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Toxicology 1 Introduction
This picture describes the basic concepts of toxicology, toxicological research fields and methods and their applications in other medicines, and a brief history of toxicology. I hope it can help everyone!
Edited at 2024-02-12 16:53:07- One Hundred Years of Solitude Character Relationship Chart
One Hundred Years of Solitude is the masterpiece of Gabriel Garcia Marquez. Reading this book begins with making sense of the characters' relationships, which are centered on the Buendía family and tells the story of the family's prosperity and decline, internal relationships and political struggles, self-mixing and rebirth over the course of a hundred years.
- One Hundred Years of Solitude Character Relationship Chart
One Hundred Years of Solitude is the masterpiece of Gabriel Garcia Marquez. Reading this book begins with making sense of the characters' relationships, which are centered on the Buendía family and tells the story of the family's prosperity and decline, internal relationships and political struggles, self-mixing and rebirth over the course of a hundred years.
- Project Management Process Template
Project management is the process of applying specialized knowledge, skills, tools, and methods to project activities so that the project can achieve or exceed the set needs and expectations within the constraints of limited resources. This diagram provides a comprehensive overview of the 8 components of the project management process and can be used as a generic template for direct application.
Toxicology 1 Introduction
- One Hundred Years of Solitude Character Relationship Chart
One Hundred Years of Solitude is the masterpiece of Gabriel Garcia Marquez. Reading this book begins with making sense of the characters' relationships, which are centered on the Buendía family and tells the story of the family's prosperity and decline, internal relationships and political struggles, self-mixing and rebirth over the course of a hundred years.
- One Hundred Years of Solitude Character Relationship Chart
One Hundred Years of Solitude is the masterpiece of Gabriel Garcia Marquez. Reading this book begins with making sense of the characters' relationships, which are centered on the Buendía family and tells the story of the family's prosperity and decline, internal relationships and political struggles, self-mixing and rebirth over the course of a hundred years.
- Project Management Process Template
Project management is the process of applying specialized knowledge, skills, tools, and methods to project activities so that the project can achieve or exceed the set needs and expectations within the constraints of limited resources. This diagram provides a comprehensive overview of the 8 components of the project management process and can be used as a generic template for direct application.
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- Outline
Toxicology 1 Introduction
1. Overview of Toxicology
toxicology
Comprehensive science that studies the damaging effects, mechanisms of action and prevention measures of exogenous factors (chemical, physical, biological factors) on organisms and environmental ecosystems. It is not a beneficial effect (such as nutrition, therapeutic effect)
modern toxicology
Using poisons as tools and based on experimental medicine and therapeutics, it has developed into a science that studies the damaging effects of chemical, physical and biological factors on the body and environmental ecology, biological mechanisms, risk assessment and management
xenobiotics
Chemical substances that exist in the external environment of human life, may come into contact with and enter the body, and exhibit certain biological effects in the body
endogenous chemicals
Products or intermediates that already exist in the body and are formed during metabolism
effect
forward
Arsenic → cure leukemia
reverse
poison
Toxicology basic functions x2
Detect the nature of harmful effects of environmental factors (hazard identification function)
Evaluate the likelihood of toxicity under specific exposure conditions (risk assessment function)
Toxicology basic tasks
Toxicity found
Mechanism research
scientific management
field of study
Describe toxicology
definition
Apply basic principles and methods of toxicology to explore the damaging effects of exogenous chemicals on organisms. Use cell and animal models to directly study toxicity, describe and identify it, provide information for safety evaluation and risk management; provide important clues for the study of toxic mechanism
means
Animal and plant experiments
object
Humans, animals, plants and factors that may disrupt the balance of the ecosystem
Task
Discover, describe and identify toxicities
Purpose
Obtain risk information for safety evaluation and management
Mechanistic Toxicology
Explain how chemicals produce toxic effects
Purpose
Build sensitive predictive tests
Safety evaluation of chemicals
Design and produce safe chemicals
Chemical Disease Diagnosis and Treatment
research focus
