 625–627, 626treproductive system toxicity, 698t

Progression stage, of carcinogenesis, 266, 267t,269–271, 270f, 270t, 276–280, 278f,278t, 287, 287t, 324

Progressor agent, 270, 270f, 270t,278–279, 278t

Prohevein, 966Prokaryotes, mutagenicity testing, 332t,

335, 336tProlactin, 712–714, 713f, 716

carcinogenicity, 248t

immune effects, 431tLeydig cell tumor development and,

745, 748tas promoting agent, 275t

Proliferating cell nuclear antigen (PCNA), 327Prolintane, biotransformation, 159Promoter region, 49Promoting agent, 275, 275t, 278–279, 278tPromotion index, 300tPromotion stage, of carcinogenesis, 266,

267–269, 267t, 268–269f, 273–280,274–275f, 275t, 278f, 278t, 287, 287t,324, 669

cell and molecular mechanisms, 271tdose-response relationships of promoting

agents, 269, 269fmodulation by physiologic factors, 269reversibility, 268–269, 276–277, 277f

Promutagen, 334Prontosil, biotransformation, 144, 144fPropachlor, 795Propafenone

biotransformation, 185tcardiotoxicity, 613, 614tclinical uses, 605

Propanil, immunosuppression by, 442Proparacaine, cardiotoxicity, 623Propellants, 1056tPropetamphos, poisoning, 777�-Propiolactone

biotransformation, 214fcarcinogenicity, 244fmutagenicity, 257

Propionic acidcarcinogenicity, 89tin food, 1056t

Propofolbiotransformation, 199f, 201cardiotoxicity, 616t, 622

Proposed Guidelines for Carcinogen RiskAssessment (EPA), 325

Propoxur, poisoning, 778Propranolol

biotransformation, 160f, 161, 182, 184t,187, 199f

cardiotoxicity, 614t, 617first-pass effect, 119

N-Propylajmaline, biotransformation, 185tPropyl chloride, cardiotoxicity, 630tPropylene glycol, 897–898

allergic contact dermatitis from, 660–661tbiotransformation, 897–898

Propylene oxide, carcinogenicity, 301fPropylfuranacetaldehyde, vasculotoxicity, 639Propyl gallate, in food, 1055tPropylthiouracil (PTU), 48

aplastic anemia and, 394tautoimmune reaction to, 461tbiotransformation, 166, 170fdevelopmental effects, 369neutropenia and, 402tthyroid toxicity, 726–727, 726f, 730

Proquanil, biotransformation, 184tProspective study, 280Prostacyclin, 69f, 163f, 173, 638–639, 662Prostacyclin synthase, 173Prostaglandin(s), 163f, 254, 445, 523, 684

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Prostaglandin D2, 662Prostaglandin dehydrogenase, 145–146Prostaglandin E2, 657, 662Prostaglandin F2�, 604, 662Prostaglandin H2, 173Prostaglandin H synthase, 136t, 162–165,

163–167f, 210, 254, 530Prostaglandin hydroperoxidase, 254fProstaglandin synthetase, 637–638Prostate gland, 683–684, 684fProstate-specific antigen (PSA), 684Prosthetic implants, 245–246, 436Protamine sulfate, 17Protease, ocular, 570Protease inhibitors

cardiotoxicity, 622nephrotoxicity, 496t

Proteasome, 65Protective fungicides, 797Protein(s)

carcinogens bound to, 257, 258fmolecular repair, 65, 65f

Proteinase, in renal cell injury, 506Protein C, 406–408Protein kinase, 52, 273Protein kinase A, 274, 611, 611f, 634fProtein kinase C, 45–46, 50, 52, 274–275,

274f, 604, 605f, 607, 632, 633f, 642,646, 669, 830, 887

Protein kinase C-�, 610, 611fProtein phosphatase 2A, 52Protein tyrosine phosphatase, 46, 52Proteinuria, 501, 501f, 824Proteolytic enzymes, snake venom, 955, 957tProteomics, 462Prothrombin time, 406–407Protoanemonin, 966Proton-ATPase, 57Proto-oncogenes, 76f, 77, 271–273, 272t,

323, 362activation, 272–273, 273tmutations, 73–75, 74f, 272, 323

Protoveratrine, 968Protriptyline, cardiotoxicity, 616t, 622Proximal tubule, 492f, 493–494

toxic injury, 500Proximate carcinogen, 251, 252fPrussic acid, occupational disease, 1138PSA. See Prostate-specific antigenPseudocholinesterase, 137–144, 138f, 139

atypical, 139Pseudoephedrine, cardiotoxicity, 615t, 618Psoralens

phototoxicity, 664pigmentary disturbances from, 666t

Psoriasis, 654, 663, 668Psychophysical test, of visual function, 574Psychotropic agents, vasculotoxicity, 639Ptaquiloside, 970Pteridine, biotransformation, 159PTH. See Parathyroid hormonePTU. See PropylthiouracilPuberty, 676, 685, 688Public Health Service, animal welfare

policy, 1151Puffer fish poisoning, 1079Pulmonary edema, 519, 522

Pulmonary embolism, 639–640Pulmonary fibrosis, 523, 524, 525,

527–528t, 530Pulmonary function effects

of nitrogen dioxide, 1004of sulfur dioxide, 994of sulfuric acid, 995–996

Pulmonary function tests, 516, 530–531, 531fPulmonary irritants, 531

immunosuppression by, 444–445Pulmonary lavage, 532Pupillary light reflex, 572Pure red cell aplasia, 393–394Purkinje fibers, 600Puromycin

hepatotoxicity, 476nephrotoxicity, 499

Putrescine, 1070, 1096biotransformation, 162

Pyrazinamidebiotransformation, 159sideroblastic anemia and, 392t

Pyrazole, 196Pyrazoloacridine, hematotoxicity, 410Pyrazophos, 797tPyrethric acid, 784Pyrethrin, 784

poisoning, 785tPyrethroid, 46

cellular dysregulation, 55timmunosuppression by, 442neurotoxicity, 548t

Pyrethroid esters, 784–787biotransformation, distribution, and

storage of, 786–787classification of, 785tpoisoning, 784–786, 785tsite and mechanism of toxicity, 786, 786fstructure, 784ftreatment of poisoning, 787

Pyrethrolol, 784Pyrethrum, 784Pyridazones, 791tPyridine, 196

biotransformation, 176Pyridinethione, neurotoxicity, 548t, 550f,

551–552Pyridium chromate, urine adulterant, 1101tPyridoxal, 45Pyridoxine, reproductive system toxicity, 695tPyrimethamine, aplastic anemia and, 394tPyrimidine dimer, 261, 326f, 668Pyrimidine transporter, 113Pyropheophorbide, 1079Pyrrolidine alkaloids

hepatotoxicity, 476tvasculotoxicity, 641t

Pyrrolizidine, 969, 1084Pyruvate dehydrogenase, 44, 46Pyruvate oxidoreductase, 1081

QQuantal all-or-none response, 19–20Quantal dose-response relationship, 18–20,

19–20f, 20t, 26Quaternium-15, allergic contact dermatitis

from, 660–661tQuercetin, 187Quinacrine

aplastic anemia and, 394tdistribution, 120f

Quinazolone, biotransformation, 159Quinestrol, cardiotoxicity, 625, 626tQuinidine, 188

autoimmune reaction to, 461tbiotransformation, 159, 182, 185t, 192cardiotoxicity, 613, 617cellular dysregulation, 55tclinical uses, 605–606hemolytic anemia and, 398laboratory tests on stat basis, 1112tlupus anticoagulant and, 407tneutropenia and, 402treabsorption, 39thrombocytopenia and, 404, 404t

Quinidine syncope, 606Quinine, 8

biotransformation, 159nephrotoxicity, 496tneurotoxicity, 543tpoisoning, 1117t

Quinolinate, cellular dysregulation, 54tQuinone, methemoglobinemia and, 395tQuinone reduction, 147–149, 148fQuinoxalindones, 791tQuintozene, 797tQuisqualate, cellular dysregulation, 54tQuotient method, of risk assessment, 1036

RRadiation

absorbed dose, 921–924aplastic anemia and, 393background, 938–940, 938f, 939tbasic concepts, 917–919cancer risk, 922–924committed effective dose, 924committed equivalent dose, 924developmental effects, 353tDNA damage and mutagenesis, 924–925dose rate, 921–922effective dose, 922–924, 922tequivalent dose, 922exposure, 921human cancer risks from, 940t, 941interaction with matter, 919–921natural radioactivity, 938–940, 938f, 939tnegligible individual risk level, 924ovarian tumor development and, 747parathyroid adenoma and, 740–741skin cancer and, 667–668toxic effects in humans

ankylosing spondylitis therapy,931–932, 932t

atomic bomb survivors, 927–929, 928fChernobyl accident, 929–931, 931fradioactive iodine-induced thyroid cancer,

929–931, 931fradium exposure, 925–927, 926–927ftinea capitis irradiation, 929, 929t, 930furanium miners, 932–935, 932–934f

Radiation therapy, 286

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Radiation weighting factor, 922, 922tRadiocontrast agents

cardiotoxicity, 616t, 625nephrotoxicity, 496t, 499, 511–512vasculotoxicity, 640, 643t

Radiodermatitis, 668Radiomimetic chemicals, 329–330Radionuclides, 8Radium

Ra-224, 927, 927fRa-226, 925–927Ra-228, 925–927skeletal effects, 926–927toxic effect in humans, 925–927, 926–927f

Radium therapy, 926Radon, 857

environmental epidemiologyenvironmental studies, 935–937meta-analysis, 937–938, 937f

exposure of uranium miners, 932–935lifetime environmental lung cancer risk from

ICRP model, 935NAS model, 935NCRP model, 935NIH analysis of underground miners, 935

lung cancer and, 525, 935–937occupational disease, 1127tresidential exposure, 936, 938, 988

Radon decay products, 932raf gene, 272tRaf protein, 52RAIDD protein, 62fRaloxifene, ovarian tumor development

and, 750–751Ramazzini, Bernardino, 5, 242, 515, 1123Ranitidine, 154Ranunculin, 966Rapamycin

biotransformation, 185tcardiotoxicity, 608, 624immunosuppression by, 448

RARE. See Retinoic acid response elementras gene, 47, 272t, 273, 274t, 323–324,

526, 642, 669Ras protein, 49, 73, 74f, 273–274Rat embryo culture test, 372Rattlesnakes, 955, 956–957t, 960–961RBE. See Relative biological effectivenessRb gene, 272t, 276, 277fRBP. See Retinal-binding proteinRb protein, 75, 274RCRA. See Resource Conservation and

