ABSTRACT
Section 1. Introduction Section 2. Risk Assessment: Introduction and Overview
Figure 24.1 The Four Major Elements of Risk Assessment Table 24.1 Hierarchy of Data Selection for Risk Assessment Figure 24.2 The Interrelationship Between the Probability (Percent) of a
Given Toxic Effect in Humans and the Number of Animals Required in a Toxicology Study to Ensure that the Same Toxic Effect can be Observed
Table 24.2 Typical Factors Considered in a Risk Assessment Figure 24.3 Factors that Influence the Risk Posed to an Individual by
Xenobiotic Exposures Figure 24.4 Representation of the Relationships between Ambient Exposure
and Critical Target Dose Figure 24.5 Diagrammatic Representation of the Possible Pharmacokinetic
Fate of a Chemical Figure 24.6 Maternal-Placental-Fetal Pharmacokinetic Relationships that
can Influence the Risk Posed by a Reproductive Toxin Figure 24.7 Diagrammatic Representation of Potential Exposure Pathways
Available to an Environmental Pollutant Figure 24.8 Example of the Distribution of a Contaminant Based on
Household Water Use Patterns Table 24.3 Comparative Assessment of Absorbed Dose from a Volatile
Pollutant in Drinking Water Table 24.4 Typical Assumptions Made in a Risk Assessment of an
Animal Carcinogen Water Pollutant Table 24.5 Major Factors that Influence a Risk Assessment Table 24.6 Criteria Defining “High-Exposure” Chemicals Figure 24.9 Relationship Between the Degree of Uncertainty Associated
with the Risk Assessment of a Chemical, the Concern for Human Exposure, and the Toxicological Information Available on the Chemical
Table 24.7 Factors that Influence Risk Management Decisions Section 3. Dose-Response Relationships
Figure 24.11 Typical Frequency Distribution of a Population Response to an Equivalent Dose of a Biologically Active Agent
Figure 24.12 Typical Sigmoid Cumulative Dose-Response Curve Figure 24.13 Various Ways of Presenting Dose-Response Data
Interpretation of LD50 Data Figure 24.16 A Simplistic Method for Assessing “Safety Ratios” for
Drugs Figure 24.17 Risk-Benefit Determinations from Dose-Response Curves Figure 24.18 A Theoretical Dose-Response Relationship Indicating the Range
of Dosage of a Toxicant to Which Representative Human Populations Might be Exposed
Figure 24.19 A Dose-Response Curve from a Typical Toxicology Study Showing Dose-Related Indices Commonly Used in Risk Assessment
Figure 24.20 A Dose-Response Curve from a Typical Toxicology Study Showing the Relationship of the Reference Dose (RfD) and Reference Concentration (RfC) to the No Observable Adverse Effect Level (NOAEL)
Figure 24.21 Benchmark Dose (BMD) Figure 24.22 Harmful Effects of a Substance Produced at Both Low and
High Doses Figure 24.23 The Determination of a Virtually Safe Dose (VSD) Figure 24.24 Determination of a Virtually Safe Dose (VSD) in the Presence
of Background Figure 24.25 The Effect of Linear Extrapolation of a Sublinear Dose-Response
Curve on the Determination of a Virtually Safe Dose (VSD) Figure 24.26 The Effect of the Shape of the Dose-Response Curve on the
Determination of a Virtually Safe Dose (VSD) Table 24.8 Mathematical Models Used in the Determination of Low-Dose
Response Relationships for Potentially Carcinogenic Agents Figure 24.27 Dose-Response Curves Extrapolated With Data from a Chronic
Bioassay Using the Weibull, Logit, Multistage, and Probit Models
Section 4. Epidemiology Figure 24.28 Common Epidemiological Study Designs Table 24.9 Human Data Commonly Used in Risk Assessment Table 24.10 Epidemiological Terms Table 24.11 Steps in the Investigation of a Cancer Cluster Table 24.12 Overall Evaluation of Human and Animal Evidence about the
Carcinogenicity of 597 Agents Table 24.13 Estimates on Causes of Cancer Table 24.14 Top 12 Most Frequently Observed Site-Specific Cancers in
Humans in the United States Figure 24.29 Age-Adjusted Male Cancer Death Rates for United States by Site
for the Years 1930 through 1996 Figure 24.30 Age-Adjusted Female Cancer Death Rates for United States by
Site for the Years 1930 through 1996 Table 24.15 Cancer Mortality Rates for Women Table 24.16 Cancer Mortality Rates for Men Table 24.17 Probability (%) of Developing Invasive Cancers Over Selected
