What is the Global Burden of Disease project?
standard for reporting health information about environmental diseases. DALY (disability-adjusted life year) used to assess mortality and morbidity of dz.
What is the single leading global cause of health loss?
undernutrition; 1/3 the disease burden in developing countries. Increase risk of infections related to poor general nutrition or deficiencies in specific nutrients.
Two leading causes of death in developed countries
ischemic heart dz and cerebrovascular dz.
In developing countries, what accounts for 5 of the 10 leading causes of death?
Infectious dz: respiratory infx, HIV, diarrheal dz, TB, malaria
About 70% of all child deaths are attributed to what five dz?
pneumonia, diarrheal dz, malaria, measles, and perinatal/neonatal problems (mostly infx)
How has worldwide mortality of under 5 yo children changed since 1980?
about 27% decline. Does not meet UN goal of 67% decline. Under 5 yo-mortality in Central and West Africa has not sig declined.
3 examples of emerging infectious diseases (EIDs)
1. newly evolved strains or organisms (MRSA, XDF TB, chloroquine-resistant malaria)
2. endemic in other species that have recently entered human population (HIV and SARS)
3. present in human populations but show a recent increase in incidence (dengue fever)
4 aspects of health and disease affected by global warming
1. increase in vector-borne diseases (dengue fever, west nile, hantavirus pulmonary syndrome)
2. malnutrition: due to disrupted crops
3. gastroenteritis and infx dz epidemics: due to contamination after natural disasters
4. CV, cerebV, resp dz: heat waves and air pollution
The concept of a poison is dependent on....
What are xenobiotics?
exogenous chemicals in air, water, food, soil that may be absorbed through inhalation, ingestion, and skin contact
Most solvents and drugs are of what chemical category?
liophilic, facilitating transport in blood by lipoproteins and penetration through PM into cells
What are the two phases of biotransformation of xenobiotics?
Phase 1: P-450 (CYP family) catalyzes hydrolysis, oxidation, or reduction. Concentrated in ER of liver cells. Can either detoxify or activate xenobiotics.
Phase 2: glucuronidation, sulfation, methylation, and conjugation with glutathione
What can be produced in Phase 1 reactions that is harmful to cells?
e.g. trichloromethyl free radical from CCL4, DNA binding metabolite from benzo[a]pyrene in cig smoke
What are some inducers of CYP?
environmental chemicals, drugs, smoking, EtOH, and hormones.
What can decrease CYP activity?
fasting or starvation
Mechanism of inducers of CYP
1. bind nuclear receptors
2. heterodimerize with retinoic X receptor
3. form transcriptional activation complex in 5'-flanking region of CYP genes
What nuclear receptors participate in CYP induction?
aryl hydrocarbon receptor, peroxisome proliferator-activated receptors, and two orphan nuclear receptors (androstane receptor and pregnane X receptor)
6 pollutants in outdoor air
2. sulfur dioxide
3. nitrogen dioxide
4. carbon monoxide
6. particulate matter
Health effects of ozone exposure
damaged mediated by free radicals, injuring respiratory epithelial cells and type 1 alveolar cells with inflammatory mediator.
Decreased lung function, chest discomfort, ozone-induced asthma (airway hyper-reactivity and neutrophilia)
Health effects of sulfur dioxide exposure
converted into sulfuric acid and sulfuric trioxide
burning sensation in nose and throat, dyspnea, asthma attacks
Health effects of particulate matter (aka soot)
fine or ultrafine particles less than 10 um in diameter are most harmful.
Inhaled into alveoli-->inflammatory mediators (macrophage inflammatory protein 1 alpha and endothelin)
irritation to eyes, throat, lungs, induce asthma attacks, promote myocardial ischemia
What gets damaged most markedly in chronic carbon monoxide poisoning?
ischemia in CNS, especially basal ganglia and lenticular nuclei
impaired memory, vision, hearing, and speech.
