PRINCIPLES OF TOXICOLOGY - Biology East Borneo

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13.11 SUMMARY 321from non-Hodgkin’s lymphoma and from melanoma are also increasing. These data were confirmedin the 1999 joint release from the CDC, NCI, and ACS.As awareness of environmental contamination and the ubiquity of synthetic chemicals arose in the1960s, specifically after the release of Rachel Carson’s Silent Spring in 1962, speculation persistedthat we were awash in a “sea of carcinogens” and that after an appropriate latency interval, a cancerepidemic would hit. As has been shown in Figure 13.1, the hypothesized epidemic of cancer has neverarrived, and considering the data indicating decreasing cancers through 1995, it would seem thatperhaps our current reductions in smoking, food consumption, and alcohol might be starting to impactthe incidence of new cancers in the United States. Considering that the stability of the cancer incidence(aside from lung cancer due primarily to smoking) occurred during a period of great industrializationin the United States, the impact of occupation and environmental pollution on cancer incidence isprobably less than what was postulated 30 years ago. That is not to say, however, that exposurereductions are not still warranted in these areas, but merely to point out that the current data indicatethat our future, with its concomitant exposure to new synthetic chemicals, is not a dire one.13.11 SUMMARYChemical-induced carcinogenesis represents a unique and complex area within toxicology. Thedifficulty in assessing the carcinogenic hazards and human risks of chemicals stems from the followingcharacteristics of chemical carcinogenesis:• It is a multistage process involving at least two distinct stages: initiation, which converts thegenetic expression of the cell from a normal to aberrant cell line; and promotion, in whichthe aberrant cell is stimulated in some fashion to grow, thereby expressing its altered state.• Since chemicals may increase cancer incidence at various stages and by different mechanisms,the term carcinogen by itself is somewhat limiting and a number of descriptive labelsare applied to the chemical carcinogens that define or describe these differences, such ascocarcinogens, initiators, promoters, and epigenetic.• Chemicals may produce or affect only a single stage or a single aspect of carcinogenesis thatleads to a number of important differences and considerations about the potential healthimpacts of chemical carcinogens. Perhaps the most important considerations are the conceptof thresholds and that qualitative differences do exist among carcinogens.• Carcinogenicity testing raises many questions about interpretations of results. Considerationssuch as mechanism (genotoxic vs. epigenetic), dose, and relevant test species,are important in determining probable human risk; thus, many additional toxicity testdata are needed to improve the extrapolation of cancer bioassay data from test speciesto humans.• A number of lifestyle-related factors influence carcinogenesis, altering the risks posed bycarcinogenic chemicals and acting to confound epidemiological evidence.Considering the complexities involved in (1) determining the mechanism of cancer causation, (2) usinganimal and human data to identify carcinogenic substances, and (3) using these data to extrapolaterisks with the aim of reducing or eliminating environmental risk factors, it should be clear to the readerthat the best approach to occupational carcinogenesis is an interdisciplinary one. As depicted in Figure13.13, identifying and reducing occupational cancer requires the interfacing of several scientificdisciplines and several kinds of health professionals:• The toxicologist is responsible for testing and identifying chemical carcinogens;through animal testing the toxicologist attempts to provide information about carcino-
322 CHEMICAL CARCINOGENESISFigure 13.13 Identifying and reducing chemical carcinogens requires an interdisciplinary approach, in whichhealth professions interface with other scientific disciplines.genic mechanisms, and about species differences or similarities that can aid in assessing thehuman risk.• Epidemiologists add human evidence to risk evaluations or ascertain if a chemical shouldor should not be considered a human carcinogen for various reasons (it may have weak orundetectable activity).• Specialists in occupational medicine provide health surveillance programs to protect thehealth status of the worker and attempt to prevent those exposures that could lead to serious,chronic health problems.• Industrial hygienists help design better methods for evaluating and preventing workerexposures; and biometrists and computer scientists aid in risk analysis, data storage, and dataanalysis.As long as these disciplines are utilized jointly and their relationship to the occupationalcarcinogenesis problem is understood, occupational health and safety professionals can have goodreason to hope for improved success in the prevention of occupational carcinogenesis.