Recovery ActReabsorption, 38f, 39–40Reaction phenotyping, 183Reactive hydrocarbon radicals, 999Reactive nitrogen species, 37t, 61, 61f,

70, 503overproduction, 59–60, 61f

Reactive oxygen species, 37t, 52, 61, 61f, 70,74f, 148–149, 148f, 254, 254f, 327,480–481, 486, 503, 507, 519–520, 523,576, 606–607, 607–608f, 610, 611f,619–620, 620f, 638, 891

overproduction, 59–60, 61fReceptor antagonism, 17Receptor tyrosine kinase, 604, 605f

Recessive mutation, 324Recombinagenic effects, 337Recombinant DNA-derived proteins,

immunosuppression by, 449Recombinational repair. See Homologous

recombinationRecommended exposure limits (REL), 1125Red blood cells, 391–392, 421f

alterations, 392–394, 392–393f, 392–394talterations in survival, 396–399nonspecific deposition of proteins on, 399oxidative damage, 397

“The Red Book,” 83, 701, 1054, 1149Redistribution of toxicants, 124Red-legged spider, 950Rednecked keelback, 955, 956–957tRedox-active reactant, 42Redox cycling, 42, 60Red squill, 801Red tide, 971Reducing agents, in food, 1056tReduction, 135, 136t, 144–152Reductive dehalogenation, 150–151, 151–152fReductive fission, 40Reduviids, 954Red wine intolerance, 1067t, 1069tReference concentration (RfC), 92, 870Reference dose, 28, 92–94, 870, 1142Reflex arc, 772, 773fRegulation. See also specific agencies

of carcinogens, 304–305, 305tinternational aspects, 305risk-benefit considerations,

305–306, 306fover toxicology, 1148–1151

Regulatory programsagencies involved, 1142approaches to toxic chemical regulation, 1142CPSC, 1147–1148current approaches, 1142–1143

negligible risk approach, 1143no risk approach, 1143trade-off approach, 1143

EPA, 1144–1147FDA, 1143–1144OSHA, 1147typology of regulatory approaches, 1142

Regulatory toxicology, 12, 12f, 1089,1141–1151

relationship between toxicology andregulatory institutions, 1141–1142

roles of science and regulation, 1151REL. See Recommended exposure limitsRelative biological effectiveness (RBE), 922Relative potency, 300t, 301Remoxipride, biotransformation, 185tRenal artery stenosis, 499Renal cell culture, 502Renal failure, 704, 880

acute, 494–496, 495–496f, 496t, 499chronic, 498–499, 499

Renal function, assessment, 501–502,501–502f

Renal vasculature, 492, 492fRenin, 717Renin-angiotensin II system, 717Repeated-dose study, 28

Repeat Insult Patch Test, 658Replication, 329–330Replication factor C, 327Reproductive capacity, evaluation, 693, 694t

female, 699–701, 700tmale, 693–699, 694t

Reproductive hazards, 674Reproductive history, cancer and, 283, 283tReproductive system. See also Reproductive

capacitybiotransformations, 689–691blood-testis barrier, 688–689DNA repair, 691–692epidemiologic studies, 704extrapolation of animal data to humans, 704gonadal function, 676–687integrative processes, 687–688reproductive biology, 675–676reproductive tests, 701–703risk factors affecting fertility

in females, 704general considerations, 703in males, 703–704

sexual behavior and libido, 688sexual differentiation, 675–676targets for chemical toxicity

central nervous system, 692gonads, 692–693, 693t

toxic effects of plants, 973toxic responses, 673–704

Reproductive system effects, 88, 94of arsenic, 820of glycol ethers, 899of lead, 832, 833t

Reproductive tests, 701–703endpoints

females, 701males, 701–703

guidelines for, 701, 702tReproductive toxicology, 31

history, 674Reptiles, 954–961

lizards, 954–955sex determination, 1021snakes, 955–961, 956t

Reserpineadrenal toxicity, 720carcinogenicity, 279treproductive system toxicity, 683t,

685t, 688Residual volume (RV), 519, 531fResiniferatoxin, 967

impairment of cellular maintenance, 60tResistance, 19Resmethrin, poisoning, 785tResorcinol

biotransformation, 44thyroid toxicity, 726

Resorcinol monobenzoate, allergic contactdermatitis from, 660t

Resource Conservation and Recovery Act(RCRA), 12, 86t, 1146

Respirator, 1124Respiratory burst, 70Respiratory hypersensitivity, in experimental

animals, 454–455Respiratory rate, 519

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Respiratory tract. See also Lung(s)mechanism of injury, 522–523occupational diseases, 1126–1130,

1127–1128tparticle clearance, 521–522particle deposition, 520–521, 520f

deposition mechanism, 521particle size and, 520–521

toxic responses, 515–533Respiratory tract toxicity

of ozone, 1001–1002of 1,1,2-trichloroethylene, 882–884

Restrictive airway disease, 531fRete testis, 683Rete testis fluid-derived growth factor, 677tret gene, 272tReticulocytes, 391, 396Retina, 568–570, 568f

development, 578structure, 577–578toxic responses, 577–584

Retinal, biotransformation, 159Retinal-binding protein (RBP), 825Retinal blood vessels, 567–569Retinal degeneration, 577Retinal ganglion cells, 566tRetinal pigmented epithelium, 566t,

569–570, 577Retinoic acid, 86, 195

biotransformation, 165, 185t, 186cellular dysregulation, 50tdevelopmental effects, 353t, 355–358, 358f,

361–362, 362f, 372–375ocular toxicity, 566t

Retinoic acid receptor, 50t, 362, 625Retinoic acid response element (RARE), 362Retinoids, 283

biotransformation, 656cellular dysregulation, 49developmental effects, 353t, 355–356thyroid toxicity, 729

Retinoid X receptor, 195Retinol

biotransformation, 153developmental effects, 355–356

Retinotoxicity, 566t, 577–584of chloroquine, 578–579of digitoxin, 579–580of digoxin, 579–580of hydroxychloroquine, 578–579of indomethacin, 580of lead, 580–582of methanol, 582–583of neurotoxicants, 580–583of organic solvents, 583–584of organophosphates, 584of tamoxifen, 580of therapeutic drugs, 578–580

Retrobulbar neuritis, 584Retrorsine, 970

biotransformation, 172hepatotoxicity, 478

Retrospective study, 280–281Reverse transcriptase inhibitors,

cardiotoxicity, 621Reversible toxic effects, 16Reversion (mutation) assay, 331

Reye’s syndrome, 64RfC. See Reference concentrationRG 7512, 195Rhodanese, 43, 218–219Rhodium, 852Rhombomere, 358, 363Ribavirin, adrenal toxicity, 720Rice oil, 440, 1075

chloracne, 665Ricin, 46, 968

impairment of cellular maintenance, 64Rifampicin

induction of cytochrome P450, 879neutropenia and, 402tthyroid toxicity, 731

Rifampin, 182, 186, 188–189, 192, 193t,195, 206

Rifamycin, urticaria from, 667tRing chromosome, 330Ringworm irradiation, 929, 929t, 930fRisk, 84

cumulative, 98–99necessary, 306

Risk assessment, 9, 11, 84f. See also Hazardidentification

air pollution, 982–988, 983f, 985tfrom bioassay data using mathematical

models, 303–304, 303–304fcancer, 324–325carcinogens in food, 1064–1066, 1064tcomparative analyses of risk, 99–101decision making, 85definitions, 84–85developmental toxicity, 375–376ecologic, 1023, 1035–1038, 1035f, 1036textrapolation of bioassay data to human

risk, 301–303genetic, 325, 325fharmonization, 91hematotoxicity, 409–411immunotoxicology, 463information resources, 99introduction and historical context, 83–84objectives, 84, 84toccupational risks, 1131–1135probabilistic, 1036–1037qualitative, 303quantitative, 303, 1064–1065reproductive system toxicology, 703–704risk of death by type of activity, 302, 302tthyroid toxicity, 733–734, 734–735f1,1,2-trichloroethylene, 884

Risk Assessment in the Federal Government:Managing the Process, 83

Risk-benefit considerations, in regulation ofcarcinogens, 305–306, 306f

Risk characterization, 84, 91–99dose-response assessment, 92–94, 92fexposure assessment, 96–99, 98f, 98tmodels derived from mechanistic

assumptions, 95nonthreshold approaches, 94–95toxicologic enhancements of models, 95–96variation in susceptibility, 99

Risk communication, 84–85Risk management, 83–84, 84fRisk perception, 85, 99–101, 100f

“Risk space” axis diagram, 100fRisperidone, cardiotoxicity, 622Ristocetin, vasculotoxicity, 636tRitonavir, 188

cardiotoxicity, 622Rizatriptan, biotransformation, 160RNA polymerase, 327

plant chemicals that inhibit, 970RNase, snake venom, 957t, 959Rod(s), 569, 578, 581Rodent carcinogenicity prediction challenge, 88Rodenticides, 800–802

anticoagulants, 801–802fluoroacetic acid, 801�-naphthyl thiourea, 801zinc phosphide, 801

Rodent whole embryo culture test, 373tRopivacaine, cardiotoxicity, 623Rosin, allergic contact dermatitis from, 660tRotenoids, 790Rotenone, 763, 790

cardiotoxicity, 609, 609fimpairment of cellular maintenance, 57,

59tparathyroid toxicity, 740

RP 73401, biotransformation, 186RU-486

carcinogenicity, 249fimmunosuppression by, 447

RU-22930, reproductive system toxicity,698t

Rubella, 352, 353t, 365, 372Rubratoxins, in food, 1077tRunning spiders, 949t, 951Russell, William, 322Ruthenium, 852RV. See Residual volumeRXR-alpha receptor, 356Ryanodine, cardiotoxicity, 608Ryanodine receptor, 624

