Thresholds in Acute and Long Term Animal Studies

Abstract

The possibilities to define thresholds in general pharmacology and toxicology depend upon the proper knowledge and determination of the most sensitive parameters and relevant targets leading to clinical effects or toxicity. We are generally confronted with the statistical summation of very numerous individual responses and effects at the enzymological, sub-cellular, cellular, organ, or systemic level. In consequence, biological actions of chemicals reveal typical dose-response characteristics described by simple mathematics, and more or less sharp thresholds. Thresholds and targets can change after single and repeated (cumulative) doses by means of altered kinetics and metabolism, by adaptation and modified sensitivity of targets and/or receptors. Most sensitive targets and parameters do not always determine the real thresholds for clinical toxicity. Threshold and specificity of carcinogens can also be modified by similar conditions mentioned. Nutritional factors play an important role in experimental car-dnogenesis, and also for the cancer incidence in man. Frequently, secondary mechanisms such as overloading, induction of cellular growth, mechanical and chemical irritation and damage, and other conditions have simulated real carcinogenic properties of chemical molecules. The important question on the existence and validity of thresholds in carc/nogenes/s must be connected with a solid evaluation of the mode of action of the individual compounds. Otherwise, mathematical calculations of safety limits, definitions of acceptable risks and no-effect levels lack any biological foundation. Finally, the individual perception and social acceptance of risks reveal certain thresholds.