Week 2 - Introduction & General Principles of Toxicology

Summary

In the first lecture of toxicology, the WHS TeamUOW explores the foundational elements and overarching concepts within this scientific discipline that studies the effects of poisons and chemicals on biological systems. Key terminologies such as poison, toxin, toxicant, and dose are defined, alongside a discussion on the vital role of dose in determining toxicity. The lesson emphasizes the multifaceted nature of toxicology, spanning descriptive, mechanistic, and regulatory activities, as well as its various branches like occupational, environmental, and food toxicology. This comprehensive overview is crucial for understanding how toxicologists assess chemical risks, classify toxic agents, and analyze exposure routes and interactions.

Highlights

• Toxicology is both a science and art involving observation and risk estimation. 🔍
• Key toxicology terms: poison, toxin, toxicant, dose, and xenobiotic. 📚
• Dose is critical in determining whether a substance acts as a poison or remedy. 💊
• LD50 measures acute toxicity, crucial for understanding lethal doses. 💀
• Toxicology branches include clinical, occupational, environmental, and more. 🌐
• Chemical interactions can be additive, synergistic, potentiate, or antagonistic. ⚗️

Key Takeaways

• Toxicology blends science and art, combining data analysis with risk prediction. 🎨
• The 'right dose' of a substance is key to differentiating a remedy from a poison. ⚖️
• Regulatory toxicology establishes safety standards and monitors exposure risks. 🛡️
• Understanding chemical interactions is crucial for assessing combined toxic effects. 🔄
• Toxicology covers numerous branches, reflecting its integral role across diverse fields. 🌍

Overview

Toxicology, often dubbed the science of poisons, investigates how various substances, including chemicals and biological agents, affect health. This introductory lecture by the WHS TeamUOW sheds light on the basic principles and concepts of toxicology, illustrating its dual nature as both a science and an art. With a foundation laid in understanding key terms like poison, dose, and xenobiotic, the lecture emphasizes the discipline's reliance on both empirical data and theoretical risk predictions, especially when extrapolating data from animal studies to humans.

A standout point in toxicology is the significance of dose; even common substances can become deadly at inappropriate levels. Paracelsus, a founding figure in the field, famously highlighted this in his teachings, stating that the right dose distinguishes a poison from a remedy. The lecture elaborates on the concept of lethal dose (LD50), explaining how it measures acute toxicity and varies significantly among substances, from ethyl alcohol to botulinum toxin.

Toxicology extends into various branches: clinical, occupational, environmental, and more, each with distinct applications and responsibilities. The interaction of chemicals, whether additive, synergistic or antagonistic, is a complex but crucial area of study, impacting how toxicologists predict and mitigate risks. With regulatory bodies and guidelines ensuring safety in the workplace, environment, and food systems, this lecture provides a crucial understanding of toxicology's scope and its integral role in safeguarding public health.

