PRINCIPLES OF TOXICOLOGY

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11.2 FEMALE REPRODUCTIVE <strong>TOXICOLOGY</strong> 219 reasons that associating these occurrences with a particular exposure is difficult. In addition, pregnancy failure occurs frequently as well, and can be due to problems with either the female or the developing embryo. There are also some fundamental differences in female germ cell production that relate to the potential mechanisms of toxic injury. In contrast to the constant cellular division required to generate millions of new sperm each day, the ovary contains all of the eggs that will ever be ovulated, and then some, by the time of birth. All mitotic divisions and the initial stages of meiosis have been completed by the middle of fetal development and result in the generation of around 10 million primary oocytes arrested in the meiotic progression. Subsequently, a rapid process of degeneration (atresia) occurs, and there are around one million primary oocytes left at birth. Atresia continues somewhat more slowly throughout life, and the mature woman has around a half a million oocytes with the potential to develop into mature eggs. In the human, a handful of the primary oocytes begins the process of folliculogenesis during each menstrual cycle, but typically only one forms a completely mature follicle and is ovulated. Estimating the number of menstrual cycles in a typical reproductive lifetime, only around 500 germ cells ever complete development. There is no further division of the germ cells prior to leaving the ovary and while there are somatic cells that divide and develop to support the maturing egg, this occurs over the course of about two weeks. Clearly, female germ cell production does not rely on mass production and rapidly dividing cell populations. Correspondingly, the overall process is less susceptible to cytotoxic compounds that operate against dividing cells. Oocyte Toxicity This being noted, however, some of the powerful antineoplastic drugs are still capable of disrupting oocyte development, including cyclophosphamide, chlorambucil, busulfan, and vinblastine. Experimental results indicate that busulfan may be capable of destroying the arrested, primordial oocytes, preventing further maturation and ovulation. Other alkylating agents appear to work only on the follicles developing at the time of exposure. For the reproductive process as a whole, this is advantageous, since other primordial oocytes are still available for future cycles of folliculogenesis. While there is experimental evidence that ovarian-derived metabolites of some polycyclic aromatic hydrocarbons (PAHs–combustion byproducts) are also capable of destroying the primordial oocytes, there is limited information on ovotoxicity relating to occupational or environmental exposures. There are no good examples of human reproductive toxicants that appear to affect egg production under such circumstances. This is surely due in part to difficulties in analyzing ovarian toxicity that have slowed down the identification of toxicants with the ability to target the ovary. Experimental findings suggest that lead, mercury, and cadmium are capable of damaging oocytes, but in light of their generalized toxicity, this is hardly surprising and probably does not occur in the absence of their major toxic effects on other systems. Somatic Ovarian and Reproductive Tract Toxicity There are a few experimental examples of toxic compounds that can have a direct effect on the somatic ovarian cells or the reproductive tract. For the ovary, such toxicity relates to successful germ cell production since the ovarian cells differentiate into layers known as the granulosa and theca, both integral to the development of mature follicles. 4-Vinylcyclohexene, an industrial compound used in the production of epoxy resins, appears to be capable of producing generalized ovarian atrophy. Similar atrophy can be produced with the antibiotic nitrofurantoin, which also has some specific toxicity toward the cells lining the follicles. The granulosa layer in particular can be targeted by metabolites of some of the phthalates. It is not clear how such toxicity relates to other effects of these compounds. The female reproductive tract is responsible for transport of the eggs and sperm to the site of fertilization and subsequent transport of any fertilized embryo to the site of implantation in the uterus. Fertilization occurs in the uterine tube, also known as the Fallopian tube or oviduct (Figure 11.3). The
Figure 11.3 Cycle of follicular development and the progression through the human female reproductive tract. Note fertilization occurring in the upper portion of the oviduct and implantation occurring after the earliest cell divisions at the blastocyst stage. (Reproduced with permission from Dean J., American Journal of Industrial Medicine, 4 (1983) 3. pp. 31–39. Figure 1.) 220
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PRINCIPLES OF TOXICOLOGY
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This book is printed on acid-free p
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vi CONTRI BUTORS PAUL J. MIDDENDORF
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viii CONTENTS 4 Hematotoxicity: Che
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x CONTENTS 12 Mutagenesis and Genet
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xii CONTENTS III APPLICATIONS 435 1
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PREFACE Purpose of This Book Princi
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ACKNOWLEDGMENTS A text of this unde
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PART I Conceptual Aspects Principle
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4 GENERAL PRINCIPLES OF TOXICOLOGY
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36 ABSORPTION, DISTRIBUTION, AND EL
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3 Biotransformation: A Balance betw
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BIOTRANSFORMATION: A BALANCE BETWEE
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BIOTRANSFORMATION: A BALANCE BETWEE
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Figure 3.5 Diagrammatic rendition o
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3.2 BIOTRANSFORMATION REACTIONS The
