PRINCIPLES OF TOXICOLOGY

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8.3 CONTACT DERMATITIS 165 light to a toxic form. Phototoxic chemicals readily absorb UV light and become excited to a higher-energy state. Once the excited chemical returns to the ground state, it releases its energy, which can lead to production of reactive oxygen species and other reactive products that damage cellular components and macromolecules, ultimately causing cell death. The resulting damage is similar to that caused by irritant chemicals (discussed in Section 8.3) that cause cell death. Phototoxicant-induced cell death triggers an inflammatory response that produces the clinical signs of phototoxicity. Dyes (eosin, acridine orange), polycyclic aromatic hydrocarbons (anthracene, fluoranthene), tetracyclines, sulfonamides, and furocoumarins (trimethoxypsoralen, 8-methoxypsoralen) are commonly encountered phototoxic drugs and chemicals. Photoallergy is very similar to contact allergic dermatitis and is a delayed type IV hypersensitivity reaction. The difference between an allergenic chemical and a photoallergenic chemical is that the photoallergenic chemical must be activated by exposure to light—most often UVA. Once activated, the photoallergen complexes with cellular protein to form a complete allergen that triggers the delayed type IV hypersensitivity reaction. Since it is a hypersensitivity reaction, previous exposure to the phototoxic chemical is required for a response. Subsequent topical or systemic exposure to the photoallergen may induce the hypersensitivity reaction, which has clinical manifestations similar to allergic contact dermatitis (see the subsection on allergic contact dermatitis). Testing for photoallergy is similar to the patch testing used for regular allergens, but the potential allergens are tested in duplicate. One set of the patches is removed during the test and irradiated with UV light. By comparing duplicate samples, the physician can determine whether the compound is allergenic and is also a photoallergen. Skin Cancer Skin cancer is the most common neoplasm in humans with half a million new cases occurring per year in the United States. Even though exposure to UV light is the primary cause of skin cancer, chemicals can also induce malignancies. UV light and carcinogenic agents induce alterations in epidermal cell DNA. These alterations can lead to permanent mutations in critical genes that cause uncontrolled proliferation of the affected cells, ultimately leading to a cancerous lesion. UVB rays are the most potent inducers of DNA damage and work by inducing pyrimidine dimers. In addition to inducing DNA damage, UV light also has an immunosuppressive effect that may reduce the surveillance and elimination of cancerous cells by the immune system. Since UVB light is the most potent inducer of DNA damage, utilization of a sunscreen that blocks UVB radiation is critical in preventing skin cancer along with the other skin effects associated with UV light exposure. Ionizing radiation is also a potent inducer of skin cancer. Fortunately, ionizing radiation is no longer used for treatment of skin ailments such as acne and psoriasis, as was done in the recent past. The best characterized chemical inducers of skin cancer are the polycyclic aromatic hydrocarbons (PAH). In the 1700s, scrotal cancer was found to be prevalent among chimney sweeps in England. The compounds that induced the cancer were later determined to be PAHs present in high concentrations in coal tar, creosote, pitch, and soot. PAHs must be bioactivated within the skin, often to a reactive epoxide, by cytochrome P450 metabolism (discussed in Section 8.2) in order to cause DNA damage. The epoxides are electrophilic and can form DNA adducts that may produce gene mutations. Other carcinogenic agents may cause DNA damage through different mechanisms, but the ultimate lesion is a gene mutation that leads to a cancerous lesion. Eye Toxicity The eye is a very complex organ composed of many different types of cells. Disease, drugs, and chemicals can injure various parts of the eye with many different manifestations of injury. The most common cause of injury in an occupational setting is exposure of the cornea and conjunctiva to agents that are splashed onto the eye. Many other effects can occur to other parts of the eye such as the retina and optic nerve (see Figure 8.2), but they are usually limited to effects caused by drugs and various diseases. This section therefore focuses on external exposure of the eye to chemicals.
166 DERMAL AND OCULAR <strong>TOXICOLOGY</strong> Figure 8.2 Diagrammatic cross section of the eye, with enlargement of details in cornea, chamber angle, lens, and retina. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 5th Ed. McGraw-Hill, 1996. Reprinted with permission.
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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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Page 213 and 214: animal origin have also been shown
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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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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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