A Quick, Simple, Conversion System to Extrapolate Safe Reference Doses from Animal Data to Human Data
By Joel 2014
When discussing the idea of chemical doses, safety has to be the number one focus and the main deciding factor when researching a drug. It is useful when designing the initial stages for testing to calculate a threshold below which the probability of harm is almost non-existent. This is how a calculated, presumed “safe” level of exposure is found. This is traditionally found by diving of a NOAEL (No Observable Adverse Effect Level), a LOAEL (Lowest Observable Adverse Effect level), using a Benchmark Dose (BMD), a Benchmark Concentration (BMC) or by uncertainty factors to address interspecies and Interindividual variation (IPCS, 1987, 1994).
When there are sources of uncertainty or unaccounted for variability, the magnitude that the NOAEL, LOAEL, BMD, or BMC exceeds the estimated exposure (the “margin of safety” or “margin of exposure) will be considered as well.
“Inter- and intraspecies considerations are an essential part of extrapolation to humans for all of these approaches (IPCS, 1999b) and were described in EHC 210 as follows:
a) Interspecies consideration: comparison of the data for animals with a representative healthy human. Species differences result from metabolic, functional and structural variations.
b) Intraspeciesor interindividual consideration: comparison of the representative healthy human with the range of variability present within the human population in relation to the relevant parameters. “
When human data is available, the relationship between dose and toxicity is easiest determined. When human data is not available it must be derived from animal test data. The process is as follows: First tests are preformed to determine a NOAEL or LOAEL. Second, the tests are analyzed to determine which safety factors or uncertainties need to be accounted for when converting data from animal to human. These allow for issues of incomplete data, differences in metabolic efficiency and differences in their pathways between animals and humans (by incorporating both toxicodynamic and toxicokinetic factors of variability), increased sensitivity among the human population, exchanges of administration type, and many other conditions.
When the NOAEL or LOAEL is analyzed with these variance facts the resultant number is called the RfD or reference dose. The NOAEL or LOAEL is decided by seeing the lowest dose that will affect the most sensitive animal species. This number is the maximum threshold before side effects of any type are first discovered after exposure, dissection, and analysis.
Even though this procedure is technically an estimate, the success of the process is quite evident when looking at the relatively few, limited, and inconclusive health incidents that have occurred because of dosage settings. Analysis of exposure limits that have been set over the past have...