Relationship between lethal toxicity in oral administration and injection to mice: Effect of exposure routes

- There are significant relationships between toxicities in different injection routes.
- Same toxic mechanism results in related toxicity between oral and injection routes.
- First-pass effect results in decrease of toxicity in oral route less than in injection.
- Rapid distribution in body leads to bias of toxicity between oral and injection routes.

The lethal toxicity (LD50) in oral administration, intravenous, intraperitoneal, intramuscular and subcutaneous injections were used to investigate relationships of log 1/LD50 from different exposure routes. Regression analysis showed that log 1/LD50 in oral route was related to the toxicity in injection route. This relationship in lethality between the two routes is apparently due to the same mechanisms of the compounds to the same species. However, the scatter in the correlation curve indicates that exposure route is an important factor that influences the relationship. Some compounds with low intestinal absorption exhibit much less toxicity in oral administration than that in the injection route. A systemic bias of log 1/LD50 between oral and injection routes indicates that tissue distribution of compounds between blood and target site is a very rapid process, leading to log 1/LD50 in injection greater than those in oral administration. Although compounds can be metabolized in the body both from oral and injection routes, first-pass metabolism occurs in oral route but not in injection route. This will result in decrease of toxicity in oral route for most compounds as compared with injection route. In addition, experimental uncertainty, differences in gender, and species can also affect relationships of log 1/LD50 between exposure routes.