Topics A50-52 Environmental Causes of Disease: Tobacco, Pollution, Alcohol, Radiation

Question 1

List 6 major outdoor air pollutants, and which one is the most dangerous?
(prob not essential to be able to recite them all)

Answer 1

1. Ozone
2. Sulfur Dioxide
3. Nitrogen Dioxide
4. Carbon Monoxide
5. Lead
6. Particulate matter: worst one

Question 2

What size particles in air pollution are the most dangerous? Why?

Answer 2

Particles < 10 micrometers are the most dangerous because when they are inhaled, they make it to the alveoli, are phagocytosed, and inflammatory rxn / ROS release occurs

Larger particles are caught in the upper respiratory tract with mucous and cilia, can be removed more safely

Question 3

What is the most common source of INDOOR pollution?

What are some others to be familiar with?

Answer 3

Most common: tobacco smoke

Others: wood smoke, microbes like Legionella, allergens like pet dander, dust mites, fungi, mold

Question 4

What does “xenobiotic” mean?

How does this differ from “toxin?”

Answer 4

Xenobiotic = exogenous chemicals in the environment that can be absorbed by the body through inhalation, ingestion, or skin contact.

“Toxin” is a vague term - technically anything can be toxic in the right concentration. Xenobiotics may or may not cause harm, depending on concentration and how they are processed by the body.

Question 5

What are the 2 major biotransformation steps (just a few very important concepts from biochem)

Answer 5

Phase I rxn: make xenobiotic more water soluble. Adds a polar group, usually with CP450 enzyme

Phase II rxn: conjugation to more polar molecule like glucuronic acid.

Goal is to make xenobiotic water soluble for excretion. The process sometimes may actually make the xenobiotic more harmful than it was.

Question 6

Tobacco is responsible for what percentage of lung cancers?

How many deaths worldwide can be contributed to tobacco every year?

What percentage of smokers survive to age 70?

Answer 6

90% lung cancers

> 4 million deaths / year worldwide

Only 50% smokers survive to age 70

Smoking is the most preventable cause of human death

Question 7

The International Agency for Research on Cancer has 4 categories of substances to say if they are carcinogenic to humans, what are they?
Which one is cigarette smoke in?

Answer 7

1: Definitely carcinogenic (cigarette smoke)
2: 2a probably carcinogenic, 2b possibly carcinogenic
3. Not classifiable if carcinogenic or not
4. Probably not carcinogenic

Question 8

Of the 4700 chemicals found in cigarette smoke, about how many are known carcinogens? How many are promoters of carcinogenic effects?

Answer 8

~ 60 carcinogens
>20 promoters

(promoters drive proliferation without causing mutations themselves. Alone they are not very problematic, but bad when mixed with carcinogens)

Question 9

Which carcinogen in cigarette smoke is also related to pancreatic cancer?

Answer 9

NNK (nicotine-derived nitrosamine ketone)

It accumulates in the pancreatic juice

Question 10

Which strong carcinogen in cigarette smoke is actually just from the burning paper?

Answer 10

Benzapyrene

Question 11

4 other harmful carbon-based components of cigarette smoke:

Answer 11

• Tar: carcinogenic
• Polycyclic hydrocarbons (PAH) - carcinogenic
• Carbon Monoxide: not carcinogenic, but creates carboxyhemoglobin -> continuous hypoxia. Major risk for fetus during pregnancy.
• Formaldehyde: not carcinogenic directly, but -> constant irritation related to carcinogenesis

Question 12

Which radioactive compound is inhaled from cigarette smoke?

Answer 12

Polonium-210: has halflife over 400 years, and emits α radiation

Question 13

Which component of cigarette smoke inhibits mucociliary movement?

Answer 13

Acrolein

Question 14

Which cancer of the genitourinary tract is most closely related to smoking? Why?

Answer 14

Bladder cancer: nitrosamines and aromatic amines are concentrated in the bladder, have more time to take part in carcinogenesis

(Note smoking cigarettes, cigars, or chewing tobacco etc have relation to oral, laryngeal, esophageal cancers)

Question 15

What are the 3 major diseases that develop in the lungs as a result of smoking?

