Chapter 8 (environmental and nutritional diseases)

Question 1

Define toxicology?

Answer 1

the science of poisons. It studies the distribution, effects and mechanisms of action of toxic agents.

Question 2

Define detoxification?

Answer 2

agents not modified on entry in the body, but most solvents and drugs are metabolized to form water-soluble products, or are activated to from toxic metabolites.

Question 3

Describe the phase 1 and phase 2 reactions of xenobiotics?

They can be activated or made into nontoxic compounds?

Answer 3

-Phase 1
hydrolysis, oxidation, reduction
-Phase 2
glucuronidation, sulfation, methylation, conjugation with glutathione.

Question 4

where are the enzymes for detoxifying located?

Answer 4

Cytochrome p-450 is most active in the ER endoplasmic reticulum of the liver.
The byproduct of the reaction is ROS that can cause cellular damage.
Some xenobiotics can be made into toxins such as:
Carbon tetrachloride made into trichloromethyl free radical and the generation of DNA-binding metabolite from benzopyrene found in cigarette smoke.

Question 5

when is activity of p450 increased or decreased?

Answer 5

increased with alcohol consumption and decreased with starvation.

Question 6

what are the major health affects of:

• ozone
• sulfur dioxide
• carbon monoxide

Answer 6

• ozone: formed in sunlight driven reaction involving nitrogen oxides (NOx). Damage endothelial lining of the lungs.
• sulfur dioxide: (coal and oil-fired plants) in the alveoli they are taken up by macrophages and neutrophils that then release mediators causing inflammation.
• carbon monoxide: it binds to Hgb to prevent oxygen transport as it has 200 fold greater affinity for CO then oxygen.

Question 7

what are the affects of heavy metals:

• lead
• mercury
• arsenic
• cadmium

Answer 7

• lead: binds to sulfhydryl groups and proteins and interferes with calcium metabolism, leading to hematologic, skeletal, neurological, GI and renal toxicities. It can compete with developing teeth and bone. It can incorporate into Hgb, bone to inhibit healing of fractures. Damage done to developing children is irreversible (in bone lead has a 20-30 year half-life).
• mercury: binds to sulfhydryls groups in certain proteins with high affinity, leading to damage in the CNS and several other organs such as the GI tract and the kidneys. Can cause cerebral palsy, deafness, blindness and major CNS defects.
• arsenic: interfered with cellular metabolism, leading to toxicites in the GI, nerves, skin and heart. the affects are: abdominal pain, diarrhea, cardiac arrhythmias, shock , respiratory distress syndrome acute encephalopathy. It interferes with the mitochondrial respiratory pathway and can cause death.
• cadmium: Toxic to the kidneys and the lungs and may cause an increase in the production of ROS. ingested from the food it can cause renal failure and end stage renal disease. Cadmium can also cause skeletal abnormalities do to calcium loss.

Question 8

what diseases have polycyclic hydrocarbons been associated with? and DDT

Answer 8

Causes lung and bladder cancer. Was common in chimney sweepers.
DDT (dichlorodiphenyltrichloroethane): A pesticide that caused neurological problems.

Question 9

Effects of alcohol?

Answer 9

tobacco is responsible for 90% of lung cancers.

Question 10

what are the affects of nicotine smoke on the body?

Answer 10

increased heart rate, and blood pressure, increased cardiac contractility and output. Nonsmoking variations of nicotine have been linked to oral cancer.

• Direct irritant effect on the tracheobronchial mucosa: producing inflammation and increased mucus production. the smoke also causes the recruitment of leukocytes to the lung, increasing local elastase production and subsequent injury to lung tissue that leads to emphysema.
• Carcinogensis: some components of cigarette smoke (polycyclic hydrocarbons and nitrosamines, are potent carcinogens.
• Atherosclerosis: 1/3 is linked to smoking, Factors such as decreased oxygen supply do to CO, and increased platelet aggregation. The hypoxia of CO with increased O2 demand decreases the threshold for ventricular fibrillation.

Question 11

what are some of the toxins in cigarettes?

Answer 11

Tar, polycyclic aromatic hydrocarbons, Phenol, benzopyrene, CO, formaldehyde, oxides of nitrogen, nitrosamine.

Question 12

how is cigarette smoke rate measured?

Answer 12

one pack daily for 20 years equals 20 pack years.

Question 13

what levels are measure in blood to determine the level of exposure to smoke one person had?