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TABLE 3.4 Important Cytochrome P450
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Figure 3.8 Cytochrome P450-catalyze
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oth of which are suitable for conju
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TABLE 3.6 Changes in Rat Hepatic Dr
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3.2 BIOTRANSFORMATION REACTIONS 75
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TABLE 3.7 Induction of Xenobiotic-M
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3.2 BIOTRANSFORMATION REACTIONS 79
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pyridoxal phosphate depletion by th
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Biotransformation: A Balance betwee
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een shown to be responsible for the
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4 Hematotoxicity: Chemically Induce
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Figure 4.1 Formation of blood. Matu
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TABLE 4.2 Leukemias and Lymphomas 4
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4.3 THE MYELOID SERIES 93 to contra
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function and response to stimuli, (
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Hypoxia can result from a variety o
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4.7 INORGANIC NITRATES/NITRITES AND
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Exposure to aromatic amines can be
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4.10 BONE MARROW SUPPRESSION AND LE
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4.12 TOXICITIES THAT INDIRECTLY INV
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4.15 ANTIDOTES FOR HYDROGEN SULFIDE
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REFERENCES AND SUGGESTED READING 10
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112 HEPATOTOXICITY: TOXIC EFFECTS O
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130 NEPHROTOXICITY: TOXIC RESPONSES
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7 Neurotoxicity: Toxic Responses of
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ions moving out of the cell brings
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an effect seen with some neurotoxic
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7.4 INTERACTIONS OF INDUSTRIAL CHEM
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• A study of the patient’s hist
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• Although much of the damage whi
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158 DERMAL AND OCULAR TOXICOLOGY Fi
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160 DERMAL AND OCULAR TOXICOLOGY P4
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162 DERMAL AND OCULAR TOXICOLOGY ca
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164 DERMAL AND OCULAR TOXICOLOGY ke
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Page 179 and 180: 168 DERMAL AND OCULAR TOXICOLOGY
Page 181 and 182: 170 PULMONOTOXICITY: TOXIC EFFECTS
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Page 201 and 202: 10.2 BIOLOGY OF THE IMMUNE RESPONSE
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Page 205 and 206: certain situations immunosuppressio
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Page 213 and 214: animal origin have also been shown
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Page 217 and 218: PART II Specific Areas of Concern P
Page 219 and 220: 210 REPRODUCTIVE TOXICOLOGY continu
Page 221 and 222: 212 REPRODUCTIVE TOXICOLOGY Underst
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Page 235 and 236: 226 Figure 11.5 Developmental tree
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Page 249 and 250: 240 MUTAGENESIS AND GENETIC TOXICOL
Page 257 and 258: 248 Figure 12.5 Example of DNA addu
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Page 275 and 276: 266 CHEMICAL CARCINOGENESIS 13.1 TH
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270 CHEMICAL CARCINOGENESIS researc
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272 CHEMICAL CARCINOGENESIS Figure
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276
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278 CHEMICAL CARCINOGENESIS TABLE 1
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280 CHEMICAL CARCINOGENESIS 13.4 MO
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286 CHEMICAL CARCINOGENESIS make a
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288 Figure 13.8 A genetic model of
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290 CHEMICAL CARCINOGENESIS Increas
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292 CHEMICAL CARCINOGENESIS may be
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294 CHEMICAL CARCINOGENESIS • The
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296 CHEMICAL CARCINOGENESIS evaluat
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298 CHEMICAL CARCINOGENESIS In rats
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302 CHEMICAL CARCINOGENESIS with ex
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316 CHEMICAL CARCINOGENESIS similar
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324 CHEMICAL CARCINOGENESIS Knudson
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326 PROPERTIES AND EFFECTS OF METAL
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332 TABLE 14.2 Target Organ Toxicit
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346 PROPERTIES AND EFFECTS OF PESTI
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368 PROPERTIES AND EFFECTS OF ORGAN
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370 TABLE 16.1 (Continued) Water So
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410 PROPERTIES AND EFFECTS OF NATUR
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PART III Applications Principles of
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438 RISK ASSESSMENT 18.1 RISK ASSES
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440 RISK ASSESSMENT control populat
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442 RISK ASSESSMENT there are some
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444 RISK ASSESSMENT • It identifi
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446 RISK ASSESSMENT chemical poses
