Toxicology
Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating exposures to toxins and toxicants. The relationship between dose and its effects on the exposed organism is of high significance in toxicology. Factors that influence chemical toxicity include the dosage, duration of exposure, route of exposure, species, age, sex, and environment. Toxicologists are experts on poisons and poisoning. There is a movement for evidence-based toxicology as part of the larger movement towards evidence-based practices. Toxicology is currently contributing to the field of cancer research, since some toxins can be used as drugs for killing tumor cells. One prime example of this is ribosome-inactivating proteins, tested in the treatment of leukemia.
The word toxicology is a neoclassical compound from Neo-Latin, first attested, from the combining forms toxico- + -logy, which in turn come from the Ancient Greek words τοξικός toxikos, "poisonous", and λόγος logos, "subject matter").
History
The earliest treatise dedicated to the general study of plant and animal poisons, including their classification, recognition, and the treatment of their effects is the Kalpasthāna, one of the major sections of the Suśrutasaṃhitā, a Sanskrit work composed before ca. 300 CE and perhaps in part as early as the fourth century BCE. The Kalpasthāna was influential on many later Sanskrit medical works and was translated into Arabic and other languages, influencing South East Asia, the Middle East, Tibet and eventually Europe.Dioscorides, a Greek physician in the court of the Roman emperor Nero, made an early attempt to classify plants according to their toxic and therapeutic effect. A work attributed to the 10th century author Ibn Wahshiyya called the Book on Poisons describes various toxic substances and poisonous recipes that can be made using magic. In the 12th century, Jewish physician Maimonides wrote Kitāb al-Sumūm wa-l-Mutaḥarriz min al-Adwiya al-Qattāla, which discussed the treatment of poisoning. A 14th century Kannada poetic work attributed to the Jain prince Mangarasa, Khagendra Mani Darpana, describes several poisonous plants.
File:Mathieu Joseph Bonaventure Orfila.jpg|thumb|left|Lithograph of Mathieu Orfila
The 16th-century Swiss physician Paracelsus is considered "the father" of modern toxicology, based on his rigorous approach to understanding the effects of substances on the body. He is credited with the classic toxicology maxim, "Alle Dinge sind Gift und nichts ist ohne Gift; allein die Dosis macht, dass ein Ding kein Gift ist." which translates as, "All things are poisonous and nothing is without poison; only the dose makes a thing not poisonous." This is often condensed to: "The dose makes the poison" or in Latin "Sola dosis facit venenum".
Mathieu Orfila is also considered the modern father of toxicology, having given the subject its first formal treatment in 1813 in his Traité des poisons, also called Toxicologie générale.
In 1850, Jean Stas became the first person to successfully isolate plant poisons from human tissue. This allowed him to identify the use of nicotine as a poison in the Bocarmé murder case, providing the evidence needed to convict the Belgian Count Hippolyte Visart de Bocarmé of killing his brother-in-law.
In the modern era, regulatory oversight of toxicology has shifted to specialized governmental and international bodies, including the U.S. Food and Drug Administration, the Environmental Protection Agency, and the World Health Organization, which enforce standardized protocols to assess chemical risks in food, drugs, and the environment. Building on Paracelsus's foundational dose-response principle, these agencies guide evidence-based safety evaluations through tiered toxicity studies and data interpretation. The FDA's Redbook 2000 exemplifies this continued evolution, serving as a pivotal guidance document for toxicological principles in assessing food additives and ingredients, ensuring public health protections aligned with contemporary scientific rigor.
Basic principles
The goal of toxicity assessment is to identify adverse effects of a substance. Adverse effects depend on two main factors: i) routes of exposure dose. To explore dose, substances are tested in both acute and chronic models. Generally, different sets of experiments are conducted to determine whether a substance causes cancer and to examine other forms of toxicity.Factors that influence chemical toxicity:
- Dosage
- * Both large single exposures and continuous small exposures are studied.