Chapters

• 00:00 - 00:30: Introduction to Toxicology The chapter introduces the field of toxicology, the study of poisons and adverse health effects caused by foreign materials, known as xenobiotics. It covers fundamental concepts and principles related to toxicology, highlighting its focus on chemicals, biological agents, and biological systems like blood.
• 00:30 - 01:00: Science and Art of Toxicology Toxicology is both a science and an art. The science aspect involves observation and data gathering, while the art aspect deals with predicting and estimating risk. An example of the art in toxicology is extrapolating data from animal testing to humans. The chapter introduces key terms, including 'poison,' defined as any agent capable of causing harm.
• 01:00 - 02:00: Key Terms in Toxicology The chapter 'Key Terms in Toxicology' discusses various fundamental concepts related to toxicology. It explains the difference between toxins and toxicants, where toxins are naturally produced by biological entities like plants and animals, while toxicants are man-made or result from human activities, such as industrial waste. Moreover, the chapter addresses the concept of toxicity, which is described as the inherent toxic properties of any given substance.
• 02:00 - 03:00: Dose Concept in Toxicology A xenobiotic is any foreign material found within an organism. Dose refers to the amount of a substance administered to an organism. A toxicologist is a scientist who studies the adverse effects of xenobiotics. Paracelsus famously stated that all substances are poisons and that the dose differentiates a poison from a remedy, emphasizing the importance of dosage in toxicology.
• 03:00 - 04:00: LD50 and Acute Toxicity The chapter discusses the contribution of a renowned toxicologist who is considered one of the pioneers in the field. His revolutionary concept of dose is emphasized, which is crucial in toxicology, as almost every chemical can be harmful or lethal depending on the dosage. The chapter uses a table to demonstrate the significance of understanding the dose required to cause death in fifty percent of exposed animals, commonly referred to as LD50.
• 04:00 - 05:00: Branches of Toxicology The chapter titled 'Branches of Toxicology' discusses the concept of LD50, or lethal dose at fifty percent, which is a measure of the toxicity of a substance. This measurement is given in milligrams of substance per kilogram of body weight. The text provides examples to illustrate the range of toxicity: Ethyl alcohol has a relatively high LD50 of 10,000 mg/kg, indicating it is less toxic compared to other substances. In contrast, the text hints at a naturally occurring toxin called butlinum toxin, though details about its LD50 are not completed in the given transcript.
• 05:00 - 06:00: Occupational Toxicology History This chapter focuses on the concept of the LD50, a measure of acute toxicity indicating the lethal dose required to kill half a population of test animals. Although a valuable metric for assessing acute toxicity, the LD50 does not account for chronic toxicity. Some substances, while showing no signs of acute toxicity, can possess carcinogenic properties, potentially leading to cancer many years post-exposure.
• 06:00 - 07:00: Regulatory Authorities This chapter introduces the broad field of toxicology, emphasizing its interdisciplinary nature. Toxicology draws on various scientific disciplines like biochemistry and biology. The chapter discusses how advancements in these fields have contributed to the growth and evolution of toxicology, particularly in enhancing safety applications.
• 07:00 - 08:00: Classification of Toxic Agents The chapter titled 'Classification of Toxic Agents' discusses the role of toxicologists in evaluating and assessing risks posed by chemicals. It explains that toxicologists work in three main categories: descriptive, mechanistic, and regulatory. Each category has unique characteristics and although they are distinct, they contribute to and support each other in understanding adverse health effects caused by chemicals.
• 08:00 - 09:00: Exposure and Its Effects This chapter focuses on the topic of exposure in chemical risk assessment and its effects. It introduces toxicology as a broad science with various branches related to its discipline, applications, and functions. The discussion emphasizes the importance of understanding mechanistic pathways in toxicology, specifically identifying mechanisms responsible for agents when conducting risk assessments.
• 09:00 - 10:00: Chemical Interactions and Tolerance This chapter discusses the various aspects of toxicology including the experiments conducted by descriptive toxicologists to understand acute and chronic toxicity. It also covers how regulatory toxicology assesses risk levels of chemicals and establishes standards for safe exposure in environments like workplaces and drinking water.
• 10:00 - 11:00: Dose-Response Relationship The chapter titled 'Dose-Response Relationship' begins by mentioning that toxicology is a broad science and discipline. It can be classified into several branches based on its applications. These branches include clinical toxicology, food and drug toxicology, forensic toxicology, occupational (or industrial) toxicology, environmental toxicology, developmental toxicology, and reproductive toxicology.
• 11:00 - 12:00: Examples of LD50 and LC50 The chapter provides examples of LD50 and LC50, but starts with an introduction to nanotoxicology, a relatively new discipline. It mentions a table that provides definitions for various disciplines in the field, suggesting the reader to refer to it for detailed understanding. The text mentions the significance of traditional occupational exposures in the context of the subject. However, definitions and specific examples of LD50 (Lethal Dose 50) and LC50 (Lethal Concentration 50) are not explicitly detailed in the provided text.
• 12:00 - 13:00: Lethal, Toxic, and Effective Doses In this chapter, the discussion revolves around the occurrence of adverse health effects caused by chemical and biological hazards. The origins of occupational toxicology are explored, crediting historical figures like Agricola, Paracelsus, and Ramazzini for initiating the study of toxic exposures in various industries such as mining, smelting, and metallurgy. Ramazzini is also acknowledged as a pioneering figure in industrial safety.
• 13:00 - 14:00: Dose-Response Curve Slopes This chapter discusses the historical development and current considerations of occupational health and safety. It highlights the work of the individual regarded as the father of occupational health, who identified occupational hazards for various workers. The chapter also explores the evolution of what is considered an acceptable level of risk in workplaces, the recognition of the link between exposures and chronic diseases, and the emergence of new hazards.
• 14:00 - 15:00: Therapeutic Index and Margin of Safety The chapter discusses the importance of assessing new risks that may arise from emerging technologies like nanotechnology. It highlights the need for preparedness in evaluating these potential risks. The terms occupational toxicology and industrial toxicology are used interchangeably, emphasizing their significance in the context of these technological advancements.
• 15:00 - 16:00: Conclusion of Toxicology Principles The chapter delves into applying toxicology principles in understanding and managing workplace chemical and biological hazards. It emphasizes the industrial toxicologist's role, who must intimately know the work environment, recognize, and prioritize hazardous exposures, recognize multiple workplace exposures, and evaluate the entire spectrum of worker exposures.