The cellular, biochemical and molecular mechanisms by which chemicals produce toxic effects on organisms
The main purpose
Develop an antidote (sodium nitrite-sodium thiosulfate)
Confirmed toxic effects (organophosphorus) found in humans and experimental animals
Exclude toxic effects (saccharin) that have nothing to do with humans and are only seen in experimental animals
Develop and produce safer drugs and guide rational clinical use of drugs (thalidomide)
Old medicine repurposed to treat poisoning (PAS-Na)
Further deepen the understanding of related basic subjects (tetrodotoxin)
Pathogenesis
Detoxification mechanism
regulatory toxicology
Purpose
Make scientific decisions based on toxicology research data
Assist government departments in formulating regulations and management measures
Ensure that chemicals entering the market are safe enough
The purpose of protecting human health and the ecological environment
Way
Standardized management of toxicology experimental methods and procedures
Good Laboratory Practice (GLP) Laboratory
3Rs principle
Substitution, reduction, optimization principles
Research Methods Model→Prototype
Experimental Study
in vivo test
For testing general toxicity
type
acute toxicity test
Subacute toxicity test
Subchronic toxicity test
Chronic toxicity test
in vitro test
definition
Toxicological research using free organs, cultured cells or organelles is mostly used for preliminary screening of acute toxic effects in the body and in-depth research on mechanisms of action and metabolic transformation processes.
population research
Clinical observation of toxicity
Volunteer trials (controlled clinical studies)
Low concentration, short time, mild, reversible
Epidemiological Investigation
descriptive epidemiological survey
Propose a hypothesis about the cause, understand the known cause and understand the severity
analytical epidemiological investigation
Test hypotheses and determine cause-and-effect relationships
experimental epidemiological research
advantage
Contact conditions are real
Provide more direct and reliable information than animal testing
shortcoming
Most observed chronic toxic effects
Indicators are non-specific
Multiple factors work together, making it difficult to determine cause and effect.
2. Application of toxicology in other branches of medicine
clinical application
As a reference for clinical diagnosis
Increase awareness of toxic hazards (fluoroalkane)
Improve clinical diagnosis and treatment levels
Application of Toxicology in Preventive Medicine
Application of Toxicology in Environmental Health
Elucidate the causes of high incidence of disease (lung cancer)
Monitor and evaluate environmental quality
Toxicity assessment and safety evaluation
An important means of formulating environmental health standards
Application of Toxicology in Occupational Health
Identify occupational hazards
Evaluation, prediction and control of occupational harmful factors
Application of Toxicology in the Field of Food Hygiene
3. Basic concepts of toxicology
1. toxicant / poison
Under certain conditions, smaller doses of substances can damage the body
Under certain conditions, small doses of chemicals entering the body can interfere with normal biochemical processes or physiological functions, cause temporary or permanent pathological changes, and even life-threatening chemicals.
purpose of classification
Helps to understand the properties of poisons
Help develop regulations
Helps with poison management
Contributes to toxicological research
Classification
According to the distribution range of uses
Industrial poisons, environmental pollutants, toxic ingredients in food, hobby products (daily chemicals), agricultural chemicals, biotoxins, medical drugs, military poisons, radioactive substances
chemical structure physical and chemical properties
Aromatic amines, gases, halogenated hydrocarbon chemicals, liquids, dusts
Toxicity level
Drama, high, low, mild, non-toxic
Physiological and biochemical mechanisms
Sulfhydryl inhibitor, ferritin former
Main parts of action
Hepatotoxicants, renal toxicants
biological effects
Carcinogens, teratogens
2. Poisoning
Refers to a disease state that occurs after an organism is affected by poisons and causes functional or organic changes.
Acute: once or multiple times within 24 hours
Subacute: ≤1 month
Subchronic: about 3 months
Chronic: ≥6 months
3. Toxicity
Chemicals can damage the body’s inherent abilities
level
Drama, high, low, mild, non-toxic
Factors affecting toxicity
Determining factor: dose
Important factors: Physicochemical properties (chemical structure), route of exposure, rate and frequency
4. Toxic effect (toxic effect)
Harmful biological changes in the body caused by poisons or drugs
Toxic effects refer to undesirable or harmful biological changes caused by the interaction between the chemical substance itself or its metabolites at the site of action, where they reach a certain amount and stay for a certain period of time, and the macromolecular components of the tissue, so it is also called an adverse reaction, damage effect or damaging effect ( PPT)
How is it produced?