SSaccharin, 11, 96, 305, 1056t, 1060

animal testing, 27carcinogenicity, 89, 89t, 279tas promoting agent, 267, 268f

Safe Drinking Water Act (SDWA), 12, 86t,873, 1014, 1146

Safe Drinking Water Reauthorization Act andAmendments, 1021

Safety, margin of, 24, 93Safrole, 196

biotransformation, 205f, 206carcinogenicity, 252fin food, 1065

St. Anthony’s fire, 969Saint-Hilaire, Etienne Geoffrey, 352St. John’s wort, 967Salicylamide, biotransformation, 203tSalicylates, 364

distribution, 120fexcretion, 124impairment of cellular maintenance, 59tlaboratory tests on stat basis, 1112tpoisoning, 113t, 1103, 1103t, 1112,

1114–1115, 1116t

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Done nomogram, 1112, 1112fSalicylic acid

biotransformation, 203octanol/water partition coefficient, 109treabsorption, 39volume of distribution, 228t

Saliva, excretion of toxic agents, 129Salmeterol, cardiotoxicity, 614t, 618Salmonella/microsome test, 32, 87, 288, 289t,

290f, 322, 331t, 335, 336t, 342SALT. See Skin-associated lymphoid tissueSAM. See S-AdenosylmethionineSandalwood oil, in photopatch test, 664tSaponin, 965Saquinavir


SARA. See Superfund AmendmentsReauthorization Act

Sarcolemmal injury, 608Sarcoma, 242Sarcoplasmic reticulum, dysfunction, 608Sarin, 775

absorption, 117mechanism of toxic action, 779octanol/water partition coefficient, 109tpoisoning, 778structure, 775f

Saturable metabolism, 236Saturation toxicokinetics, 229–230, 229f, 230tSax, Karl, 322Saxitoxin, 45–46, 1078

cellular dysregulation, 55t, 564S-binding protein, 194Scaritoxin, 1079Scatchard plot, 120, 121fSchmiedeberg, Oswald, 5Schrader, Gerhard, 8Schwann cells, 538–539SCID mice, 462Science and Judgment in Risk Management, 83Scientific Frontiers in Developmental

Toxicology and Risk Assessment (NRC),377–378

Scillaren, 968Scleroderma, 461tScombroid poisoning, 1067t, 1070, 1070tScopolamine, 972

octanol/water partition coefficient, 109ttransdermal delivery, 656

Scorpion, 55t, 947–948, 948tScrombrotoxicosis, 1070SD. See Standard deviationSDWA. See Safe Drinking Water ActSeafood toxins, 1078–1080Sea kraits, 955, 956–957tSea snakes, 955, 956–957tSea turtle poisoning, 1080Sea urchin poisoning, 1079Secobarbital

biotransformation, 192distribution, 120

Secretory granules, 712–713, 720Sedimentation, particle deposition in

respiratory tract, 521Sediment quality triad, 1030Sediment toxicity testing, 1029

Selectin, 70Selection technique, 331–332Selective estrogen receptor modulators

(SERM), ovarian tumor developmentand, 750–751

Selective herbicides, 790Selective serotonin reuptake inhibitors,

cardiotoxicity, 616t, 622Selective toxicity, 24–25Selenate, 845

cellular uptake, 816Selenide, 845

biotransformation, 167Selenite, 845

biotransformation, 42Selenium, 20, 283, 845–847

anticarcinogenicity, 847biliary excretion, 475biological interactions, 847biotransformation, 206deficiency, 845–846, 1052dose effect in humans, 847ecotoxicology, 1024essentiality, 845, 846ftoxicity, 846toxicokinetics, 845vasculotoxicity, 644

Selenium-binding protein, 509Selenocysteine, 845, 846fSelenomethionein, 845, 846fSelenoprotein P, 43, 845, 846fSelf-tolerance, 459SEM. See Simultaneously extracted metalsSemen analysis, 697Seminal vesicles, 683–684, 684fSeminiferous epithelium, duration of cycle, 680Seminiferous tubules, 680, 680f, 682f, 689Semiquinone radical, 148–149, 619–620,

620f, 891Senecionine, biotransformation, 172, 176,

189t, 190–191, 190fSeneciphylline, hepatotoxicity, 478Sensitization reaction, 15Sensitization test, 28Sentinel

air pollution, 986, 1000wildlife, 1014, 1018, 1025, 1038

Sequestrants, 1056tSerine-threonine protein kinase, 274SERM. See Selective estrogen receptor

modulatorsSerotonin, 720

biotransformation, 160, 207vasculotoxicity, 636t

Sertoli cells, 676–677, 680, 681, 682f, 689,692–693, 695, 698, 741

Sertoli cell secreted growth factor, 677tSertraline

cardiotoxicity, 622thyroid toxicity, 734, 734f

Seryl-tRNA synthetase, 212fSesquiterpene lactone, allergic contact

dermatitis from, 660tSevoflurane, cardiotoxicity, 616t, 622Sex chromosomes, 675Sex determination

species-dependent, 1021

temperature-dependent, 1021Sex hormone binding globulin, 1020Sex-linked recessive lethal test, 336–337Sexual assault, poisoning/drug abuse related

to, 1099–1100, 1099tSexual behavior, 676, 688SGF, 677tShampoo, ocular toxicity, 576Shaver’s disease, 527tShellfish poisoning

amnesic, 1078–1079paralytic, 1078

Shellfish toxins, 1078–1080Shock, 635Short-chain dehydrogenase/reductase

superfamily, 146Short-term exposure limit (STEL), 97, 871Short-term tests

for carcinogen identification, 288–293,288t, 290f, 297–298, 322

for hazard identification, 87–88Sialic acid, distribution, 120fSick-building syndromes, 993, 993t, 1130Sickness behavior, 71Side effects, 15–16Sideroblastic anemia, 392–393, 392f, 392tSiderosis, transfusional, 842Siderotic lung disease, 527tSignaling network, 48Signal transduction, 51f, 274f, 275

apoptotic, 610–611cardiac hypertrophy and, 604, 605fchemically altered

with antiproliferative effect, 52with proliferative effect, 50–52

in development, 377t, 378, 378fdysregulation, 49–52, 51ftoxicant-signal transducer interactions, 56

Significance, 92Sildenafil (Viagra), 685

cardiotoxicity, 616t, 624–625Silica

autoimmune reaction to, 460t, 461biotransformation, 41carcinogenicity, 285tin food, 1055timmunosuppression by, 444–445lung damage caused by, 525, 526–529, 528toccupational disease, 1127t, 1130

Silicon-based materials, immunosuppressionby, 450–451

Silicon dioxide. See SilicaSilicosis, 115, 444, 515, 526–528, 528t, 1126Silicotuberculosis, 515, 528tSilo-filler’s disease, 46f, 1003Siloxane, immunosuppression by, 451Silver, 45, 854–855

reproductive system toxicity, 695Silver finisher’s lung, 527tSilver nitrate, 854

methemoglobinemia and, 395tSilver sulfadiazine, 855Silver sulfide, 855Silymarin, 970Simultaneously extracted metals (SEM), 1017Simvastatin, thyroid toxicity, 734, 734fSingle-cell gel electrophoresis assay, 334–335

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Single-phase chemical behavior, 1015in air, 1015in soil, 1015in water, 1015

Single-strand annealing pathway, 263Sinoatrial node, 600Sinusoids, hepatic, 473, 475f

activation of sinusoidal cells, 482–483, 483fdamage to, 476t, 478

sis gene, 272tSister chromatid exchange, 67, 291–292

assay for, 340, 341fhuman population monitoring, 343

Sjörgen-Larson syndrome, 156Skeletal effects

of aluminum, 849of cadmium, 824–825of lead, 832of radium, 926–927toxic effects of plants, 973

Skeletal muscle, toxic effects of plants, 973Skeletal remains, forensic toxicology, 1094SKF 525A, 1052

biotransformation, 167Skin

absorption through, 117–119, 117f,654–656

acne, 664–665as barrier, 653–657biotransformations, 656–657cancer, 667–669

arsenic and, 668mouse skin tumor promotion, 668–669polycyclic aromatic hydrocarbons

and, 668radiation and, 667–668

contact dermatitis. See Contact dermatitisexposure to occupational chemicals,

1124–1125factors influencing cutaneous responses,

654tgranulomatous disease, 666histology, 653–654, 655fpesticide absorption, 769phototoxicology, 662–664pigmentary disturbances, 665–666,

666f, 666tsolvent absorption, 874tinea capitis irradiation, 929, 929t, 930ftoxic effects of plants, 966–967toxic epidermal necrolysis, 667toxic responses, 653–669urticaria, 666–667, 667t

S6 kinase, 604, 605fSkin-associated lymphoid tissue (SALT),

420t, 421Skin irritation test, 27–28Skin necrosis, warfarin-induced, 407–408Skin tests, 661–662, 662tSlit-lamp biomicroscope, 572Slow acetylator, 209, 211Small granule-containing cells, 720S9 mixture, 334–335Smog, 979–980, 987. See also Air pollution

chronic exposure, 1000–1007short-term exposure, 999–1000

Smoking. See Cigarette smoking

Smooth musclebronchial, 522vascular, 631–632, 632f, 634–635, 637t,

638Snake(s), 955–961, 956tSnakebite treatment, 961Snake venom, 46, 60t, 113, 955

enzymes, 955–960, 957themostatic properties, 958, 958timpairment of cellular maintenance, 60tpolypeptides, 960snakebite treatment, 961toxicology, 960–961, 960t

Sneezing, 117Soap, ocular toxicity, 576Society of Toxicologic Pathologists, diagnostic

criteria for Leydig cell tumors, 744Sodium acetriozate, vasculotoxicity, 636tSodium arsenate, 1135Sodium arsenite, 818, 1135

immunosuppression by, 443Sodium benzoate, in food, 1055tSodium bicarbonate, urinary

alkalinization, 1115Sodium borate, 791tSodium-calcium exchange, cardiac, 602Sodium channel, 45–46, 55t, 56–57

cardiac, 600, 600–601feffect of pyrethroid esters, 786

Sodium channel blockers, 605–606cardiotoxicity, 613

Sodium chlorate, 791tSodium chloride, LD5, 13tSodium cyanide, 801Sodium-dependent taurocholate peptide,

