PRINCIPLES OF TOXICOLOGY

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TABLE 13.12 Potential Occupational Carcinogens Listed by NIOSH 13.8 OCCUPATIONAL CARCINOGENS 303 Acetaldehyde Formaldehyde 2-Acetylaminofluorene Gallium arsenide Acrylamide Gasoline Acrylonitrile Heptachlor Aldrin Hexachlorobutadiene 4-Aminodiphenyl Hexachloroethane Amitrole Hexamethyl phosphoramide Aniline Hydrazine o-Anisidine Kepone Arsenic Malonaldehyde Arsine Methoxychlor Asbestos Methyl bromide Benzene Methyl chloride Benzidine 4,4′-Methylenebis(2-chloroaniline) Benzidine dyes Methylene chloride Benzo[a]pyrene 4,4′-Methylenedianiline Beryllium Methyl hydrazine 1,3-Butadiene Methyl iodide tert-Butylchromate α-Naphthylamine Cadmium (dust and fume) β-Naphthylamine Calcium arsenate Nickel carbonyl Captafol Nickel (insoluble, and soluble compounds) Captan Nickel subsulfides (and roasting operations) Carbon black 4-Nitrobiphenyl Carbon tetrachloride p-Nitrochlorobenzene Chlordane 2-Nitronaphthalene Chlorinated camphene 2-Nitropropane Chloroform N-Nitrosodimethylamine Bis(chloromethyl) ether Phenylglycidyl ether Chloromethyl methyl ether Phenylhydrazine β-Chloroprene N-Phenyl-β-naphthylamine Chromic acid Polychlorinated biphenyl Chromates Propane sultone Chromyl chloride β-Propiolactone Coal tar pitch volatiles Propylene dichloride Coke oven emissions Propylene imine DDT Propylene oxide 2,4-Diaminoanisole Rosin core solder pyrolysis products o-Dianisidine Silica, crystalline o-Dianisidine-based dyes Silica, Christobolite 1,2-Dibromo-3-chloropropane Silica, quartz Dichloroacetylene Silica, Tridymite p-Dichlorobenzene Silica, Tripoli 3,3′-Dichlorobenzidine Talc, asbestiform Dichloroethyl ether 2,3,7,8-Tetrachlorodibenzo-p-dioxin 1,3-Dichloropropane 1,1,2,2-Tetrachloroethane Dieldrin Tetrachloroethylene Diesel exhaust Titanium dioxide Diglycidyl ether Toluene-2,4-diisocyanate 4-Dimethylaminoazobenzene Toluenediamine (continued)
304 CHEMICAL CARCINOGENESIS TABLE 13.12 Continued Dimethyl carbamoyl chloride o-Toluidine 1,1-Dimethylhydrazine p-Toluidine Dimethyl sulfate 1,1,2-Trichloroethane Dinitrotoluenes Trichloroethylene Di-sec-octyl phthalate 1,2,3-Trichloropropane Dioxane Uranium Environmental tobacco smoke Vinyl bromide Epichlorohydrin Vinyl chloride Ethyl acrylate Vinyl cyclohexene dioxide Ethylene dibromide Vinylidene chloride Ethylene dichloride Welding fumes Ethyleneimine Wood dust Ethylene oxide Zince chromates Ethylene thiourea Source: NIOSH Pocket Guide, 1999. 13.9 CANCER AND OUR ENVIRONMENT: FACTORS THAT MODULATE OUR RISKS TO OCCUPATIONAL HAZARDS Increased awareness of the ubiquity of synthetic, industrial chemicals in our environment has led a number of scientists to try to determine what role environmental exposures play in cancer causation. The USEPA devotes a great deal of its resources to this question as do other federal, international and private agencies such as the Agency for Toxic Substances and Disease Registry (ATSDR) of the Centers for Disease Control (CDC), the American Cancer Society (ACS), and the World Health Organization’s (WHO) International Agency for Research on Cancer (IARC) (see Table 13.14). While each organization researching the impact of our occupations, lifestyles, diets, and environmental exposures on cancer have differing agendas and views as to the predicted cancer risks associated with environmental exposures or our daily routines, there is widespread agreement that the most substantial risks, and the greatest causes of cancer, are those factors that are controlled by the individual (e.g., diet, smoking, alcohol intake). The importance of this fact is twofold: (1) it should be recognized that cancer is a phenomenon associated with normal biologic processes, and is therefore impacted by those factors that may affect our normal biologic processes (e.g., diet); and (2) many environmental risk factors exist, and these, in combination with hereditary risk factors, may frequently provide overwhelming influences in epidemiological studies of occupational hazards. Thus, the risk factors not being studied (and so frequently not controlled for) may mask or exacerbate the response being studied and so confound any study that is not normalized in a manner that removes all potential influences from the association being studied. Estimates of the contribution of various factors to the rate of cancer in humans were perhaps first put forth by Doll and Peto, who produced the results plotted in Figure 13.10. As can easily be seen in Figure 13.10, the vast majority of the cancers were thought to be related to lifestyle factors; tobacco and alcohol use, diet, and sexual behavior accounted for 75 percent of all cancers in this initial analysis. Conversely, industrial products, pollution, and occupation were thought to be related to only 7 percent of all cancers. Currently, the contributions of diet, disease, and viral agents are still being researched as perhaps the most common causes of cancer. In the years following Doll and Peto’s initial assertions, some scientists have questioned whether such a large proportion of the cancers in humans had such clearly defined causal associations. However, the most recent evidence accumulated by researchers in this area indicates that less than 1 percent of today’s cancers result from exposure to environmental pollution, and diet has since been identified as a key risk factor for cancer in nearly 200 epidemiologic studies. More importantly, the view that there
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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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Page 261 and 262: 252 MUTAGENESIS AND GENETIC TOXICOL
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354 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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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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