Biologically active
Reach target site
Amount of achievement, duration effect
Interact with target molecules
Change the microenvironment
Influencing factors
chemical factors
body factors
environmental conditions
combination of compounds
Classification
Time of occurrence
acute toxic effect
Toxic effects that occur in a short period of time (2W) after one or more exposures to chemicals in a short period of time (24 hours)
chronic toxic effect
Slowly toxic effects of long-term or lifelong exposure to small doses of chemicals
delayed effect toxic
After the body is exposed to a chemical substance, the symptoms of poisoning are absent or the symptoms of poisoning seem to have recovered, and the toxic effects appear after a certain period of time.
Such as CO and organophosphorus pesticide poisoning; exposure to dust for 20 years, pneumoconiosis
Immediate effect toxic
Toxic effects that occur within a short period of time after the body comes into contact with chemicals
remote toxic effect
After chemicals act on the body or stop contact, toxic effects that are different from the pathological changes of poisoning will occur after several years.
site of occurrence
local toxic effect
Damage caused directly by certain exogenous chemicals at the contact site of the body
systemic toxic effect
Toxic effects caused by chemicals reaching other tissues and organs through blood circulation
Is it reversible?
reversible effect
The damage caused can gradually recover after exposure to the chemical ceases. Seen in low dose, short time, and mild damage
irreversible effect
After stopping exposure to chemicals, the damage cannot be restored and may even worsen. Depends on regeneration capacity
biological effects
Hypersensitivity is allergic reaction
Hapten Endogenous protein = Antigen Antibody = allergic reaction
For allergic reactions caused by chemicals at low doses, it is difficult to observe a dose-response relationship. Various expressions
A pathological immune response produced by the body to foreign chemicals.
idiosyncratic reaction
Abnormal reactions to certain chemicals due to genetic factors. related to genetic polymorphisms
Patients who are congenitally deficient in NADH-cytochrome b5 reductase activity are abnormally sensitive to chemicals that can cause methemoglobinemia (such as nitrites). Due to a mutation in codon 127, protulin AA replaces protofilament AA and loses activity.
5. Biological effects of chemicals on the body
non-adverse effect
Features
The biological changes that occur are temporary and reversible
Does not cause changes in body shape, growth, development and lifespan
Does not reduce the body's ability to maintain homeostasis
Does not reduce the ability to compensate for additional stress conditions
Does not affect changes in body functional capacity indicators
Does not increase the body's susceptibility to harmful environmental factors
Performance
Compensatory capacity is normal
Functional capacity remains unchanged
Biochemical indicators are normal
No pathological damage
Normal shape and development
Lifespan is not shortened
adverse effect
Features
Changes are permanent, reversible or irreversible
Changes in body functional capacity, load capacity, etc.
Decreased ability to maintain homeostasis in the body
Reduced ability to compensate for additional stress states
Increased susceptibility to other harmful agents
Performance
Reduced stress capacity
dysfunction
biochemical changes
Pathological damage
die
6. Spectrum of toxic effects
Effects range from subtle abnormal changes in physiological and biochemical normal values to overt clinical manifestations of intoxication, up to death. Changes in the nature and intensity of toxic effects constitute the toxic effect spectrum of chemical substances
A series of toxic effects caused by chemical substances coming into contact with the body
include
Increased load of the body on exogenous chemicals
Physiological and biochemical changes of unknown significance
subclinical changes
clinical poisoning
die
4. Biological markers
definition
Detection indicators used for chemicals and their metabolites that enter tissues or body fluids through biological barriers, as well as the biological effects they cause, are divided into three categories: exposure, effect and susceptibility biological markers (biomarkers, biological markers)
effect
Accurately determine the actual level of chemical exposure of the body
Facilitates early detection and prevention of specific damage
Elucidate the mechanism of toxic action
Establish dose-response relationships
Performing inter-species extrapolation of toxicological data
Illuminating the relationship between toxic exposure and health damage
Classification of biological markers
1. Biomarker of exposure (biomarker of exposure)
It is the measurement of chemical substances and their metabolites present in various tissues, body fluids or excreta, or their reaction products with endogenous substances, which can provide information on exposure to chemical substances.
