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MindMap Gallery Medicine-General toxic effects mind map

Medicine-General toxic effects mind map

This is a mind map about general toxic effects in medicine, which mainly includes acute toxic effects, local irritation effects, short-term, subchronic and chronic toxic effects, etc.

Edited at 2023-12-02 22:02:27

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Medicine-General toxic effects mind map

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Outline

General toxic effects

Overview

General toxicity: The body's non-specific toxic reaction to exogenous chemicals, which is a concept corresponding to special toxicity (carcinogenesis, mutagenicity, teratogenesis, reproductive and developmental toxicity, etc.).

Purpose: 1. Observe the manifestation and nature of the toxic effects of exogenous chemicals 2. Conduct dose-response (effect) relationship studies 3. Determine the target organs of toxic effects 4. Determine whether the damaging effects are reversible

Extrapolate the results to others

Assess the hazards and risks of exogenous chemicals to humans

acute toxic effects

1. The concept of acute toxicity

It refers to the short-term health damage and fatal effects that occur after the body (human or experimental animal) is exposed to a certain dose of an exogenous chemical once or multiple times within 24 hours.

No more than 3 times within 24 hours, and there is a certain time interval, such as the interval between intragastric administration > 4 hours

2. Purpose of acute toxicity test

1. Determine the lethal dose of poisons and other acute toxicity parameters 2. By observing the symptoms of animal poisoning and death, preliminarily evaluate the toxic effect characteristics of poisons on the body, target organs, dose-response (effect) relationship and the risk of damage to the human body. 3. Provide exposure dose design basis for subsequent subacute, subchronic and chronic toxicity test studies and other toxicological tests, and provide basic data for the selection of observation indicators 4. Provide preliminary clues for toxicological mechanism research

Other toxicity parameters: Absolute lethal dose/concentration (LD100) / (LC100) Minimum lethal dose (MLD or LD01) Maximum non-lethal dose (MNLD or LD0) Maximum tolerated dose or concentration (MED/MTC) Lowest observed adverse effect level (LOAEL) No observed adverse effect level (NOAEL)

3. Key points of acute toxicity test methods

(1) Classic acute toxicity test

1.Basic method

Animal: Usually rodents are used (rats preferred)

Dose groups: at least three groups of medium, high and low, usually 5-7 groups, where obvious toxicity and mortality can be observed, a dose-effect curve is generated, and the LD50 is calculated

Animal gender: generally both, each group has at least 5 animals of the same gender

Observation indicators: changes in skin, coat, eyes and mucous membranes, respiration, circulation, autonomic nervous system and central nervous system, changes in limb activities and behavioral patterns, body weight (measured before exposure, weekly after exposure, and at death), Anatomical observation and recording of lesions, histopathological examination

2.Calculation method of LD50

curve fitting method

Interpolation

Modified Kou's method

Horn's method

3. Disadvantages and limitations of classic acute toxicity tests

1. Use a large amount of animals

2. The information obtained is limited (death is only one of many observation endpoints, death is rapid, and target organ lesions are difficult to display)

3. LD50 is only an approximate value and is affected by many factors, so the measured value fluctuates greatly.

(2) Acute toxicity surrogate test

1.Limited test

When the toxicity of the test substance is very low

Rodents (rats and mice), half male and half male, intragastric dose >10g/kg body weight or = maximum available concentration/maximum intragastric volume, observed continuously for 14 days, if no death occurs, the acute toxicity tolerance dose is greater than the exposure dose . If death occurs, try another method.

2. Fixed dose method

Fixed dose: 5, 50, 300 or 2000mg/kg

3. Acute toxicity classification test method

Several groups of animals (three per group, choosing the female or more sensitive sex) are tested with one of several doses: 5, 50, 300, 2000 mg/kg body weight (if necessary, the dose can be increased to 5000 mg/kg )

4. Up-down method

Death is the end point, and sequential dosing is used, with only one animal used at each step, and the dose depends on the survival of the previously dosed animal.

(3) Observation of acute toxic effects

Poisoning manifestations: respiratory system, genitourinary system, digestive system, nervous system, skin and hair, mucous membranes, eyes, etc.

Start, End, Weekly Weighing

Record the time, degree, duration of abnormality, death events, and estimate target organs

All animals were grossly dissected, gross pathological changes were recorded, and histopathological observations were made.

4. Acute toxicity classification

GHS: Oral: <5 extremely toxic; <50 highly toxic; <300 moderately toxic; <2000 low toxicity; actually non-toxic GHS: Skin: <50 extremely toxic; <200 highly toxic; <1000 moderately toxic; <2000 low Toxic; actually non-toxic GHS: Gas: <100 extremely toxic; <500 highly toxic; <2500 moderately toxic; <5000 low toxicity; >5000 actually non-toxic

local irritation

If the in vitro skin corrosion test is positive, it does not need to be done

1. Skin irritation test

Including single or multiple skin irritation tests, intact skin and damaged skin irritation tests

skin irritation

Reversible local inflammatory changes after skin contact/application of test substance

skin corrosion

Irreversible local tissue damage after skin contact/application of test substance

No skin irritation test required

1. Strong acids and bases. 2. Strong transdermal absorption (transdermal LD50<200mg/kg). 3. In the acute dermal toxicity test, skin irritation still occurred at doses up to 2000 mg/kg.