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CONTRIBUTORSLOUIS ADAMS, PH.D. Prof
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CONTENTSPREFACExvACKNOWLEDGMENTSxvi
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CONTENTSix7.3 Agents that Act on th
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CONTENTSxi15.4 Herbicides 35615.5 F
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CONTENTSxiii21.6 Population Issues
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xviPREFACE• The approach is scien
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PRINCIPLES OF TOXICOLOGY
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1 General Principles of ToxicologyG
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1.2 WHAT TOXICOLOGISTS STUDY 5Delay
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1.3 THE IMPORTANCE OF DOSE AND THE
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1.4 HOW DOSE-RESPONSE DATA CAN BE U
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1.5 AVOIDING INCORRECT CONCLUSIONS
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1.6 FACTORS INFLUENCING DOSE-RESPON
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1.6 FACTORS INFLUENCING DOSE-RESPON
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26 GENERAL PRINCIPLES OF TOXICOLOGY
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36 ABSORPTION, DISTRIBUTION, AND EL
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2.4 DISPOSITION: DISTRIBUTION AND E
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2.5 SUMMARY 53the transfer from liv
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REFERENCES AND SUGGESTED READING 55
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58 BIOTRANSFORMATION: A BALANCE BET
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60Figure 3.3 Xenobiotic metabolism
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TABLE 3.4 Important Cytochrome P450
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88 HEMATOTOXICITY: CHEMICALLY INDUC
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100 HEMATOTOXICITY: CHEMICALLY INDU
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5 Hepatotoxicity: Toxic Effects on
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5.1 THE PHYSIOLOGIC AND MORPHOLOGIC
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5.1 THE PHYSIOLOGIC AND MORPHOLOGIC
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5.2 TYPES OF LIVER INJURY 117cause
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5.2 TYPES OF LIVER INJURY 119Exampl
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5.2 TYPES OF LIVER INJURY 121TABLE
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5.2 TYPES OF LIVER INJURY 123to pro
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5.3 EVALUATION OF LIVER INJURY 125f
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6 Nephrotoxicity: Toxic Responses o
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6.1 BASIC KIDNEY STRUCTURES AND FUN
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6.1 BASIC KIDNEY STRUCTURES AND FUN
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6.2 FUNCTIONAL MEASUREMENTS TO EVAL
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6.3 ADVERSE EFFECTS OF CHEMICALS ON
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146 NEUROTOXICITY: TOXIC RESPONSES
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8 Dermal and Ocular Toxicology: Tox
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8.2 FUNCTIONS 159corneum is the pri
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8.3 CONTACT DERMATITIS 161TABLE 8.2
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8.3 CONTACT DERMATITIS 163mucous me
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8.3 CONTACT DERMATITIS 165light to
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8.4 SUMMARY 167The structure of the
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9 Pulmonotoxicity: Toxic Effects in
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9.1 LUNG ANATOMY AND PHYSIOLOGY 171
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9.2 MECHANISMS OF INDUSTRIALLY RELA
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9.2 MECHANISMS OF INDUSTRIALLY RELA
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9.3 SUMMARY 185Industrially Related
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190 IMMUNOTOXICITY: TOXIC EFFECTS O
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11 Reproductive ToxicologyREPRODUCT
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11.1 MALE REPRODUCTIVE TOXICOLOGY 2
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11.2 FEMALE REPRODUCTIVE TOXICOLOGY
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11.3 DEVELOPMENTAL TOXICOLOGY 225de
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11.3 DEVELOPMENTAL TOXICOLOGY 227af
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11.3 DEVELOPMENTAL TOXICOLOGY 229ri
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11.3 DEVELOPMENTAL TOXICOLOGY 231to
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11.4 CURRENT RESEARCH CONCERNS 233T
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11.4 CURRENT RESEARCH CONCERNS 235
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12 Mutagenesis and Genetic Toxicolo
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12.2 GENETIC FUNDAMENTALS AND EVALU
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TABLE 12-1. Correspondence of the G
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12.3 NONMAMMALIAN MUTAGENICITY TEST
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12.4 MAMMALIAN MUTAGENICITY TESTS 2
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12.4 MAMMALIAN MUTAGENICITY TESTS 2
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12.5 OCCUPATIONAL SIGNIFICANCE OF M
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REFERENCES CITED AND SUGGESTED READ
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13 Chemical CarcinogenesisCHEMICAL
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13.1 THE TERMINOLOGY OF CANCER 267H
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13.3 CARCINOGENESIS BY CHEMICALS 26
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Page 314 and 315: 13.9 CANCER AND OUR ENVIRONMENT 305
Page 328 and 329: 13.10 CANCER TRENDS AND THEIR IMPAC
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Page 334 and 335: 14 Properties and Effects of Metals
Page 336 and 337: 14.2 SPECIATION OF METALS 327Most o
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Page 340 and 341: 14.4 TOXICITY OF METALS 331reflex i
