Hazard Identification for Noncancer Effects. In addition to EPA guidance on procedures for the identification of carcinogens, EPA has published guidelines for assessing several specific types of chronic noncancer effects including mutagenicity [1], developmental toxicity [2], neurotoxicity [3], and reproductive toxicity [4], as well as a framework for using studies of these and other effects in inhalation risk assessment [5].

Under these guidelines for identification of chronic hazards other than cancer, scientists review the health effects literature and characterize its strengths and weaknesses, using a narrative approach rather than a formal classification scheme. Data on different endpoints are arrayed and discussed, and the effects (and their attendant dose/exposure levels) described. Particular attention is given to the critical effect (defined as the first adverse effect, or its known precursor, that occurs to the most sensitive species as the dose rate of an agent increases) in well-designed studies. Information is presented in a narrative description that discusses factors such as the methodological strengths and weaknesses of individual studies (as well as the overall database), the length of time over which the studies were conducted, routes of exposure, and possible biological modes of action. Assessors consider the severity of effects, which may range from severe frank effects that can cause incapacitation or death to subtle effects that may occur at the cellular level but are early indicators of toxicity. Not all effects observed in laboratory studies are judged to be adverse. The distinction between adverse and non-adverse effects is not always clear-cut, and professional judgment is applied to identify adverse effects. These observations are integrated into a presentation that gives a concise profile of the toxicological properties of the pollutant.

Dose-Response Assessment for Noncancer Effects. The reference concentration (RfC) for inhalation and the reference dose (RfD) for oral exposure are the primary Agency consensus quantitative toxicity metrics for use in noncancer risk assessments for chronic exposure. The RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. It can be derived from a NOAEL , LOAEL , or benchmark concentration , with uncertainty factors generally applied to reflect limitations of the data used. The RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. It can be derived from a NOAEL, LOAEL, or benchmark dose, with uncertainty factors generally applied to reflect limitations of the data used. The RfC and RfD are derived after a thorough review of the health effects data base for an individual chemical, and identification of the most sensitive and relevant endpoint (the "critical effect") and the principal study(ies) demonstrating that endpoint. Inhalation RfCs are derived according to the Agency's Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry [5].

Derivation of an RfC or RfD typically begins with identification of the critical effect from the available human and animal study data, followed by identification of a LOAEL or, preferably, a NOAEL. Some assessments fit a model to the dose-response relationship and interpolate a benchmark concentration (or the corresponding oral benchmark dose), usually the exposure at which 5-10 percent of the study population is predicted to respond. The 95% lower confidence limit on the benchmark concentration/dose (BMCL/DL) replaces the use of the NOAEL and better represents all of the data of the dose-response curve. For RfC development, inhalation LOAELs, NOAELs, or BMCLs are adjusted for continuous exposures, and data from animal studies are used to derive a human equivalent concentration (HEC) based on dosimetric adjustments [5]. (For RfD development, these conversions are usually not required.) The RfC or RfD are then derived by consistent application of uncertainty factors (UFs) to account for recognized uncertainties in the extrapolation from the experimental data and exposure conditions [5]. RfCs and RfDs (and similar dose-response assessment values) presented here were developed by EPA, the US Agency for Toxic Substances and Disease Registry, and the California EPA, and were selected for use by a priority system.

The process by which most acute inhalation dose-response assessment values are derived differs from the chronic RfC methodology in two important ways. First, "acute" may connote exposure times varying from a few minutes to two weeks. The time frame for the value is critical, because the safe dose (or the dose that produces some defined effect) may vary substantially with the length of exposure. Second, some acute dose-response assessments include more than one level of severity. A typical assessment may have values for level 1 (at which only mild, transient effects may occur), level 2 (above which irreversible or other serious effects may occur), and level 3 (above which life-threatening effects may occur). Therefore, many acute assessments present dose-response assessment values as a matrix, with one dimension being length of exposure and the other a severity-of-effect category. Table 2 presents acute values for all three severity levels where assessed, but where assessments include multiple durations or averaging times, only values for the 1-hour exposure time are presented. The only exceptions are ATSDR assessments, which have a 24-hour to 2-week time frame, and a few California EPA values that have time frames slightly different from 1 hour (e.g., 6 hours for benzene, 4 hours for arsenic, etc.).

Unlike linear dose-response assessments for cancer, noncancer risks generally are not expressed as a probability of an individual suffering an adverse effect. Instead, "risk" for noncancer effects typically is quantified by comparing the exposure to the reference level via a ratio known as the "hazard quotient" (HQ; i.e., the exposure divided by the appropriate chronic or acute value). For a given air toxic, exposures at or below the reference level (HQ=1) are not likely to be associated with adverse health effects. As exposures increase above the reference level (i.e., HQs increase above 1), the potential for adverse effects also increases. The HQ, however, should not be interpreted as a probability of adverse effects.

References

• U.S. EPA. 1986. Guidelines for Mutagenicity Risk Assessment. 51 FR 34006-34012. Available on-line at http://www2.epa.gov/risk/guidelines-mutagenicity-risk-assessment.
• U.S. EPA. 1991. Guidelines for Developmental Toxicity Risk Assessment. 56 FR 63798-63826. Available on-line at http://www2.epa.gov/risk/guidelines-developmental-toxicity-risk-assessment.
• U.S. EPA. 1998. Guidelines for Neurotoxicity Risk Assessment; Notice 60. 63 FR 26926-26954. Available on-line at http://www2.epa.gov/risk/guidelines-neurotoxicity-risk-assessment.
• U.S. EPA. 1996. Guidelines for Reproductive Toxicity Risk Assessment. National Center for Environmental Assessment. EPA/630/R-96/009. Available on-line at http://www2.epa.gov/risk/guidelines-reproductive-toxicity-risk-assessment.
• U.S. EPA. 1994. Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry. Office of Research and Development, Washington, DC. EPA/600/8-90/066F. Available on-line at http://www2.epa.gov/risk/methods-derivation-inhalation-reference-concentrations-and-application-inhalation-dosimetry.