Poisons dose-response effects

Koplovitz, I., Menton, R., Matthews, C., Shutz, M., Nalls, C., and Kelly, S., Dose-response effects of atropine and HI-6 treatment of organophosphorus poisoning in guinea pigs, Drug Chem. Toxicol., 18,119-136,1995. 

Natural and synthetic chemicals affect every phase of our daily Hves ia both good and noxious manners. The noxious effects of certain substances have been appreciated siace the time of the ancient Greeks. However, it was not until the sixteenth century that certain principles of toxicology became formulated as a result of the thoughts of Philippus Aureolus Theophrastus Bombastus von Hohenheim-Paracelsus (1493—1541). Among a variety of other achievements, he embodied the basis for contemporary appreciation of dose—response relationships ia his often paraphrased dictum "Only the dose makes a poison."... 

Kinetic toxicology, also known as metabolic or pharmacologic toxicology, involves toxicants that are transported and metabolized in the body. Such substances are called systemic poisons and they are studied under the discipline of systemic toxicology. Systemic poisons may cross cell membranes (see Chapter 3) and act on receptors such as cell membranes, bodies in the cells, and specific enzyme systems. The effect is dose responsive, and it is terminated by processes that may include metabolic conversion of the toxicant to a metabolic product, chemical binding, storage, and excretion from the organism. 

We have seen that, in order to be poisonous and before it can cause harm, a chemical first has to get inside the body. The question is how much of it gets into the body. What is the real dose The internal or real dose of a chemical may be very small even if the amount swallowed or inhaled is large. This is because some chemicals (including some drugs) are very poorly absorbed. However, this is not the only reason that some chemicals are of low toxicity. The internal dose of the chemical may be detoxified very quickly by metabolism, be absorbed into fat, be bound to some other molecule, or just be excreted rapidly. But as the external dose rises so does the internal dose and a point may be reached where the detoxification or excretion processes are overwhelmed. Then the chemical will become toxic. This is one reason why we can see a relationship between the dose of a chemical and the response (effect). The chemical may cause an effect or even damage at low doses but this may not be detectable until some function is compromised. 

Evans, R.D., R.S. Harris, and J.W.M. Bunker. 1944. Radium metabolism in rats, and die production of osteogenic sarcoma by experimental radium poisoning. Am. J. Roentgenol. 52 353-373. Faustman, E.M., B.C. Allen, R.J. Kavlick, and C.A. Kimmel. 1994. Dose-response assessment for developmental toxicity. I. Characterization of database and determination of no observed adverse effect levels. Fundam. Appl. Toxicol. 23(4) 478-486. ... 

The dose-response relationship measures the correlation that occurs as one modifies the amount (dose) of a chemical substance to which a living material is exposed and the severity of the effect (response). This is commonly used with pharmaceuticals to determine the most effective amount of medication to be administered to have the desired beneficial effect. If the amount of medicine administered is too small (below the therapeutic level), the intended beneficial effect does not occur if the dose is increased and the amount administered is too large (above therapeutic range) toxicity may become evident. Toxicologists hold that the dose-response relationship applies not only to therapeutic agents but also to all chemical substances, that is, the dose makes the poison . The underlying principal is that the biological effects (beneficial or deleterious) of chemicals are due to the amounts of active material at the site, or sites, of action and that the concentration or the amount of the substance at the site (internal dose) is related to the amount of chemical administered (external dose). 

In the presence of TTX, the response of the preparation to GABA was not altered even after perfusion with deltamethrin for sixty minutes. Figure 5 shows dose response curves to GABA obtained before and after perfusion of 10 mM deltamethrin. This concentration of deltamethrin is 1,000 times greater than the threshold concentration for an effect on the sodium channels, indicating that the sodium channel effect is much more important to the poisoning process than any effect on the GABA system. 

The Merriam Webster s Collegiate Dictionary defines toxicology as a science that deals with poisons and their effect and with the problems involved (as clinical, industrial, or legal). The science of toxicology has been instrumental in developing the animal and early human trials to develop new pharmaceuticals. The dose-response relationship is the defining principle of this science. 

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