126, 127fSodium dichromate, 826Sodium diethyldithiocarbamate, 839

poisoning, 778–779Sodium dodecyl sulfate, occupational

disease, 1127tSodium ferrocyanide, in food, 1055tSodium gold thiosulfate, allergic contact

dermatitis from, 661tSodium hydroxide

occupational disease, 1127tocular toxicity, 575skin burns, 658t

Sodium-iodide symporter, 725–726Sodium lauryl sulfate, irritant dermatitis

from, 657Sodium nitrite, 1117Sodium-potassium ATPase, 55t, 57, 398, 529

cardiac, 604–606, 608effect of pentachlorophenol, 798inhibition, 604–606

calcium channel blockers, 368potassium channel blockade, 606sodium channel blockade, 605–606

of neurons, 773renal, 493–494, 497f, 504retinal, 579–580

Sodium salicylate, developmental effects, 367Sodium sulfoxone, oxidative hemolysis

and, 397tSoft tissue, calcification, 973Soil

single-phase chemical behavior, 1015soil-air interphase, 1016soil-water interphase, 1016

Soil fungicides, 797Solanine, 972Solvents

absorption, 874abuse, 872–873, 872falcohols, 893–895aromatic hydrocarbons, 889–893autoimmune reaction to, 461tbiotransformation, 876

in children, 877carcinogenicity, 871cardiotoxicity, 629, 630tchlorinated hydrocarbons, 880–889chronic encephalopathy, 871–872, 872tclassification, 869–870definition, 869determinants of inherent toxicity, 870in drinking water, 870, 873elimination, 875environmental contamination, 873–874exposure, 870–871, 870fin food, 1056tglycol ethers, 898–900glycols, 896–898immunosuppression by, 435–446interactions between solvents, 871, 876lipophilicity, 874ocular toxicity, 566t, 576physiologically based toxicokinetic

models, 877retinotoxicity, 583–584sensitivity to, 877–880

children, 877–878clock time and, 880dietary effects, 880disease and, 880elderly, 878exercise effects, 879–880gender differences, 878genetic polymorphisms, 878–879P450 inducers, 879P450 inhibitors, 879

toxic effects, 869–905toxicokinetics, 874–877transport and distribution in body, 874–876volatility, 874

Soman, 775mechanism of toxic action, 779–780structure, 775ftreatment of poisoning, 784

Somatic cellsformation of chromosomal alterations, 330formation of gene mutations, 328–329health impact of genetic alterations, 323–324

Somatic mutation, 32Somatostatin, 713Somatotrophs, 712, 713fSomatotropic hormone, vasculotoxicity, 636tSorbic acid, in food, 1055tSorbitan monostearate, in food, 1057tSorbitol, in food, 1065Sorbitol dehydrogenase, 698Sorivudine, biotransformation, 149–150, 150fSOS chromotest, 335

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Sotalolcardiotoxicity, 614t, 617clinical uses, 606

Spanish toxic oil syndrome, 1075Sparfloxacin, cardiotoxicity, 615t, 621Sparteine, biotransformation, 180, 181f,

185t, 187–188Spatially distributed model, 1031Special transport, 109–111Species-dependent sex determination, 1021Species differences, 25–26

in biotransformation, 134, 137Specific-locus mutation assay, 322Spectral discrimination, 574Sperm, 680f, 687

YFF, 675Spermatids, 679–680, 680fSpermatocytes, 679, 680f, 899Spermatogenesis, 329–330, 329f, 676,

677–681, 679–680f, 681, 681t, 692evaluation, 680, 696

Spermatogonia, 678–680, 680f, 682fSperm count, 674, 695, 697, 703Spermine, 684Sperm motility, 697, 703Sphingolipids, inhibition of biosynthesis, 970Sphingomyelinase, 611, 611fSphingosine, 611, 611fSphingosine N-acetyltransferase, 503, 509Spiders, 947–952, 949tSpironolactone, 127, 180, 195, 628

adrenal toxicity, 718–719biotransformation, 138f, 169, 208cellular dysregulation, 50tLeydig cell tumor development and, 748treproductive system toxicity, 689t, 698tthyroid toxicity, 729, 734, 734f

Spleen, 420, 420tSplenic macrophages, 423Split adjuvant test, 28Spongiosis, 554Sporidesmin, hepatotoxicity, 476t, 479t, 486Squalene epoxide, 554Squalene monooxygenase, 855Squamous cell carcinoma, 663, 668–669SR 4233, biotransformation, 148src gene, 272tSrc protein, 52SRY gene, 675Stabilizers, in food, 1056tStandard deviation (SD), 19Stannic chloride, 856Stannous chloride, 856Stanosis, 528tStanozol, cardiotoxicity, 626t, 627Staphylococcus aureus food poisoning, 1081Stas, Jean Servials, 1093STAT (transcription factor), 70Staurosporine, cardiotoxicity, 625Stavudine (d4t)

cardiotoxicity, 615t, 622immunosuppression by, 448

Steatoda species, 949t, 951STEL. See Short-term exposure limitStellate cells. See Ito cellsStem cells, 68STEPS program, 354

Sterigmatocystinbiotransformation, 189tin food, 1077t

Steroid(s)biotransformation, 656–657cardiotoxicity, 625–628

Steroidal, 1084Steroid hormones, 7

biosynthesis, 717, 718fbiotransformation, 134–135, 198carcinogenicity, 248, 254, 283distribution, 120fas promoting agent, 275t

Steroid hormone-secreting cells, 712Steroidogenesis, 693Steroidogenic enzymes, inhibitors, 689tSteroid 5�-reductase, 698Sterol regulatory element binding protein, 62fStevioside, 1063Stibine, 853Stilbene(s), 7Stilbene oxide, biotransformation, 141fStinging nettle, 966Stink bugs, 954Stiripentol, biotransformation, 207Stochastic model, 1031

ecologic risk assessment, 1037, 1037fStorage depot, 108, 120–122

bone, 122distribution to, 39fat, 121–122kidney, 121liver, 121plasma proteins, 120–121, 120f, 121t

Storage fungi, 1076Stratum corneum, 117–119, 654–655, 657,

663, 1124Streptokinase, toxicity, 408–409Streptomyces avermitilis, 787Streptomycin

aplastic anemia and, 394tcardiotoxicity, 615t, 621coagulation factor inhibitor development

and, 406tdistribution, 120fneurotoxicity, 543turticaria from, 667t

Streptonigrin, genetic effects, 329Stress, in pregnancy, 366Stress proteins, 76, 498, 1023Stroke, 639Stroke volume, 602Strontium, 122Structural alert, 255, 256f, 342Structure/activity relationships, 86–87Strychnine, 45–46, 801

biotransformation, 176cellular dysregulation, 54tLD5, 13tpoisoning, 1093, 1096, 1116t

Styrene, 870, 892–893biotransformation, 184t, 189t, 876, 892carcinogenicity, 281thepatotoxicity, 880occupational disease, 1127t, 1133ocular toxicity, 566tpartition coefficient, 233t

physiologic toxicokinetic model, 232, 234retinotoxicity, 583–584

Styrene-7,8-epoxide, biotransformation,141f, 216

Styrene oxide, 892carcinogenicity, 281t

Subacute exposure, 14Subacute toxicity study, 28Subchronic exposure, 14Subchronic toxicity study, 28–29Subcompartment, 232Subcutaneous administration, 119Sublethal effects, 1022–1023Substance abuse, 1092Substance P, 903

immune effects, 431tSubtilisin, occupational disease, 1128Succimer. See DMSASuccinate dehydrogenase, 44, 537, 819Succinylcholine

biotransformation, 139idiosyncratic reactions to, 16

Sudden cardiac death, 603Sugars

adrenal toxicity, 720intestinal absorption, 1053t

Suicide attempt. See Poisoned patientSuicide inactivation, 150, 175, 192Sulbactam, hemolytic anemia and, 399Sulfadimethoxine, biotransformation, 199fSulfamethazine

biotransformation, 209, 209fcarcinogenicity, 89tthyroid toxicity, 726f, 727–728, 728f

Sulfamethoxazolebiotransformation, 209, 209fthyroid toxicity, 726

Sulfamethoxypyridazineaplastic anemia and, 394toxidative hemolysis and, 397t

Sulfamonomethoxine, thyroid toxicity, 727Sulfanilamide, 7, 144

biotransformation, 209oxidative hemolysis and, 397tin photopatch test, 664t

Sulfaphenazole, 187Sulfasalazine, 208

biotransformation, 209megaloblastic anemia and, 393toxidative hemolysis and, 397t

Sulfate(s), air pollution, 989, 994–997Sulfate conjugation, 126, 136tSulfate transporter, 816Sulfathiazole, biotransformation, 199fSulfation, 135, 136t, 197, 197f, 203–206,

203t, 205f, 729Sulfenic acid, 46Sulfhemoglobin, 397Sulfinpyrazone, biotransformation, 198, 199fSulfisoxazole

aplastic anemia and, 394tbiotransformation, 199f

Sulfitebiotransformation, 165poisoning, 1067t

Sulfite oxidase, 156, 218, 844–845deficiency, 1070t, 1071

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Sulfobromophthaleinexcretion, 126octanol/water partition coefficient, 109t

Sulfonamides, 48allergic contact dermatitis from, 660taplastic anemia and, 394tbiotransformation, 166cellular dysregulation, 57distribution, 120f, 121mechanism of action, 791tmethemoglobinemia and, 395tnephrotoxicity, 496tphototoxicity, 663tselective toxicity, 25thyroid toxicity, 724–727, 726–727f

Sulfonation. See SulfationSulfonylurea, 791tSulforaphane, 149, 217Sulfotransferase, 40, 203–206, 213, 253fSulfoxide reduction, 146–147, 147fSulfur, as pesticide, 763Sulfur dioxide

air pollution, 987–990, 987f, 993–994,997–998, 1000

chronic effects, 994general toxicology, 993–994immunosuppression by, 445lung damage caused by, 520, 522, 525, 528tNational Ambient Air Quality Standards,

981tpulmonary function effects, 994respiratory system toxicity, 993

Sulfuric acid, 791tacid rain, 994–995, 995fair pollution, 989, 994–997, 998–999, 1003chronic effects, 996–997effect on mucociliary clearance and

macrophage function, 996general toxicology, 995as herbicide, 764ocular toxicity, 575pulmonary function effects, 995–996

Sulfurous acid, ocular toxicity, 575Sulindac, biotransformation, 146, 147f, 160,

167, 169–171, 176Sulisobenzone, in photopatch test, 664tSumatriptan, biotransformation, 160Summer haze, 989Sunburn, 662Suntan, 662–663Superfund, 9, 86tSuperfund Amendments Reauthorization

Act (SARA), 12Supermethrin, immunosuppression by, 442Superoxide anion, 40, 42f, 70, 148, 148f, 174,

