PRINCIPLES OF TOXICOLOGY - Biology East Borneo

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482 EXAMPLE <strong>OF</strong> RISK ASSESSMENT APPLICATIONSPbB fetal,0.95 = GSD 1.645 i × (PbS × BKSF × IR S × EF S )+ PbB adult,0 × R fetal / maternalATwhere PbBfetal,0.95 = The 95th percentile blood lead concentration for fetuses born towomen similarly exposed to lead in dust. This lead concentrationindicates that the likelihood of a greater blood lead concentrationis 5 percent. The 95th percentile is often used as a regulatory targetby USEPA.1.645GSD i = Individual geometric standard deviation for the variability in leadexposure and absorption. The value of 1.645 is the t value used tocalculate the 95th percentile from a lognormal blood lead distribution.The USEPA recommends a value of 1.8 for the GSD in afairly homogenous population.PbS = Soil or dust lead concentration in µg/g.BKSF = Biokinetic slope factor increased in typical adult blood lead concentrationto average daily lead uptake (µg/dL blood lead increaseper µg/day lead uptake). The BKSF obtained from reliablehuman studies is 0.4 µg/dL per µg/day.IRS = Daily intake of soil or dust. The USEPA recommends 0.05 g/dayas 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 ordust released from the gastrointestinal tract and absorbed is 0.12.EFS = Exposure frequency for contact with lead in dust. The USEPA recommendsa typical value of 219 days/year.AT = Total period over which dust exposure occurs. This value is typicallyassumed to be 365 days/year.PbBadult,0 = Background blood lead concentration for women of child-bearingage. A representative value is 2.0 µg/dL.Rfetal/maternal = Ratio of fetal blood lead concentration to the maternal blood leadconcentration at birth. The value typically assumed by USEPA is0.9.Assume that workers employed as furniture refinishers may ingest lead in dust during a particularphase of the operation for 3 days a week (approximately 150 days/year). Sampling of the lead-contaminateddust indicates an average lead concentration of 1300 µg/g. What is the calculated 95thpercentile blood lead concentration of a fetus of an exposed female worker? This calculation isillustrated below.PbB fetal,0.95 = 1.8 1.645 ×(1300 µg / g × 0.4 µg / dL ⋅ g / day × 0.05 g / day × 0.12 × 150 days / year)365 days / year+ 2.0 µg / dL × 0.9PbB fetal,0.95 = 7.8 µg/dL
19.4 PETROLEUM HYDROCARBONS: ASSESSING EXPOSURE AND RISK TO MIXTURES 483Interpretation of Risk Assessment Results and CommentFor pregnant workers, this indicates that there is a 5 percent likelihood that the fetal blood leadconcentration may exceed 7.8 µg/dL in similarly exposed pregnant women. The calculated leadconcentration is below the CDC and USEPA level of concern of 10 µg/dL. A greater exposurefrequency, a higher dust lead concentration, or exposure to a highly soluble form of lead (such as leadchloride or lead acetate) may result in a calculated PbB fetal,0.95that could potentially exceed 10 µg/dL.In practice, blood lead concentrations could also be measured in women of child-bearing age to providereassurance that they were not being overexposed.Although the preceding equation does not evaluate inhalation exposures to lead, it could easily bemodified to do so. The Agency for Toxic Substances and Diseases Registry (ATSDR) has summarizedhuman inhalation studies of lead and determined biokinetic slope factors relating the air leadconcentration to increases in blood lead. For example, individuals exposed to lead concentrations inair ranging from 3.2 to 11 µg/m 3 had average blood lead increases of 1.75 µg/dL for every µg/m 3 leadin air. Individuals in the study reviewed by ATSDR were exposed for 23 h/day for 18 weeks. Giventhat workers would not be exposed to the workplace atmosphere for 23 h/day, it would be reasonableto assume that only half the air breathed in a day was from the affected workplace (i.e., a correctionfactor of 0.5). If the above equation is modified to reflect exposure to lead in air at a concentration of0.5 µg/m 3 , the equation would be revised as follows:PbB fetal,0.95 = 1.8 1.645 ×(1300 µg / g × 0.4 µg / dL ⋅ µg / day ⋅ 0.05 µg / day ⋅ 0.12) ⋅ 150 days / year365 days / year+ (0.5 µg / m3 × 1.75 µg / dL ⋅ µg / m 3 ⋅ 0.5) ⋅ 150 days / year365 days / year+ 2.0 µg / dL ⋅ 0.9PbB fetal,0.95 = 8.2 µg/dL when inhalation exposure to lead is added to ingestion of lead19.4 PETROLEUM HYDROCARBONS: ASSESSING EXPOSURE AND RISK TOMIXTURESChemical mixtures present special problems to risk assessors. Mixtures may be made up of hundredsof individual chemicals that are inadequately characterized with regard to their toxicity. Further, it isoften difficult or impractical to completely characterize the composition of the mixture. Such is the casewith 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 mixturespecifictoxicity information to evaluate the risks of complex chemical mixtures. Mixture-specifictoxicity information is preferred since the risk assessor does not have to make assumptions regardingthe toxicological interaction of the chemicals of the mixture. However, use of mixture-specific toxicityinformation is only useful when the mixture in question is the same as the toxicologically characterizedmixture. This is an important caveat for risk assessments of petroleum hydrocarbon mixtures. Afterbeing released to the environment, petroleum mixtures “weather” with time. Weathering causes theloss of more volatile, water-soluble, and degradable petroleum hydrocarbons. As a result, weatheredpetroleum fuel mixtures may no longer be chemically or toxicologically similar to the unweatheredfuel. Until toxicological data are available for weathered petroleum mixtures, risk assessments ofweathered 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 certaincompounds 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, indicatorchemicals typically used in risk assessments of unleaded gasoline include benzene, ethylbenzene,
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CONTRIBUTORSLOUIS ADAMS, PH.D. Prof
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CONTENTSPREFACExvACKNOWLEDGMENTSxvi
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CONTENTSix7.3 Agents that Act on th
