PRINCIPLES OF TOXICOLOGY

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from non-Hodgkin’s lymphoma and from melanoma are also increasing. These data were confirmed in the 1999 joint release from the CDC, NCI, and ACS. As awareness of environmental contamination and the ubiquity of synthetic chemicals arose in the 1960s, specifically after the release of Rachel Carson’s Silent Spring in 1962, speculation persisted that we were awash in a “sea of carcinogens” and that after an appropriate latency interval, a cancer epidemic would hit. As has been shown in Figure 13.1, the hypothesized epidemic of cancer has never arrived, and considering the data indicating decreasing cancers through 1995, it would seem that perhaps our current reductions in smoking, food consumption, and alcohol might be starting to impact the 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 industrialization in the United States, the impact of occupation and environmental pollution on cancer incidence is probably less than what was postulated 30 years ago. That is not to say, however, that exposure reductions are not still warranted in these areas, but merely to point out that the current data indicate that our future, with its concomitant exposure to new synthetic chemicals, is not a dire one. 13.11 SUMMARY 13.11 SUMMARY 321 Chemical-induced carcinogenesis represents a unique and complex area within toxicology. The difficulty in assessing the carcinogenic hazards and human risks of chemicals stems from the following characteristics of chemical carcinogenesis: • It is a multistage process involving at least two distinct stages: initiation, which converts the genetic expression of the cell from a normal to aberrant cell line; and promotion, in which the 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 labels are applied to the chemical carcinogens that define or describe these differences, such as cocarcinogens, initiators, promoters, and epigenetic. • Chemicals may produce or affect only a single stage or a single aspect of carcinogenesis that leads to a number of important differences and considerations about the potential health impacts of chemical carcinogens. Perhaps the most important considerations are the concept of thresholds and that qualitative differences do exist among carcinogens. • Carcinogenicity testing raises many questions about interpretations of results. Considerations such as mechanism (genotoxic vs. epigenetic), dose, and relevant test species, are important in determining probable human risk; thus, many additional toxicity test data are needed to improve the extrapolation of cancer bioassay data from test species to humans. • A number of lifestyle-related factors influence carcinogenesis, altering the risks posed by carcinogenic chemicals and acting to confound epidemiological evidence. Considering the complexities involved in (1) determining the mechanism of cancer causation, (2) using animal and human data to identify carcinogenic substances, and (3) using these data to extrapolate risks with the aim of reducing or eliminating environmental risk factors, it should be clear to the reader that the best approach to occupational carcinogenesis is an interdisciplinary one. As depicted in Figure 13.13, identifying and reducing occupational cancer requires the interfacing of several scientific disciplines 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 CARCINOGENESIS Figure 13.13 Identifying and reducing chemical carcinogens requires an interdisciplinary approach, in which health professions interface with other scientific disciplines. genic mechanisms, and about species differences or similarities that can aid in assessing the human risk. • Epidemiologists add human evidence to risk evaluations or ascertain if a chemical should or should not be considered a human carcinogen for various reasons (it may have weak or undetectable activity). • Specialists in occupational medicine provide health surveillance programs to protect the health 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 worker exposures; and biometrists and computer scientists aid in risk analysis, data storage, and data analysis. As long as these disciplines are utilized jointly and their relationship to the occupational carcinogenesis problem is understood, occupational health and safety professionals can have good reason to hope for improved success in the prevention of occupational carcinogenesis.
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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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372 PROPERTIES AND EFFECTS OF ORGAN
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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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