PRINCIPLES OF TOXICOLOGY

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482 EXAMPLE <strong>OF</strong> RISK ASSESSMENT APPLICATIONS PbBfetal,0.95 = GSDi 1.645 × (PbS × BKSF × IRS × EFS) + PbBadult,0 × Rfetal / maternal AT where PbBfetal,0.95 = The 95th percentile blood lead concentration for fetuses born to women similarly exposed to lead in dust. This lead concentration indicates that the likelihood of a greater blood lead concentration is 5 percent. The 95th percentile is often used as a regulatory target by USEPA. GSDi 1.645 = Individual geometric standard deviation for the variability in lead exposure and absorption. The value of 1.645 is the t value used to calculate the 95th percentile from a lognormal blood lead distribution. The USEPA recommends a value of 1.8 for the GSD in a fairly homogenous population. PbS = Soil or dust lead concentration in µg/g. BKSF = Biokinetic slope factor increased in typical adult blood lead concentration to average daily lead uptake (µg/dL blood lead increase per µg/day lead uptake). The BKSF obtained from reliable human studies is 0.4 µg/dL per µg/day. IRS = Daily intake of soil or dust. The USEPA recommends 0.05 g/day as a typical value. AFS = Absorbed fraction of lead in dust from the gastrointestinal tract. The USEPA recommended value for the fraction of lead in soil or dust released from the gastrointestinal tract and absorbed is 0.12. EFS = Exposure frequency for contact with lead in dust. The USEPA recommends a typical value of 219 days/year. AT = Total period over which dust exposure occurs. This value is typically assumed to be 365 days/year. PbBadult,0 = Background blood lead concentration for women of child-bearing age. A representative value is 2.0 µg/dL. Rfetal/maternal = Ratio of fetal blood lead concentration to the maternal blood lead concentration at birth. The value typically assumed by USEPA is 0.9. Assume that workers employed as furniture refinishers may ingest lead in dust during a particular phase of the operation for 3 days a week (approximately 150 days/year). Sampling of the lead-contaminated dust indicates an average lead concentration of 1300 µg/g. What is the calculated 95th percentile blood lead concentration of a fetus of an exposed female worker? This calculation is illustrated below. PbBfetal,0.95 = 1.8 1.645 × + 2.0 µg / dL × 0.9 (1300 µg / g × 0.4 µg / dL ⋅ g / day × 0.05 g / day × 0.12 × 150 days / year) 365 days / year PbBfetal,0.95 = 7.8 µg/dL
19.4 PETROLEUM HYDROCARBONS: ASSESSING EXPOSURE AND RISK TO MIXTURES 483 Interpretation of Risk Assessment Results and Comment For pregnant workers, this indicates that there is a 5 percent likelihood that the fetal blood lead concentration may exceed 7.8 µg/dL in similarly exposed pregnant women. The calculated lead concentration is below the CDC and USEPA level of concern of 10 µg/dL. A greater exposure frequency, a higher dust lead concentration, or exposure to a highly soluble form of lead (such as lead chloride or lead acetate) may result in a calculated PbB fetal,0.95 that could potentially exceed 10 µg/dL. In practice, blood lead concentrations could also be measured in women of child-bearing age to provide reassurance that they were not being overexposed. Although the preceding equation does not evaluate inhalation exposures to lead, it could easily be modified to do so. The Agency for Toxic Substances and Diseases Registry (ATSDR) has summarized human inhalation studies of lead and determined biokinetic slope factors relating the air lead concentration to increases in blood lead. For example, individuals exposed to lead concentrations in air ranging from 3.2 to 11 µg/m 3 had average blood lead increases of 1.75 µg/dL for every µg/m 3 lead in air. Individuals in the study reviewed by ATSDR were exposed for 23 h/day for 18 weeks. Given that workers would not be exposed to the workplace atmosphere for 23 h/day, it would be reasonable to assume that only half the air breathed in a day was from the affected workplace (i.e., a correction factor of 0.5). If the above equation is modified to reflect exposure to lead in air at a concentration of 0.5 µg/m 3 , the equation would be revised as follows: PbBfetal,0.95 = 1.8 1.645 × (1300 µg / g × 0.4 µg / dL ⋅ µg / day ⋅ 0.05 µg / day ⋅ 0.12) ⋅ 150 days / year 365 days / year + (0.5 µg / m3 × 1.75 µg / dL ⋅ µg / m 3 ⋅ 0.5) ⋅ 150 days / year 365 days / year + 2.0 µg / dL ⋅ 0.9 PbBfetal,0.95 = 8.2 µg/dL when inhalation exposure to lead is added to ingestion of lead 19.4 PETROLEUM HYDROCARBONS: ASSESSING EXPOSURE AND RISK TO MIXTURES Chemical mixtures present special problems to risk assessors. Mixtures may be made up of hundreds of individual chemicals that are inadequately characterized with regard to their toxicity. Further, it is often difficult or impractical to completely characterize the composition of the mixture. Such is the case with petroleum fuels such as gasoline and diesel fuel that contain hundreds of organic compounds. The USEPA indicates that when adequate information is available, it is preferable to use mixturespecific toxicity information to evaluate the risks of complex chemical mixtures. Mixture-specific toxicity information is preferred since the risk assessor does not have to make assumptions regarding the toxicological interaction of the chemicals of the mixture. However, use of mixture-specific toxicity information is only useful when the mixture in question is the same as the toxicologically characterized mixture. This is an important caveat for risk assessments of petroleum hydrocarbon mixtures. After being released to the environment, petroleum mixtures “weather” with time. Weathering causes the loss of more volatile, water-soluble, and degradable petroleum hydrocarbons. As a result, weathered petroleum fuel mixtures may no longer be chemically or toxicologically similar to the unweathered fuel. Until toxicological data are available for weathered petroleum mixtures, risk assessments of weathered petroleum mixtures are typically performed using either an “indicator chemical” or a “surrogate” chemical approach. The indicator chemical approach to petroleum hydrocarbon risk assessment assumes that certain compounds in a petroleum hydrocarbon mixture can be used to represent the environmental mobility, exposure potential, and toxicological properties of the entire petroleum mixture. For example, indicator chemicals typically used in risk assessments of unleaded gasoline include benzene, ethylbenzene,
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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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410 PROPERTIES AND EFFECTS OF NATUR
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Page 437 and 438: 428 PROPERTIES AND EFFECTS OF NATUR
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Page 445 and 446: 438 RISK ASSESSMENT 18.1 RISK ASSES
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Page 451 and 452: 444 RISK ASSESSMENT • It identifi
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Page 487: 19.3 LEAD EXPOSURE AND WOMEN OF CHI
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Page 505 and 506: 20 Occupational and Environmental H
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Page 511 and 512: treatment, or medical removal from
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Page 529 and 530: 22.2 EXPOSURE LIMITS 525 The TLVs
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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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