PRINCIPLES OF TOXICOLOGY - Biology East Borneo

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88 HEMATOTOXICITY: CHEMICALLY INDUCED TOXICITY <strong>OF</strong> THE BLOOD(hemolytic anemia, which reduces the oxygen transport capacity of blood), and hydrogen sulfide.Exposure to hydrogen sulfide can be a significant industrial hygiene concern in the refining ofpetroleum products and the biological degradation of silage (fermented corn, grain, etc., used to feedlivestock) and sewage. As for the number of workers affected, benzene and hydrogen sulfide probablyconstitute the most significant risk factors for toxicity.Hematotoxicity is also an important concern in the administration of pharmaceuticals. For example,dapsone (used to treat leprosy) and primaquine (used to treat malaria) can produce a fatal hemolyticanemia in certain genetically predisposed individuals (those with a deficiency in glucose-6-phosphatedehydrogenase). Unfortunately, individuals most likely to require primaquine or dapsone therapy livein tropical areas of Africa, Asia, and the Mediterranean and are most likely to inherit a deficiency inglucose-6-phosphate dehydrogenase. Of widespread concern are the risks of bone marrow injury andsuppression caused by cancer chemotherapeutics, complications that can often limit the administrationof cancer-curing drugs. Another longstanding problem involves carbon monoxide poisoning, whichresults from exposure to improperly ventilated combustion products. Outside the workplace, the mostcommon occurrences of hematotoxicity involve carbon monoxide poisoning, due to faulty gas heating,and adverse hematologic effects due to prescription medications.Fortunately, hematotoxicity is rarely encountered due to the resiliency of bone marrow, theredundancy of various hematologic controls and functions, and the implementation of more conservativeoccupational hygiene standards. However, when it occurs it is often life threatening. Likewise,examples of hematotoxicity resulting from exposure to environmental chemicals are relatively rareand generally involve foods or medications. Although hematotoxicity is not prevalent, it is useful forindustrial hygienists, toxicologists, and occupational physicians to be aware of the chemicals that causehematotoxicity, relevant signs and symptoms, and any antidotes and treatments that are available.4.2 BASIC HEMATOPOIESIS: THE FORMATION <strong>OF</strong> BLOOD CELLS AND THEIRDIFFERENTIATIONAll blood cells originate from undifferentiated mesenchymal cells, which are located in the bonemarrow. The various stages of blood cell formation are depicted in Figure 4.1. From stem cells,clones of immature blood cells differentiate along one of two pathways: the myelogenous seriesor the lymphocytic series. The myeloid series gives rise to erythrocytes, macrophages, platelets,neutrophils, eosinophils, and basophils. The lymphoid series gives rise to T (thymus) and B(Bursa) lymphocytes.Bone marrow production of blood cells is highly dependent on, and controlled by, a number ofgrowth factors. Erythropoietin, a glycoprotein growth factor produced in the peritubular cells of thekidney, is essential for the differentiation and maturation of red blood cells. Under conditions ofhypoxia (low oxygen), such as that occurring at higher altitudes or during anemia (a reduction in redblood cells or hemoglobin content) affliction, the release of erythropoietin by the kidney is enhanced.Conversely, the release of erythropoietin is inhibited by polycythemia (the increased number ofcirculating red blood cells) or hyperoxia. Other important glycoproteins that act alone or in conjunctionwith erythropoietin to control red blood cell formation include interleukins such as IL3, IL1, and IL2;granulocyte-macrophage colony stimulating factor (GM-CSF); insulin-like growth factor; and granulocytecolony stimulating factor.White blood cell formation also depends upon stimulation and control by various growth factors.IL3 stimulates all of the myeloid series cells. GM-CSF stimulates the formation of granulocytes andmacrophages. Additionally, specific G-CSF and M-CSF proteins stimulate the granulocyte series orthe macrophage series, respectively. These growth factors, unlike erythropoietin, are produced byvarious cells including T lymphocytes, macrophages, fibroblasts, and endothelial cells. All the growthfactors work in concert to regulate different stages of myeloid and lymphoid differentiation andreplication.
Figure 4.1 Formation of blood. Mature differentiated blood cells arise from a pluripotential stem cell via sequential complex interactions of regulatory molecules and cellular controlswithin the bone marrow environment. Disruption of the differentiation and maturation process gives rise to the various types of chemically induced blood deficits and/orleukemias/lymphomas.89
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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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Page 68 and 69: 2.5 SUMMARY 53the transfer from liv
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Page 72 and 73: 58 BIOTRANSFORMATION: A BALANCE BET
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Page 130 and 131: 5.2 TYPES OF LIVER INJURY 117cause
Page 132 and 133: 5.2 TYPES OF LIVER INJURY 119Exampl
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Page 142 and 143: 6 Nephrotoxicity: Toxic Responses o
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6.3 ADVERSE EFFECTS OF CHEMICALS ON
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6.3 ADVERSE EFFECTS OF CHEMICALS ON
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REFERENCES AND SUGGESTED READING 14
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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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Figure 13.1 Schematic diagram of th
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Figure 13.4 Metabolic activation of
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13.4 MOLECULAR ASPECTS OF CARCINOGE
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Figure 13.7 DNA damage leads to p53
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13.5 TESTING CHEMICALS FOR CARCINOG
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13.5 TESTING CHEMICALS FOR CARCINOG
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13.6 INTERPRETATION ISSUES RAISED B
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13.7 EMPIRICAL MEASURES OF RELIABIL
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13.8 OCCUPATIONAL CARCINOGENS 301TA
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13.8 OCCUPATIONAL CARCINOGENS 303TA
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13.9 CANCER AND OUR ENVIRONMENT 305
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13.10 CANCER TRENDS AND THEIR IMPAC
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13.11 SUMMARY 321from non-Hodgkin
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14 Properties and Effects of Metals
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14.2 SPECIATION OF METALS 327Most o
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14.3 PHARMACOKINETICS OF METALS 329
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14.4 TOXICITY OF METALS 331reflex i
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14.4 TOXICITY OF METALS 333Several
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14.5 SOURCES OF METAL EXPOSURE 335H
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14.6 TOXICOLOGY OF SELECTED METALS
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14.7 SUMMARY 343Zinc is required fo
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15 Properties and Effects of Pestic
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15.1 ORGANOPHOSPHATE AND CARBAMATE
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15.3 INSECTICIDES OF BIOLOGICAL ORI
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15.3 INSECTICIDES OF BIOLOGICAL ORI
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15.4 HERBICIDES 357ClClO CH 2 C OOH
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15.5 FUNGICIDES 359temperatures as
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15.7 FUMIGANTS 361thallium sulfate-
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16 Properties and Effects of Organi
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TABLE 16.1 Physicochemical Properti
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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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