Symptoms of acute CO poisoning
characteristic generalized cherry-red color of the skin and MM
brain edema, punctate hemorrhages, hypoxia-induced neuro changes
8 examples of indoor air pollutants
1. tobacco smoke
5. wood smoke
Health effects of bioaerosol exposure
microbes causing Legionnaires' dz, viral pneumonia, cold
allergens from pet danger, dust mites, and fungi/molds -->rhinitis, eye irritation, and asthma
Health effects of radon exposure
Health effects of formaldehyde
0.1 ppm or higher-->dyspnea, burning in eyes and throat, asthma; carcinogen
Four heavy metals most commonly associated with harmful effects in humans
Health problems associated with subclinical lead poisoning
low intellectual capacity, behavior problems, etc
At about twice the max allowed level of lead, what health problems can develop?
increased nerve conduction velocity, increased level of erythrocyte protoporphyrin, decreased vitamin D metabolism, and decreased calcium homeostasis
At about four times the max allowed level of lead, what health problems can develop?
decreased hemoglobin synthesis
At about ten times the max allowed level of lead, what health problems can develop?
encephalopathy, nephropathy, frank anemia, and colic
Where is most lead absorbed into?
bone and developing teeth
Why are children more susceptible to lead poisoning than adults?
higher intestinal absorption (50% versus <15%) and more permeable blood-brain barrier
Bone consequences of lead poisoning in children
interferes with normal remodeling of cartilage and primary bone trabeculae in epiphyses, causing radiodense "lead lines" of increased bone density, also appears in gums
inhibits healing of fx by increasing chondrogenesis and delaying cartilage mineralization.
Hematopoietic consequences of lead poisoning in children
inhibits delta-aminolevulinic acid dehdyratase and ferrochelatase-->microcytic hypochromic anemia
What is used to dx lead poisoning?
detection of elevated blood levels of lead and free (or zinc-bound) red cell protoporphyrin
Morphological changes in lead poisoning
1.Ringed sideroblasts (iron-laden mitochondria) in marrow
2. Microcytic hypochromic anemia with mild hemolysis
3. punctate basophilic stippling of RBCs
CNS and PNS changes in lead poisoning
CNS: brain edema, demyelination of cortical neurons, diffuse astrocytic proliferation
PNS: peripheral demyelinating neuropathy in motor nerves of most commonly used muscles--wristdrop and footdrop
GI and renal changes in lead poisoning
GI: lead colic
Renal: proximal tubular damage, interstitial fibrosis, renal failure, "saturnine gout"
What is especially susceptible to methyl mercury?
developing CNS due to lipid solubility. Binds with high affinity to thiol groups.
What is the main protective mechanism against mercury-induced CNS and kidney damage?
intracellular glutathione acting as a thiol donor
Arsenic trioxide is used to tx what disease?
relapsing acute promyelocytic leukemia.
Three most toxic forms of arsenic
1. arsenic trioxide
2. sodium arsenite
3. arsenic trichloride
Mechanism of arsenic toxicity
interference with mitochondrial ox phos, since trivalent arsenic can replace the phosphates in ATP
Neurological effects of arsenic toxicity
2-8 weeks after exposure
sensorimotor neuropathy--paresthesias, numbness and pain
Most serious consequence of chronic arsenic exposure
development of CA in almost all tissues, particularly lungs and skin.
Skin changes in arsenic exposure
hyperpigmentation and hyperkeratosis-->basal and squamous cell carcinoma. Appears on palms and soles (unlike skin tumors induced by sunlight)
Mechanism of cadmium toxicity
1. obstructive lung dz, due to necrosis of alveolar macrophages
2. kidney damage, due to tubular damage progressing to ESRD
3. skeletal problems, due to calcium loss (osteoporosis and osteomalacia)
4. elevated risk of lung CA due to ROS causing DNA damage
Vinyl chloride: associated disease
Polychlorinated biphenyls, dioxins, and herbicides: associated diseases
folliculitis and acneiform dermatosis
Benzene and 1,3-butadiene: associated disease
Chemicals associated with male infertility
lead, phthalate plasticizers, and cadmium
Chemicals associated with female infertility/stillbirths
lead and mercury
Chemicals associated with teratogenesis
mercury, polychlorinated biphenyls
Chemicals associated with urinary system toxicity
mercury, lead, glycol ethers, solvents
Chemicals associated with bladder CA
naphthylamines, 4-aminobiphenyl, benzidine, rubber products
Chemicals associated with peripheral neuropathies
solvents, acrylamide, methyl chloride, mercury, lead, arsenic
Chemical associated with ataxic gait
Chemicals associated with CNS depression
chlordane, toluene, acrylamide, mercury
Chemicals associated with cataracts
alcohols, ketones, aldehydes, solvents, UV
Chemicals associated with respiratory fibrosis
silica, asbestos, cobalt
Chemicals associated with respiratory irritation
ammonia, sulfur oxides, formaldehyde
Chemicals associated with respiratory hypersensitivity
Chemicals associated with COPD
grain dust, coal dust, cadmium
Chemicals associated with lung CA
radon, asbestos, silica, bis(chloromethyly)ether, nickel, arsenic, chromium, mustard gas, uranium
Chemicals associated with nasal CA
isopropyl EtOH, wood dust
Chemicals associated with heart disease
CO, lead, solvents, cobalt, cadmium
How is benzene metabolized?
