As one grows older and develops more leisure time, it seems a common practice to undertake courses and seminars to stimulate one’s mind and satisfy one’s soul. Thus, my wife Elie is auditing a course each semester at Columbia College; this semester is Victorian poetry (Tennyson and the like). My cousin Mel has been taking courses for years at William Paterson University on music appreciation—he sits and listens to Beethoven, Bach, etc. And of course there is always Daf Yomi, an endeavor adopted by innumerable alte kockers. (I include myself.)
In a similar vein, I recently undertook a course in basic toxicology as it relates to drug testing in advance of clinical trials. Toxicology is the study of toxins or poisons and their effects on humans. In toxicology, we are concerned with how variations in the dose, duration of exposure to the chemical, and mode of administration of the chemical affect its impact on the animal or human. These issues are relevant to exposure to potential carcinogens in the environment or in the occupational setting, and how such exposures may lead to the development of cancer. But, in addition, toxicology addresses newly developed drugs, which are really also fundamentally toxins (albeit with good intentions and potential benefits for the recipient) and how they should be utilized when introduced into human trials. Thus, toxicologists do extensive pre-clinical testing on potential new drugs prior to human testing to assess their toxicity and hopefully eliminate those that are clearly too dangerous to be introduced into general use.
The two major factors that affect toxicity are the route of exposure (intravenous or IV, subcutaneous injection, intramuscular injection, oral ingestion, dermal application, etc.) and the dose, frequency and duration of exposure. The most rapid effect occurs with IV administration, as the drug/chemical is then immediately introduced into the bloodstream and therefore has immediate access to target organs. A single high dose of a drug may give a dramatic acute response, but it may also clear or be eliminated rapidly. In contrast, repetitive frequent administrations of a drug may hinder elimination of the drug and result in a different set of chronic toxicities.
Another variation that occurs with the site of exposure is local versus systemic toxicity. Inhalation of a drug or toxin can lead to pulmonary toxicity, like bronchospasm or bronchitis. Likewise, dermal administration of a drug can irritate the skin and cause a rash or allergic reaction that is non-systemic.
Systemic exposure to a drug, e.g., via the bloodstream, can cause systemic effects, like fever, fatigue. loss of appetite, or nausea and vomiting. Furthermore, because the drug is conveyed to where the blood is distributed, the organs generally most prone to toxicity are those which receive the largest proportions or fractions of the blood flow—the heart, the liver and the kidneys. While it is also true that the brain receives approximately 25% of blood circulation, it is relatively protected, as we have stated on several occasions in the past, by the blood-brain barrier. It is estimated that 27% of toxicity from drugs is cardiovascular in nature and 14% is hepatic.
Another interesting fact I learned is that 28% of adverse effects occur in the target organ of the drug, while the remainder are “off-site.” Thus, perhaps because too high a dose is administered or the metabolism of the drug is awry, the effect of the drug may be exaggerated. For example, a hypertension drug may give too strong an effect and thus the patient may become hypotensive. Or a diabetic patient may become hyperglycemic because of under-dosing or lack of response to the correct dose. Alternatively, other systems in the body may have untoward effects on the drug. A patient receiving penicillin may develop an immunologic or allergic response. The use of halothane, a well-known anesthetic, may trigger an idiosyncratic reaction in the operating room.
When a toxicologist begins to administer a new drug to humans (after the laboratory and animal assessments), his/her goal is to establish two metrics—the NOAEL (no observed adverse effect level—the highest dose at which there was no toxic or adverse effect) and the LOAEL (lowest dose at which there was an observed toxic or adverse effect). We have not yet said anything about the effectiveness of the drug. Hopefully there is a minimum dose at which the drug is effective which lies somewhere between the NOAEL and the LOAEL.
Usually, we try to find the therapeutic index for the new drug. This is a measure of the relative safety of the drug. The ED50 (Effective Dose 50) is the dose at which 50% of the population has a good therapeutic effect. The TD50 (Toxic Dose 50) is the dose at which 50% of the population has a toxic reaction. The therapeutic index (TI) is the ratio of the two: TD50/ED50. The smaller the ratio, the better.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: ain1@columbia.edu.
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