254, 254f, 397, 397f, 503, 519, 529,544, 545f, 607, 607f

Superoxide dismutase, 42–43, 42–43f, 70, 148,397, 397f, 525, 544–545, 545f, 840, 848

cardiac, 607, 607focular, 566t, 570

Supraventricular arrhythmia, 602Supraventricular tachycardia, 602Suprofen, biotransformation, 199f, 202Suramin, distribution, 120fSurface-active agents, in food, 1057tSurface-finishing agents, in food, 1057t

Surfactants, ocular toxicity, 576Survivin, 77Susceptibility

biomarkers, 1019individual variation, 85, 99

Swainsonine, 971–973Sweat, excretion of toxic agents, 129Sweat duct, 119Sympathomimetic agents, 555

cardiotoxicity, 618–619vasculotoxicity, 636t

Sympathomimetic syndrome, 1111, 1111tSyncytiotrophoblast, 687Syndesmochorial placenta, 123, 123t, 687Synergistic effect, 17, 1057tSyphilis, 353tSyrian hamster embryo cells, 293Syrup of ipecac, 17, 1100, 1114–1115Systemic hypersensitivity, 462–463Systemic lupus erythematosus, 461tSystemic photoallergy, 664Systemic toxicity, 16

TT25, 3012,4,5-T, 1092

developmental effects, 358–359immunosuppression by, 439poisoning, 792structure, 791f

T-2 toxinin food, 1077timmunosuppression by, 446vasculotoxicity, 640, 641t

Tabun, 775mechanism of toxic action, 779–780structure, 775ftreatment of poisoning, 784

Tachycardia, 602–603Tacrine, biotransformation, 185t, 186, 189tTacrolimus. See FK506Talc

lung damage caused by, 528tvasculotoxicity, 643t

Talcosis, 528tTallow, 1055tTamoxifen, 17, 76

biotransformation, 156, 157f, 159, 167, 169,185t, 186

carcinogenicity, 248, 249f, 286developmental effects, 368Leydig cell tumor development and, 748tocular toxicity, 566tovarian tumor development and, 750–751reproductive system toxicity, 682, 692retinotoxicity, 580

Tanning response, 662–663Tantalum carbide, lung damage caused by, 527tTardive dyskinesia, 555Target internal effective dose, 95Target molecule, 38t

attributes, 44–45, 44fdestruction, 47dysfunction, 46–47effects of toxicants, 44f, 46–48neoantigen formation, 47–48

reaction with ultimate toxicant, 36f,44–48, 44f

types of reactions, 44f, 45–46Target organ, 16, 108Target tissue, 108Tartar emetic, 1114Taurine conjugation, 212Taxol, biotransformation, 185tTBG. See Thyroxine-binding globulinTCA. See Trichloroacetic acidTCAD, cellular dysregulation, 54–55tTCDD. See 2,3,7,8-Tetrachlorodibenzo-p-dioxinTCE. See 1,1,2-TrichloroethyleneT cell(s), 420, 421–422t, 425–428, 459

allergic contact dermatitis, 659development and differentiation, 429fproliferative capacity, 435subsets, 431, 432f

T-cell anergy, 459T-cell receptor (TCR), 422, 425–426, 428, 459TCP. See Tricresyl phosphateTCR. See T-cell receptorTD50, 91, 301, 301fTDI. See Toluene diisocyanateTear film, 567Tears, 567TEBG. See Testosterone-estradiol

binding proteinTEF. See Toxicity equivalence factorsTegafur, biotransformation, 149, 150fTEL. See Tetraethyl leadTellurates, 855Tellurides, 855Tellurium, 855

neurotoxicity, 553t, 554Tellurium dioxide, 855Telodrin, poisoning, 771tTemazepam, biotransformation, 199fTemelastine, biotransformation, 177Temephos, 779Temperature-dependent sex determination, 1021Tenoxicam, biotransformation, 184t, 187TEPP. See TetraethylpyrophosphateTeratogenicity. See also specific compounds

determination, 31of environmental chemicals, 1025of plant chemicals, 973

Teratology, 31, 351–352Terazosin, adrenal toxicity, 720Terbutaline, cardiotoxicity, 614t, 618p-Terbutylphenol, pigmentary disturbances

from, 666fTerfenadine

biotransformation, 182, 185t, 191–192cardiotoxicity, 606, 616t, 621–624

Terrestrial ecotoxicology, 1022, 1026–1027acute and chronic toxicity testing, 1026field testing, 1026–1027

p-Tert amylphenol, pigmentary disturbancesfrom, 666f

Testes. See also Testicular functionbiotransformations, 689–691, 690tdevelopment, 675endocrine function, 741–746growth factors isolated from, 677tLeydig cell tumors, 741–746local factors modulating functions, 678t

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Testicular biopsy, 695Testicular feminization, 676Testicular function, 676–682

apoptosis, 676–677, 679fLeydig cells, 681–682Sertoli cells, 681, 682fspermatogenesis, 677–681, 679–680f, 681t

Testicular histology, 695–696, 696fTesticular weight, 695��-Testolactone, reproductive system

toxicity, 689tTestosterone, 604, 676, 678t, 688f, 742,

742–743f, 1021, 1052tbiotransformation, 175f, 180, 181f, 182,

186, 196, 199fcarcinogenicity, 248, 249fcardiotoxicity, 626t, 627immunosuppression by, 447Leydig cell tumor development and, 745,

747–748tsexual differentiation and, 675–676thyroid effects, 724transdermal delivery, 656vasculotoxicity, 636t

Testosterone-estradiol binding protein(TEBG), 1021

Testosterone 7�-hydroxylase, 186Testosterone 15�-hydroxylase, 186Tetrabromodibenzofuran, chloracne, 665tTetracaine

biotransformation, 139cardiotoxicity, 623

3,3�,4,4�-Tetrachloroazobenzene,chloracne, 665t

3,3�,4,4�-Tetrachloroazoxybenzene, chloracne,665f, 665t

2,5,2�,5�-Tetrachlorobiphenyl, as promotingagent, 270t

2,3,4,4-Tetrachlorobut-3-enoic acid chloride,biotransformation, 41t

Tetrachlorocarbanilide, in photopatch test,664t

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCCD),9, 45, 74f, 75, 149, 193–194, 193t

absorption, 109, 114, 118action, 49carcinogenicity, 279t, 281t, 284, 301f, 659cellular dysregulation, 50t, 52chloracne, 665, 665f, 665tdistribution, 38, 122, 124formation, 791immunosuppression by, 438–440LD50, 25occupational disease, 1127toctanol/water partition coefficient, 109tphototoxicity, 663poisoning, 792as promoting agent, 267, 268f, 275, 275treproductive system toxicity, 691risk associated with, 86thyroid toxicity, 729as ultimate toxicant, 37tvasculotoxicity, 646

2,3,7,8-Tetrachlorodibenzofuran,chloracne, 665f

Tetrachloroethanein food, 1074t

immunosuppression by, 446Tetrachloroethyl-L-cysteine (TFEC),

nephrotoxicity, 498, 504, 506Tetrachloroethylene (PERC), 870,

884–885, 885fbiotransformation, 190, 884carcinogenicity, 89t, 884–885environmental contamination, 873in food, 1074tlung damage caused by, 528tnephrotoxicity, 507–508, 884, 885f

Tetrachlorosalicylanilide, photoallergy, 664Tetracycline, 1066

aplastic anemia and, 394tcardiotoxicity, 621coagulation factor inhibitor development

and, 406tdevelopmental effects, 353tdistribution, 120fphototoxicity, 663tvolume of distribution, 228t

n-Tetradecane, 903Tetradecanoyl phorbol acetate (TPA)

carcinogenicity, 274–275t, 275–276, 297irritant dermatitis from, 657as promoting agent, 267, 268f, 269,

269f, 669Tetradecanoyl phorbol acetate response

element, 49Tetradecylsulfate, vasculotoxicity, 643tTetraethyl lead (TEL), 814, 833–834Tetraethylpyrophosphate (TEPP), 775Tetrafluoroethylene

biotransformation, 508nephrotoxicity, 508–509, 509f

Tetrahydrocannabinol (THC), 1101biotransformation, 184–185t, 187immunosuppression by, 449reproductive system toxicity, 681

Tetramethrinbiotransformation, 787poisoning, 785t

Tetramethylthiuram, 661fTetranitromethane, lung damage caused by, 526Tetrodotoxin, 12, 46, 1067t, 1079

cellular dysregulation, 55t, 56LD5, 13tas ultimate toxicant, 37t

Texturizers, 1057tTFEC. See Tetrachloroethyl-L-cysteineTGF. See Transforming growth factorThalassemia, 392Thalidomide, 9, 11–12

developmental effects, 353–354, 353t, 372,374–375

reproductive system toxicity, 674Thallium, 855–856

absorption, 113neurotoxicity, 543tteratogenicity, 856

Thallium sulfate, 801Thallous sulfate, 855Thapsigargin, as tumor promoter, 669THC. See TetrahydrocannabinolTheca cells, 685, 693Theobromine, cardiotoxicity, 624Theophrastus, 3

Theophyllinebiotransformation, 158, 184–185tcardiotoxicity, 616t, 624laboratory tests on stat basis, 1112tpharmacologic food reaction, 1071tpoisoning, 1117t

action level, 1113vasculotoxicity, 640

Therapeutic drug monitoring, 1089,1104–1106, 1104f, 1105t

appropriate use, 1105tdrugs commonly monitored, 1105tpanic value, 1106

Therapeutic index, 23–24Theriac, 1109Thermopsine, 973Thevetin, 1084Thiabendazole


Thiadiazole, impairment of cellularmaintenance, 59t

Thiazide diuretics, thrombocytopenia and, 404Thickeners, 1056tThimerosal, allergic contact dermatitis from,

660–661tThioacetamide, 72

biotransformation, 170fimpairment of cellular maintenance, 63

Thioacetamide S-oxide, biotransformation, 41tThioamide, biotransformation, 170fThiobenzamide, biotransformation, 170f, 171Thiobis-chlorophenol, in photopatch test,