hepatic CYP2E1 to toxic metabolites that disrupt differentiation of hematopoietic cells in bone marrow-->aplasia and acute myeloid leukemia
Polycyclic hydrocarbons: diseases associated
lung and bladder CA
Examples of organochlorides
DDT, PCBs, dioxin-->pesticides
Diseases associated with organochlorides
1. endocrinopathies, having anti-estrogen or anti-androgen effects
2. folliculitis and chloracne dermatosis
3. PCBs induce CYPs-->abnormal drug metabolism
Inhalation of mineral dusts cause what disease?
pneumoconioses: chronic, non-neoplastic lung disease
Toxins in tobacco smoke
tar, polycyclic aromatic hydrocarbons, phenol, benzopyrene, nitrosamine (carcinogenesis and tumor promotion)
formaldehyde and nitrogen oxides (toxic to cilia)
What two drugs interact in forming laryngeal CA?
tobacco and EtOH
How is ethanol metabolized?
biotransformed into acetaldehyde in liver by alcohol dehydrogenase (mainly), microsomal ethanol-oxidizing system, and catalase.
ADH in cytosol of hepatocytes
Then, acetaldehyde is converted to acetate by acetaldehyde dehydrogenase (ALDH)
MEOS involves CYPs (esp CYP2E1)
What produces a majority of the toxic effects of alcohol consumption?
Acetaldehyde. Responsible for acute effects of EtOH and for developing oral CA
Allelic variation of what enzyme affects 50% of Asians?
ALDH; very low ALDH activity due to base substitution (ALDH2*2) of one allele
People who cannot oxidize acetaldehyde have what abnormal enzyme?
homozygous for ALDH2*2; nausea, flushing, tachycardia, and hyperventilation
What causes hepatic steatosis and lactic acidosis in alcoholics?
Increased NADH/NAD ratio
How do gram-negative bacteria in the intestinal flora respond to alcohol?
release of endotoxin (lipopolysaccharide) to stimulate TNF production and cytokines from macrophages and Kupffer cells-->hepatic injury
Gastric changes in acute alcoholism
gastritis and ulceration
CNS changes in acute alcoholism
depressant, first affecting subcortical structures (high brain stem reticular formation) modulating cerebral cortical activity.
At higher levels, cortical neurons and then lower medullary centers are depressed.
What vitamin deficiency is common in alcoholics?
thiamine (vitamin B1); causing peripheral neuropathies and Wernicke-Korsakoff syndrome
CV effects of alcohol
dilated congestive cardiomyopathy
heavy EtOH causes decreased levels of HDL
EtOH is most harmful during which trimester of preg?
Mechanism of EtOH-induced laryngeal and esophageal CA
People with this allele who drink are at higher risk of developing esophageal CA
one copy of ALDH2*2 allele
What compound in red wine may have protective effects against CV dz?
activates protein deacetylases of the Sir2 family, including histone deacetylases
Estrogen therapy alone is only used in these patients
increased risk of uterine CA in other patients
Findings by the WHI in 2002
combined therapy caused a reduction in fx, but increased risk of breast CA and venous thromboembolism; no effect on preventing CV dz in patients over 60. 10 million drop in therapy in 5 years.
HRT: risk highest and latency times shorter for developing these CA
lobular carcinomas and ductal-lobular CA
CV protective effect of HRT based on:
younger women: response of estrogen receptors regulating calcium homeostasis in blood vessels
Four types of diseases associated with OCs
1. thromboembolism: due to generation of acute-phase response, with increase in CRP and coagulation factors and reduction in anticoagulants
2. CV disease
3. reduce incidence of endometrial and ovarian CA; small increase in breast CA incidence during first 5 years of use
4. Hepatic adenoma
Disease associated with orally administered anabolic steroids
Metabolism of acetaminophen
95% by phase 2 enzymes, excreted as glucuronate or sulfate conjugates
5% through CYPs (especially CYP2E) to NAPQI, a reactive metabolite. Conjugated to glutathione.