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CONTENTSxi15.4 Herbicides 35615.5 F
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CONTENTSxiii21.6 Population Issues
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xviPREFACE• The approach is scien
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PRINCIPLES OF TOXICOLOGY
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1 General Principles of ToxicologyG
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1.2 WHAT TOXICOLOGISTS STUDY 5Delay
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1.3 THE IMPORTANCE OF DOSE AND THE
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1.4 HOW DOSE-RESPONSE DATA CAN BE U
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1.5 AVOIDING INCORRECT CONCLUSIONS
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1.6 FACTORS INFLUENCING DOSE-RESPON
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1.6 FACTORS INFLUENCING DOSE-RESPON
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26 GENERAL PRINCIPLES OF TOXICOLOGY
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36 ABSORPTION, DISTRIBUTION, AND EL
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2.4 DISPOSITION: DISTRIBUTION AND E
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2.5 SUMMARY 53the transfer from liv
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REFERENCES AND SUGGESTED READING 55
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58 BIOTRANSFORMATION: A BALANCE BET
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60Figure 3.3 Xenobiotic metabolism
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TABLE 3.4 Important Cytochrome P450
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88 HEMATOTOXICITY: CHEMICALLY INDUC
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100 HEMATOTOXICITY: CHEMICALLY INDU
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5 Hepatotoxicity: Toxic Effects on
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5.1 THE PHYSIOLOGIC AND MORPHOLOGIC
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5.1 THE PHYSIOLOGIC AND MORPHOLOGIC
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5.2 TYPES OF LIVER INJURY 117cause
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5.2 TYPES OF LIVER INJURY 119Exampl
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5.2 TYPES OF LIVER INJURY 121TABLE
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5.2 TYPES OF LIVER INJURY 123to pro
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5.3 EVALUATION OF LIVER INJURY 125f
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6 Nephrotoxicity: Toxic Responses o
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6.1 BASIC KIDNEY STRUCTURES AND FUN
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6.1 BASIC KIDNEY STRUCTURES AND FUN
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6.2 FUNCTIONAL MEASUREMENTS TO EVAL
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6.3 ADVERSE EFFECTS OF CHEMICALS ON
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146 NEUROTOXICITY: TOXIC RESPONSES
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8 Dermal and Ocular Toxicology: Tox
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8.2 FUNCTIONS 159corneum is the pri
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8.3 CONTACT DERMATITIS 161TABLE 8.2
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8.3 CONTACT DERMATITIS 163mucous me
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8.3 CONTACT DERMATITIS 165light to
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8.4 SUMMARY 167The structure of the
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9 Pulmonotoxicity: Toxic Effects in
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9.1 LUNG ANATOMY AND PHYSIOLOGY 171
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9.2 MECHANISMS OF INDUSTRIALLY RELA
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9.2 MECHANISMS OF INDUSTRIALLY RELA
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9.3 SUMMARY 185Industrially Related
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190 IMMUNOTOXICITY: TOXIC EFFECTS O
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11 Reproductive ToxicologyREPRODUCT
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11.1 MALE REPRODUCTIVE TOXICOLOGY 2
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11.2 FEMALE REPRODUCTIVE TOXICOLOGY
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11.3 DEVELOPMENTAL TOXICOLOGY 225de
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11.3 DEVELOPMENTAL TOXICOLOGY 227af
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11.3 DEVELOPMENTAL TOXICOLOGY 229ri
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11.3 DEVELOPMENTAL TOXICOLOGY 231to
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11.4 CURRENT RESEARCH CONCERNS 233T
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11.4 CURRENT RESEARCH CONCERNS 235
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12 Mutagenesis and Genetic Toxicolo
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12.2 GENETIC FUNDAMENTALS AND EVALU
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TABLE 12-1. Correspondence of the G
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12.3 NONMAMMALIAN MUTAGENICITY TEST
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12.4 MAMMALIAN MUTAGENICITY TESTS 2
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12.4 MAMMALIAN MUTAGENICITY TESTS 2
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12.5 OCCUPATIONAL SIGNIFICANCE OF M
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REFERENCES CITED AND SUGGESTED READ
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13 Chemical CarcinogenesisCHEMICAL
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13.1 THE TERMINOLOGY OF CANCER 267H
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13.3 CARCINOGENESIS BY CHEMICALS 26
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Figure 13.1 Schematic diagram of th
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Figure 13.4 Metabolic activation of
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13.4 MOLECULAR ASPECTS OF CARCINOGE
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Figure 13.7 DNA damage leads to p53