Classification
In vivo dose markers
It can reflect the content of specific chemicals and their metabolites in the body, that is, the internal dose or target dose.
biological effect dose symbol
It can reflect the content of reaction products formed by the interaction between chemical substances and their metabolites and certain tissue cells or target molecules. Helps accurately establish dose-response relationships
2. Biomarker of effect
It can detect abnormalities in the body's physiology, biochemistry, behavior, etc. or pathological and histological changes, and reflect information on the harmful health effects related to different target doses of chemicals or their metabolites.
early biomarkers
Changes produced at the molecular level after chemicals interact with tissue cells
Structural and/or functional change effect markers
Cause tissue and organ dysfunction or morphological changes
biological markers of disease effects
Causes subclinical or clinical manifestations in the body, often used for screening and diagnosis of diseases
3. Biomarker of susceptibility
An indicator that reflects the body's sensitivity to the toxic effects of chemicals. Genetic factors play a very important role
Mainly used for screening and monitoring of susceptible groups, and taking effective measures for targeted prevention
5. Dose and dose-response relationship
dose
Refers to the amount of a chemical substance that the body is exposed to or the amount of a test substance given to the body in an experiment (external dose), or the amount of a chemical substance absorbed into the blood (internal dose) or the amount that reaches the target organ and interacts with it (target dose, biologically effective dose)
Exposure dose (external dose)
It refers to the exposure dose of exogenous chemicals to the body, which can be a single exposure or exposure to a certain concentration for a certain period of time.
absorbed dose
A dose in which a foreign chemical crosses one or more biological barriers and is absorbed into the body
Delivered dose Target dose Biologically effective dose
Refers to the dose of exogenous chemicals and/or their metabolites that reach the target (such as tissues, cells) after absorption
effect graded effect
Biological changes caused by contact of chemicals with the body, which can be expressed by some measurement value
response qualitative effect
The proportion of individuals in the exposed population that undergo biological changes after exposure to a certain dose of a chemical. Expressed as a percentage (%) or ratio
dose-response relationship
Represents quantitative effect-intensity relationships between chemical dose and ontogeny
dose-quality response relationship
Represents the relationship between chemical dose and qualitative effect-incidence rate in a certain population
6. Dose-response curve
Dose-dose response curve format
Represented by a curve, a curve is obtained by drawing a scatter plot with the measurement unit representing quantity-reaction intensity or the percentage representing quality-reaction as the ordinate and dose as the abscissa.
type
S-shaped curve
definition
It is a typical dose-response curve, which is mostly seen in the dose-mass-response relationship. It is divided into two forms: symmetric S-shaped curve and asymmetric S-shaped curve. Whether it is a symmetric or asymmetric S-shaped curve, the slope is maximum at 50% response rate, and the relationship between dose and response rate is relatively constant. The dose that causes a 50% reaction rate is often used to express the toxicity of a chemical substance. Such as LD50
Classification
Symmetrical S-shaped curve
When the differences in sensitivity of all individuals in a population to a certain chemical substance are normally distributed, the relationship between dose and response rate is a symmetrical S-shaped curve.
