A Better Approach To Cancer Risk Characterization:

The regulatory upper-bound potency measures (like EPAs upper-bound cancer potency, q₁*) based on the linearized multistage (LMS) model tend to overstate the risks.  Sometimes this overstatement may be by several orders of magnitude.  Sometimes this overstatement may be in the form of positive risks when the real risks are zero.

EPA and others have been developing a new approach to cancer risk characterization.  The new approach is based on benchmark doses (BMD's) and margin-of-exposure (MOE) characterizations. 

A benchmark dose (BMD) is a characterization of the dose corresponding to a specified increase in the probability of a specified response.  For example, an ED₁₀ is the estimated dose corresponding to an increase of 0.10 in the probability of the specified response relative to the probability of that same response at dose zero. 

A margin of exposure (MOE) is defined as the benchmark dose divided by the dose from exposure.  If the benchmark dose is the ED₁₀, then the margin of exposure is the ED₁₀ divided by the dose from exposure.  The smaller the dose from exposure the larger the margin of exposure.

A margin of exposure can be calculated for any specified response.  For example, if cancer were the specified response of concern, then the relevant dose metric would usually be assumed to be the lifetime average daily dose and be expressed in units of mg of chemical per kg of body weight per day (i.e., mg/kg-day).  In this case, the ED₁₀ would be in units of mg/kg-day, the dose from exposure would be expressed in the same units (mg/kg-day), and the margin of exposure would be the corresponding ratio (a unitless number equal to the ED₁₀ divided by the dose from exposure).

Benchmark doses based on the ED₁₀ and margin-of-exposure characterizations together provide a more realistic treatment of data than the regulatory potency measure (q₁*) based on the linearized multistage model.

The recommendation to use the ED₁₀ to characterize the dose-response relationship and margins of exposure to characterize the risk is consistent with classical assessments of toxicity and safety.

Using the ED₁₀ to characterize the dose-response relationship is consistent with the use of classical measures of toxicity like the no-observed-adverse-effect-level (NOAEL) to reflect dose levels that are likely to be without appreciable risks of deleterious effects.  These classical measures of toxicity are based on the idea of using the observed data to determine a dose level at which there is no detectable increase in the occurrence of adverse health effects (no increase compared to the probability of response at dose zero).

Using margins of exposure to characterize the degree of safety is consistent with use of allowable daily intake by the U.S. Food and Drug Administration, reference dose and reference concentration by the U.S. Environmental Protection Agency, minimum risk level by the U.S. ATSDR, and tolerable intake by the World Health Organization.  For example, the U.S. EPA describes the reference dose as ...an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without appreciable risk of deleterious effects during a lifetime.

For example, chemicals which cause increased cell proliferation and increased incidence of species-specific lesions are not suitable for analysis by the linearized multistage (LMS) model, which is the basis for the EPA upper-bound cancer potency (q₁^*).  Instead, the margin of exposure (MOE) approach is recommended for chemicals with highly nonlinear dose-response relationships.  The MOE approach can result in acceptable levels which are higher than those obtained by the LMS approach by roughly two orders of magnitude.