Toxicity (dose-response assessment)
Dose-response assessment takes the toxicity data gathered in the hazard identification step from animal studies and exposed human population studies and describes the quantitative relationship between the amount of exposure to a chemical (or dose) and the extent of toxic injury or disease (or response). Generally, as the dose of a chemical increases, the toxic response increases either in the severity of the injury or in the incidence of response in the affected population (
EPA, 1989 ;
EPA, 1993 ). In toxicity-assessment step, the relationship between the magnitude of the administered, applied, or absorbed dose and the probability of occurrence and magnitude of health effect(s) (e.g. tumor incidence in the case of cancer) is determined.
Dose-response assessment for carcinogens and non-carcinogens differ in toxicity values use and how these toxicity values are derived. In general, toxicity values provide a measure of toxic potency of the chemical in question. These toxicity values are:
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Reference Dose (RfD) for oral/dermal pathways or Reference Concentration (RfC) for inhalation pathway – Noncarcinogens: A
chronic RfD is defined as an estimate (with uncertainty spanning perhaps an order of magnitude or greater) of a daily exposure level for the human population, including sensitive subpopulations, that is likely to be without an appreciable risk of deleterious effects during a lifetime. It has the unit of mg of pollutant per kg of body weight per day (mg/kg-day). Chronic RfDs are specifically developed to be protective for long-term exposure to a chemical, usually, for exposure periods between seven years (approximately 10 percent of a human lifetime) and a lifetime. After selection of a critical health effect study and a critical health effect through review of toxicity literature in the hazard identification step, the RfD is derived by dividing the NOAEL (or LOAEL) for the critical toxic effect by uncertainty factors (UFs) and a modifying factor (MF). The uncertainty factors generally consist of multiples of 10, with each factor representing a specific area of uncertainty inherent in the extrapolation from the available data (e.g. 10 for extrapolation from animals to humans; 10 for interhuman variability; 10 when LOAEL is used instead of NOAEL in deriving RfD; 10 when NOAEL is obtained from a subchronic study rather than a chronic study). A modifying factor ranging from>0 to 10 is included to account for additional uncertainties in the critical study and in the entire data based on a qualitative professional assessment. The default value for the MF is 1.The NOAEL is selected based on the assumption that if the critical toxic effect is prevented, then all toxic effects are prevented (EPA, 1989). The derivation of toxicity value, RfD/RfC, for noncarcinogens assumes that they are threshold chemicals, meaning there is a threshold below which no adverse effects are observed in test species. This dose level (i.e. NOAEL) in animals is simply adjusted by a number of factors (UFs and MF) to determine the safe dose level in humans (i.e. RfD) as shown by the following equation:
