PRINCIPLES OF TOXICOLOGY

448 RISK ASSESSMENT
• Estimating Exposures to Dioxin-like Compounds (USEPA 1994)
• Superfund Exposure Assessment Manual (USEPA 1988a)
• Selection Criteria for Mathematical Models Used in Exposure Assessments (USEPA 1988b)
• Standard Scenarios for Estimating Exposure to Chemical Substances During Use of Consumer
Products (USEPA 1986a)
• Pesticide Assessment Guidelines, Subdivisions K and U (USEPA 1984, 1986b)
• Methods for Assessing Exposure to Chemical Substances, Volumes 1–13 (USEPA 1983–
1989)
Once doses have been estimated for all exposure pathways, they can be directly compared to toxicity
constants such as USEPA reference doses (RfDs) and Agency for Toxic Substances and Disease
Registry minimal risk levels (MRLs) to assess noncancer risks, or alternatively, multiplied by cancer
slope factors to obtain an estimate of cancer risk. Another word of caution is in order, however. Toxicity
constants, including cancer slope factors, may be specific for particular exposure routes (MRLs vary
by exposure route and exposure duration) since target organ dose, and for some chemicals the target
organ itself, can be exposure route-dependent. As mechanistic data play a greater role in the risk
assessment process, it is also likely that multiorgan carcinogens will have organ-specific cancer slope
factors in recognition of organ-specific cancer mechanisms and dose–response curves.
While the administered dose and absorbed dose are common dose measures, they do not reflect the
amount of the chemical or its metabolite(s) that ultimately produce the toxic response (except in cases
where chemicals exert their action locally, as in the case of strong acids or bases that produce
dermatotoxicity on contact). The toxic response is more closely linked to the dose in the target tissue
of interest (see Figure 18.2 for a schematic showing the relationships between exposure and various
dose measures). For example, solvent-induced neurobehavioral toxicity may be a function of peak
brain concentration of the parent compound, whereas liver toxicity from the same chemical may be
related to the hepatic tissue concentration of one or more metabolites over time [called the area under
the tissue concentration–time curve (AUC)]. The identification of such internal dose measures that are
mechanistically linked to various toxicities holds promise for improving the risk assessment process.
Figure 18.2 The relationship between exposure and various measures of dose. [From Exposure Factors Handbook,
Vol. 1, General Factors, USEPA (1997).]