Poisons are quantitative concepts depending on dosage. Xenobiotics are exogenous environmental chemicals (air, water, food, soil) that may be absorbed via inhalation, ingestion or skin contact. Most solvents and rungs are lipophilic, easing transport through the plasma membrane. Xenobiotics undergo phase I reactions (hydrolysis, oxidation, reduction) usually via cytochrome P-450 (CYP) in the liver; phase II reactions (glucuronidation, sulfation, methylation, conjugation) to make water solube to be excreted. The reactions may detoxify or activate compounds to cause cellular injury. Byproducts of the reaction may releast ROS.
- Ozone (O3) from industrial or vehicle exhaust injures respiratory tract type 1 alveolar cells. Affects asthma, emphysema.
- Particulate matter (soot) – <10μm most harmful where they are phagocytosed in the alveoli, induce inflammation. Larger particles are removed by the nose or mucociliary epithelium.
- Carbon monoxide (CO) – Lethal coma within 5min of suicide involving average car in closed garage. Higher affinity than oxygen for haemoglobin (carboxyhaemoglobin), reducing oxygen carrying capacity. Acute poisoning causes cherry-red skin, oedematous brain, punctate haemorrahge.
- Lead – Lead paints (older houses), leaded gasoline, contaminated toys, mining, batteries. Maximal allowed blood level 10μg/dL. Higher absorption and CNS-sensitivity in children 80-85% incorporated into bone and developing teeth where it competes with calcium. High levels disrupt neutrotransmitters in brain, if wevere causes oedema, demyelination (peripheral in adults), cortical necrosis. Reduces remodeling of cartialge and primary bone trabeculae in epithyses, causing metaphyseal densities (lead lines). Inhibits healing of fractures with delayed cartilage mineralisation. Suppressed haemoglobin synthesis with mirocytic hypochromic anaemia. Lead colic from GIT.
- Mercury – Contaminated fish (inorganic mercury from earth’s crust converted to organic methyl mercury by bacteric entering and concentrating in food chain), mecury in dental amalgams, gold mining. Developing brain is extremely sensitive.
- Arsenic – Interfers with mitochondria. Increase risk of cancers in almost all tissues, esp lungs and skin.
- Cadmium – Mining, electroplating, nickel-cadmium batteries. Contamination of food. Obstructive lung disease (necrosis of alveolar macrophages) and renal damage which may progress to end-stage renal disaese, calcium loss with skeletal changes.
- Organic solvents – Benzene (rubber workers) increases risk of AML.
- Hydrocarbons – Fossil fuels, steel workers, tar and soot (chimney sweeps). Lung and bladder cancer.
- Organochlorines – DDT (dichlorodiphenyltrichloroethane, pesticide), PCM (polychlorinated biphenyls), dioxin. Anti-oestrogenic and anti-androgenic activity.
- Mineral dusts – Coal dust, silica, asbestos, beryllium. Pneumoconioses.
- Vinyl chloride – Liver angiosarcoma
Nicotine increases HR, BP, addiction. Tobacco has >60% carinogens. Increase risk of emphysema, chronic bronchitis, atherosclerosis, MI, peptic ulcers. Cancers of the lung, lip, mouth, pharynx, oesophagus, pancreas, bladder, kidney, cervix. Cigarette smoking causes 90% of lung cancers. Smokeless tobacco (snuff, chewing tobacco) increases oral cancer. Maternal smoking increases spontaneous abortions, preterm births, IUGR.
50% of Western world drinks alcohol, 5-10% have chronic alcoholism. Legal limit for driving in NZ (>/=20yo) is 80mg/100mL (blood) or 400mcg/L (breath). Drowsiness occurs at 200mg/100mL, stupor at 300. Higher levels tolerated by chronic alcoholics (increased ethanol metabolism). Most ethanol transformed to acetaldehyde by liver alcohol dehydrogenase (ADH) and other enzymes. 50% of Asians have very low ADH levels. Acute alcoholism causes reversible hepatic steatosis (fat droplets in hepatocytes), acute gastritis, ulceration, CNS depression. Chronic alcoholism caues heaptitis, cirrhosis, gastritis, ulcers, thiamene deficiency (peripheral neuropathies, Wernicke-Korsakoff syndrome), congestive cardiomyopathy, HTN, acute and chronic pancreatitis, fetal alcohol syndrome. Cnacer of the oral cavity and oesophagus (acetaldehyde esp with smoking), liver, breast.
(Adverse drug reactions, ADRs).
- Hormone replacement therapy (HRT) – Most contain oestrogens and progesterone. Oestrogen alone increases uterine cancer (hence only used in those with hysterectomy). Increased risk of breast cancer (esp lobular), thromboembolism (esp 1st 2yrs). Protective atherosclerosis/CAD <60yo.
- Oral contraceptives – Increased risk of thromboembolism, CAD, endometrial and ovarian cancers, hepatic adenoma.