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448 RISK ASSESSMENT • Estimating
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450 RISK ASSESSMENT Figure 18.3 Est
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452 RISK ASSESSMENT • As discusse
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454 RISK ASSESSMENT divided by a de
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456 RISK ASSESSMENT Because low-dos
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458 RISK ASSESSMENT TABLE 18.1 Expe
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460 RISK ASSESSMENT leading to impo
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462 RISK ASSESSMENT characterizatio
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464 RISK ASSESSMENT Figure 18.7 Sim
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466 RISK ASSESSMENT The RPF values
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468 RISK ASSESSMENT producing the e
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470 RISK ASSESSMENT TABLE 18.4b Can
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472 RISK ASSESSMENT TABLE 18.7 Acti
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474 RISK ASSESSMENT A second reason
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476 RISK ASSESSMENT Barnard, R. C.,
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19 Example of Risk Assessment Appli
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19.3 LEAD EXPOSURE AND WOMEN OF CHI
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19.4 PETROLEUM HYDROCARBONS: ASSESS
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19.4 PETROLEUM HYDROCARBONS: ASSESS
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19.5 RISK ASSESSMENT FOR ARSENIC 48
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19.5 RISK ASSESSMENT FOR ARSENIC 48
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19.6 REEVALUATION OF THE CARCINOGEN
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REFERENCES AND SUGGESTED READING RE
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20 Occupational and Environmental H
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20.1 DEFINITION AND SCOPE OF THE PR
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20.4 HUMAN RESOURCES IMPORTANT TO O
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treatment, or medical removal from
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Academic practices welcome complica
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Occupational and environmental medi
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512 EPIDEMIOLOGIC ISSUES IN OCCUPAT
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22 Controlling Occupational and Env
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22.2 EXPOSURE LIMITS 525 The TLVs
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modified “reference doses” to r
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observation process, followed by re
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• Hazard-specific training to ens
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22.3 PROGRAM MANAGEMENT 533 Conside
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Figure 22.1 22.3 PROGRAM MANAGEMENT
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fundamental viability of the work p
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Figure 22.2. 22.3 PROGRAM MANAGEMEN
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• Physical assessment and fit tes
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The study was designed to minimize
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TABLE 22.3 Margins of Safety at For
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top, and numerous slots with smalle
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TABLE 22.5 Comparison of Time-Weigh
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• Housing or building code violat
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• Environmental exposure limits,
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GLOSSARY Glossary absorption The mo
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GLOSSARY 557 antipyretic An agent t
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GLOSSARY 559 chloracne An acne-like
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GLOSSARY 561 eczema A superficial i
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GLOSSARY 563 hemolytic anemia Anemi
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GLOSSARY 565 lipoprotein Any of a g
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GLOSSARY 567 necrosis Death of one
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pernicious anemia The progressive,
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GLOSSARY 571 cells have both endoth
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GLOSSARY 573 tolerance The ability
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576 INDEX Allergic reaction (contin
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578 INDEX Biotransformation (contin
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580 INDEX Children’s health statu
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582 INDEX Diet and nutrition (conti
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584 INDEX Estrogens: endocrine disr
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586 INDEX Hair, toxic agent excreti
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588 INDEX hnmunoglobulins: autoimmu
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590 INDEX Loop of Henle, structure
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592 INDEX Mixed exposure patterns,
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594 INDEX Nutritional deficiencies,
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596 INDEX Pesticides (continued) Pe
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598 INDEX Relative potency factor (
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600 INDEX Solvents (continued) phys
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602 INDEX Tumorigenesis (continued)
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PRINCIPLES OF TOXICOLOGY

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