664tThiocarbamate, biotransformation, 171Thiocarbamide, biotransformation, 171Thiocyanate

aplastic anemia and, 394tpoisoning, 1116tthyroid toxicity, 726, 726f

Thioether methyltransferase, 206Thioglycolate, allergic contact dermatitis

from, 660t6-Thioguanine

biotransformation, 208resistance, 337

Thiol methyltransferase, 208Thiopental, biotransformation, 178f, 180Thiophanate, 797tThiophenol, biotransformation, 199fThiophosgene, 799Thiopurine methyltransferase, 208Thioredoxin, 65, 65fThioredoxin reductase, 65fThioridazine

biotransformation, 185tcardiotoxicity, 616t, 622

2-Thiothiazolidine-4-carboxylic acid (TTCA),904, 904f

Thiothixene, cardiotoxicity, 622Thiouracil, thyroid toxicity, 726Thiourea

in food, 1065lung damage caused by, 519in photopatch test, 664tthyroid toxicity, 726, 726f

Thiram, 797t

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Thiuram, allergic contact dermatitis from,660–661t

Thiyl radical, 46THM Act, 86tThorium dioxide, 731

carcinogenicity, 286thepatotoxicity, 476t, 478

Thorotrast. See Thorium dioxideThreshold concept, in developmental toxicity,

359–360Threshold dose, 19, 21–22, 92, 92fThreshold limit value (TLV), 870–871,

1089, 1126ceiling limit, 1126data for specific chemicals, 1155–1176short-term exposure limit, 1126time-weighted average, 1126

Threshold of regulation, 1050Thrombin, 405, 406t, 632, 636tThrombin-like enzymes, snake venom,

955–957, 957–958tThrombocytes, 403Thrombocytopenia, 403–405, 404t

heparin-induced, 404–405, 404t, 408immune-mediated, 404t

Thrombosis, 408, 635, 636t, 640Thrombotic thrombocytopenic purpura, 405Thromboxane A2, 163f, 173, 405, 511, 638

vasculotoxicity, 643tThromboxane B2, 645Thromboxane synthase, 173Thujone, 971Thymectomy, ovarian tumor development

and, 749, 752Thymidine kinase, 288, 291fThymidine kinase forward mutation assay,

331t, 337Thymidylate synthetase, 359, 359f, 377Thymine glycol, 327Thymol, in food, 1055tThymoleptics, vasculotoxicity, 636tThymulin, 848Thymus, 420tThyrocytes, 725Thyroglobulin, 728Thyroid cancer

radioactive iodine-induced, 929–931, 931ftinea capitis irradiation, 929, 929t, 930ftreatment with radioactive iodine, 931

Thyroid C cellsmechanisms of toxicity, 736, 736fmorphologic alterations and proliferative

lesions, 736–737structure and function, 734–736, 735f

Thyroid follicular cellsalterations in colloid, 728–729chemicals that disrupt hormone secretion,

728–729hepatic microsomal enzyme induction and,

729–731, 729–731finhibition of hormone synthesis, 725–728inhibition of 5�-monodeiodinase, 731–733,

732–733fmechanisms of tumorigenesis, 725, 725f,

733–734, 734–735fpigmentation, 728–729risk assessment, 733–734, 734–735f

species differences in thyroid hormoneeconomy, 723–725

Thyroid hormones, 247, 604, 713, 723–737binding to serum proteins, 724, 724tbiotransformation, 198, 199f, 202–203, 205blockage of release, 728cardiotoxicity, 627t, 628chemicals that disrupt secretion, 728–729distribution, 120finhibition of synthesis, 725–728metabolism, 730

Thyroid peroxidase, 725inhibition, 726–728, 726–728f

Thyroid-stimulating hormone (TSH), 712–715,713f, 724–727, 729–731, 734

Thyroperoxidase, 44, 724Thyrotoxicosis, 704Thyrotrophs, 712–713, 713fThyrotropin, carcinogenicity, 247, 248tThyrotropin-releasing hormone (TRH), 713, 724Thyroxine-binding globulin (TBG), 724, 730Tiaramide, biotransformation, 146Tick(s), 952

disease transmission, 952Tick paralysis, 952Ticlopidine

aplastic anemia and, 394tbiotransformation, 166, 168feffect on platelets, 405thrombocytopenia and, 404t, 405

Tidal volume, 530TIE. See Toxicity identification evaluationTienilic acid, 192

biotransformation, 184t, 189thepatotoxicity, 476t

Tight junction, 536, 536f, 567, 569, 571, 689Timolol, biotransformation, 185tTin, 856

lung damage caused by, 528tTinea capitis irradiation, 929, 929t, 930fTin hydride, 856Tirapazamine, biotransformation, 147, 147fTissue, storage of toxicants, 120–122Tissue macrophages, 433Tissue plasminogen activator, 681Tissue repair

apoptosis, 67regeneration of tissue, 67–69side reactions, 69–71

Tissue-specific bioassay, 294–295, 294tTitanic acid, 857Titanium, 857

carcinogenicity, 246tTitanium carbide, lung damage caused by, 527tTitanium dioxide, 857

carcinogenicity, 89, 89tTitanocene, 857TLC. See Total lung capacityTLV. See Threshold limit valueTMA. See Trimellitic acid anhydrideTMB-4, treatment of organophosphate

poisoning, 783TMP. See 2,2,4-TrimethylpentaneTMPOH. See 2,4,4-Trimethyl-2-pentanolTNF. See Tumor necrosis factorTobacco smoking. See Cigarette smokingTobramycin

cardiotoxicity, 615t, 621laboratory tests on stat basis, 1112ttherapeutic monitoring, 1105t

Tocainidecardiotoxicity, 613clinical uses, 605

�-Tocopherol, 66f, 71, 607, 613allergic contact dermatitis from, 660teffect on coagulation, 406t

TOCP. See Tri-o-cresyl phosphateTolbutamide

aplastic anemia and, 394tbiotransformation, 175f, 182, 184t, 187drug interactions, 407neutropenia and, 402t

Tolerance, 17dispositional, 17ozone, 1003pollution-induced community

tolerance, 1024Tolmetin, biotransformation, 199f, 202Toluene, 891–892

biotransformation, 43, 876, 891–892cardiotoxicity, 630tdevelopmental effects, 353tenvironmental contamination, 873immunosuppression by, 445neurotoxicity, 891–892occupational disease, 1127tpoisoning, 113treproductive system toxicity, 674retinotoxicity, 583–584solvent abuse, 872toxicokinetics, 875, 875f

Toluene diisocyanate (TDI)hypersensitivity reaction to, 456lung damage caused by, 520occupational disease, 1127t, 1129skin burns, 658t

Toluene sulfonamide resin, allergic contactdermatitis from, 660t

Toluidine blue, oxidative hemolysis and, 397tTomatine, 1051Tomoxetine, biotransformation, 185tTopical exposure, 14Topoisomerase, 1020Topoisomerase II inhibitor, 402–403Topotecan, hematotoxicity, 410Toremifene

biotransformation, 185tovarian tumor development and, 750–751

Torsemide, biotransformation, 184tTotal body clearance, 228Total lung capacity (TLC), 518–519, 530TOTP. See Tri-o-tolyl phosphateToxaphene, 774

poisoning, 771tToxemia of pregnancy, 365Toxic agents, classification, 13Toxic amblyopia, 584Toxicant, ultimate, 36, 37tToxication, 38f, 40–42, 41t. See also

Biotransformationelectrophile formation, 40, 41tfree radical formation, 40–42, 42fnucleophile formation, 42redox-active reactant formation, 42

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Toxic dose, 23–24, 24fspectrum, 13, 13t

Toxic effectsirreversible, 16reversible, 16

Toxic endpoint, 23Toxic epidermal necrolysis, 667Toxicity. See also Hazard identification

delayed, 16immediate, 16individual differences, 26local, 16mechanisms, 35–78not initiated by reaction with target

molecules, 48selective, 24–25species differences, 25–26systemic, 16

Toxicity equivalence factors (TEF), 86Toxicity identification evaluation (TIE), 1028Toxicity reduction evaluation (TRE),

1028–1029Toxicodynamics, 93, 93fToxicogenomics, 12Toxic oil syndrome, 399Toxicokinetics, 93, 93f, 108

classic, 225–230apparent volume of distribution,

227–228, 228tbioavailability, 230clearance, 228, 229fcomputer software, 230elimination, 226–227, 227thalf-life, 228–229, 229fone-compartment model, 225–226,

226–227fsaturation toxicokinetics, 229–230,

229f, 230ttwo-compartment model, 226,

226–227fphysiologic, 230–237

anatomic parameters, 232–233basic model structure, 231–232, 231fblood compartment, 236–237compartments, 232diffusion-limited compartments,

234–235, 234fliver compartment, 235–236, 236flung compartment, 235, 235fperfusion-limited compartments,

233–234, 234fphysiologic parameters, 233thermodynamic parameters, 233transport parameters, 233

in pregnancy, 364–365Toxicologist, 11Toxicology

analytic, 1089–1107areas, 11–13, 12fbehavioral, 32clinical, 3, 13, 1109–1120computational, 463definition, 3, 11descriptive, 12, 12fdevelopmental, 31, 351–378, 578ecotoxicology, 1013–1038environmental, 3, 13, 1013–1014

experimental, 5food, 1049–1084forensic, 5, 12, 1089–1107genetic, 99, 321–346history

Age of Enlightenment, 4–5antiquity, 3–4Middle Ages, 4modern, 5–8, 6tafter World War II, 8–10

inhalation, 7–8, 515mechanistic, 11–12, 12fmolecular, 3occupational, 1089, 1123–1138regulatory, 12, 12f, 1089, 1141–1151regulatory controls over, 1148–1151reproductive, 31respiratory, 515scope, 3

Toxicology Data Network (TOXNET), 99Toxic Substances Control Act (TSCA), 9, 12,

86, 86t, 305t, 1030, 1142–1143,1145–1146, 1148–1150

Toxic syndrome, 1111Toxidrome. See Toxic syndromeToxins, 13. See also specific toxins

bacterial, 1080–1082with enzymatic activity, 46intestinal absorption, 1053tprotein, detoxication, 43seafood, 1078–1080

TOXNET. See Toxicology Data NetworkToxogonin, treatment of organophosphate

poisoning, 783–784Toxoplasmosis, 353t, 365TPA. See Tetradecanoyl phorbol acetateTrachea, 516, 517fTracheobronchial clearance, 522Tracheobronchial tree, 117Tranexamic acid, 409Transcription, 327

dysregulation, 49, 50tTranscription factor, 50, 68, 327

AP-1, 46E2F, 74f, 274, 276, 277f

Transcription-repair coupling factor, 67Transcuprein, 840Transdermal drug delivery, 655–656Transferrin, 71, 120, 120f, 681, 815, 842,

