A toxicological basis to derive a generic interspecies uncertainty factor

Area of Science:

• Toxicology
• Risk Assessment
• Biostatistics

Background:

• Determining appropriate uncertainty factors (UF) for interspecies extrapolation in toxicology is critical for accurate human risk assessment.
• Existing methods for UF derivation often lack robust statistical and toxicological grounding, potentially leading to over- or under-protection.

Purpose of the Study:

• To propose and validate a new method for deriving a statistically and toxicologically based interspecies uncertainty factor (UF).
• To quantify interspecies variation in susceptibility to toxic substances using binary comparisons.
• To establish UF values across different levels of phylogenetic relatedness.

Main Methods:

• Quantifying interspecies variation in susceptibility using binary interspecies comparisons.
• Converting these comparisons into a 95% uncertainty factor (UF).
• Categorizing comparisons into four phylogenetic levels: species within genus, genera within family, families within order, and orders within class.

Main Results:

• The proposed 95% interspecies UF ranges from 10 (species within genus) to 65 (orders within class).
• Mammalian toxicology studies commonly used in human risk assessment fall into the orders-within-class category, receiving a 65-fold UF.
• The method allows for adjustment of UF values based on the desired level of protection.

Conclusions:

• The developed method provides a scientifically rigorous approach to deriving interspecies uncertainty factors.
• This new UF framework enhances the accuracy and reliability of human health risk assessments based on animal studies.
• The tiered UF approach accommodates varying degrees of phylogenetic relatedness and desired safety margins.