Week 2 - Introduction & General Principles of Toxicology Transcription

• 00:00 - 00:30 hi and welcome to the first lecture in toxicology today we're going to discuss the general principles of toxicology and cover some fundamental concepts in toxicology toxicology is the science of poisons or the study of the adverse health effects of xenobiotics including any foreign material such as chemicals and biological agents as well as biological systems such as blood
• 00:30 - 01:00 toxicology can be considered as both a science and art and art while the observational and data gathering phase is the science of toxicology the prediction and estimation of risk is the art of toxicology for example the extrapolation of data from animal testing to human beings is considered the art of toxicology there are some key terms that we should be familiar with poison is any agent capable of producing
• 01:00 - 01:30 a deleterious or adverse effect or response toxins are toxic substances that are produced by biological systems such as plants animals fungi and bacteria toxicant refers to toxic substances produced by human activities such as industrial contaminants diesel exhaust emissions and so on toxicity is the intrinsic toxic property of any agent
• 01:30 - 02:00 xenobiotic is any foreign material that is found within an organism dose is the amount of a substance administered to an organism and of course a toxicologist is a scientist who studies the adverse effects of xenobiotics all substances are poisons there is none which is not a poison the right dose differentiates a poison from a remedy paracelsus said this
• 02:00 - 02:30 he is considered one of the fathers of toxicology and formulated many revolutionary toxicological views including the concept of dose now dose is an important construct in toxicology because virtually every known chemical has the potential to cause injury or death depending on the dose this table illustrates the importance of the concept of dose the table lists the dose required to cause death in fifty percent of exposed animals
• 02:30 - 03:00 this is referred to as the ld50 or lethal dose at fifty percent and is measured in milligrams per kilogram body weight for example the ld50 for ethyl alcohol is 10 000 milligrams per kilogram body weight which is quite high on the spectrum of doses required for ld50 hence are relatively less toxic on the other hand you have the toxicant but linum toxin a naturally occurring toxin which has an ld50 of
• 03:00 - 03:30 0.0001 milligrams per kilogram body weight and thus considered extremely toxic don't forget that the ld50 is a measure of acute toxicity or acute lethality and therefore not a measure of chronic toxicity for instance some less toxic substances do not produce any evidence of acute toxicity but may have carcinogenic properties and cause cancers many years after exposure
• 03:30 - 04:00 you too can be a toxicologist in two easy lessons but each of 10 years yes actually toxicology is quite a broad science integrating knowledge from many branches of science such as biochemistry biology and so on toxicological developments are due mainly to the theoretical expansion and technical improvements of such branches of science so modern toxicology applies safety
• 04:00 - 04:30 evaluation and risk assessment to the discipline and toxicologists are the scientists that explore the mechanisms by which chemicals produce adverse health effects the professional activities of toxicologists fall into three main categories these include descriptive mechanistic and regulatory each of these are distinct and they have their distinctive characteristics and each contributes to the other
• 04:30 - 05:00 but all are very important to chemical risk assessment toxicology is a very broad science that can be classified into several branches related to its discipline applications and functions and interconnections between different areas of toxicology understanding the mechanistic pathway of an agent is very important when conducting risk so mechanistic toxicology identifies the mechanisms that are responsible for
• 05:00 - 05:30 toxic effects while the descriptive toxicologist conducts experiments or for acute or chronic um and for chronic texas toxicity testing and tests procedures to provide toxicological data on a particular agent regulatory toxicology determines the risk levels of chemicals and establishes exposure standards for example for workplace chemicals drinking water and other exposure
• 05:30 - 06:00 standards as i mentioned before toxicology is a very broad science and a broad discipline and can be classified into several branches related to its applications these include clinical toxicology food and drug toxicology forensic toxicology occupational toxicology which is also known by its other term industrial toxicology environmental toxicology developmental toxicology reproductive toxicology and
• 06:00 - 06:30 the relatively new discipline which is nanotoxicology now this table provides definitions for each of these disciplines i i will not go into defining each of these but these are there for you to look at and study and know the definitions should you ever require them traditionally occupational exposures have played a significant role in the