Answer 13

Cotinine levels, a metabolite of nicotine

Question 14

what is alcohol responsible for? statistics?

Answer 14

50% of adults in western world drink alcohol
5-10% have chronic alcoholism
responsible for 100000 deaths annually
50% of deaths are caused by drunken driving.

Question 15

what happens to alcohol after consumption?

Answer 15

all ethanol is absorbed unchanged into the blood. 80 mg/dL is the legal blood limit in most states. drowsiness kicks in at 300mg/dL.
chronic alcoholics develop a resistance to alcohol and metabolize it at a higher rate.
Alcohol is metabolized by 3 enzymes: alcohol dehydrogenase, cytochrome P-450 isoenzymes.
the proportion of alcohol exhaled is proportional to the amount in the blood (breath test).

Alcohol dehydrogenase is the most important and breaks down alcohol into acetaldehyde.
Alcohol can compete for the p450 enzymes (CYP2E1 isoform) potentiating the affects of other drugs.

acetaldehyde is converted to acetate by acetaldehyde dehydrogenase and then used by the mitochondrial respiratory chain

Question 16

what are the toxic affects of alcohol metabolism?

Answer 16

• Alcohol oxidation by alcohol dehydrogenease causes a decrease in NAD+ (nicotinamide adenine dinucleotide) and increase in NADH. NAD is needed for fatty acid oxidation and thus alcoholics accumulate fat in the liver.
• Acetaldehyde toxicity: after ethanol consumption the person experiences flushing, tachycardia, hyperventilation do to the accumulation of acetaldehyde.
• ROS generation: CYP2E1 metabolism of ethanol by th eliver produces ROS and this causes lipid peroxidation of cell membranes.
• Endotoxin release: a product of gram-negative bacteria from intestinal flora, which stimulates tumor necrosis factor and other cytokines from circulating macrophages from kupffer cells in the liver causing cell injury.

Question 17

what are the CNS affects of alcohol?

Answer 17

while alcohol causes reversible liver damage it can also cause gastric ulcers.
In CNS alcohol is a depressant, 1st affecting subcortical structures that modulate cerebral cortical activity. motor, and intellectual areas are depressed and so is the respiratory center, which may cause respiratory arrest.

Question 18

what are some of the alcoholic affects on other organs?

Answer 18

• LIVER: hepatitis, cirrhosis (portal hypertension) and increases hepatocellular carcinoma
• GI tract: ulcers and esophageal varicies (do to cirrhosis) and gastric bleeding.
• Neurologic effects: thiamine deficiency. Wernicke-korsakoff syndrome: loss of movement, intellectual disability as vitamin B thiamine is needed for glucose metabolism in the brain.
• Cardiovascular effects: moderate amount has been linked to increased HLD and decreased platelets protecting from coronary disease. However heavy drinking causes heart disease.
• pancreatitis
• fetal birth defects, retardation
• carcinogenesis (unknown mechanism of injury)
• malnutrition

Question 19

Describe the injury caused by therapeutic drugs abuse?

Answer 19

Menopausal hormone therapy: administration of estrogen and progesterone. The therapy used on post-menoupaussal women could slow the progression of osteoporosis and reduce the likelyhood of myocardial infraction. however in some studies it was found that the therapy caused venous thrombosis and increased risk of breast cancer. Later on studies showed that the age of the women type and dose of hormone administered.

• Estrogen-progestin increases the risk of breast cancer while estrogen along in women with hysterectomy is associated with a borderline reduction in the risk of breast cancer.
• a therapeutic window is seen in the sense that women who start therapy under the age of 60 have a better outcome.

Oral contraceptives: they have been associated with venous thrombosis and hepatic adenoma.

Aspirin: overdose is associated with gastric bleeding as thromboxane A2 is inhibited and GI bleeding could occur.

Question 20

what are the affects of Cocaine, opiates and marijuana?