Asymmetrical S-shaped curve
The distance at which the curve changes from gentle to steep is shorter at the left end of the abscissa, and the curve stretches longer at the right end. Indicates that as the dose increases, the response rate changes in a skewed distribution
straight line
Changes in chemical dose are directly proportional to changes in reaction
interference curve
Toxic effects can interfere with the curve. In some toxicity studies, there is an "all or nothing" dose-response relationship, where the effect occurs over a narrow dose range and is a linear dose-response relationship with an extremely steep slope.
parabola
A curve that is steep at first and then gentle is similar to a logarithmic curve in mathematics, also known as a logarithmic curve. Convert the dose to logarithm and this curve can be transformed into a straight line
Conversion of dose-response curves
In order to more accurately calculate important toxicological parameters such as LD50 and obtain the slope of the curve, it is necessary to convert the S-shaped curve into a straight line
Change the reaction rate on the ordinate to reaction frequency, and convert the symmetric S-shaped curve into a Gaussian curve. Under this distribution curve, the dose that causes half of the subjects to respond is regarded as the median dose, and several standards are divided based on this, including within 1, 2 or 3 standard deviations on both sides of it. 68.3%, 95.5% and 99.7% of the total subjects
7. Selective toxicity
A chemical substance only causes damage to certain organisms, tissues and organs, and is harmless to other types of organisms, tissues and organs.
Causes of Selective Toxicity of Chemical Substances
Species and cytology differences: e.g. plants, bacteria
Differences in biological transformation processes: such as bacteria and mammals
Different tissues and organs have different affinity to substances: such as CO and the herbicide paraquat
Differences in the ability of different tissues and organs to repair damage caused by substances: such as brain tissue, liver, kidney
8. Toxicity parameters and safety limits
Toxicity parameters
Lethal dose (upper limit parameter)
1. Absolute lethal dose (LD100)
The lowest dose or concentration of a chemical required to cause death in all test subjects. Due to individual differences, LD100 often has great fluctuations
2. Median lethal dose LD50
A dose or concentration that causes the death of half of the experimental animals in a group of subjects
3. Minimal lethal dose (MLD or LD01)
The dose of a chemical that causes death in individual members of a test subject. Theoretically, doses below this level cannot cause death
4. Maximum tolerance dose (MTD or LD0) Maximum non-lethal dose
The highest dose at which a chemical does not cause death in a test subject. LD0 is affected by individual differences and has large fluctuations.
Lower limit parameter
1. The lowest observed adverse effect level (LOAEL)
Refers to the lowest dose of an exogenous chemical that causes certain harmful effects on the body (human or experimental animals) under specified exposure conditions.
2. No observed adverse effect level (NOAEL) maximum no-effect dose (ED0) (lower limit parameter)
The highest dose at which a chemical does not cause detectable harmful effects in the body under specified exposure conditions. Only the no-observed adverse effect level (NOAEL) can be determined
Notice
For the same chemical, different LOAELs and NOAELs will be obtained using different species of animals, exposure methods, contact times and observation indicators.
Specific experimental conditions should be noted when expressing these two toxicity parameters.
LOAEL and NOAEL are not static
3. Threshold
NOAEL or NOEL is usually used as an approximation of the threshold
What are the commonly used indicators of toxicity: upper limit parameter ←
LD0 and LD100 are often used as the basis for selecting dose ranges in acute toxicity tests.
Median lethal dose (LD50/LC50)
Indicates the magnitude of acute toxicity
The smaller the LD50 value, the more toxic it is
The larger the LD50 value, the lower the toxicity
Factors affecting LD50
Chemical type
species of animal
laboratory environment
Feeding conditions
time of exposure
Route of exposure
Test substance concentration
Solvent properties
experimenter technique
Zac（LD50/Lim ac）
LD84/LD16
dose-response curve slope
Threshold dose Minimal effect level (MEL)
The lowest dose required for a chemical to cause the slightest abnormal change in a small number of subjects, divided into acute and chronic
Classification
acute threshold dose (Limac)
Result from one contact with chemicals
chronic threshold dose (Limch)
Income from repeated exposure over a long period of time
toxic effect zone
One of the important parameters indicating the toxicity and toxic effects of chemical substances. It is divided into acute toxic effect zone and chronic toxic effect zone.
Classification
acute toxic effect zone (Zac)
Zac=LD 50/Lim ac (median lethal dose/acute threshold dose)
chronic toxic effect zone (Zch)
Zch=Lim ac/Lim ch (acute threshold dose/chronic threshold dose)
safety limits
That is, health standards are the limit requirements for harmful factors in environmental media, including allowable daily intake (ADI), threshold limit value (TLV) and reference dose (RfD), etc.