• 06:30 - 07:00 occurrence of adverse health effects due to chemical and biological hazards hazards now from the traditional perspective we have to credit agricola and paracelsus as well as ramazini for starting this trend in occupational toxicology so for example agricola and paracelsus they determined toxic exposures in mining smelting and metallurgy while ramazzini who is also considered one of the fathers of industrial or other he's
• 07:00 - 07:30 actually considered the father of occupational health and occupational medicine and he determined occupational hazards for minors chemists metal workers tanners and many more do you think our workplaces today are safe yes but the level of risk considered acceptable has decreased over time and the recognition of the causal link of exposures to chronic diseases has increased in addition there are new hazards that
• 07:30 - 08:00 may arise with the emergence of new technologies such as nanotechnology so we really must be prepared to assess these potential new risks what about the interactions so again i'm interchanging using the occupational toxicology and changing it to industrial toxicology um and they mean the same thing occupational and industrial toxicology so industrial toxicology is the
• 08:00 - 08:30 application of the principles and methodology of toxicology to our understanding and management of chemical and biological hazards encountered at the workplace the industrial toxicologist must have an intimate knowledge of the work environment be able to recognize and prioritize hazardous exposures recognize multiple exposures in the workplace and evaluate the entire spectrum of exposures experienced by the workers for example
• 08:30 - 09:00 non-occupational exposures now the industrial toxicology itself as a discipline draws on occupational hygiene industrial epidemiology occupational medicine and regulatory toxicology now let's talk a little bit about these regulatory authorities for example in the us we've got the food and drug administration which are responsible for drugs cosmetics and food additives the environmental protection agency which regulates chemicals such as
• 09:00 - 09:30 agrochemicals toxic substances air pollutions you have the occupational safety and health administration primary responsibilities to ensure the safe and healthy conditions of the workplace and you've got the national institute for occupational safety and health and they're responsible for the prevention of work-related injury and illness what about regulatory authorities in australia well the main one is safe work australia
• 09:30 - 10:00 which was established in 2009 and they've got the leading responsibility for the development of policies to improve work health and safety in australia the second one is nicknas the national industrial chemicals notification and assessment scheme and nicknass aims to protect the health of public the general public workers and the environment from the harmful effects of industrial chemicals so nicknas is a
• 10:00 - 10:30 little bit more specialized looking at industrial chemicals now let's look at classification of toxic agents toxic agents can be classified based on what the classifier is looking at so you could base it in terms of target organs and here we could easily identify them as liver toxicants kidney toxicons hematopoietic toxicants that simply means blood and the blood system in terms of applications we could
• 10:30 - 11:00 classify them as pesticides solvents metals and in terms of effects we can classify them as carcinogenic or mutagenic and so on and lastly based on the source we can classify them as synthetic man-made toxicants or natural toxins which are produced by plants and animals toxic agents may also be classified in terms of their physical state such as solid gaseous or liquid states
• 11:00 - 11:30 chemical reactivity is another way of classifying them and this will be looking at the nature which could be explosive or flammable or an oxidizing nature the chemical structure such as inorganic and organic compounds aliphatic and aromatic hydrocarbons potential toxicity ranging from extremely toxic to little or no toxicity and lastly the mechanism of action and an example of this is the
• 11:30 - 12:00 cholinesterase inhibitor these are enzyme inhibitors another one is methymoglobin produces now there are some characteristics that are related to exposure itself for instance the root and site of exposure the root of the exposure can influence the toxicity the greatest effect and most rapid response of a toxic agent can occur when the chemical or toxicant is introduced
• 12:00 - 12:30 directly into the bloodstream for example intravenously in descending order of effectiveness after that direct intravenous root we have the inhalational root which is the most common indirect root of entry into the body others include intraperitoneal which is into the abdominal cavity subcutaneous which is just under the skin intramuscular intradermal which is just below the skin and into the soft tissues under the skin and oral and thermal
