A/50-52 ENVIRONMENTAL CAUSES OF DISEASE (Leiel)

Question 1

Effect of tobacco

• Whys of consuming tabaccco?
• Annually deaths
• List some tobacco smoke constituents

Answer 1

• The most common exogeneous cause of human cancers
• Cigarette smoking, smokeless tobacco (snuff, chewing)
• Cigarette smoking causes 4 million death annually
• Tobacco smoke constituents:
  • Tar - Carcinogenesis
  • Polycylic aromatic hydrocarbo - Carcinogenesis
  • Nicotine - Ganglionic stimulation and depression, tumor promotion. ADDICTIVE!
  • Phenol - Tumor promotion, mucosal irritation
  • Benzopyerene - Strong carcinogenic (paper!!)
  • CO - Impaired o2 transport and utilization
  • Formaldehyde - Toxicity to cilia, mucosal irritation
  • Oxides of N - Toxicity to cilia, mucosal irritation
  • Nitrosamine - carcinogenesis

Question 2

What are the common carcinogenic effects of tobacco?

Answer 2

• Components of the smoke are potent carcinogens
• responsible for 90% of lung cancers
• Risk for lung cancer correlates with the number of cigarettes smoked per day
• tobacco is related to other cancers as well: oral cavity, esophagus, larynx, pancreas, urinary bladder.

Question 3

What are the vascular effects of tobacco?

Answer 3

tobacco, at its two forms, can cause Buerger’s disease:

• is a recurring progressive inflammation and thrombosis of small and medium arteries and veins of the hands and feet. Ulcerations and gangrene in the extremities are common complications.

Question 4

What are the respiratory effect of tobacco?

Answer 4

30-fold increase in risk for respiratory diseases

Chronic bronchitis! pathology:

• Goblet cell metaplasia in the bronchioles
• Mucous gland hyperplasia (Reid-index ↑)
• Mucous plugging in the small bronchi, bronchioles
• Smooth muscle hypertrophy
• Neutrophilic infiltrate accumulation
• Continuous inflammation, mucopurulent exudate
• Tissue destruction
• Fibrosis of the brochial wall
• Atrophy of the mucous membrane
• Permanent dilatation of the small bronchi (distal to the segmental bronci)
• Pulmonalsclerosis

emphysema: cigarette smoke → recruitment of leukocytes production → increased elastase → injury to the lung tissue → emphysema

Question 5

What are the tobacco effects on the gastointestinal ?

Answer 5

• erosions
• aggravates Crohn’s disease

Question 6

What are the tobacco effects on pregnancy?

Answer 6

• CO → fetal hypoxia
• increased risk for spontaneous abortions and preterm birth
• dysmaturity → small baby

Question 7

List the reasons for air pollution

Answer 7

• Outdoor air pollution
  
  • ozone
  • sulfur dioxide, particles and acid aerols
  • Carbon monoxide (CO)
• Indoor air pollution
  
  • Tobacco smoke, CO, NO, asbestos
  • Wood smoke
  • Randon
  • Bioaerols

Question 8

Ozone air pollution

Answer 8

the most intractable air pollutants, with levels that, in some cities, exceeds EPA standarts.

Formed by a sunlight driven reactions:

• Automobile exhaust → Nitrogen Oxides
• (NO)x + CO + fine particulate matter → smog (air pollution)

Its toxicity is related to the production of ROS which injures epithelial cells and type 1 alveolar cells in the respiratory tract.

Low levels of ozone are detrimental to lung function, especially in individuals with underlying lung disease.

Question 9

sulfur dioxide, particles and acid aerols air pollution

Answer 9

• Are emitted by coal and oil-fired power plants and industrial processes burning this fuels.

Particles are the most harmful components of this mixtures: those with a diameter of less than 10μm are the most harmful as they are able to reach the airspaces → phagocytosed by macrophages and PMNI → release of mediators → respiratory inflammatory reaction. Larger ones are removed in the nose

Question 10

Carbon monoxide (CO) air pollution

• Productions
• chronic poisoning
• acute poisoning

Answer 10

Productions: Automotive engines/home heating with oil/cigarette smoke/industries using fossil fuels → carbonaceous materials → imperfect oxidation → CO

chronic poisoning: low-level persistant exposure to CO → carboxyhemoglobin accumulation (Hg has higher affinity to CO than O2. Carboxy-Hg is a stable structure) → hypoxia → CNS depression

acute poisoning: is a consequence of accidental exposure or suicide attempt and is marked by characteristic generalized cherry-red color of the skin and mucous membrane. Hypoxia leads to neuronal changes and brain edema

Question 11

What are indoor air pollution?

Answer 11

Inside our homes.

• Tobacco smoke, CO, NO, asbestos
• Wood smoke: predisposes to lung infection. May contain carcinogenic polycylic hydrocarbon.
• Randon: radioactive gas derived from uranium. Occupational hazard
• Bioaerols: microbiologic agents causing infectious diseases (Legionnaires’ disease, viral pneumonia) or less severe symptoms (eye irritation, asthma) by mold, dust mites etc.

