acute toxicity

Definition of Acute Effects: Acute effects are those that occur soon after a brief exposure to a chemical agent.
- Can be a single exposure or multiple exposures within a short time frame (generally < 24 hours).
- Observable effects typically within the first few days after exposure, mostly within the first 2 weeks.
Chronic Effects: Appear only after repetitive exposure to a substance, requiring continual exposure over months.

Irreversible (covalent):
- Example: Inhibition of cholinesterase by organophosphate insecticides; lead inhibits sulfhydryl (-SH) containing enzymes.
- Example: Fluoroacetate (rodenticide) inhibits aconitase (enzyme in the TCA cycle) by substituting for its natural substrate, citrate.
Reversible (non-covalent):
- Example: Inhibition of cytochrome oxidase by carbon monoxide (CO) binding to the Fe in the heme group, blocking redox function.
Uncoupling of Biochemical Reactions:
- Example: Interference of ATP synthesis by dinitrophenol.
Removal of Metal Cofactors:
- Example: Dithiocarbamate (fungicide) binds (chelates) Cu²⁺ needed for enzymes such as alcohol dehydrogenase, increasing alcohol sensitivity.

Carbon Monoxide (CO) Poisoning:
- CO binds to hemoglobin and blocks O₂ binding.
Formation of Methemoglobin:
- Induced by aromatic amines and nitrates which promote methemoglobin formation (oxidized hemoglobin, Fe³⁺).
Hemolytic Processes:
- Release of hemoglobin from red blood cells due to damage, causing anemia. Can be produced by metals and plant toxins (e.g., saponins, gossypol).

Inhibition of Cell Division and DNA Replication:
- Example: Antibiotics such as actinomycin D and alkylating agents like pyrolizidine alkaloids (plant toxin).
Inhibition of Transcription (RNA from DNA):
- Example: Inhibition of RNA polymerase by antibiotics like rifampicin.
Inhibition of Translation (protein synthesis):
- Example: Inhibition by antibiotics like cycloheximide and mycotoxins (plant toxins).
Effects resulting from interference with DNA and RNA synthesis:
- a. Cytostatic Action: Decreased cell division and tissue growth.
- b. Immunosuppressive Action: Suppressed growth and function of immune cells, increasing infection risk (TCDD, PCBs, aflatoxin).
- c. Mutagenic Action: Chemically-induced DNA changes due to agents like polycyclic hydrocarbons.
- d. Carcinogenic Action: Biological response leading to uncontrolled cell proliferation (growth).

Sensitization: Increased sensitivity to a xenobiotic (chemical or biotoxin) due to repeated exposure.
- Xenobiotic (hapten) reacts with immunogenic protein forming specific antibodies. Subsequent exposures may cause allergic reactions (e.g., penicillin, plant proteins).

Causes local effects on mucous membranes, typically strong reactive chemicals.
- Examples include chemical dermatitis (chloracne) from organochlorines and irritating gases like SO₂ (air pollutant).

The nervous system is highly susceptible to toxic chemicals due to its complexity.

Anesthetic Action:
- Accumulation of toxicants in lipid membranes of nerve cells, inhibiting O₂/nutrient transport (e.g., alcohol, ether).
Interference with Neurotransmission:
- The nervous system is organized into:
  - Central Nervous System (CNS): Brain and spinal cord.
  - Peripheral Nervous System (PNS): Connects CNS to the rest of the body.
- Nerve cells (neurons) transmit signals in one direction through synaptic transmission using neurotransmitters.

Approximately 10¹⁰ neurons exist with significant support cells in the CNS. Neurons are interconnected, creating vulnerability to damage.

Functions rely on precise binding of chemical transmitters to receptor sites; chemicals can mislead systems, causing toxicity.

Limited detoxifying enzymes are present in the nervous system (e.g., mixed function oxidases).

Neurons cannot metabolize anaerobically; oxygen deprivation can lead to irreversible damage.

Blood-Brain Barrier:
- Composed of endothelial cell tight junctions, preventing many chemicals' penetration into the brain.
- Some small and lipid-soluble molecules can penetrate.
Cerebrospinal Fluid:
- Provides separation from potentially harmful molecules in the blood.
Redundancy and Plasticity:
- Brain can compensate for damage, with intact regions taking over lost functions.

Rest State: Neuron membrane is polarized (-70 mV).
- More potassium flows out than sodium comes in due to permeability differences.
Signal Transmission:
- Upon stimulus, sodium channels open, allowing Na⁺ influx, causing depolarization and action potential propagation (upswing to +30 mV).
- Repolarization occurs via potassium efflux.

Moves unidirectionally due to refractory periods and opening/closing of ion channels.

At the presynaptic terminal, Ca²⁺ channels open, leading to neurotransmitter release (e.g., acetylcholine [ACh]) which binds to receptors on the postsynaptic neuron, inducing signal transfer.

Sodium Channels:
- Essential for action potential generation.
- Effects include increased Na⁺ influx by substances like DDT and pyrethroids.
- Toxins like tetrodotoxin block Na⁺ channels externally.
Calcium Regulatory Mechanisms:
- Essential for transmitter release; disruption leads to major neural dysfunctions.
Acetylcholine Mechanisms:
- Includes toxics such as botulinum toxin, which prevents ACh release leading to paralysis.

Acetylcholine Receptors: Recognize ACh, with agonists such as nicotine stimulating ion influx.
GABA Receptors: Mediate inhibition via chloride channels; disruption leads to heightened neuronal activity.
- Examples of pesticides affecting GABA include cyclodiene types.
Organophosphate Effects: Inhibit acetylcholinesterase (AChE), increasing ACh levels and causing over-excitation.

Unique structure with components affecting motor and sensory neurons, reducing muscle contractions and pain.