Industrial Chemicals and Toxicants Study Notes

Historical Context: Occupational diseases became prevalent during the Industrial Revolution; specific industries carry unique risks, including mining (silicosis), asbestos work (asbestosis and mesothelioma), and paper/printing (skin diseases).
Exposure Routes: Primary routes are inhalation and skin contact affecting workers exposed to gases, vapours, aerosols, solvents, dusts, and fibres.
General Toxic Effects: Exposure can lead to allergic reactions, respiratory diseases, contact dermatitis, skin cancer, and kidney damage (e.g., from uranium dioxide).

Industrial Applications: Used in alloys, plating, batteries, and pigments for inks, paints, plastics, rubber, and enamel.
Absorption: Poorly absorbed from the gut ( $5\text{--}8\%$ ), but up to $40\,\%$ of an inhaled dose is absorbed, making cigarette smoke a significant source.
Toxic Effects:
- Chronic: Primarily causes kidney damage.
- Acute: Can cause testicular damage and lung irritation/damage.
- Carcinogenicity: Linked to testicular tumours and tumours at exposure sites in animals.
Itai-Itai Disease: Occurred in Japan due to rice contaminated with cadmium; characterized by osteomalacia and brittle bones (calcium metabolism disorders).

Kidney Accumulation: Cadmium accumulates as a complex with the protein metallothionein, a low molecular weight protein involved in metal transport.
Pathways:
- Due to similarity to zinc, cadmium induces metallothionein production ( $80\text{--}90\,\%$ of cadmium is bound to it in vivo).
- The complex is filtered by the glomerulus and reabsorbed by proximal tubular cells.
- Proteases degrade the complex, releasing cadmium that damages cells or recombines with more metallothionein.
Testicular Damage: Occurs via effects on vasculature; cadmium reduces blood flow, leading to ischaemic necrosis and loss of spermatozoa.
Persistence: The half-life of cadmium in the body is between $7$ and $30$ years, excreted primarily via kidneys.

Selective Toxicity: Designed to be toxic to specific organisms while ideally sparing others (e.g., warfarin is effective against rats because they lack a vomit reflex).
Metabolism Example: Malathion is safely hydrolyzed in mammals to an acidic metabolite, but in insects, it is oxidized to malaoxon, which inhibits cholinesterase.
Classification: Grouped by target as insecticides, fungicides, herbicides, and rodenticides.
Exposure Sources: Accidental food contamination, occupational exposure in agricultural workers, and improper use or lack of protection during spraying.

Background: Replaced organochlorine insecticides like DDT due to lower environmental persistence, despite being up to $100$ times more toxic to mammals.
Mechanism of Action: Inhibits the enzyme acetylcholinesterase ( $AChE$ ) by mimicking the neurotransmitter acetylcholine ( $ACh$ ).
Physiological Effect: The organophosphorus compound binds to the enzyme, preventing the hydrolysis of $ACh$ . Accumulation of $ACh$ leads to excessive nerve stimulation.
Toxicity Levels: In mammals, $50\,\%$ inhibition of total body $AChE$ leads to toxic effects; $80\text{--}90\,\%$ inhibition is lethal.
Symptoms: Headaches, nightmares, salivation, increased tear formation, diarrhoea, and lung passage constriction; death usually results from neuromuscular paralysis and central depression.

Historical Context: Recognized as a poison since Hippoocrates (circa $300$ BC).
Primary Sources: Car exhausts (from tetraethyl lead), lead-based paint, leaded petrol, lead-glazed cooking vessels, batteries, and cigarette smoke.
Population Susceptibility: Children are more susceptible as they absorb higher amounts from the gastrointestinal tract; traffic policemen have higher blood lead levels due to exhaust exposure.
Distribution: After absorption, $97\,\%$ of lead is taken up by red blood cells (half-life $2\text{--}3$ weeks); it eventually redistributes to the liver, kidney, or is deposited in hydroxyapatite crystals in bone and teeth.

Nervous System Impact: A major target, especially in children, leading to encephalopathy, mental retardation, seizures, and cerebral palsy.
Biochemical Markers:
- ALAD Inhibition: Inhibition of aminolaevulinic acid dehydrase ( $ALAD$ ) is the most sensitive measure of exposure.
- Clinical Correlation: At blood levels of $0.4\,\mu g/ml$ , $ALAD$ is inhibited by $50\,\%$ . At $1\text{--}2\,\mu g/ml$ , encephalopathy occurs.
- Urinary ALA: The detection of aminolaevulinic acid ( $ALA$ ) in urine is the most useful diagnostic method for poisoning.
Haem Synthesis: Lead interferes with ferrochelatase, aminolaevulinate synthetase ( $ALAS$ ), and $ALAD$ , resulting in anaemia.
Physical Signs: Chronic exposure indicators include skeletal changes in children (bands on long bones), a "lead line" on the gums, and interstitial nephritis.
Organic Lead: Triethyl lead (from tetraethyl lead combustion) is lipid-soluble, absorbed through skin, and causes rapid-onset delusions, hallucinations, and ataxia.