Answer 20

Cocaine: made from coca plant, its affects are:
-Cardiovascular effects: Cocain is a sympathomimetic agent, in the CNS it blocks the reuptake of dopamine and at adrenergic nerve endings, where it blocks the reuptake of both E and NE while stimulating the presynaptic release of NE. This causes overestimation of the synapses causing: tachycardia, hypertension and peripheral vasoconstriction and promotes thrombus formation by facilitating platelet aggregation.
CNS effects: causes high fever
Effects on fetus: abnormal CNS development and spontaneous abortion.
-cocaine can cause perforation of the nasal septum in snorters, decreased in lung diffusing capacity and the development of dilated cardiomyopathy.
-Heroin: effects range from euphoria (intense excitement), hallucinations, somnolence, and sedation. Sudden death: related to overdose do to profound respiratory depression, arrhythmia, cardiac arrest, pulmonary edema. Infections in the lungs skin subcutaneous tissue and heart valves, liver is common. The avaliability of prescription opiates (oxycodon) has become a widespread problem.
-Marijuana: about 10% of the THC (tetrahydrocannabinol) is absorbed during smoking of the drug. Beneficial effect are the decrease intraocular pressure in glaucoma. the affects of the drug as still under research but in the short term the user has sensory and motor impairment and in the long term they loose the ability to judge time, speed and distance.

Question 21

Describe the injuries caused by physical agents?

Answer 21

-Mechanical trauma, thermal trauma, electrical injury, radiation.
-MECHANICAL: depends on tissue affected and shape of object: Abrasion: scraping affecting superficial layer, Contusion: bruise, blunt trauma and bleeding. Laceration: tear or disruptive stretching of tissue caused by the application of force by a blunt object.
Thermal injury: 3rd and 4th degree burns the full thickness of the skin is affecting including the layer of cells needed for regeneration. Burns affecting 50% or more of the body are quite fatal. The body pushes fluid to the site of the burns causing hypovolemic shock and there is also a loss of protein do to the burn. Organ failure do to sepsis is the leading cause of death in burns.
ELECTRICAL: 2 types of injury can occur: burns, ventricular fibrillation or cardiac and respiratory center failure. The duration of exposure can determine the level of injury and may even cause burns to internal organs.

Question 22

what types of injury occur as a result of hyperthermia? as well as hypothermia

Answer 22

• heat cramps: loss of electrolytes through sweating, cramping of voluntary muscles
• Heat exhaustion: failure of the cardiovascualr system to compensate for hypovolemia and secondary water depletion.
• Heat stroke: thermoregulatory mechanisms fail, sweating ceases. Necrosis of the muscles and myocardium may occur. Arrhythmia, disseminated intravascular coagulation and other systemic effects are common.
• Malignant hyperthermia: genetic condition do to mutations in gene such as RTR1 that control calcium levels in skeletal muscles cells.

Hypothermia: common in homeless with inadequate clothing, and dilated blood vessels do to alcohol.

• Direct effects: physical distruptions within cells and high salt concentrations incident to the crystallization of the intra- and extracellular water.
• Indirect effects: result of circulatory changes; trench-foot of soldiers who spent time in water-logged tranches causing gangrena of the feet. It depends on the duration of the temperature drop, short, slow drop will induce vasoconstriction.

Question 23

Describe the injury caused by ionizing radiation?

Answer 23

it can be divided into ionizing and non-ionizing radiation. nonionizating radiation such as UV, infrared, microwaves Ionizing radiation has the power to remove electrons which can cause a cascade referred to as ionization.
Extent of radiation damage is determined by: field size, rate of delivery (time for the cell to recover), cell proliferation; highly dividing cell are more prone to injury, but p53 protects from this.
Hypoxia may reduce the effectiveness of radiation therapy as ionization of water can produce ROS but hypoxia prevents this.
Vascular damage: Damage to endothelial cells
Radiation can cause firbosis as tissue damage release cytokine and chemokine that activate firboblasts.

Radiation can severely affect lymphopenia along with shrinkage of the lymph nodes and spleen. Radiation directly destroys lymphocytes which can quickly regenerate. Radiation also kills bone marrow progenitor cells.

Question 24

Describe malnutrition?

Answer 24

• primary malnutrition: food is needed for energy, amino acids, fats, needed for building blocks for structural synthesis, Vitamins and minerals for enzyme function.
• Secondary malnutrition: dietary intake of nutrients in adequate and malnutrition resulting in nutrient malabsorption.

Question 25

Describe the 2 forms of SAM (sever acute malnutrition)?

Answer 25

• Marasmus: diet is lacking in calories, (somatic compartment is affected here) there is a loss of muscle mass and growth retardation in children.
• kwashirokor: protein deprivation is relatively greater than the reduction in total calories. generalized edema develops masking protein loss in abdomen. This is seen in children who are weaned too early. children affected have hypopigmentation, loss of hair color. Fatty liver is seen do to loss of carrier proteins component of lipoproteins.

there are 2 protein compartments in the body: somatic (proteins in skeletal muscles) and visceral compartment represented by protein stores in the visceral organs, primarily the liver. Marasmus the somatic is affected, in kwashirokor the viceral component is affected.
loss of viceral protein causes loss of abdominal circumference, loss of somatic causes loss of arm circumference.

