PRINCIPLES OF TOXICOLOGY

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ders, such as diabetes and phenylketonuria. In turn, genetically based developmental disorders still surpass all of the environmental phenomena that can affect development in terms of proportional importance within the population. This section will cover the toxicology relevant to all stages of development from fertilization onward. This will include the action of toxicants on the mother that affect the ability to establish and maintain pregnancy, as well as direct actions on the fetus. The developmental stages can be divided into 1) the preimplantation stage, where toxicity generally affects the entire organism and there is typically an all or none response (i.e., there is repair or the developing organism is aborted), and 2) the later embryonic and fetal stages, where specific structural defects can occur. The most sensitive period for teratogenesis, the production of congenital defects, is during organogenesis in the embryonic period. Mammalian development can be thought of as an expansive flow diagram (Figure 11.5). Following fertilization there is a very particular sequence of events that is followed, directed by the expression of certain genes at certain times. From a toxicological point of view, disruptions during this relatively linear phase generally derail the entire developmental sequence. Certain developmental steps serve as branch points and once particular branches are followed, the occurrence of events on that branch will not necessarily affect other branches. As development progresses, many smaller branches are reached, which may each relate to the development of certain tissues, cell types, or regions of a structure. Toxicologically, when specific sequences are affected, the response may be restricted to the features that develop out of that particular sequence. This illustrates how very specific defects can occur in response to toxicants or other environmental factors and exhibit clear time dependence. Spontaneous Abortion and Embryonic Loss 11.3 DEVELOPMENTAL <strong>TOXICOLOGY</strong> 225 Recent improvements in the ability to measure human chorionic gonadotropin, a very early indicator of the presence of an embryo, have allowed reasonable estimates of early pregnancy loss. Overall, more than 50 percent of fertilized eggs/embryos are lost through spontaneous abortion. Around 30 percent are lost after implantation but before the first menstrual period is missed. An additional 20–25 percent are lost after they have been clinically recognized as a pregnancy. There are also probably substantial pre-implantation losses, but these are much harder to accurately estimate. Presented another way, it appears that the chance of achieving a full-term pregnancy for any one menstrual cycle in which fertilization is likely to have occurred (based on non-contracepted intercourse with ovulation) is around 25 percent. The preponderance of embryonic loss occurs during what was described as the linear phase of development. Based on chromosomal analysis of spontaneously aborted embryos, approximately two-thirds of this loss can be explained by gross genetic abnormalities. Around 10 percent can be attributed to a known environmental cause, and a cause cannot be determined for the remainder. While some of the genetically associated loss could be related to environmentally mediated DNA damage, it is clear that most is due to major chromosomal aberrations associated with germ cell production and fusion. Once again, the potentially chemically induced responses are hidden within an extremely high background rate of embryonic loss. In general, the response to toxicological insult during the early embryonic stage is considered to be an all or none event, where damage up to minor cell death is completely repairable and major cellular disruption or death results in abortion of the pregnancy. This is based on the flexibility of the cells in the early embryo, which allows them to functionally replace a few lost cells. As development progresses, most cell lines become committed to a particular fate and such compensation is less likely. The limited responses available during early embryogenesis mean that typically the endpoint of concern for toxic exposures is spontaneous abortion. While this criterion has held over the years for most toxicants, there are recent experimental results which suggest that very early exposure to ethylene oxide and some other mutagens may cause responses that are manifest much later in development. This implies that the exposure may result in a sublethal injury that is not repaired, nor are all of the
226 Figure 11.5 Developmental tree indicating the time during human gestation at which the development of various major organ systems becomes a separate progression from the rest of the organs and tissues. The branching corresponds roughly to the periods of tissue-specific teratogenic sensitivity.
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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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166 DERMAL AND OCULAR TOXICOLOGY Fi
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168 DERMAL AND OCULAR TOXICOLOGY
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170 PULMONOTOXICITY: TOXIC EFFECTS
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Page 199 and 200: 10 Immunotoxicity: Toxic Effects on
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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
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Page 225 and 226: 216 REPRODUCTIVE TOXICOLOGY gonadot
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Page 229 and 230: Figure 11.3 Cycle of follicular dev
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Page 257 and 258: 248 Figure 12.5 Example of DNA addu
Page 267 and 268: TABLE 12-3 NTP and Gene-Tox Evaluat
Page 275 and 276: 266 CHEMICAL CARCINOGENESIS 13.1 TH
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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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314 CHEMICAL CARCINOGENESIS Figure
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316 CHEMICAL CARCINOGENESIS similar
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322 CHEMICAL CARCINOGENESIS Figure
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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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