• 12:30 - 13:00 other exposure characteristics include duration and frequency of exposure for example in the case of occupational exposures both time and frequency of exposure are important parameters to be considered in the case of experimental animals usually exposure to chemicals falls into four categories acute subacute subchronic and chronic exposures now acute exposure is classified or
• 13:00 - 13:30 defined rather as exposure less than 24 hours and is often due to a single administration acute inhalational exposure refers to continuous exposure for less than 24 hours but most commonly for about 4 hours repeated exposure is divided into three categories subacute which refers to continuous exposure for less than one month subchronic between one and three months and chronic greater than three months
• 13:30 - 14:00 now the spectrum of undesired effects of chemicals is important it's another important concept and for example each drug may produce a number of effects but usually only one effect that is associated with the primary objective of that particular drug used for treatment this is considered the desirable effect so any other effect outside of the desirable effect is considered undesirable effect or side effects
• 14:00 - 14:30 now some side effects are always deleterious to human beings and then others and these are referred to as adverse deleterious or toxic effects and then others may have other beneficial effects now individuals may come in contact with a combination of different chemicals simultaneously due to medication occupational or environmental exposures diet and lifestyle factors and so different interactions such as
• 14:30 - 15:00 drug to drug interaction drug chemical interaction and chemical to chemical interaction is important now let's look at the types of undesired effects there are different types allergic reactions idiosyncratic reactions immediate versus delayed toxicity reversible versus irreversible and local versus systemic let's look at these quickly one by one now chemical energy is an
• 15:00 - 15:30 immunologically mediated adverse reaction to a chemical resulting from previous or prior sensitization to that chemical or another chemical with a similar structure so terms other terms such as hypersensitivity allergic reaction and sensitization reaction describe this allergic reaction once sensitization has occurred allergic reactions may result from exposures to
• 15:30 - 16:00 relatively minute doses of that particular chemical sensitization reactions are sometimes very severe and could even be fatal since the allergic response is an undesirable adverse effect it is also considered a toxic response chemical idiosyncrasy refers to genetically determined abnormal reactivity to a chemical the response observed is usually qualitatively similar to that observed in all individuals
• 16:00 - 16:30 but may take the form of extreme sensitivity to low doses or extreme insensitivity to high doses of a chemical for example some individuals are abnormally sensitive to nitrites and certain other chemicals which have the ability to oxidize the iron in the red blood cells to produce methymoglobin and this methymoglobin is incapable of carrying oxygen to the tissues and is therefore toxic
• 16:30 - 17:00 another type of toxic effect is the immediate versus delayed toxicity immediate toxicity effects occur or rapid or develop rapidly and usually after a single administration over substance or a single exposure to a chemical they do not produce delayed effects such as the effects irritant effects are produced by ammonia gas
• 17:00 - 17:30 some toxic effects of chemicals are reversible and others are irreversible if a chemical produces pathological injury or damage to a tissue the ability of that tissue to regenerate largely determines whether the effect is reversible or irreversible for the liver for example the liver has a very high regeneration ability and therefore most injuries to the liver are reversible however injuries to the central nervous system
• 17:30 - 18:00 are largely irreversible the differentiated cells of the central nervous system or the nervous system generally cannot be replaced or regenerated lastly carcinogenic and pterogenic effects um pterogenic simply means effects it affects the growing fetus of the growing baby in the womb these chemicals are also considered irreversible an important distinction between types
• 18:00 - 18:30 of undesired effects or toxic effects is based on the site of toxic action local effects occur at the site of first contact between the biological system and the toxic substance for example irritation and corrosive effects of chemicals on the skin systemic effects in contrast require absorption and distribution of the toxicant from its entry point to the distant site where its deleterious effects are produced