Question 12

Effect of alcohol

• Annual deaths
• Blood levels

Answer 12

• alcohol consumption is responsible for more than 100000 deaths annually: 50% are related to accidents caused by drunken driving, suicides etc and 25% are related to liver cirrhosis.
• consumption → ethanol absorption in the stomach and intestine → distribution in all tissues and body fluids in a direct proportion to blood level.
  
  • 80 mg/dL: legal definition of drunk driving
  • 200 mg/dL: drowsiness
  • Chronic alcoholism can tolerate levels of 700 mg/dL due to accelerated ethanol metabolism.

Question 13

Alcohol metabolism (enzymes, locations)

Answer 13

1. ethanol → acetaldehyde
   
   • In the liver, by 3 enzyme systems: alcohol DHG, catalase and cytochrome P450 isoenzyme. The 1^s enzyme, located in the cytosol, is the most important one.
   • The cytochrome P450 enzymes (mainly CYP2E1), located in the SER, participate in case of high blood ethanol levels.
2. acetaldehyde → acetate
   
   • Acetate is then utilized in the mitochondrial respiratory chain.

Question 14

Toxic effects of ethanol metabolism

Answer 14

Decrease of NAD:

• the 1st part of the metabolism goes along with NAD → NADH conversion. That means- NAD is consumed. As this is required for fatty acid oxidation in the liver, its deficiency leads to fat accumulation
• as this is required for lactate → pyruvate conversion, its deficiency leads to lactic acid accumulation.

ROS production: during the metabolism of ethanol by CYP2E1 → lipid peroxidation of cell membrane

Release of endotoxin from the gram- bacteria of the intestinal flora → release of TNF → cell injury

Question 15

Acute alcoholism

Answer 15

• Gastric changes: acute gastritis and ulceration
• Hepatic changes: accumulation of fat droplets in the cytoplasm of hepatocytes (hepatic steatosis)
• CNS changes: alcohol act as a depressant. Can affect medullary centers, such as those regulating respiration → respitratory arrest

Question 16

Chronic alcohol

Answer 16

Shortened life span

• liver: fatty changes, alcoholic hepatitis, cirrhosis (→ portal hypertension, hepatocellular carcinoma)
• GI: can cause massive bleeding from gastritis, ulcers or esophageal varices
• CNS: thiamine deficiency → peripheral neuropathies, Wernicke-Korsakoff syndrome (which may cause vision changes, ataxia and impaired memory).
• cardiovascular system: injury to the myocardium → dilated congestive cardiomayopathy.

Heavy consumption (as opposed to moderate) increased HDL → increased risk for CHD

• increased risk for acute and chronic pancreatitis
• during preganacy → fetal alcohol syndrome: microcephaly, growth retardation, facial abnormalities
• increased incidence of cancer in the oral cavity, esophagus, liver, female breast

Question 17

What are the categories of injury by physical agents?

Answer 17

• Injury by mechanical trauma
• Thermal injury
• Electrical injury

Question 18

Injury by mechanical trauma

• What is the injury depends on?
• What are the patterns of injury?

Answer 18

• The type of injury depends on:
  
  • Shape of colliding object
  • Amount of energy discharged at impact
  • Tissues or organs impacted
• patterns of injury In soft tissues:

1. abrasion: removal of the epidermal layer of the skin (or part of it)
2. contusion: damage to blood vessel with extravasation of blood into the tissue
3. laceration: tear of disruptive stretching of tissue caused by the application of force by a blunt object. Bridging blood vessels remain intact
4. incised wound: by a sharp instrument, bridging vessels are severed.
5. puncture wound: by long narrow instrument. 2 terms: penetrating or Perforating

→ one should remember that in case of an automobile injury victim, the presence of an internal wound should be suspected.

Question 19

On what is the clinical significance of thermal burns depends?

Answer 19

Depth of the burn:

• Partial thickness:
  
  • 1^st degree: only epidermis
  • 2^nd degree: epidermis + superficial dermis
  • Morphology: pink or mottled with blisters, painful
• Full thickness:
  
  • 3^rd and 4^th degrees, destruction of the epidermis and dermis with loss of dermal appendages (→ no cell regeneration)
  • Morphology: white or charred, dry and anesthetic (because of nerve ending destruction)

Percentage of body surface involved:

• <50% → potentially fatal
• <20% → shift of body fluid into the intestinal compartment → risk for hypovolemic shock. Edema

Possible presence of internal injury

• From inhalation of hot and toxic fumes. Produces inflammation that may cause A.W. obstruction

Promptness and efficacy of therapy

• Fluid, electrolyte management,
• Control of wound infections: most common offender is pseudomonas aeruginosa. S.aureus and candida might also be involved. This may lead to pneumonia, septic shock, ARDS and MOF

Question 20

Hyperthermia

Answer 20

Prolonged exposure to elevated temperature can result in:

• Heat cramps: are due to loss of electrolytes via sweating
• Heat exhaustion: water depletion → hypovolemia → failure of the cardiovascular system to compensate for it → prostration, collapse
• Heat stroke: failure of thermoregulatory mechanisms, cessation of sweating, increase of core body temperature. Generalized peripheral vasodilation, peripheral pooling of blood, decreased effective circulatory volume

Question 21

Hypothermia

Answer 21

Prolonged exposure to low temperature.

