Develop new chemicals with high efficiency and low toxicity

Speculate the toxic mechanism of new chemicals

Predicting the toxic effects of new chemicals

Predicting safe exposure limits for new chemicals

benzene

Isomers have different biological activities

Toxicity of benzene ring compounds with two groups: para position > ortho position > meta position

Certain enzymes and receptors have stereoconfiguration specificity, which may be affected at all stages of biotransformation.

Enzymes often interact with their substrates in a highly stereo- and enantioselective manner, and different isomers may be metabolized in different ratios

Methane and ethane: noble gases

Propane: anesthesia, fat solubility

CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH3

Alkanes, alcohols, ketones and other hydrocarbons

molecular saturation

Solid chemicals (the greater the water solubility of the homologue, the greater the toxicity)

Gaseous chemicals (water solubility affects its site of action)

Large fat/water partition coefficient

Small fat/water partition coefficient

Hydrophilic small molecules (<200)

Ionic compounds (small ions)

1Influence the activity of chemicals

2 Affects the depth of entry into the respiratory tract

3 Affect the solubility entering the respiratory tract

Highly volatile liquid chemicals easily form vapor and are easily inhaled through the respiratory tract

Reduce exposure dose after volatile compounds are added to feed

Transdermal absorption of liquid substances, high volatility, low harm

The LC50 values ​​of benzene and styrene are both 45mg/L, that is, their absolute toxicity is the same. Benzene is easy to volatilize, and the volatility of styrene is only 1/11 of benzene. It is difficult for styrene to form high concentrations in the air. In fact, it is more Benzene is much less harmful.

The larger the blood/gas distribution coefficient, the easier it is for gaseous substances to be absorbed into the blood across the respiratory membrane through simple diffusion.

It is known that the blood/gas distribution coefficients of ethanol, ether, carbon disulfide, and ethylene are 1300, 15, 5, and 0.4 respectively, so (ethanol) is the most easily absorbed?

In a closed, long-term airless space, toxic gases may stratify due to different specific gravity.

The toxic smoke of a fire is relatively light, so you should crawl on your stomach to escape.

Ionization degree: refers to the pH value when a chemical is 1/2 ionized and 1/2 non-ionized, that is, the pKa value of the chemical

Chargeability: affects air chemical deposition and respiratory tract obstruction

(1) Anatomical and physiological differences

(2) Differences in metabolism

(3) Genetic differences between species

genetic polymorphism

Metabolic enzyme polymorphisms

Individual differences in repair function

Receptor and toxicity specificity and sensitivity

Health status

gender

age

nutritional status

lifestyle

Changes in ambient temperature can cause varying degrees of changes in physiological, biochemical systems and internal environment stabilization systems, such as changes in ventilation, circulation, body fluids, intermediate metabolism, etc., and affect the absorption, metabolism, and toxicity of chemicals.

High temperature causes animal skin capillaries to dilate, blood circulation and respiration to accelerate, gastric juice secretion to decrease, sweating to increase, and urine output to decrease. Increased absorption of chemicals absorbed through the skin and respiratory tract; decreased absorption through the gastrointestinal tract, increased sweat excretion, and decreased urinary excretion.

Effects of 58 compounds on rat LD50 at different environmental temperatures (8℃, 26℃ and 36℃)

High humidity can cause heat dissipation to be easy in winter and difficult to dissipate in summer, increasing the load on the body's body temperature regulation. High humidity and high temperature can reduce the evaporation of sweat, increase the hydration of the skin's stratum corneum, further increase the absorption rate of percutaneously absorbed chemicals, and prolong the contact time because chemicals tend to adhere to the skin surface.

Generally little change. An increase in air pressure often affects the concentration of atmospheric pollutants, and a decrease in air pressure can increase the toxicity of CO due to lower oxygen partial pressure.

Toxins can enter the body through different routes. Due to different pathways, poisons undergo different processes in the body, which also has a significant impact on the effects of poisons.

Rate of absorption by various exposure routes

Acute, subacute, subchronic and chronic exposure

For many exogenous chemicals, the toxicity of acute high-dose exposure is different from that of low-dose exposure over a longer period of time. Generally, the former can cause immediate toxicity or delayed toxicity. Repeated exposure may cause acute effects in addition to low-level or chronic effects after each dose.

Test compounds are often dissolved or diluted in solvents, and sometimes co-solvents are used. You must be careful when choosing solvents and co-solvents because some solvents or co-solvents can change the physical and chemical properties and biological activities of the compounds.

The solvent or co-solvent selected should be non-toxic and unreactive with the test compound, and the test compound should be stable in solution.

Example: During the teratogenicity test, it was found that the solvent DMSO itself has teratogenic effects. Some solvents can also react with the test poison, changing the chemical structure of the test poison, thereby affecting the toxicity. For example, when propylene glycol is used as a solvent, it can react with dichlorvos and dibromophosphorus.

The volume of test poison administered orally does not generally exceed 2-3% of body weight. The intravenous dose for rats is <0.5ml, and for larger animals is 2ml. Excessive volume may affect toxicity.

Excessive volume of water-soluble poison → excess water in the body

When vegetable oil is used as a solvent, the volume is too large → diarrhea, which reduces the absorption of poisons.

Concentrated solutions are absorbed faster than dilute solutions and have stronger toxic effects. At the same dose, high concentrations cause more deaths.

In toxicological tests, especially during skin contact and respiratory tract contact with foreign compounds, attention should be paid to preventing cross-contact and absorption of compounds.

A certain dose of exogenous chemicals can cause severe poisoning when administered to animals all at once. If administered several times, it may only cause mild or even no toxic effects.

Circadian rhythm is controlled by certain regulatory factors in the body

Adjusted by external environmental factors such as food, light, etc.

Seasonal differences related to animal hibernation response or climate

1. Addition joint action

2. Independent action

The combined effect of alcohol and vinyl chloride

Difference Between Addition of Responses and Addition of Dose

1. Synergistic effect

2. Potentiation joint action

3. Antagonistic joint action

definition

The formation mechanism of electrophiles

definition

Characteristics of free radicals

Types of free radicals

Nucleophile: An electron-rich atom, molecule, or group that has no tendency to acquire electrons, but has the ability to donate electrons. Nucleophile formation is a less common mechanism of poison activation.

Formation of redox reactants