• 18:30 - 19:00 most substances except highly reactive materials or chemicals produce systemic effects for some materials or chemicals both local and systemic effects can be observed for example in the case of tel which is tetraethyl lead you can observe both effects most chemicals that produce systemic toxicity usually elicit their major toxicity in only one or two organs and these are referred to as the target
• 19:00 - 19:30 organs the target organ toxicity is often not the site of the highest concentration of the chemical for example lead is concentrated mostly in the bone but its toxicity is due to its effects in the soft tissues particularly the brain target organs that are more frequently involved in systemic toxicity include the central nervous system the circulatory system that's blood and bone marrow and in specific organs such as liver
• 19:30 - 20:00 kidneys lungs and the skin as well now this slide presents some examples of workplace chemicals and their associated systemic toxicity it's a good idea to know some of these i won't go into details about these but you have neurotoxic chemicals hepatitis hematotoxic which is blood hepatotoxic nephrotoxic and pulmonary toxicity cs2 is carbon disulfide tel tetratyle
• 20:00 - 20:30 lead ops organic phosphates c6h6 is benzene ccl4 is carbon tetrachloride and tdi is toluene diisocyanate chemical interactions now chemical interactions um as individuals come across various chemicals due to their workplace medication diet etc it's
• 20:30 - 21:00 necessary to consider how different chemicals may interact with each other in our body we have different effects these include one the first one is the additive effect now the additive effect is the combined effect of two chemicals where their effect is summative and this is illustrated mathematically by two plus three is equal to five for example exposure to organophosphates and pesticides will result in the
• 21:00 - 21:30 additive cholinesterase enzyme activity inhibition the synergistic effect which is another important effect that we should be aware of is the combined effect of two or more chemicals where that combined effect is far greater than the sum of each individual chemical mathematically this is illustrated as 2 plus 2 is equal to 20. for example both carbon tetrachloride and ethanol are hepatotoxic chemicals
• 21:30 - 22:00 but together they produce a markedly higher toxic effect than individually potentiation is where one substance has no toxic effect on any certain organ or system but when that substance is added to another chemical it makes that particular chemical much more toxic so this is mathematically illustrated by zero plus two is equal to 10. an example of this is
• 22:00 - 22:30 isopropanol which is not hepatotoxic but it can increase the hepatic or the liver toxicity of carbon tetrachloride when they're exposed together the last interaction is antagonism here what happens is when two chemicals are administered together they interfere with each other's actions or activities and this can be mathematically represented by four plus six is equal to eight uh and what happens here is that here
• 22:30 - 23:00 uh the chemicals are interfering with each other's actions and therefore diminish uh diminishing the combined toxicity an example is using chelating agents to decrease metal toxicity tolerance is a term that refers to the state of decreased responsiveness of the body to a toxic effect of a chemical resulting from a previous exposure to
• 23:00 - 23:30 that chemical or a structurally similar one and there are two major mechanisms responsible for the development of tolerance the first is a decreased amount of the toxicant reaching the site of the effect and this is called dispositional tolerance second is a reduced responsiveness of a tissue to that chemical now we're going to discuss the concept of dose response relationship dose response relationship is one of the
• 23:30 - 24:00 most important and fundamental concepts of toxicological risk assessment this relationship is applied to quantitatively characterize the relationship between exposure and the degree of a specific response or a specific endpoint such as death upon increasing a dose the number of affected individuals would be expected to increase in the exposed population as there are differences in individual
• 24:00 - 24:30 susceptibility to toxic effects this variation of responses exhibits a normal distribution as shown on the diagram in the right the top diagram so normally you'll have a few individuals who respond to the lowest possible doses and a few individuals will only respond to very high doses the rest or the majority will respond to the median or the intermediate doses and therefore the maximum response you'll always find is in that median or intermediate
• 24:30 - 25:00 zone however instead of the frequency response curve which is which always looks like a bell curve or a normal shaped curve the cumulative dose response curve is what is used in toxicology and this is usually a sigmoid shaped curve and that's illustrated on the right hand side the bottom graph this is the cumulative rear dose response relationship at lower doses there is no adverse