Cachexia: loss of appetite do seen in tumors as a result of TNF being secreted by tumor cells. These factors directly stimulate the degradation of skeletal muscle proteins, and also stimulate fat mobilization from lipid stores.

Question 26

Describe anorexia nervosa and bulimia?

Answer 26

• Anorexia nervosa: self induced starvation resulting in marked weight loss. marked with decrease in gonadotropin-releasing hormone. Decreased thyroid hormone: cold intolerance, bradycardia. Anemia, lymphopenia, hypoalbuminemia, there is an increased susceptibility to cardiac arrhythmia and sudden death as a result of hypokalemia (low K+)
• bulimia: patient eats food then induces vomiting. associated with electrolyte imbalance (hypokalemia) which predispose to cardiac arrhythmias. Pulmonary aspiration of gastric contents. esophageal and stomach ruptures.

Question 27

Describe the consequences of vitamin deficiency?

Answer 27

A single vitamin deficiency is not usually seen.
-Vitamin A: maintenance of normal vision, regulation of cell growth and differentiation and regulation of lipid metabolism. Found in animal liver, fish, eggs and milk and butter. Retinol is the chemical name of vitamin A.
Vitamin A plays a role in stimulating the immune system and can be injected to reduce eye problem. Vitamin A is also used to decrease the chance of developing eye problems. (skipped pages 328)

Question 28

what does obesity predispose on to?

Answer 28

type 2 diabetes, dyslipidemia (abnormal amount of lipid in the blood), cardiovascular disease, hypertension and cancer.

Question 29

how do we measure body fat levels?

Answer 29

BMI (body mass index); in kg/m^2 of the body.
18.5 - 25kg/m2 are normal
25-30 are overweight
over 30 is obese.

Question 30

what regulates the level of fat?

Answer 30

LEP gene producing Leptin by fat cells tells the body the amount of fat accumulated and can regulate appetite.

Peripheral or afferent system generates signals from various sites: leptin from fat, insulin from the pancreas ghrelin from the stomach and peptide YY from the ileum and colon. Ghrelin stimulates food intake.
Arcuate nucelus in the hypothalamus process and integrates the peripheral signals and generate new signals.
the efferent system made up of the hypothalamic neurons and arcuate nucleus control food intake and energy expenditure.
People with impaired leptin production eat aggressively.

Question 31

What is adiponectin?

Answer 31

it have been called the fat-burning molecule, or “guardian angel against obesity” it directs fat to muscles for their oxidation. increases insulin sensitivity. It has anti-diabetic, anti-inflammtory, anti-atherogenic, anti0proliferative and cardioprotective effects.
Its decreased in fat individuals contributing to diabetes.

Question 32

what does ghrelin and peptide YY responsible for?

Answer 32

Ghrelin stimulates food intake and increases before a meal. Its attenuated in obese individuals.
Peptide YY is secreted from endocrine cells in the ileum and colon in response to the consumption of food, it decreases appetite and augments a sense of fullness. It also reduces gastric emptying and intestianl motility (ilea brake) all of which contribute to satiety).

Obese mice have shown that their microbiomes are more capable of getting energy out of food. Obese mice microbiomes transplanted into lean mice caused weight gain.

Question 33

what are the clinical consequences of obesity?

Answer 33

excessive free fat causes inflammasome response and this stimulates secretion of IL-1 which induces insulin resistance.
Obese persons have hypertriglyceridemia and low HDL cholesterol levels, factors that increase the risk of coronary artery disease.
Non-alcoholic fatty liver disease is commonly addociated with obesity and type 2 diabetes. It can progress to fibrosis and cirrhosis.
Cholelithiassis is six times more common in obese than in lean subjects. the mechnaism is mainly an increase in total body cholesterol which augments biliary excretion of cholesterol in bile which in turn predisposes affected persons to the formation of cholesterol-rich gallstones.

Greater weight means greater trauma to joints causing osteoarthritis.

Question 34

what is the link between cancer and obesity?

Answer 34

Unknown but here are some theories:
-High insulin levels as a result of increased insulin resistance causes the secretion of IGF-1 that stimulates cell growth.
adiponectin may be suppresses in obese patients, and since adiponectin can suppress p53 and p21 causing cell death, neoplasm may occur.