- Route of exposure
- * Ingestion, inhalation or skin absorption
- Other factors
- * Species
- * Age
- * Sex
- * Health
- * Environment
- * Individual characteristics
Testing methods
Toxicity experiments may be conducted in vivo or in vitro, or in silico.''In vivo'' model organism
The classic experimental tool of toxicology is testing on non-human animals. Examples of model organisms are Galleria mellonella, which can replace small mammals, Zebrafish, which allow for the study of toxicology in a lower order vertebrate in vivo and Caenorhabditis elegans. As of 2014, such animal testing provides information that is not available by other means about how substances function in a living organism. The use of non-human animals for toxicology testing is opposed by some organisations for reasons of animal welfare, and it has been restricted or banned under some circumstances in certain regions, such as the testing of cosmetics in the European Union.''In vitro'' methods
While testing in animal models remains as a method of estimating human effects, there are both ethical and technical concerns with animal testing.Since the late 1950s, the field of toxicology has sought to reduce or eliminate animal testing under the rubric of "Three Rs" – reduce the number of experiments with animals to the minimum necessary; refine experiments to cause less suffering, and replace in vivo experiments with other types, or use more simple forms of life when possible. The historical development of alternative testing methods in toxicology has been published by Balls.
Computer modeling is an example of an alternative in vitro toxicology testing method; using computer models of chemicals and proteins, structure-activity relationships can be determined, and chemical structures that are likely to bind to, and interfere with, proteins with essential functions, can be identified. This work requires expert knowledge in molecular modeling and statistics together with expert judgment in chemistry, biology and toxicology.
In 2007 the American NGO National Academy of Sciences published a report called "Toxicity Testing in the 21st Century: A Vision and a Strategy" which opened with a statement: "Change often involves a pivotal event that builds on previous history and opens the door to a new era. Pivotal events in science include the discovery of penicillin, the elucidation of the DNA double helix, and the development of computers.... Toxicity testing is approaching such a scientific pivot point. It is poised to take advantage of the revolutions in biology and biotechnology. Advances in toxicogenomics, bioinformatics, systems biology, epigenetics, and computational toxicology could transform toxicity testing from a system based on whole-animal testing to one founded primarily on in vitro methods that evaluate changes in biologic processes using cells, cell lines, or cellular components, preferably of human origin." As of 2014 that vision was still unrealized.
The United States Environmental Protection Agency studied 1,065 chemical and drug substances in their ToxCast program using in silica modelling and a human pluripotent stem cell-based assay to predict in vivo developmental intoxicants based on changes in cellular metabolism following chemical exposure. Major findings from the analysis of this ToxCast_STM dataset published in 2020 include: 19% of 1065 chemicals yielded a prediction of developmental toxicity, assay performance reached 79%–82% accuracy with high specificity but modest sensitivity when compared with in vivo animal models of human prenatal developmental toxicity, sensitivity improved as more stringent weights of evidence requirements were applied to the animal studies, and statistical analysis of the most potent chemical hits on specific biochemical targets in ToxCast revealed positive and negative associations with the STM response, providing insights into the mechanistic underpinnings of the targeted endpoint and its biological domain.
In some cases shifts away from animal studies have been mandated by law or regulation; the European Union prohibited use of animal testing for cosmetics in 2013.
Dose response complexities
Most chemicals display a classic dose response curve – at a low dose, no effect is observed. Some show a phenomenon known as sufficient challenge – a small exposure produces animals that "grow more rapidly, have better general appearance and coat quality, have fewer tumors, and live longer than the control animals".A few chemicals have no well-defined safe level of exposure. These are treated with special care. Some chemicals are subject to bioaccumulation as they are stored in rather than being excreted from the body; these also receive special consideration.
Several measures are commonly used to describe toxic dosages according to the degree of effect on an organism or a population, and some are specifically defined by various laws or organizational usage. These include:
- LD50 or LD50 = Median lethal dose, a dose that will kill 50% of an exposed population
- NOEL = No-Observed-Effect-Level, the highest dose known to show no effect
- NOAEL = No-Observed-Adverse-Effect-Level, the highest dose known to show no adverse effects
- PEL = Permissible Exposure Limit, the highest concentration permitted under US OSHA regulations
- STEL = Short-Term Exposure Limit, the highest concentration permitted for short periods of time, in general 15–30 minutes
- TWA = Time-Weighted Average, the average amount of an agent's concentration over a specified period of time, usually 8 hours
- TTC = The Threshold of Toxicological Concern concept has been applied to low-level contaminants, such as the constituents of tobacco smoke