Safety limit = NOAEL/safety factor, the latter is the product of the difference between species (×10) and the difference between individuals (×10)
safety limit effect
It is an important part of the national health regulations promulgated
It is the basis for the management department to implement health supervision and management.
It is a criterion for proposing prevention and control requirements and evaluating improvement measures and effects.
Factors to consider when choosing a safety factor
Acute toxicity level of chemicals
Accumulation capacity and volatility in the body
Observation indicators for measuring LOAEL or NOAEL
Consequences of chronic poisoning
Species and individual differences
Are the poisoning mechanism and metabolic process clear?
Acceptable daily intake (ADI)
The total amount of a specific chemical substance that a normal adult is allowed to take into the body from the external environment on a daily basis. At this dose, lifelong daily intake of this chemical does not pose any measurable health hazard to human health
Maximum allowable concentration (MAC)
The highest concentration at which a foreign chemical can exist in the environment without causing any harmful effects to the human body
Threshold limit value (TLV)
The vast majority of workers are repeatedly exposed on a daily basis to concentrations that do not cause harmful effects. Due to differences in individual sensitivity, it is not ruled out that a small number of workers may experience discomfort, worsening of previous diseases, or even suffer from occupational diseases at this concentration.
Reference dose (RfD)
An estimate of the average daily exposure dose to a chemical in the environmental medium. The expected lifetime risk of non-carcinogenic or non-mutagenic harmful effects in a population exposed to this level of chemical substances over a lifetime is so low as to be undetectable
Potency and Efficacy
Used to compare the toxic effects of two or more chemicals
Intensity refers to the difference in dose for equal effects. Equal effects, the smaller the dose, the greater the intensity
Efficacy is the difference in effect, and the maximum effect Emax represents the level of efficacy. Depends on the inherent activity and toxic effects of the chemical itself
9. Past, present and future of toxicology
Alternative experimentation (3R)
Alternatives (3R) refer to substitution, reduction, and refinement, including bacterial culture, human and mammalian cell tissue culture, specific animal organs, non-biological artificial systems, or computer analysis programs.
Replacement and update of toxicological methods (3R principle)
The first "R" is Replacement
Use simple biological systems such as cultured bacteria, mammalian and human tissues, cells, special animal organs or non-biological construction systems to replace animal testing.
The second “R” is to reduce the number of animals used (Reduction)
On the premise of ensuring the quality of the experiment, select appropriate animals and methods, improve the experimental design, and reduce the amount of animals used.
The third "R" is refinement and improvement technology (Refinement)
Try to reduce unnecessary pain and harm to animals during the experiment.
Add a new R principle
The fourth “R” responsibility (Responsibility)
To enhance people's ethical concepts, they should not only be responsible for animals, but also for humans, and ensure that after various products enter the market, they will not cause harm to consumers under normal and foreseeable conditions of use.
extrapolation from experimental animals to humans
The effects of chemicals on experimental animals can be extrapolated to humans.
Experimental animals must be exposed to high doses and are a necessary and reliable method to detect potential harm to humans.
Possible exposure routes for adult healthy (male and female non-pregnant) laboratory animals and humans are basic options
Basic hypothesis of extrapolation from experimental animals to humans
Humans are the most sensitive animal species
Biological processes in humans and experimental animals include the metabolism of chemicals, which are related to body weight (or body surface area)
It is the premise of all experimental biology and medicine
Uncertainty in extrapolating animal experiments to humans Reasons
Animals cannot report toxic effects involving subjective feelings
The dose of poison is higher than the actual dose to which people are exposed
From small numbers of experimental animals to large numbers of people
Diversity in contact with people
The basic purpose of toxicity evaluation tests
Manifestations and properties of toxic effects of test substances
Dose-response (effect) studies
Determine the target organ of toxic effects
Determine reversibility of damage
Toxicology research progress and introduction of new knowledge
Environmental Genome Project
Toxicogenomics/Proteomics
systems toxicology