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13.5 TESTING CHEMICALS FOR CARCINOG
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13.5 TESTING CHEMICALS FOR CARCINOG
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13.6 INTERPRETATION ISSUES RAISED B
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13.7 EMPIRICAL MEASURES OF RELIABIL
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13.8 OCCUPATIONAL CARCINOGENS 301TA
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13.8 OCCUPATIONAL CARCINOGENS 303TA
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13.9 CANCER AND OUR ENVIRONMENT 305
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13.10 CANCER TRENDS AND THEIR IMPAC
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13.11 SUMMARY 321from non-Hodgkin
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14 Properties and Effects of Metals
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14.2 SPECIATION OF METALS 327Most o
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14.3 PHARMACOKINETICS OF METALS 329
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14.4 TOXICITY OF METALS 331reflex i
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14.4 TOXICITY OF METALS 333Several
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14.5 SOURCES OF METAL EXPOSURE 335H
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14.6 TOXICOLOGY OF SELECTED METALS
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14.7 SUMMARY 343Zinc is required fo
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15 Properties and Effects of Pestic
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15.1 ORGANOPHOSPHATE AND CARBAMATE
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15.3 INSECTICIDES OF BIOLOGICAL ORI
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15.3 INSECTICIDES OF BIOLOGICAL ORI
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15.4 HERBICIDES 357ClClO CH 2 C OOH
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15.5 FUNGICIDES 359temperatures as
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15.7 FUMIGANTS 361thallium sulfate-
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16 Properties and Effects of Organi
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TABLE 16.1 Physicochemical Properti
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16.2 BASIC PRINCIPLES 371TABLE 16.2
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16.2 BASIC PRINCIPLES 373Once absor
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16.2 BASIC PRINCIPLES 375the additi
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16.3 TOXIC PROPERTIES OF REPRESENTA
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16.10 TOXIC PROPERTIES OF REPRESENT
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16.15 TOXIC PROPERTIES 403observed
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16.18 SULFUR-SUBSTITUTED SOLVENTS 4
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17 Properties and Effects of Natura
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17.3 NATURAL ROLES OF TOXINS AND VE
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17.4 MAJOR SITES AND MECHANISMS OF
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17.5 TOXINS IN UNICELLULAR ORGANISM
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17.6 TOXINS OF HIGHER PLANTS 417phy
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17.6 TOXINS OF HIGHER PLANTS 419whi
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17.6 TOXINS OF HIGHER PLANTS 421TAB
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17.7 ANIMAL VENOMS AND TOXINS 423of
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17.7 ANIMAL VENOMS AND TOXINS 425ac
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17.7 ANIMAL VENOMS AND TOXINS 427co
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Page 444 and 445: 18 Risk AssessmentRISK ASSESSMENTRO
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534 CONTROLLING OCCUPATIONAL AND EN
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556 GLOSSARYaliphatic Organic compo
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558 GLOSSARYbenign tumor A new tiss
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560 GLOSSARYcytokinesis The divisio
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562 GLOSSARYerythropoietic stimulat
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564 GLOSSARYinhalation route The mo
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566 GLOSSARYmitochondria Small sphe
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568 GLOSSARYoral route The entry of
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570 GLOSSARYporphyrin Any of a grou
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572 GLOSSARYspirometry The measurem
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INDEXAbsorbed dose, defined, 4Absor
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INDEX 577Area under the tissue conc
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INDEX 579animal studies, 297cellula
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INDEX 581speciation of, 327-328Corp
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INDEX 583organ-specific activities,
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INDEX 585Follicle-stimulating hormo
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INDEX 587fatty liver, 120-122hepato
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INDEX 589Isoniazid metabolism, path
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INDEX 591Mechanistic toxicology, as
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INDEX 593Nephropathy:defined 130nep
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INDEX 595neurobehavioral sequelae,
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INDEX 597Probability density functi
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INDEX 599Rodenticides, 360.-361sodi
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INDEX 601Safe Human Dose (SHD) appr
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INDEX 603drug metabolism factors, 7
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