Answer 15

1. Chronic bronchitis: smoke irritation causes inflammation and also goblet cell metaplasia that -> more mucous in lungs, good breeding ground for bacteria
2. Emphysema: smoke destroys elastic fibers and alveoli become distended (centriacinar emphysema specifically from smoking)
3. Lung cancer: covered later

Question 16

What are the two vascular diseases associated with cigarette smoke?

Answer 16

1. Atherosclerosis: high association with MI, dry gangrene. Increased platelet aggregation.
2. Buerger’s Disease: necrosis in fingers due to hypersensitivity against materials in cigarette smoke -> proliferation of fibroblasts and thrombus formation inside small peripheral arteries + inflamm of arterial wall (thrombangitis obliterans)

Question 17

What are the 2 most important enzymes to know for alcohol metabolism?

Answer 17

1. ADH - Alcohol dehydrogenase: most important. Converts ethanol into acetaldehyde intermediate (more toxic than ethanol). Creates NADH from NAD+
2. CYP2E1: a CYP450 isoform that also converts ethanol to acetaldehyde, but only when ADH is overloaded from high ethanol concentration. Other drugs compete to use this enzyme, meaning alcohol has synergistic effects with them. Uses NADPH and creates ROS

(catalase has a minor role for ethanol degradation; aldehyde dehydrogenase performs the final step of converting acetaldehyde to acetic acid)

Question 18

What are 3 major mechanisms of cell injury from alcohol metabolism?

Answer 18

1. Increase of NADH and decrease of NAD+ means that fatty acid oxidation is impaired, causing fat accumulation in the liver and lactic acidosis
2. Acetaldehyde intermediate is toxic. Many Asian people are deficient in in ALDH -> poor removal of acetaldehyde, causing flushing, tachycardia, and hyperventilation.
3. Metabolism by CYP2E1 -> ROS that cause lipid peroxidation of cell membranes

Question 19

How much alcohol is the “healthy limit” for men vs women?

Answer 19

Men: 80g pure alcohol (2 liters of 4% alcohol)

Women: 1/4 of that. Only 20g / 0.5 liters

Question 20

What are the 3 steps of changes in the liver as a result of chronic alcohol consumption?

Answer 20

1. Fatty degeneration / fatty change: from NADH/NAD imbalance, plus acetaldehyde blocks enzyme that makes VLDL. Can see vacuoles, nucleus pushed to periphery.
2. Alcoholic hepatitis: necrosis sites surrounded by PMNs and see horseshoe-shaped Mallory bodies. May get jaundice
3. Cirrhosis: whole liver is diffusely replaced with pseudolobules with connective tissue. Liver is firm and nodular, interferes with blood flow and functions. Portal HTN and hepatocellular carcinoma may result. Largely irreversible.

Question 21

What are Mallory Bodies (or Mallory-Denk bodies)

Answer 21

Ubiquinated cytokeratin intermediate filaments in hepatocytes, seen in alcoholic liver disease. Appear eosinophilic.

Question 22

What disease develops in alcoholics as a result of thiamine deficiency?

Answer 22

Wernicke-Korsakoff Syndrome: vision changes, ataxia, confusion, and impaired memory. May be permanent brain damage.

Question 23

What are the changes to the heart as a result of alcoholism?

Answer 23

Alcoholic Cardiomyopathy: all chambers are dilated, whole heart becomes globular-shaped. Clinically, has biventricular insufficiency due to both sides being dilated. Thrombi frequently seen

May be “cor borvinum” - heart like an ox. Heart weighs over 1 kg

Question 24

What changes in the pancreas as a result of alcoholism?

Answer 24

Histo: “Dilated duct” is characteristic. Contains protein plaques due to altered pancreatic juice becoming thicker, functions like plaque

May develop either acute or chronic fibrotizing pancreatitis.

Maldigestion occurs from loss of acini, massively decreased enzymes.

Question 25

What is the most severe consequence to the brain as a result of alcoholism?

Answer 25

Atrophy: brain may weigh 900g instead of 1300. Sulci are deep, gyri are thin.

Question 26

What are some of the characteristics of fetal alcohol syndrome?

Answer 26

Mental and growth retardation, microcephaly Facial abnormalities: epicanthal folds, flat midface, smooth filtrum, thin upper lip

Question 27

4 categories of injury caused by physical agents: | 1 of them is in the title for this topic

Answer 27

1. Mechanical trauma 2. Thermal injury 3. Electrical injury 4. Ionizing radiation injury

Question 28

What are some different types of soft tissue injuries?

