Parameters for grading the toxic severity of test chemicals : a review article in the advancement of unknown drugs into the clinic

Abstract

Grading of toxic severity of a test chemical is a routine procedure in experimental toxicology to support regulatory policy in categorisation and harmful labeling decisions. Harmful labeling decision is usually made on the basis of lethal dose administered to study animal. However, the toxic property of a chemical compound is diverse in which the undesired biological mechanism manifested on treated study animal may not cause death within the period of the experiment. The length of time at which undesired biological effects manifest on study animal depend on the amount of administered dose. The adverse effect of higher dose usually manifests within a shorter period of time than the lower doses. The scientific basis of drug action is the interaction of a drug with its receptor or biological target by which undesired biological changes manifested at the cellular, organs or organismal level depending on the amount of administered test chemical. Drug metabolism is an important biological process to be considered in the study of pharmacological activity of test chemical compounds. It is one of the primary mechanisms by which a chemical compound is inactivated or activated depending on the metabolic enzyme systems involved in biotransformation. Biotransformation of test chemical perhaps leads to the production of reactive metabolites that could be more toxic, mutagenic or carcinogenic than parent chemical compound which could elicit different biological responses such as loss of appetite and suppressed immune response among others. The metabolic and immune systems are highly interrelated in which the proper function of one is highly dependent on the other. Metabolic dysfunction for instance leads to deteriorated immune system which can be evaluated by clinical parameters such as differential blood cell counts (i.e., T-lymphocytes and B-lymphocytes) and immunoglobulin concentration in blood serum. In conclusion, Grading of toxic severity of test chemicals should take into account not only the estimate of hazards on the basis of lethal dose administered into the biological system but also the different biological responses (immunological and physiological) and the length of time at which biological responses manifested in the course of metabolism. Quantitative analysis of undesired biological responses as toxic severity and toxic reaction rate is paramount for grading the toxic severity of test chemical compounds on study subject which allow better identification of real risks to public health safety.