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MALATHION 121 3. HEALTH EFFECTS route to route, between species, and between subpopulations within a species. The biological basis of PBPK models results in more meaningful extrapolations than those generated with the more conventional use of uncertainty factors. The PBPK model for a chemical substance is developed in four interconnected steps: (1) model representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan and Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The numerical estimates of these model parameters are incorporated within a set of differential and algebraic equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations provides the predictions of tissue dose. Computers then provide process simulations based on these solutions. The structure and mathematical expressions used in PBPK models significantly simplify the true complexities of biological systems. If the uptake and disposition of the chemical substance(s) is adequately described, however, this simplification is desirable because data are often unavailable for many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The adequacy of the model is, therefore, of great importance, and model validation is essential to the use of PBPK models in risk assessment. PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste sites) based on the results of studies where doses were higher or were administered in different species. Figure 3-4 shows a conceptualized representation of a PBPK model. A PBPK model for dermal exposure was developed by the California Office of Environmental Health Hazard Assessment (Rabovsky and Brown 1993). Unlike most PBPK models developed and validated by using laboratory animals, this model was unique as it directly dealt with human exposure cases. The model was used to estimate the exposure doses of southern California residents who may have been exposed to aerial sprays of malathion mixed with a corn-syrup protein bait. Urine samples were collected
MALATHION 122 V E N O U S BLOOD 3. HEALTH EFFECTS Figure 3-4. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance Inhaled chemical Exhaled chemical Urine V max Lungs Liver Fat Slowly perfused tissues Richly perfused tissues Kidney Skin Source: adapted from Krishnan et al. 1994 K m Ingestion GI Tract Feces Chemicals in air contacting skin Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by ingestion, metabolized in the liver, and excreted in the urine or by exhalation. A R TE R IAL BL O O D
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TOXICOLOGICAL PROFILE FOR MALATHION
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MALATHION iii UPDATE STATEMENT A To
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MALATHION viii Managing Hazardous M
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MALATHION xi PEER REVIEW A peer rev
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MALATHION xiv 3.2.3.2 Systemic Effe
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MALATHION xvii LIST OF FIGURES 3-1.
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MALATHION 1 1. PUBLIC HEALTH STATEM
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MALATHION 11 1. PUBLIC HEALTH STATE
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MALATHION 14 2. RELEVANCE TO PUBLIC
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MALATHION 24 3. HEALTH EFFECTS oral
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MALATHION 26 3. HEALTH EFFECTS sing
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≤
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MALATHION 30 3. HEALTH EFFECTS Resp
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MALATHION 32 3. HEALTH EFFECTS Rena
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MALATHION 40 3. HEALTH EFFECTS the
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a Key to figure 1 2 3 4 5 6 Species
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a Key to figure 15 16 17 18 Species
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a Key to figure 24 25 26 27 28 29 S
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a Key to figure 40 41 42 43 44 45 S
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a Key to figure 55 56 57 58 59 60 S
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a Key to figure 67 68 69 70 Species
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a Key to figure 83 84 85 86 87 88 8
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a Key to figure 91 Species (Strain)
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a Key to figure 93 94 Species (Stra
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≤
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≤
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MALATHION 64 3.2.2.2 Systemic Effec
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MALATHION 66 3. HEALTH EFFECTS 1965
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MALATHION 68 3. HEALTH EFFECTS Hepa
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MALATHION 171 5. PRODUCTION, IMPORT
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MALATHION 173 5. PRODUCTION, IMPORT
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MALATHION 175 6.1 OVERVIEW 6. POTEN
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MALATHION 177 6. POTENTIAL FOR HUMA
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MALATHION 187 6.3.2.1 Air 6. POTENT
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MALATHION 216 7. ANALYTICAL METHODS
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MALATHION 224 7.3.1 Identification
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MALATHION 226 8. REGULATIONS AND AD
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MALATHION 238 9. REFERENCES *Agency
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MALATHION 240 9. REFERENCES *Barnes
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MALATHION 242 9. REFERENCES *Brown
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MALATHION 248 9. REFERENCES Ehrich
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MALATHION 250 9. REFERENCES EPA. 20
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MALATHION 252 9. REFERENCES *Gaines
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MALATHION 256 9. REFERENCES Jianmon
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MALATHION 258 9. REFERENCES Kimbrou
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MALATHION 262 9. REFERENCES *Mackis
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MALATHION 264 9. REFERENCES Mohn G.
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MALATHION 266 9. REFERENCES NIOSH.
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MALATHION 268 9. REFERENCES *Prabha
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MALATHION 272 9. REFERENCES *Singar
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MALATHION 276 9. REFERENCES Viccell
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MALATHION 278 9. REFERENCES Yess NJ
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MALATHION 280 10. GLOSSARY Ceiling
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MALATHION 282 10. GLOSSARY Mutagen
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MALATHION 284 10. GLOSSARY Risk—T
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MALATHION A-2 APPENDIX A are not ex
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MALATHION A-4 APPENDIX A Was a conv
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MALATHION A-6 APPENDIX A Was a conv
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MALATHION A-8 APPENDIX A If an inha
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MALATHION A-10 Uncertainty Factors
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MALATHION B-2 Interpretation of Min
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MALATHION B-4 APPENDIX B (8) NOAEL
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1 2 3 4 12 → → → → → Key
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MALATHION C-1 APPENDIX C. ACRONYMS,
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MALATHION C-3 APPENDIX C MFO mixed
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MALATHION C-5 > greater than $ grea
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