PRINCIPLES OF TOXICOLOGY

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eflex in response to orally ingested toxicants, including metals. Metals may also be excreted in the sweat and saliva or incorporated into growing hair and fingernails. The body’s attempt to excrete excess mercury and lead in the saliva often results in visible “lead lines” along the gums. However, urine and feces remain the primary route of excretion for most ingested metals. Usually, excretion consists of a combination of these pathways, which may differ according to the route of exposure and the speciation of the metal. Inhaled elemental mercury vapor, for instance, is excreted in the urine, feces, and breath, while ingested elemental mercury is primarily excreted in the feces. Methyl mercury is excreted very slowly, primarily in the feces after transformation to inorganic forms of mercury. 14.4 TOXICITY <strong>OF</strong> METALS 14.4 TOXICITY <strong>OF</strong> METALS 331 Acute Exposure The numerous toxic effects of metals may be broadly divided into two main modes of action. The first is related to the fact that many metals have a strong affinity for common protein moieties, such as the sulfhydryl (–SH) group. By forming covalent bonds with these groups, metals may inhibit the activity of important enzymes or disrupt the integrity of cell membranes. The other way in which metals may exert toxicity is by competing with and displacing essential cations. For instance, lead can displace the essential element zinc in certain zinc-requiring enzymes, thus inhibiting their function. Acute toxicity is caused by a relatively large dose of a metal over a short period of time. The duration of time from initial exposure to the onset of clinical symptoms is usually short, typically on the order of hours or days. Because of their generally disruptive effects on cell membranes, metals can produce various localized effects at their initial point of contact. Common symptoms of acute metal poisoning by the oral route include nausea, vomiting, and damage to the intestinal mucosa and gastrointestinal tract. Acute inhalation exposure to metals often results in nose and throat irritation, coughing or wheezing, and damage to the lungs and the respiratory lining. Acute dermal exposure can result in localized rash and skin irritation or discoloration. Certain metals tend to target specific organs or systems. Acute exposure to high lead levels may result in severe neurological symptoms, including convulsions or coma, as well as disruption of the hematopoietic system, specifically heme production. The toxic effects of acute mercury poisoning can vary depending on the form present in the body. Exposure to large amounts of elemental mercury vapors or methyl mercury is more likely to cause central nervous system effects than is exposure to inorganic mercury because of differences in transport to the brain. Methyl mercury, because of its lipophilic nature, can easily cross the blood-brain barrier while inorganic mercury cannot. Elemental mercury vapors can cross membranes with relative ease. Chronic Exposure Long-term exposure to low levels of some metals may result in gradual development of symptoms and often, but not always, less severe symptomology than observed in acute events. Carcinogenicity, as discussed in the next section, may be the result of chronic exposure to a few metals. Also, some metals can be stored for long periods within biological tissues. Lead may displace calcium in developing bone, resulting in long-term storage and slow release of this metal, which may cause toxic symptoms that persist long after the exposure has ceased. Damage to and impaired function of the kidneys and liver are typical effects of chronic exposure to many metals, probably due to the role of these two organs in concentrating, detoxifying, and excreting toxic metals. Mucosal degeneration and inhibition of hepatic and renal enzymes are common results of chronic metal overexposure. Chronic lead, chromium, mercury, and cadmium poisoning are commonly associated with kidney damage, while the role of the liver in copper storage and excretion makes this organ vulnerable to damage from chronic copper exposure.
332 TABLE 14.2 Target Organ Toxicity of Selected Metals and Metalloids Cardiovascular System Endocrine System Skin Hematopoietic System Bone Gastrointestinal Tract Respiratory System Metal Kidney Nervous System Liver Aluminum + + Arsenic + + + + + + + Beryllium + + Bismuth + + + Cadmium + + + + + + Chromium + + + + + Cobalt + + + + + + Copper + + + Iron + + + + + + Lead + + + + + Manganese + + Mercury + + + + Nickel + + + Selenium + + + Strontium + Thallium + + + + + + Tin (organic) + + Zinc + + +
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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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274 CHEMICAL CARCINOGENESIS Figure
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276
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278 CHEMICAL CARCINOGENESIS TABLE 1
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382 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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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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