PRINCIPLES OF TOXICOLOGY

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After all, it is commonly assumed in interspecies extrapolation that the target tissue dose required to produce a biological effect of a given intensity is quantitatively equivalent across species. Therefore, dose–response curves generated with measures of target tissue dose should be readily extrapolatable across species since they obviate the need for consideration of interspecies differences in the toxicokinetics of an administered dose. Unfortunately, dose–response curves of this nature are rare primarily because of the technical difficulties inherent in internal dose measurement. This is likely to change, however, as advancements are made in analytical chemistry and physiologically based pharmacokinetic (PBPK) models find their way into the mainstream. Such models are powerful tools with which to estimate internal dose measures from an endless variety of exposure scenarios to physiologically diverse receptors. As such, they are particularly valuable for the purpose of interspecies extrapolation. Biological monitoring is another means of exposure assessment. When it is conducted to measure a chemical or its metabolites in the urine, blood, or tissue (including hair and fingernails) of an exposed individual, the chemical and its metabolites are referred to as biomarkers of exposure. Other potential biomarkers include DNA and protein adducts, mutations, chromosomal aberrations, genes that have undergone induction, and a host of other “early” cellular or subcellular events thought to link exposure and effect. The characterization and quantification of these latter biomarkers is known as molecular dosimetry. If found to be correlated with susceptibility, exposure, and effect, these biomarkers could considerably alter conventional approaches to risk assessment. Perhaps the best known example of such a correlation is urinary aflatoxin-DNA adducts and liver cancer. While molecular dosimetry holds promise for risk assessment, it is yet to be developed well enough for routine application. Despite advancements in analytical chemistry, mathematical modeling, and biomonitoring, exposure assessment remains a challenge. It is important to realize that most exposure assessments result in estimates rather than definitive values. This stems in part from the fact that site- or situation-specific values are rarely available for all of the input variables necessary to calculate exposure. Despite the challenge, efforts should continue toward conducting exposure assessments that reflect realistic exposures, rather than worst-case scenarios to which no one is exposed. The identification of the dose metric that best correlates with various toxicities should also be a priority. Since this depends on a thorough knowledge of a chemical’s mode of action, advancement in exposure assessment is inextricably linked to advances in toxicology. 18.4 DOSE–RESPONSE ASSESSMENT In this portion of the risk assessment, the dose–response relationships for the toxicities of concern must be measured, modeled, or assumed, in order to predict responses to doses estimated in the exposure assessment. While dose–response relationships could theoretically be obtained for a variety of effects from each chemical of potential concern, in practice attention is usually centered on the most sensitive effect of the chemical. In risk assessment, two fundamentally different types of dose–response relationships are thought to exist. One is the threshold model, in which all doses below some threshold produce no effect, while doses above the threshold produce effects that increase in incidence or severity as a function of dose. The second model has no threshold—any finite, nonzero dose is thought to possess some potential for producing an adverse effect. The derivation of these two types of dose-response relationships and their use to provide estimates of risk are very different, as described in the following sections. Threshold Models 18.4 DOSE–RESPONSE ASSESSMENT 449 It has long been held that for all toxicities other than cancer, there is some dose below which no observable or statistically measurable response exists. This dose, called the threshold dose, was graphically depicted in Chapter 1 (see also Figure 18.3). Conceptually, a threshold makes sense for most toxic effects. The body possesses a variety of detoxification and cell defense and repair
450 RISK ASSESSMENT Figure 18.3 Estimation of a safe human dose (SHD). The first step is identification of the target organ or effect most responsive to the chemical (in this case, target organ 1 in the upper panel). Dose–response data for this effect are used to identify no-observable-adverse-effect-level (NOAEL) and/or lowest-observable-adverseeffect-level (LOAEL) doses in order to approximate the threshold dose. Either the NOAEL or LOAEL is divided by a series of uncertainty factors to generate the SHD.
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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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10 Immunotoxicity: Toxic Effects on
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10.2 BIOLOGY OF THE IMMUNE RESPONSE
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10.2 BIOLOGY OF THE IMMUNE RESPONSE
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certain situations immunosuppressio
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10.5 TESTS FOR DETECTING IMMUNOTOXI
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10.6 SPECIFIC CHEMICALS THAT ADVERS
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10.6 SPECIFIC CHEMICALS THAT ADVERS
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animal origin have also been shown
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The mainstay of treatment of multip
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PART II Specific Areas of Concern P
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210 REPRODUCTIVE TOXICOLOGY continu
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212 REPRODUCTIVE TOXICOLOGY Underst
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214 REPRODUCTIVE TOXICOLOGY spermat
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216 REPRODUCTIVE TOXICOLOGY gonadot
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218 REPRODUCTIVE TOXICOLOGY TABLE 1
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Figure 11.3 Cycle of follicular dev
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222 REPRODUCTIVE TOXICOLOGY Figure
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224 REPRODUCTIVE TOXICOLOGY TABLE 1
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226 Figure 11.5 Developmental tree
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228 REPRODUCTIVE TOXICOLOGY is clea
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230 REPRODUCTIVE TOXICOLOGY genital
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232 REPRODUCTIVE TOXICOLOGY to occu
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234 REPRODUCTIVE TOXICOLOGY these r
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236 REPRODUCTIVE TOXICOLOGY Two imp
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238 REPRODUCTIVE TOXICOLOGY Sundara
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240 MUTAGENESIS AND GENETIC TOXICOL
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248 Figure 12.5 Example of DNA addu
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TABLE 12-3 NTP and Gene-Tox Evaluat
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266 CHEMICAL CARCINOGENESIS 13.1 TH
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268 CHEMICAL CARCINOGENESIS TABLE 1
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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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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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Page 405 and 406: 396 PROPERTIES AND EFFECTS OF ORGAN
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Page 445 and 446: 438 RISK ASSESSMENT 18.1 RISK ASSES
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Page 485 and 486: 19 Example of Risk Assessment Appli
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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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