2. Eye irritation test

Prerequisite: In vitro skin irritation/corrosion test negative

Eye irritation

Reversible inflammatory changes on the surface of the eyeball after contact with the test substance

Eye corrosive

Irreversible tissue damage caused by contact with the test object on the surface of the eyeball

Test method: Rabbit eye irritation test (Draize test): The test substance is dropped into the conjunctival sac of one eye of each test animal in one dose, and the other untreated eye is used as a self-control. Observe the irritation and corrosion effects on rabbit eyes within the specified time, and score according to the specified grading standards.

Observation indicators: conjunctiva (redness, bulbar conjunctival edema, secretions); cornea (degree of turbidity, extent); iris (hyperemia, swelling, pericorneal hyperemia)

Observation period: sufficient to evaluate the reversibility and irreversibility of stimulating effects (usually 7 days, which can be extended to 21 days if necessary)

Alternative experiments: 1. Use experimental animal tissue instead of rabbit eyes (fertilized chicken egg chorioallantoic membrane CAM) 2. Hemolysis test to detect cell membrane damage 3. Detect hemoglobin denaturation (the corneal transparency becomes lower, that is, protein denaturation) 4. Cytotoxicity test (Primary cultured cells from target organs, non-eye tissue cells) 5. Biological model replacement/other non-biological testing methods

3. Skin allergy test

Skin allergy, also known as allergic contact dermatitis or skin sensitization, is an immunogenic skin reaction of the skin to chemicals.

Immunogenic response of the skin to chemicals

1. Partial closed skin coating method 2. Guinea pig maximum test (GPMT) 3. Regional lymph node test

Divided into two steps: induced contact and stimulated contact (P145)

Induced exposure: repeated exposure to the skin with a low or medium concentration of test substance. This stage generally takes 10-14 days. Provocative exposure: After an interval of 10-14 days, treat the uninfected skin area with a provocative dose of test substance lower than the induction dose.

Human body: itching, erythema, edema, papules, blisters, fused blisters, etc.; Experimental animals: erythema or edema, etc.

Short-term, subchronic and chronic toxic effects

I. Overview

(1) Accumulation effect

When exogenous chemicals enter the body continuously and repeatedly, and the rate or total amount of absorption exceeds the rate or total amount of metabolic conversion and excretion, the chemical may gradually increase and be retained in the body. When exogenous chemicals enter the body continuously and repeatedly, and the rate or total amount of absorption exceeds the rate or total amount of metabolic conversion and excretion, the chemical may gradually increase and be retained in the body.

Toxicological significance: it is the basis for chronic poisoning

material accumulation

After the body is repeatedly exposed to chemicals, chemical analysis methods can be used to detect the accumulation of its original form or metabolites in the body.

function accumulation

Undetectable, but corresponding chronic toxicity may occur

Tolerance is one of the manifestations of accumulated toxicity. It is generally believed that tolerance occurs when the poison is affected and has an obvious reaction.

(2) Basic concepts

Short-term toxic effects/repeated dose toxic effects/subacute toxic effects: Toxic effects produced by experimental animals or humans being exposed to exogenous chemicals for 14 to 30 days.

Preliminary determination of NOAEL and LOAEL

(The rodent repeated-dose oral toxicity test stipulates that the exposure period is 28 days)

Subchronic toxicity: Poisoning effects caused by continuous and long-term exposure of experimental animals/humans to exogenous chemicals (1/10 life cycle)

Basically determine NOAEL and LOAEL

Rodents 90 days

Chronic toxicity: Toxic effects caused by long-term exposure of experimental animals/humans to exogenous chemicals

Rodents at least 12 months/lifetime

(3) Test purpose

1. Observe the spectrum of toxic effects, toxic effect characteristics and target organs of long-term exposure to the test substance; 2. Explore the toxicity mechanism of the test substance; 3. Observe the reversibility of the toxic effects of long-term exposure to the test substance; 4. Determine the effects of long-term exposure to the test substance. The dose-response (effect) relationship of toxic effects, determining the no-observed adverse effect level ((NOAEL)) and the lowest level of observed adverse effects ((LOAEL)), provides a reference for formulating safety limits for human exposure 5. Observe the differences in the toxic effects of different animals on the test substance to provide a basis for determining the appropriate safety factor and extrapolating the test results to humans.

2. Research methods

(1) Short-term toxicity and subchronic toxicity

1. Selection of experimental animals

(1) Species and strains

(2) Gender, age, number of animals

(3) Animal microbial levels and feeding conditions

2. Route of exposure and period of exposure

Once a day, give continuously/give 5 or 6 times a week

Oral (feeding/gavage), respiratory tract (2 to 6 hours a day), and injection exposure

3. Dose selection and grouping

At least 3 dose groups, 1 negative control group

The dose refers to LD50 and actual human intake, and the dose interval is reduced by 2 to 4 times.

1. Short-term toxicity data of the same animal strain and the same exposure route (10%~25% LD50 is the high-dose group, and the lowest-dose group is more than 3 times the human intake)

2. Drugs, 10, 30, 100 times the intended dosage in rats. Non-rodent: 5, 15, 50 times. Food, covering 100 times the expected human intake

4. Observation indicator selection

The scope of observation indicators in short-term repeated dose tests is broadened, and subchronic toxicity tests focus on observing meaningful and sensitive endpoints and toxic damage indicators.

5. Observation time

(2) Chronic toxicity test

1. Experimental animals and exposure routes

2. Selection of dose and duration of exposure

(3) Result evaluation

Comprehensive analysis of all observation and test results, comprehensive application of theoretical methods of toxicology, statistics, biology and other related disciplines for evaluation, combined with the results of acute toxicity tests, genetic toxicity tests and reproduction tests, as well as possible human data and epidemic Medical survey data

Provide toxicological basis for risk management of hazardous chemicals