Toxicity Assessment

Broadly speaking, toxicity is the degree to which a substance is poisonous. Most chemicals, toxic or otherwise, enter the body through eyes, respiratory tract, digestive tract, and skin. Two levels of toxicity are defined: acute “short‐term” exposure that initiates poisoning and chronic “long‐period” exposure that causes anemia, leukemia, and death.

In the context of the third stage of the risk assessment process, toxicity is defined by the dose–response relationship for each surrogate chemical. The output takes the form of mathematical constants for insertion into risk calculation equations. In addition to providing a set of mathematical constants for calculating risk, the toxicological assessment should also analyze the uncertainty inherent in these numbers and describe how this uncertainty may affect the estimates of risk.

In a prudent approach to public health protection, the EPA has built several safety factors into its methods for establishing reference doses and carcinogenic slope factors (USEPA 2002a, 2002b, 2005). Virtually, all errors of uncertainty are made in the direction of public health protection to insure that risks are overestimated rather than underestimated. Four examples of this protective approach follow:

• For noncarcinogens, extrapolation of animal reference doses to humans utilizes two safety factors of ten, one for animal‐to‐human extrapolation, a second for variation for toxic sensitivities within the human population.
• For carcinogens, the linearized multistage model assumes the upper‐bound 95% confidence level of extrapolated data (i.e. it is likely to be conservative 19 out of 20 times).
• For carcinogens, the linearized multistage model extrapolates data from the 10–90% carcinogenesis range observed in experimental animals to the regulatory target of 0.0001% carcinogenesis, a step which could overstate risk by several orders of magnitude.
• Although evidence indicate that, like noncarcinogens, nongenotoxic carcinogens have thresholds below which they fail to influence cellular differentiation or division, they are treated mathematically like genotoxic carcinogens according to the linearized multistage dose–response model.