Age Intervals, by Sex, United States, 1994-1996 Table 24.18 Cancer Death Rates Per 100,000 Population for Selected
Countries: Males
Table 24.20 Known and Suspect Human Carcinogens Table 24.21 Reproductive Endpoints to Indicate Reproductive
Dysfunction Table 24.22 Possible Environmental Risk Factors for Spontaneous
Abortion Table 24.23 Probabilities of Spontaneous Abortion Table 24.24 Factors Known to Cause Fetal Growth Retardation in
Humans Table 24.25 Frequency of Selected Adverse Pregnancy Outcomes in
Humans Table 24.26 Criteria for Recognizing a New Teratogen in the Human Figure 24.31 Schematic Diagram of Critical Periods of Human
Development Table 24.27 Causes of Malformation in Humans Table 24.28 Incidences of Human Birth Defects Table 24.29 Known Human Teratogens Table 24.30 Etiologic Agents for Congenital Malformations in Humans
and Domestic Animals Section 5. Relative Risk Tables
Table 24.31 Lifetime Risk and Annual Average Risk of Death from Cancer in the United States
Table 24.32 Cancer Risks from Radiation Exposure Table 24.33 Everyday Cancer Risks from Common Carcinogens Table 24.34 Risk of Death in the United States
Section 6. Standard Risk Assessment Reference Values Table 24.35 The Duration of Studies in Experimental Animals and Time
Equivalents in the Human Figure 24.32 Interspecies Extrapolation of Metabolic Rate Figure 24.33 Schematic Representation of Developmental Changes in
Hepatic Metabolism and Renal Elimination Table 24.36 Summary of Drug Absorption in Neonates, Infants, and
Children Table 24.37 Plasma Protein Binding and Drug Distribution in Neonates,
Infants, and Children Table 24.38 Renal Function in the Neonate, Infant, and Child Table 24.39 Drug Metabolism in the Neonate, Infant, and Child Table 24.40 Developmental Patterns for the Ontogeny of Important Drug
Metabolizing Enzymes in Man Table 24.41 Comparative Mammalian Reference Values for Relative Dose
Calculations Table 24.42 Reference Comparative Physiological Values Table 24.43 Body Fluid Volumes for Men and Women Table 24.44 Comparative Mammalian Organ Weights Table 24.45 Typical Human Exposure Values Used in Risk
Assessments Table 24.46 Mean Body Weight of Children by Age Table 24.47 Constants for Estimating Surface Area of Mammals Table 24.48 Median Total Body Surface Area for Humans by Age Table 24.49 Total Body Surface Area For Humans by Height and Weight
by Activity Level Table 24.52 Summary of Human Inhalation Rates for Men, Women, and
Children by Activity Level Section 7. Physiologically Based Pharmacokinetic Modeling
Figure 24.34 Diagram of a Typical Physiologically Based Pharmacokinetic Model
Table 24.53 Reference Physiological and Biochemical Values Used in PBPK Models
Table 24.54 EPA Recommended Reference Physiological Values for Use in PBPK Modeling
Section 8. Risk Assessment Calculations Table 24.55 Risk Assessment Calculations
Section 9. Toxicity Classifications Table 24.56 Combined Tabulation of Toxicity Classes Figure 24.35 Toxicity Classifications Based on Acute Oral LD50 Figure 24.36 Toxicity Classifications Based on Acute Dermal LD50 Figure 24.37 Toxicity Classifications Based on Acute Inhalation LC50 Figure 24.38 Toxicity Classifications Based on Acute Aquatic LC50 Table 24.57 EPA, IARC, and EEC Classification Systems for
Carcinogens Table 24.58 Criteria for Determining the Human Relevance of Animal
Bioassay Results Section 10. Glossary: Risk Assessment Terms, Abbreviations, and Acronyms References
The purpose of this chapter is to provide information to familiarize the reader with the basic concepts and process of risk assessment and to provide a handy and quick reference source for standard assumptions, terminology, equations, and values used in performing these assessments. Although the information presented in this chapter is generally representative of the risk assessment process as currently practiced by regulatory bodies such as the U.S. Environmental Protection Agency, risk assessment is an ever evolving discipline. As such, methods and procedures are often modified or replaced to reflect current scientific practice and theory.