• 25:00 - 25:30 health effect observed but as the doses increase the number of individuals affected starts to increase so the range of increasing effect with increasing dose starts to rise quickly at higher doses which is the maximum effect range every single individual will be affected so from the dose response relationship depending on the end point of measure there are several different um
• 25:30 - 26:00 important concentrations that can be determined so these include the ld50 which is the lethal dose 50. and i've mentioned this previously it's the dose that will cause 50 percent um fatality in the exposed population now lc50 is similar to ld50 but only applies to airborne toxicants or airborne chemicals so it's the concentration of an air toxicon that will produce 50 fatality in
• 26:00 - 26:30 an exposed population the no observed adverse effect level is the highest dose below the threshold point at which you will observe uh an adverse effect or rather that at which no adverse effect are detected so you have a threshold value above which you will detect an adverse effect um and then you have below that threshold value is the no observable address effect level so based on that um principle
• 26:30 - 27:00 the lowest observed adverse effect level will be the lowest level just above that threshold point at which you will observe an adverse effect now here's a couple of examples of ld50 and ld60 or lc50 rather formaldehyde is a toxic chemical used as a disinfectant or a biocide and in the manufacture of resins and adhesives it's also an indoor air pollutant
• 27:00 - 27:30 now the acute toxicity for this chemical is an oral ld of 50 in rats it's about 800 milligrams per kilogram body weight and this means that if this dose of formaldehyde is orally administered to a group of rats it'll cause death in half of those animals now the inhalational lc50 in rats is 590 milligrams per cubic meter of air and this means that if a group of rats
• 27:30 - 28:00 are exposed to this concentration of airborne formaldehyde for a specific time usually four hours half of those animals will die so lethality or fatality is one of the most important endpoints that's determined in toxicological studies but there are other endpoints that we should be aware of so we know about the lethal dose which is the test where the response is actually death
• 28:00 - 28:30 but you also have a toxic dose where the response that you obtain is an undesirable effect or a side effect other than death such as liver injury now the effective dose is quite different in that this is actually a desirable effect that we're looking for and an example is um anesthesia so inhalational anesthesia if you you want the desired effect of numbing or putting
• 28:30 - 29:00 a person to sleep and that's a desired effect so that's the effective dose so we can say that the affected dose is usually less toxic than the toxic dose which is in turn less toxic than the lethal dose another important concept that we should be aware of is the slope of the curve now the ld50 for both chemicals chemical a and chemical b is almost the same but if you look at
• 29:00 - 29:30 the slope of that dose response curve for those two it's quite different so for chemical a a flat dose response curve shows that a large change in dose is actually required before a significant change in response is observed but for chemical b which has a steep dose response curve a relatively small change in those can cause a large change in response so the slope of the curve is a concept that you should keep in mind
• 29:30 - 30:00 when looking at different chemicals the therapeutic index or ti is an approximate statement about the relative safety of a drug or chemical and is expressed as the ratio of the lethal dose or the toxic dose to the effective dose so the ti would be equal to the ld50 divided by the ed50 of the chemical so imagine if the ed50 of a drug is
• 30:00 - 30:30 approximately 20 and the ld50 is 200 the therapeutic index would be 200 divided by 20 which is 10 and that number is indicative of a relatively safe drug the last concept we'll look at is the margin of safety now the median or the middle or the intermediate doses that i mentioned earlier in the normal bell curve indicates nothing about the slope of the dose response curves for therapeutic and
• 30:30 - 31:00 toxic effects and so to overcome this deficiency instead of the median dose the ed99 is used for the desired effect and the ld1 for the undesired or toxic effect and this is used to calculate the margin of safety such that the margin of safety is equal to the ld1 divided by the ed99 of that particular chemical or drug for non-drug chemicals such as workplace chemicals for example the term margin of
• 31:00 - 31:30 safety is an indicator of the magnitude of the difference between an estimated exposure dose to a human population and the no observed adverse effect level determined in experimental animals so in this week's lecture we have covered the basic principles of toxicology and looked at some of the fundamental concepts in toxicology