THE JAPANESE SOCIETY OF TOXICOLOGY

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About JSOT / What is Toxicology?

Takemi Yoshida
11th President
Emeritus Professor Showa University
Chairman of the Board of Directors, Council on Pharmacists’ Credentials
Takemi Yoshida Toxicology is a discipline that aims to identify unintended adverse reactions (toxicity) in living organisms (and sometimes ecosystems) caused by the interaction of a parent compound or its metabolites with biomolecules when drugs or chemical substances are ingested, absorbed, distributed, metabolized and excreted by the organism, and to elucidate the mechanism by which such toxicity is expressed. In pharmacology, the processes involved in the onset of therapeutic effects of drugs prescribed for treatment, prevention or diagnosis of disease are referred to as pharmacokinetics and pharmacodynamics, while in toxicology, the processes involved in the onset of toxicity are referred to as toxicokinetics and toxicodynamics. Toxicology is not only concerned with evaluating the safety of investigational drugs through relevant toxicity testing; it deals with a very wide range of chemical substances, including food additives, agrochemicals, industrial chemicals, environmental chemicals, metals, cosmetics and natural substances. One notable role of toxicology is in evaluating the safety of chemical substances through toxicity testing in animal models or via in vitro studies alternative to animal testing, when direct testing in humans is not possible, to determine their toxicity and extrapolate the findings to humans.

The toxicity of drugs and chemical substances involves a dose-response relationship. Starting with a faint toxic reaction, the range of adverse reactions widens as the ingested amount increases, triggering a variety of reactions with biomolecules to reach the expression of systemic toxicity. Toxicity can also change significantly depending on the duration of exposure (single exposure versus prolonged exposure) and can manifest itself as a highly complex pattern of symptoms affecting the central to the peripheral organs and tissues. These include organ toxicity, affecting the liver, kidneys, lungs and heart; allergic reactions and immunotoxicity; neurotoxicity affecting the central and peripheral nervous systems; and teratogenicity and carcinogenicity. Historically, Japan has had the irretrievable experience of witnessing drug-induced diseases including thalidomide-induced deformities and subacute myelo-optico-neuropathy (SMON) caused by quinoform, as well as environmental hazard such as Minamata disease caused by methyl mercury.

Because identification of adverse reactions to drugs and chemical substances and elucidation of the expression mechanism requires extensive knowledge of interspecies differences, differences among individuals, racial differences, gender- and age-related differences, as well as the impact on groups susceptible to chemical substances, such as fetuses and newborns, toxicology is a highly diverse and multidisciplinary science that embraces both basic and applied science.

Toxicology reveals the very wide-ranging adverse effects that drugs and other chemical substances have on living organisms and provides data to evaluate the hazards and risks associated with them. Modern society is said to make use of around 100,000 different types of chemical substances, including drugs, but a very large number of chemical substances have not been subjected to toxicity tests to evaluate their safety. The role of toxicology is to develop accurate methods of evaluating the toxicity of this vast number of chemical substances and to utilize the findings to assess their safety for humans and the environment by improving the speed and sophistication of the process and through quantification and measures to boost data accuracy. The toxicity of a large number of drugs and chemical substances has already been determined and their expression mechanisms uncovered. These are catalogued in Casarett and Doull's Toxicology, a publication that is periodically updated.

Thomas Kuhn introduced the term “paradigm shift” in his great book The Structure of Scientific Revolutions. The multifaceted science of toxicology has also undergone a shift with the incorporation of rapidly advancing scientific techniques and its scope has now widened to include nanotoxicology, which addresses developments in nanomaterials that are the product of nanotechnology. This represents a new direction beyond the toxicity of conventional materials.

Advances in molecular biology have spawned molecular toxicology, enabling us to increase the number of molecules involved in biological reactions with chemical substances in order to evaluate the toxicological events in minute and precise detail. Advances in IT technology have led to advances in image analysis techniques, while the discovery of fluorescent proteins and advances in gene transfer technology enable us to see the intracellular migration of target biomolecules under the stimulus of chemical substances and observe the processes leading to toxicity expression. Gene knockout technology helps us to identify the toxicological target molecules of chemical substances. Advances in gene manipulation technology are contributing significantly to the establishment of systems for in vitro toxicity assessment using ES cells and iPS cells.

Advances in omics scientific techniques facilitating comprehensive analysis have brought about a paradigm shift of toxicology to a multidisciplinary science, including analysis of the dose-response relationship in adverse biological reactions to chemical substances. The ability to comprehensively observe changes in genes, proteins and metabolites due to the toxic effects of chemical substances is helping to advance the field of toxicoinformatics.

Other new developments include microRNA toxicology, epigenetic toxicology and systems toxicology. Combining and utilizing these scientific techniques and quantitative structure-activity relationships has given birth to predictive toxicology as a means of dealing with vast numbers of chemical substances.

In light of the above, a key challenge for toxicology in contemporary society is to establish high-powered systems for evaluating the effects on reproductive and developmental toxicity as well as neurotoxicity affecting behavioral and cognitive systems due to exposure to trace chemicals in the environment during prenatal and growing years.

Toxicology as a multidisciplinary science helps to create a better living environment through evaluation of the safety of pharmaceuticals and chemical substances. I hope as a conclusion that the ultimate goal of the toxicological science is to contribute to a safer and more secure society and to sound longlife and happiness.

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