Local reactions: freezing or chilling of cells and tissue causes injury by two mechanisms:

• Direct effect: mediated by physical disruption within cells and high salt concentrations
• Indirect effects: are the result of circulatory changes:

Decreased temperature → chilling → vasoconstriction, increased permeability → edema, ischemic injury → degenerative changes in peripheral nerves

Question 22

Electrical injury

Answer 22

Injuries from either low or high voltage currents may be:

1. burns
2. ventricular fibrillation, cardiac and respiratory center failure

The type of injury and its severity depends on the amperage and path of the electric current within the body.

• low voltage current:
  
  • continuous current flow → heat → burns
  • it induces tetanic muscle spasm → prolonges the grasping of the wire → more severe burn
• high voltage current: produces in addition paralyses of the medullary center and extensive burns

Question 23

Injury by ionizing radiation

Answer 23

Radiation: energy that travels in the form of waves or high-speed particles. Divided into:

• non ionizing: UV, infra-red, microwaves, sound waves → does not displace bound electrons from atoms
• ionizing: X-ray, γ-ray and high energy neutrons: α and β particles
  
  • sufficient energy to displace bound electrons from atoms → collision of electrons with other molecules → release of more electrons. IONIZATION
  • used for the treatment of cancer, diagnostic imaging, therapeutic or diagnostic isotopes. On the other hand, it is also mutagenic, carcinogenic and teratogenic

Question 24

Units of ionizing radiations

Answer 24

R=Roentgen: measures radiation exposure

Gy=gray: energy absorbed by the tissue

Sv=Sievert: the biologic effect exerted by equal dose of different types of radiation

The equivalent dose: absorbed dose (Gy) X relative biological effectiveness of the radiation (depends on the volume, type of radiation, duration). Unit: Sv

Ci=curie: the disintegration per second of a spontaneously disintegrating radionuclide

Question 25

Biological affect of ionizing radiation depends on:

Answer 25

sensitivity of the proliferating tissue: rapidly dividing cells are more vulnarable to injury as it damages the DNA

• compatible with survival in non-dividing cells (except in extremely high doses) → brain, myocardium
• If severe DNA damage occurs during mitosis the cell die
• tissue with high rate of cell turnover (gonads, bone marrow, lymphoid tissue, mucosa of the GI) are extremely vulnerable to radiation

Vascular damage: damage to endothelial cells may cause narrowing or occlusion of blood vessels → impaired healing, fibrosis and chronic ischemic atrophy

Rate of delivery: fractional doses enable the cells to repair. Only if the repair is incomplete than there would be a cumulative effect

Hypoxia: by the production of free radicals form the radiolysis of water.

Field size: the larger the field exposed, the higher the damage.

Question 26

Ionizing radiation carciogenesis and fibrosis pathways

Answer 26

DNA damage and carcinogenesis

• Ionizing radiation impairs the DNA. The repair system might restore it to normal, however, such mutations might persist (the repair system doesn’t worlk) and cause mutations. If the cell cycle checkpoints does not functioning → abnormal clone → tumor

Fibrosis

• Ionizing radiation → vascular damage, killing of stem cells, release of cytokines that promote inflammation and fibroblast activation → fibrosis

Question 27

What is the morphology of ionizing radiations

Answer 27

• changes in chromosomes (breaks, translocation)
• atypical mitosis
• nuclear swelling. Pyknosis or lysis might occur
• condensation and clumping of chromatin
• apoptosis
• cytoplasmic changes: swelling, mitochondrial distortion, ER degeneration
• light microscopy: vascular changes, interstitial fibrosis

Question 28

Ionizing radiation effect on organ system/total body

• The most sensitive organs and the effects:
• Total body irradiation

Answer 28

• hematopoietic and lymphoid system: shrinkage of the lymph node and spleen. Lymphopenia, thrombocytopenia (platelet count decreases), lymphopenia
  
  • Hematopoietic cells: erythrocytes are radioresistant but anemia developes due to destruction of marrow.
• GI: mucosal injury, ulceration, fibrosis of the wall
• gonads: testis and ovaries are destructed. Atrophy and fibrosis of the gonads occurs later.

Total body irradiation

• Associated with total body exposure to levels higher than 1 Sv and causes acute radiation syndromes which impairs the CNS, GI and the hematopoietic system.