Answer 28

- Abrasion: scraping or rubbing of superficial layer - Contusion: bruising, damage to superficial vessels - Laceration: tearing/stretching via an object more blunt than incision. Bridging vessels are intact - Incision: sharp instrument cuts bridging vessels - Puncture wound: instrument penetrates the tissue

Question 29

What are 4 important hemorrhages that result from trauma to the head?

Answer 29

1. Epidural hematoma: skull fracture, middle meningeal artery rupture. Lose consciousness, lucid interval, lose consciousness again and die. 2. Subdural hematoma: slow progression, bridging veins torn from rapid movement of skull (fall, car crash, etc.) 3. Subarachnoid: often ruptured aneurysms. Rapid onset, "thunderclap" headache. Vomiting, lose consciousness 4. Intraparenchymal

Question 30

What factors do the extent of mechanical trauma depend on?

Answer 30

- Shape of the colliding object - Energy put into the impact - Which tissue/organ is injured

Question 31

How do you rank the different degrees of burns?

Answer 31

Partial thickness: 1 and 2 - 1st degree: only epidermis - 2nd degree: epidermis + superficial dermis. May have blisters. Full thickness: 3 and 4 - 3rd degree: extends through entire dermis. Stiff, white to brown. Painless at site of burn. - 4th degree: goes even deeper, appears black (eschar).

Question 32

What are 3 major risks to life from burns / fires?

Answer 32

1. Hypovolemic shock: fluids move to interstitial area and much fluid is lost 2. Infection due to lost protection of skin (Pseudomonas especially) 3. Inhalation injury: life-threatening pulmonary edema often develops within 24-48 hours of exposure after being in burning building

Question 33

What are the 3 types of hyperthermia?

Answer 33

1. Heat cramps: caused by electrolyte loss from sweating, usually occurs during exercise. Muscles cramp. 2. Heat exhaustion: most common type. Person collapses from hypovolemia due to sweating. Usually after fainting and rest, they recover fine 3. Heat stroke: life-threatening, uncompensated rise in core body temperature. High temperature with high humidity means sweating is ineffective and even stops. Have generalized peripheral vasodilation, arrhythmias, maybe DIC.

Question 34

At around what hypothermic body temperature does loss of consciousness occur, along with what other serious symptoms of hypothermia?

Answer 34

Around or below 32C / 90F. Als see bradycardia, atrial fibrillation.

Question 35

What are the 2 mechanisms of injury for electrical injury?

Answer 35

1. Burns: require longer exposure to electrical source 2. Normal electrical impulses are disrupted: major risk is ventricular fibrillation, but can also paralyze respiratory muscles

Question 36

What are the 3 forms of ionizing radiation?

Answer 36

1. X and γ rays: high frequency EM radiation. These are "indirectly" ionizing because they react with H2O first to make ROS. (α/β radiation is directly ionizing) 2. α particles: 2 protons and 2 neutrons, steal electrons to stabilize themselves. Most harmful one but it's easily blocked, has short range. Dangerous to ingest. 3. β particles: either high-energy electron or positron emission. Positrons can cause γ rays to be released.

Question 37

Radiation definitions: Grays Sieverts

Answer 37

Grays: energy absorbed by target tissue. Joules/kg Sieverts: "equivalent dose" - basically the energy absorbed multiplied by the relative biologic "effectiveness" of the radiation

Question 38

Which tissues are most susceptible to mutagenic/carcinogenic effects of radiation?

Answer 38

Cells that divide rapidly: Most sensitive is bone marrow. Most frequent ionizing radiation problems are acute or chronic myeloid leukemias Next most affected are breast, lung, salivary glands (Skin, bone, GI tract are not affected much)

Question 39

What is the most important intracellular target of ionizing radiation? What are some ways that it can be damaged?

Answer 39

DNA Can cause base damage, single and double-stranded breaks, and cross-links between DNA and proteins. Double-stranded break is most dangerous

Question 40

Which type of non-ionizing radiation is dangerous? Why?

Answer 40

UV light, mostly in UVB spectrum <310nm. Causes thymidine dimers to form in DNA. Need nuclear excision repair Melanoma is closely related to burning at young ages, before puberty.