849–850, 987Transformation in cell culture, 288t, 293Transforming growth factor-� (TGF-�), 68–69,

69f, 78, 497–498, 677tcarcinogenicity, 248, 249f

Transforming growth factor-� (TGF-�), 49, 52,62f, 69, 69f, 72, 427t, 497–498, 523,604, 677, 677t, 883

Transfusional siderosis, 842Transgenic animals

carcinogenicity testing, 669mutagenicity testing, 337–338

Transgenic mice, 294timmunotoxicity testing, 462models of carcinogenesis, 297

Transition, 328Translocated herbicides, 790Translocation (chromosome alteration),

323–324, 330reciprocal, human population

monitoring, 343Transmissible spongiform

encephalopathy, 1082Transthyretin, 71Transversion, 328TRE. See Toxicity reduction evaluationTremetol, 1084TRH. See Thyrotropin-releasing hormoneTRI. See 1,1,1-TrichloroethaneTriallate, 797tTriamcinolone, cardiotoxicity, 627–628Triamterene

megaloblastic anemia and, 393tnephrotoxicity, 496t

Triaryl phosphate, adrenal toxicity, 718Triazine

mechanism of action, 791treproductive system toxicity, 698t

Triazolam, biotransformation, 185tTriazolopyrimidines, mechanism of action, 791tTribromosalicylamide, photoallergy, 664Tribromosalicylanililde, in photopatch

test, 664tS,S,S,S-Tributyl phosphorotrithioate (DEF),

poisoning, 778Tributyltin, 856

cellular dysregulation, 52ecotoxicology, 1017t

Trichlorfonbiotransformation, 782mechanism of toxic action, 779poisoning, 777–778

Trichloroacetic acid (TCA), 870,881–883, 882f

Trichlorocarbanilide, in photopatch test, 664t1,1,1-Trichloroethane (TRI), 870

cardiotoxicity, 630tenvironmental contamination, 873in food, 1074tsolvent abuse, 873

Trichloroethanol, 881biotransformation, 199f

Trichloroethene, immunosuppression by, 4461,1,2-Trichloroethylene (TCE), 26, 870,

880–884air pollution, 993autoimmune reaction to, 461tbiotransformation, 189t, 190f, 191–192, 876,

881–882, 882fcancer epidemiology, 881carcinogenicity, 279t, 882–884cardiotoxicity, 630tin food, 1065, 1074, 1074timmunosuppression by, 445–446kidney cancer, 883liver cancer, 882–883lung cancer, 883–884mode of action in target tissues, 882neurotoxicity, 548toccupational disease, 1127treabsorption, 39retinotoxicity, 583–584risk assessment, 884

Trichlorofluoromethane, cardiotoxicity,629, 630t

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Trichloromethane. See ChloroformTrichloromethyl radical, 40, 887Trichloronate, poisoning, 777–7782,4,5-Trichlorophenol, chloracne, 6652,4,5-Trichlorophenoxyacetic acid. See 2,4,5-T1,1,1-Trichloropropene oxide, 143Trichlorotrifluoroethane, cardiotoxicity, 630tTrichlorotrifluoroethylene, cardiotoxicity, 630tTrichodermin, in food, 1077tTrichomes, 966Trichothecenes

in food, 1077–1078, 1077timmunosuppression by, 446vasculotoxicity, 640

Triclosan, in photopatch test, 664tTricresyl phosphate (TCP), adrenal

toxicity, 718Tri-o-cresyl phosphate (TOCP), 7, 16

biotransformation, 139neurotoxicity, 551reproductive system toxicity, 691

Tricyanoaminopropene, thyroid toxicity, 726Tricyclic antidepressants

cardiotoxicity, 615t, 622cellular dysregulation, 56contaminated, 1092poisoning, 1103t, 1119–1120reproductive system toxicity, 685tvasculotoxicity, 639

Trien, 841Triethylene melamine, developmental

effects, 357Triethylene tetramine, 818Triethyltin, 856

neurotoxicity, 553tTrifluoperazine

aplastic anemia and, 394tcardiotoxicity, 622vasculotoxicity, 639

Trifluoroacetaldehyde, reproductive systemtoxicity, 691

Trifluoroacetyl chloride, 47biotransformation, 41t

Trifluorobromomethane, cardiotoxicity, 630tTrifluoroethanol, reproductive system

toxicity, 691Trifluoroiodomethane, cardiotoxicity, 629, 630tTrifluorothymidine resistance, 337Trifluperidol, biotransformation, 185tTrigeminal nerve, 5231,2,4-Trihydroxybenzene, 890fTrimellitic acid anhydride (TMA),

hypersensitivity reaction to, 456Trimethadione

aplastic anemia and, 394tbiotransformation, 185tdevelopmental effects, 353t

Trimethoxypsoralen, phototoxicity, 663tTrimethroprim, thyroid toxicity, 726Trimethylamine, biotransformation, 169,

169f, 171, 176Trimethylaminuria, 171Trimethyl lead, 833Trimethyl pentane, 1252,3,5-Trimethylpentane, 262,2,4-Trimethylpentane (TMP), 901

nephrotoxicity, 500

as promoting agent, 267, 268f2,4,4-Trimethyl-2-pentanol (TMPOH), 901Trimethyltin, 856

neurotoxicity, 543t, 544Trimetrexate, biotransformation, 203tTrimipramine, biotransformation, 176Trinitroglycerin, biotransformation, 216fTrinitrophenol, occupational disease, 1127tTrinitrotoluene, methemoglobinemia and, 395tTriparanol, adrenal toxicity, 718–719Tripelennamine

aplastic anemia and, 394tbiotransformation, 198, 199f

Triphenylmethane, allergic contact dermatitisfrom, 660t

Triphenyl phosphate, allergic contact dermatitisfrom, 660t

Triphenyltin, 856Triptans, biotransformation, 160Tris(2,3-dibromopropyl)phosphate,

biotransformation, 189tTri-o-tolyl phosphate (TOTP), poisoning,

777–778Troglitazone, 186, 188

hepatotoxicity, 471, 477fTroleandomycin, 188, 191, 195–196

biotransformation, 185tTrophic level, transfer of contaminants,

1024–1025Trophic structure, of community, 1024Trophoblastic tissue, 687Tropiramate, therapeutic monitoring, 1105tTropisetron, biotransformation, 185tTroponin, 603Trovafloxacin, cardiotoxicity, 621TRPM-2, 677True acetylcholinesterase, 137True bugs, 954Trypan blue, developmental effects, 352Trypsin inhibitors, 1051Tryptamine, biotransformation, 160Tryptophan, 399

autoimmune reaction to, 461tbiotransformation, 207

Tryptophan reversion assay, 331tTSCA. See Toxic Substances Control ActTSCA 799.9780, 435–436TSH. See Thyroid-stimulating hormoneT syndrome, 784–786, 785tTTCA. See 2-Thiothiazolidine-4-carboxylic acidTuberculin-type hypersensitivity, 453Tubocurarine

cellular dysregulation, 54tLD5, 13t

Tubular excretion, 124Tubular reabsorption, 125Tubular secretion, 124Tubulin, 46, 330Tubuloglomerular feedback, 494Tulipalin-A, 966Tulip fingers, 966Tuliposide A, allergic contact dermatitis

from, 660tTumor, 242

background incidence, 30–31, 30fTumor necrosis factor-� (TNF-�), 62f, 68–72,

69f, 423, 427t, 428–429, 523

cardiotoxicity, 627t, 628Tumor necrosis factor-� (TNF-�), 427t, 428,

456, 456fTumor necrosis factor receptor-1, 63Tumor promoter, 77Tumor suppressor genes, 26, 76f, 271, 272t,

273, 323functions, 272, 272tinactivation, 323–324mutations, 75, 75f, 323

Tungsten carbide, lung damage caused by, 527tTunnel vision, 587Turbulent flow, 1015Turkey X disease, 1076Turmeric, in food, 1055tTurner’s syndrome, 675Two-compartment model, 226, 226–227fTyramine, 1066, 1067t, 1071t

biotransformation, 160, 169vasculotoxicity, 636t

Tyrosine ester sulfotransferase, 204Tyrosine hydroxylase, 720, 830Tyrosine kinase, 273, 275, 607, 1020

UUbiquitin, 65UDP-glucose dehydrogenase, 198fUDP-glucose pyrophosphorylase, 198fUDP-glucuronic acid, 197–203, 198f,

219, 1052tUDP-glucuronosyltransferase, 41t, 49, 140,

145f, 149, 164f, 193–194, 196–203,198f, 200f, 210, 213, 253f, 656,729–730

ocular, 571Ultimate carcinogen, 251–252, 252fUltimate toxicant, 36, 37tUltimobranchial body, 737Ultraviolet light

abnormal sensitivity to, 663adverse responses to, 662–663DNA damage due to, 326f, 327immunosuppression by, 450ocular toxicity, 577skin cancer and, 668

Umbelliferone, 158Uncertainty factors, 93–94, 93f, 375Uncoupler, 58, 59t, 609, 609fUndesired effects, 15–16Uneconomic form, 25Unleaded gasoline, 827–828

carcinogenicity, 89t, 247, 279nephrotoxicity, 504, 507–508as promoting agent, 267–268

Unscheduled DNA synthesis, 66, 293,334–335, 691–692

Uranium, 857Uranium-238, decay series, 932, 932fUranium miners, 932–935, 932–934f

lung cancer risk estimated from undergroundminer epidemiology, 933–934,933–934f

lung dose from radon exposure,934–935, 934f

radon exposure in underground mines,932–933

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Uranium tetrafluoride, 857Uranyl fluoride, 857Urbanization, 979–980Urea formaldehyde resin, allergic contact

dermatitis from, 660tUremia, 1113tUrethane

biotransformation, 189t, 190, 190fcarcinogenicity, 244, 244f, 274t, 281timmunosuppression by, 444

Urethral glands, 684Uric acid, distribution, 120fUrinAid, 1101Urinalysis, 501–502, 1104

biological monitoring, 1137forensic urine drug testing, 1100–1102,

1100–1101tpostmortem, 1098

Urinary acidification, 1115Urinary alkalinization, 1115Urinary excretion, 124–125, 125f, 198, 203,

