Hundreds of years ago, Swiss chemist and Renaissance physician Paracelsus (1493–1541) made a basic observation that became the underlying principle of toxicology: “All things are poison and nothing is without poison; only the dose makes a thing not a poison.” Or, in short: “The dose makes the poison.”
This means that almost any substance—even water and oxygen—may cause harm with its inherent toxic properties in a high enough concentration if it is absorbed or ingested into the body. Any substance’s toxicity depends on various factors, including the nature of the exposure, how long it lasts, and how substantial it is.
There is nothing that is inherently therapeutic or inherently toxic. They’re all a function of “dose.”
Hamilton Morris
In any standard pharmacology textbook toxicology is typically defined as the science of poisons or poisoning, but it is exceedingly difficult to strictly define poison itself. At the heart of this paradox is the dose makes poison principle observed by Paracelsus.
Writing mostly in German, the modern translation of the main idea was this: “What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison.”
This observation provided the foundation for the definition of the no-adverse effect level (NOAEL) as the highest tested dose or concentration of a substance, at which no adverse effect is found. Paracelsus’s work made modern scrutiny of the threshold concept and separation of hazard and risk possible by asserting that smaller doses may prevent adverse effects.
Life of Paracelsus
Paracelsus was born sometime in late 1493, although the name was an academic one he chose himself. Despite this clear nod to his work and use of an academic name, Paracelsus refused to base his teaching and thinking solely on classic traditions and beliefs. He refused to wear traditional clothing and he communicated in German, not in Latin. He also quickly became a vocal critic of Hippocrates and other more established colleagues.
Paracelsus was well-educated and even brilliant, but like many people who may be ahead of their time, he was also somewhat widely disliked and misunderstood by contemporaries. He looked and acted unusual, and had difficulty getting his work published.
Sometimes this was more due to his ideas. He was forced from a position at the University of Basel after less than a year after a legal dispute over fees and the controversy brought other issues—such as what would today be considered malpractice by others—to light. His Carinthian Trilogy in particular was written in 1538, but the book was not published until 1564, over 20 years after his death, showing the long arc toward appreciation of his writings.
The Work of Paracelsus
Paracelsus is famous for the concepts of target organs and occupational diseases in miners and others. His clinical toxicology on mercury was his best-known work, particularly since mercury was an important drug at that time despite its frequent side effects.
Thanks to the work of Paracelsus, the idea of no-observed-adverse-effect level (NOAEL) remains an important aspect of risk assessment in drug development. NOAEL is the highest dose of a drug that does not significantly increase adverse effects compared to controls in studies.
Dose and Toxicity
This all leads to the idea of dose and toxicity: all chemicals, natural or of human manufacture, are potentially toxic at some dose. People have died from excess water (water intoxication) and oxygen (oxygen toxicity), substances vital for life, and survived even highly toxic substances such as venom in smaller quantities.
This fundamental concept is the dose-response relationship: it is the amount of the substance that causes toxicity, not the substance itself. This principle is crucial to risk assessment from chemicals and their safe use, and forms the foundation of the study of toxicology.
Toxicity is how seriously a substance might damage cells, tissue, or an organism, and a number of factors can affect it:
- Dose
- Dose-time relationship
- Exposure amount/times
- Exposure route
- Species, sex/gender, size and age of impacted organism
- Chemical activity of organism
- Possibility of absorption, distribution, and excretion
- Presence of other substances
Beneficial Uses for Toxic Substances
Particularly in smaller amounts, some toxic substances can have beneficial applications. Some toxins are used as antiseptics, cleaning agents, dyes, fertilizers, medications, perfumes, pesticides, preservatives, and sweeteners. And even powerful hallucinogens may be used medicinally in microdoses.