- Anabolic steroids – Inhibits LSH/FSH and increaeses oestrogens. Stunted growth in adolescents, gynaecomastia, testicular atrophy, hirsutism, hepatic cholestasis.
- Acetaminophen (paracetamol) – Overdose caues hepatocellular injury, centrilobular necrosis and liver failure.
- Aspirin (acetylsalicylic acid) – Chronic aspirin toxicity (salicylism) >3g/day causes HA, tinnitus, hearing impairment, N/V/D, acute erosive gastritis, petechial haemorrhages, analgesic nephromathy (esp with acetaminophen).
Drugs of Abuse
- Cocaine – Snorted or injected IV/SC; crack is pure form which is heated to produce vapors for inhalation (far more potent). Intense euphoria, symathomimetic causing raised HR, HTN, vasoconstriction, MI, arrhythmias, spontaneous abortion. Chronic use may cuase perforated nasal septum (if snorted), reduced DLCO (if inhaled), dilated cardiomyopathy.
- Heroin – Opioid derivative related to morphine, usualy injected IV/SC. Induces euphoria, hallucinations, sedation. May be cut/diluted with quinine which is toxic to CNS, kidneys, auditory. May cause sudden death, respiratory depression, arrhythmia, cardiac arrest, severe pulmonary oedema, endocarditis (esp tricuspid S.aureus) with septic emboli, opportunistic infections, HIV, foreign-body granulomas from talc (lung, but also spleen, liver, LN), renal amyloidosis, focal glomerulosclerosis.
- Methamphetamine (speed, meth) – Induces dopamine release in the brain with euphoria followed by a ‘crash’. Cuases violence, confusion, psychotic paranoia/hallucinations.
- MDMA (ecstasy) – Increased serotonin with increased effect of dopamine and euphoria, hallucinogen. May be spiked with other drugs (meth, cocaine).
- Marijuana (pot, Cannabis, THC tetrahydrocannabinol) – Antinausea (eg chemotherapy), analgesia (esp difficult to treat chronic pain), sensory perception distortion, psychomotor impairment, tachycardia ± increased BP. May cause laryngitis, pharyngitis, bronchitis, cough, hoarseness, mild airway obstruction, carcinogens.
- Chronic vapor inhalation of paints, pain thinners, toluene glues causes dementia.
- Abrasion – Scraping or rubbing with removal of the superficial layer.
- Contusion (bruise) – Damage to vessels with extravasation of blood.
- Laceration – Tear/disruptio of tissue from blunt trauma. Most have intact bridgning vessels and jagged, irregular edges.
- Incision – Sharp trauma with severed bridging vessels.
- Puncture – Long narrow instrument. Penetrating when pieces the tissue, perforationg wwhen traverses a tissue to create an exit wound.
- Thermal burn – Superficial (previously 1st degree) confined to epidermis; partial thickness (2nd degere) involves dermis; full-thickness (3rd degree) extends into subcutaneous tissue with anaethesia (destroyed nerve endings), may also damage underlying muscle (4th degree). The greater the area, the increased risk of shock, sepsis, respiratory insufficiency.
- Hyperthermia – Heat cramps from loss of electrolytes (sweating) with muscles cramps. Heat exhaustion is collapsed due to failued cardiovascular compensation for hypovolaemia. Heat stroke is failed thermoregulatory mechamisms leading to core temperature >40deg, multi-organ dysfunction, hyperkalaemia, tachycardia, arrythmias, rhabdomyolysis.
- Hypothermia – Vasoconstriction and increased vascular permeability with oedema and hypoxia, infarction.
Current may cause ventricular fibrillation, bruns at entry and exit as well as internal organs (if long enough). Alternatic current (AC) induces tetanic muscle spasm, with irreversible clutching, spasm of chest wall muscles.
Biological effect depends on dose, rate of delivery, field size, cell proliferation (rapidly dividing cells more vulnerable esp gonads, marrow, lymphoid, GIT mucosa), hypoxia (reduced effect due to less ROS), vascular damage (leading to stenosis/occlusion, impaired healing, fibrosis, ischaemic atrophy moths-years later). Radiation causes ionisation with reactive oxygen species, chromosomal structural changes, apoptosis. Initially vessels are dilated, then endothelial swelling and vacuolation, necrosis, rupture or thrombose, endothelial proliferation, collagenous hyalinisation with thickened media, intestitial collagen with scarrign and contractions, stenoses. At high dosease lymphopenia occurs within hours with shrinkage of LN and spleen, regeneration after weeks-months. Dose-dependent haematopoietic precursor stem cell injury with transient or permanent aplastic anaemia. Initial rise in granulocytes before falling by end of the week, near zero by second week. Fibrosis in irradiated field weeks-months later from replacement of dead parenchymal cells, esp lungs, salivary glands, colorectal and pelvic regions.
Protein Energy Malnutrition (PEM)
Inadequate intake of proteins and calories, or deficiency in digestion/absorption; defined as BMI <16 kg/m2 or weight <80% normal for age/height/sex.