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Page 352 and 353: 14.7 SUMMARY 343Zinc is required fo
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Page 366 and 367: 15.4 HERBICIDES 357ClClO CH 2 C OOH
Page 368 and 369: 15.5 FUNGICIDES 359temperatures as
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16.2 BASIC PRINCIPLES 371TABLE 16.2
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16.2 BASIC PRINCIPLES 373Once absor
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16.2 BASIC PRINCIPLES 375the additi
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16.3 TOXIC PROPERTIES OF REPRESENTA
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16.10 TOXIC PROPERTIES OF REPRESENT
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16.15 TOXIC PROPERTIES 403observed
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16.18 SULFUR-SUBSTITUTED SOLVENTS 4
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17 Properties and Effects of Natura
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17.3 NATURAL ROLES OF TOXINS AND VE
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17.4 MAJOR SITES AND MECHANISMS OF
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17.5 TOXINS IN UNICELLULAR ORGANISM
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17.6 TOXINS OF HIGHER PLANTS 417phy
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17.6 TOXINS OF HIGHER PLANTS 419whi
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17.6 TOXINS OF HIGHER PLANTS 421TAB
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17.7 ANIMAL VENOMS AND TOXINS 423of
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17.7 ANIMAL VENOMS AND TOXINS 425ac
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17.7 ANIMAL VENOMS AND TOXINS 427co
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17.7 ANIMAL VENOMS AND TOXINS 429Fi
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17.8 TOXIN AND VENOM THERAPY 431One
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18 Risk AssessmentRISK ASSESSMENTRO
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18.1 RISK ASSESSMENT BASICS 439Step
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18.1 RISK ASSESSMENT BASICS 441For
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18.2 HAZARD IDENTIFICATION 443chemi
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18.3 EXPOSURE ASSESSMENT: EXPOSURE
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18.3 EXPOSURE ASSESSMENT: EXPOSURE
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18.4 DOSE-RESPONSE ASSESSMENT 449Af
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18.4 DOSE-RESPONSE ASSESSMENT 451me
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18.4 DOSE-RESPONSE ASSESSMENT 453Fi
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18.4 DOSE-RESPONSE ASSESSMENT 455No
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18.4 DOSE-RESPONSE ASSESSMENT 457Fi
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18.4 DOSE-RESPONSE ASSESSMENT 459Ge
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18.5 RISK CHARACTERIZATION 461likel
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18.6 PROBABILISTIC VERSUS DETERMINI
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18.7 EVALUATING RISK FROM CHEMICAL
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18.7 EVALUATING RISK FROM CHEMICAL
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18.8 COMPARATIVE RISK ANALYSIS 469r
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18.8 COMPARATIVE RISK ANALYSIS 471T
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18.9 RISK COMMUNICATION 473TABLE 18
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480 EXAMPLE OF RISK ASSESSMENT APPL
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500 OCCUPATIONAL AND ENVIRONMENTAL
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21 Epidemiologic Issues inOccupatio
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21.3 TYPES OF EPIDEMIOLOGIC STUDIES
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21.5 DISEASE AND HUMAN HEALTH EFFEC
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21.8 MEASUREMENT OF ASSOCIATION OR
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21.9 BIAS 519increased or decreased
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524 CONTROLLING OCCUPATIONAL AND EN
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556 GLOSSARYaliphatic Organic compo
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558 GLOSSARYbenign tumor A new tiss
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560 GLOSSARYcytokinesis The divisio
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562 GLOSSARYerythropoietic stimulat
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564 GLOSSARYinhalation route The mo
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566 GLOSSARYmitochondria Small sphe
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568 GLOSSARYoral route The entry of
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570 GLOSSARYporphyrin Any of a grou
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572 GLOSSARYspirometry The measurem
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INDEXAbsorbed dose, defined, 4Absor
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INDEX 577Area under the tissue conc
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INDEX 579animal studies, 297cellula
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INDEX 581speciation of, 327-328Corp
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INDEX 583organ-specific activities,
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INDEX 585Follicle-stimulating hormo
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INDEX 587fatty liver, 120-122hepato
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INDEX 589Isoniazid metabolism, path
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INDEX 591Mechanistic toxicology, as
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INDEX 593Nephropathy:defined 130nep
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INDEX 595neurobehavioral sequelae,
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INDEX 597Probability density functi
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INDEX 599Rodenticides, 360.-361sodi
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INDEX 601Safe Human Dose (SHD) appr
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INDEX 603drug metabolism factors, 7
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