An inhalation reference concentration (RFC) is defined as 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 appreciable risk of deleterious noncancer health effects during a lifetime. The methods for derivation of RFC estimates presented in this document include general principles of dose-response assessment for noncancer toxicity. Evaluation of noncancer toxicity requires determination of the critical toxic effect from an array of toxicity data on different target tissues and endpoints of various severities within specific disease continuums. The typical assessment requires designation of a no-observed-adverse-effect level (NOAEL). General guidance on how to evaluate toxicity data and on data base requirements is presented. Because the various species used in inhalation toxicology studies do not receive identical doses in comparable respiratory tract regions when exposed to the same aerosol or gas, dosimetric adjustments are applied for interspecies extrapolation. Dosimetry adjustments are used to calculate human equivalent concentrations (HEC) estimates from observed NOAEL values. The dosimetry adjustments are based on the type of toxicant (particles versus gases, and within gases, for the three categories defined on the basis of major determinants of uptake) and on the type of toxic effect (in the respiratory tract or sites remote to the respiratory tract). Alternative approaches (e.g., benchmark) to the NOAEL/LOAEL approach are presented. Guidance on the applications of uncertainty factors and assignment of confidence statements is also provided.