- Marasmus – Weight <60% with loss of muscle from catabolism, with only marginal reduction in visceral protein compartments, hecne serum albumin normal/minimally reduced, T-cell immune deficiency, anaemia, vitamin deficiencies.
- Kwashiorkor is protein deprivation > calorie deprivation esp children weaned too early and fed exclusively carbohydrates. Causes loss of viscelra protein compatrment leading to hypoalbuniaemia and generalised oedema, relative sparing of subcutaneous fat and muscle mass, fatty liver.
- Cachexia – In AIDS or advanced cancers esp GI, panreatic, lung cancers. Mortality from atrophy of diaphragm and respiratory muscles. Protein and lipids mobolised due to agents produced by tumours.
Vitamin Deficiencies and Toxicities
Vitamins A, D, E and K are fat soluble, more easily stored, but may be poorly absorbed in fat malabsorption disorders. All other vitamins are water-soluble. Deficiencies may be primary (dietary) or secondary (poor absorption, transport, storage or metabolim).
- Vitamin A – Retinoids including retinol, retinal, retinoic acid. From preformed animal-derived foods (liver, fish, eggs, milk) and carotenoids from yellow and leafy green vegatables (esp β-carotene converted to retinol). Required for normal vision, cell growth/differentiation (deficiency -> ), metabolism, resistance to infection.
- Deficiency – Night blindness, epithelial keratinizing squamous metaplasia (causing dry eyes and conjunctiva, plaques, loss of respiratory mucociliary epithelium).
- Toxicity (hypervitaminosis A) – HA, dizziness, stupor, blurred vision, weight loss/anorexia, N&V. Stibulation of osteoclasts leading to bone resorption and fractures.
- Vitamin D – Mostly endogenous synthesis by conversion of precursor via UVB radiation forming cholecalciferol (vitamin D<sun>3, or ingested ergosterol -> D3; these are converted to 25-hydroxycholecalciferol in the liver then to 1,25-dihydroxycholecalciferol in the kidney (regulated by PTH/hypocalcaemia, hypophosphataemia). Activated vitamin D is esentially a steroid hormone, stimulating intestinal calcium and phosphate absorption, renal calcium reabsorption, stimulates osteoclasts (in presence of PTH), stimulates osteoblasts to mieralise bone (with phosphate). Hypocalcaemia increases PTH thus activating renal vitamin D activation (this increased calcium absorption), stimulates osteoclasts, increased renal calcium reabsorption and phosphate excretion; hypophosphataemia imapires mineralisation of bone.
- Deficiency – Rickets in children and osteomalacia in adults with excess unmineralised matrix. Overgrowth of physes with inadequate provisional calcification, distorted irregular masses of cartilage projecting into marrow cavities, excess unmineralised osteoid, enlargement and lateral expansion of the osteochondral junctions, overgrowth of capillaries and fibroblasts in disorganised zone with microfractures, skeletal deformities. Sofetening with flattening of the occipital and parietal bones, frontal bossing and quared head (excess osteoid), chest rachitic rosary (cartilage and osteoid costochondral overgrowth), pidgeon breast deformity (inward bending of rib metaphyses, anterior protrusion of sternum), lumbar lordosis, bowing of legs. Osteomalacia ith microfractures, insufficiency fractures. Hypophosphataemia due to phosphaturia (PTH stimulation), normal serum calcium (mobilisation from bones). Increased susceptibility to TB (Vitamin D for cathelicidin, antimicrobial peptide of the defensin family).
- Toxicity (hypervitaminosis D) – Excess oral ingestion. Metastatic soft tissue calcifications esp renal, bone pain, hypercalcaemia.
- Vitamin C (ascorbic acid) – Provides hydroxylation of procollagen for stable collagen more resistent to enzymatic degradation, esp blood vessels. Also acts as a antioxidant. Deficiency causes scurvy, with haemorrhages (gums, skin, subperiosteal, joints), inadequate synthesis of osteoid, impaired healing.
Particularly central obesity, there is increased risk of insulin resistance, hyperinsulinaemia, type 2 diabetes, hypertrigliceridemia, low HDL, CAD, NASH (may progress to fibrosis and cirrhosis), cholelithasis (increased cholesterol turnover with augmented biliary excretion of cholesterol), hypoventilation/pickwickian syndrome with hypersomnolence, osteoarthritis. Increased risk of adenocarcinomas of the oesophagus, thyroid, coon, kidney, endometrium, gallblader.
Diet and Cancer
- Exogenous carcinogens – Aflatoxin increases HCC esp with Hep B. Food additives, artificial sweeteners and pesticides are indeterminate.
- Endogenous synthesis from dietary components – Nitrosamines and nitrosamides from nitrites and amines in preservatives and common vegetables increase risk of gastric carcinoma.
- High animal fat and low fibre increases risk of colon cancer