211, 215Urine, pH, 125Urine adulterants, 1101, 1101tUrine volume, 501Urokinase, 409Uroporphyrinogen decarboxylase, 193Urticaria, 666–667, 667t

contact, 666Urushiols, 47, 966Use-in-pregnancy rating, 375Uterus, 686, 686fUveal blood vessels, 567–569

VVagina, 686, 686–687Valinomycin, impairment of cellular

maintenance, 59tValproic acid, 86

biotransformation, 180, 181f, 189t,199f, 690t


developmental effects, 353t, 356, 372,374–375

hepatotoxicity, 476, 476tlaboratory tests on stat basis, 1112treproductive system toxicity, 690ttherapeutic monitoring, 1105t

Valpromide, 143Valrubicin, cardiotoxicity, 619Vanadate

cellular uptake, 816impairment of cellular maintenance, 60t

Vanadium, 857–858immunosuppression by, 444lung damage caused by, 528treproductive system toxicity, 695t

Vanadium pentoxide, 858Vancomycin

nephrotoxicity, 496ttherapeutic monitoring, 1105t

Vanishing bile duct syndrome, 477–478Vapors. See also Solvents

absorption in lungs, 115–116toxic effects, 869–905

Varicella virus infection, 353tVascular permeability factor, 659Vascular reactivity, 637Vascular space, 232Vascular system. See also Blood vessels;

Vasculotoxicitydisturbances of structure and function,

632–635, 634–635ffunctions, 598physiology, 631–632, 631–634ftoxic effects of plants, 969toxic responses, 631–647

Vascular tone, 632, 638Vasculitis, 635Vasculotoxicity

of alkylamines, 640–642of analgesics and anti-inflammatory

agents, 639of antibacterial agents, 643tof anticoagulants, 643tof antineoplastic agents, 639of aromatic hydrocarbons, 645–646of autonomic agents, 639of endotoxin, 640of gases, 646–647of homocysteine, 637, 640of hydrazinobenzoic acid, 640, 641tof industrial agents, 640–647, 641tmechanisms, 635–639, 637t, 638fof metals, 644–645of natural products, 640, 641–642tof nitroaromatics, 645of oral contraceptives, 639–640, 644tof pharmaceutical agents, 639–640, 643–644tof phosphodiesterase inhibitors, 640of psychotropic agents, 639of radiocontrast agents, 640, 643tof T-2 toxin, 640, 641tof vitamin D, 640

Vas deferens, 684Vasoactive chemicals, in plants, 969Vasoconstriction, 635

coronary, 606Vasodilation, 635Vasopressin, 632Vasospasm, coronary, 606VC. See Vital capacityVCAM, 657Vehicle, 14Venezuelan equine encephalitis virus, 353tVenlafaxine, cardiotoxicity, 622Venom. See Animal toxinsVeno-occlusive disease, 478Ventilation, 518–519Ventilation rate, 235Ventilatory unit, 517–518, 518fVentricular arrhythmia, 602–603Ventricular fibrillation, 603, 613Ventricular tachycardia, 603VEP. See Visual-evoked potentialsVerapamil

biotransformation, 176, 185t, 186cardiotoxicity, 614t, 617clinical uses, 606nephrotoxicity, 510

Veratramine, 968Veratridine, cellular dysregulation, 55t

Verlukast, biotransformation, 176f, 183Vesnarinone, biotransformation, 166VHL gene, 883Vicks inhaler, 1101–1102Vidarabine

Leydig cell tumor development and, 748treproductive system toxicity, 683tthyroid toxicity, 734, 734f

Videx (ddI), immunosuppression by, 449Vinblastine, 46

genetic effects, 330reproductive system toxicity, 691t, 693tvasculotoxicity, 636t

Vinca alkaloids, neurotoxicity, 552Vinclozolin

acute toxicity, 797tbiotransformation, 690tdevelopmental effects, 369reproductive system toxicity, 674, 676,

682, 690t, 691Vincristine

absorption, 113neurotoxicity, 548t, 552reproductive system toxicity, 691t, 693tvasculotoxicity, 636t

Vinyl acetate, biotransformation, 140fVinyl chloride

air pollution, 992fautoimmune reaction to, 460, 460tbiotransformation, 189t, 192, 876, 1135carcinogenicity, 257, 281t, 284, 285t, 299t,

301, 1135EPA regulations, 1147hepatotoxicity, 471, 476t, 478occupational disease, 1127t, 1130, 1135vasculotoxicity, 641t

S-5-Vinyl-thiooxazolidone, 1072tViolin spider, 949t, 950–951Vipers, 955, 956–957tVirtually safe dose, 95Viscotoxins, 959Visible light, ocular toxicity, 577Visual acuity, 574Visual cortex. See Central visual systemVisual-evoked potential (VEP), 572–573Visual function, testing, 571–574

behavioral and psychophysical methods, 574electrophysiologic techniques, 572–574evaluation of ocular irritancy and toxicity,

571–572ophthalmologic evaluation, 572

Visual system, central. See Central visualsystem

Vital capacity (VC), 519, 530, 531fVitamin A, 20, 847, 1051–1052

developmental effects, 374hepatotoxicity, 476t, 478, 479t, 480reproductive system toxicity, 695ttoxicity, 1067t, 1072t

Vitamin B12, 839deficiency, 393, 393f, 393t

Vitamin C, 815, 842, 1003distribution, 120f

Vitamin D, 663, 738, 740–741, 831, 973adrenal toxicity, 720–721, 721–732fvasculotoxicity, 640, 643t

Vitamin D receptor, 625

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Vitamin E, 283, 847reproductive system toxicity, 695t

Vitamin K, 406, 408Vitamin K-dependent coagulation factors,

406–407, 406tVitamin K epoxide, 142, 406Vitamin K epoxide reductase, 45Vitellogenin, 1019Vitreous humor analysis, 1094VOC. See Volatile organic compoundsVolatile organic compounds (VOC).

See also Solventsair pollution, 987

Volatile substances, analytic toxicology, 1090Volume of distribution, 119–120

apparent, 227–228, 228tVomitoxin, immunosuppression by, 446von Willebrand factor, 406tVX

mechanism of toxic action, 780structure, 775f

WWallerian degeneration, 538Waltzing syndrome, 550Warfarin, 801–802

biotransformation, 145, 184–185t, 187,192

developmental effects, 353tdistribution, 120effect on coagulation, 406timpairment of cellular maintenance, 64octanol/water partition coefficient, 109tpoisoning, 801–802skin necrosis and, 407–408structure, 800ftoxicology, 407vasculotoxicity, 643t

Warren, Stafford, 7–8Wasp(s), 954Wasp honey, 972Water

air-water interphase, 1016single-phase chemical behavior, 1015soil-water interphase, 1016

Water bugs, 954Water moccasins, 955, 956–957tWater pollutants, toxic, EPA regulations,

1146Water quality criteria, 1146Whale oil, 763Wheal and flare reaction, 455Wheel bug, 954White muscle disease, 846Whole-effluent tests, 1028WHO system

classification of pesticides by hazard,802, 802t

grading hematotoxicity, 411, 411tWidow spiders, 949–950, 949tWildlife. See EcotoxicologyWildlife sentinel, 1014, 1018, 1025, 1038Wiley Bill, 6–7Willardiine, 971Wilson’s disease, 816, 818, 840–841Witthaus, Rudolph A., 1093Wood alcohol. See MethanolWood dust, carcinogenicity, 284, 285tWorker health surveillance, 1133–1135Work force, United States, 1123–1124Working level, 932WT1 gene, 272tWY-14,643, 196

as promoting agent, 268, 268f, 275t

XXanthine dehydrogenase/oxidase, 42, 60, 61f,

136t, 152, 156–159, 157–158f, 844Xanthinuria, 159X chromosome, 675Xenobiotic, 133Xenobiotic biotransforming enzymes

allelic variants, 134basic properties, 134distribution, 136–137, 136tin lung, 523nomenclature, 136ocular, 566t, 570–571phase I, 135–196, 136t, 251, 252f, 480,

566t, 570, 656phase II, 135–136, 136t, 196–219, 197f,

251, 480, 566t, 570, 656of reproductive system, 689–691in skin, 656–657

Xenobiotic-responsive element (XRE), 149,193–194, 217

Xenoestrogens, 49, 53, 675–676, 1021reproductive system toxicity, 674

Xeroderma pigmentosum, 73, 262, 327, 668X-rays, 918

leukemia and, 403XRE. See Xenobiotic-responsive elementXylene, 892

environmental contamination, 873reproductive system toxicity, 674retinotoxicity, 583–584urticaria from, 667t

Xylitol, in food, 1065

YY chromosome, 675Yeast assay, for recombinagenic effects, 337Yellow jackets, 954Yellow phosphorus, 801Yohimbine, 188Yusho, 1075

ZZalcitabine (ddC)

cardiotoxicity, 615t, 622impairment of cellular maintenance, 59timmunosuppression by, 448

Zatosetron, biotransformation, 185tZearalenone, 1021

cellular dysregulation, 49, 50tin food, 1077–1078reproductive system toxicity, 676

Zidovudine (AZT)cardiotoxicity, 615t, 621–622immunosuppression by, 448impairment of cellular maintenance, 59tmegaloblastic anemia and, 393tpigmentary disturbances from, 666t

Zinc, 847–848absorption, 114assessment of zinc status, 848carcinogenicity, 246t, 848cellular uptake, 816deficiency, 367–368, 695, 695t, 848distribution, 120f, 121effect on granulocytes, 400essentiality, 837host factors influencing toxicity, 815intestinal absorption, 1053tmetabolism, 847in neurologic disorders, 848occupational disease, 1127t, 1128in prostatic secretions, 684reproductive system toxicity, 695t, 698sideroblastic anemia and, 392ttoxicity, 848toxicokinetics, 847–848vasculotoxicity, 644

Zinc finger, 847Zinc oxide, 848Zinc phosphide, 800f, 801, 801

poisoning, 801Zineb, 797t, 799Zingerone, in food, 1055tZiram, 797t, 799Zirconium, granulomatous reactions to, 666Zolmitriptan, biotransformation, 160Zomepirac

adrenal toxicity, 720biotransformation, 41t, 199f

Zona fasciculata, 716–719Zona glomerulosa, 716–717Zona pellucida, 687Zona reticularis, 716–719Zonisamide, biotransformation, 160, 185tZoonotic disease, 1130Zoxazolamine, 194Zygote, 357, 687

1236 INDEX

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t nephrotoxicity

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t toxicokinetics

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