Consequence of acetaminophen overdose
GSH is depleted, so NAPQI accumulates, causing centrilobular necrosis and liver failure
Tx of acetaminophen overdose
N-acetylcysteine, which restores GSH
may need liver transplant in serious overdoses
Mechanism of disease in aspirin overdose
Salicylate causes alkalosis due to stimulating respiratory center in the medulla-->metabolic acidosis to compensate-->accumulation of pyruvate and lactate-->uncoupling of ox phos and inhibition of Krebs cycle
Also, formation of non-ionized forms of salicylates that can diffuse into brain and produce nausea-->coma
Consequences of chronic aspiring toxicity (salicylism)
1.H/A, dizziness, tinnitus, confusion, hearing impairment, n/v/d, drowsiness-->convulsions and coma.
2. acute erosive gastritis-->GI bleeding and gastric ulceration
3. bleeding tendency, petechial hemorrhages
Proprietary analgesic mixtures of ASA and phenacetin or acetaminophen, when taken over several years, can lead to this disease:
analgesic nephropathy: tubulointerstitial nephritis with renal papillary necrosis
Drugs associated with acute dystonic reactions and parkinsonian syndrome
hydralazine and procainamide
Abx associated with hepatic steatosis
Drugs associated with hepatic cholestasis
chlorpromazine, estrogens, contraceptives
Drugs associated with asthma
Drug associated with acute pneumonitis
Drugs associated with interstitial fibrosis
busulfan, nitrofurantoin, bleomycin
Drugs associated with acute tubular necrosis
aminoglycoside abx, cyclosporin, amphotericin B
Drug associated with glomerulonephritis
Drugs associated with cardiomyopathy
Drugs associated with arrhtyhmias
theophylline, hydantoins, digoxin
Drugs associated with skin changes
antineoplastic agents, sulfonamies, hydantoins, some abx, many others
Drugs associated with granulocytopenia, aplastic anemia, and pancytopenia
antineoplastic agents, immunosuppressives, and chloramphenicol
Drugs associated with hemolytic anemia and thrombocytopenia
penicillin, methyldopa, quinidine, and heparin
CV effects of cocaine
sympathomimetic; blocks dopamine reuptake in CNS and epi/NE at adrenergic nerve endings. Also stimulates release of NE. Can precipitate lethal arrhythmias
Causes coronary artery vasoconstriction and enhances platelet aggregation.
Increases oxygen demand while causing vasoconstriction-->MI
CNS effects of cocaine
hyperpyrexia and seizures
likely due to aberrations of dopaminergic pathways that control body temperature
Cocaine effects on pregnancy
decreased blood flow to placenta--fetal hypoxia and spont AB
Mechanism of sudden death in heroin use
profound respiratory depression, arrhythmia and cardiac arrest, and severe pulmonary edema
Mechanism of pulmonary injury in heroin use
edema, septic embolism from endocarditis, lung abscess, opportunistic infections, and FB granulomas from talc and other adulterants
Sites of infections due to heroin use
skin and subQ tissue, heart valves, liver, and lungs
endocarditis: right heart valves (esp tricuspid due to S. aureus)
Viral hepatitis due to shared needles, HIV
Skin changes in heroin use
abscesses, cellulitis, and ulcerations--.scarring, hyperpigmentation and thrombosed veins
Renal changes in heroin use
amyloidosis secondary to skin infections
Heavy proteinuria and the nephrotic syndrome are induced.
How do meth and MDMA work?
meth: releases dopamine in the brain, which slows glutamate release
MDMA: increased serotonin release
How does THC work?
endogenous cannabinoid receptors CB1 and CB2 and endocannabinoids regulate the hypothalamic-pituitary-adrenal axis to modulate control of appetite, food intake, and energy balance, fertility and sexual behavior
Factors influencing mechanical trauma
shape of colliding object, amount of NRG discharged at impact, and tissues/organs bearing the impact
wound produced by scraping or subbin-->removal of superficial layer (e.g. skin abrasions removed only the epidermal layer)
bruise, blunt object-->damage to vessels and extravastion of blood into tissues
tear or disruptive stretching of tissue due to application of force by a blunt object; intact bridging blood vessels and jagged, irregular edges
inflicted by a sharp instrument with severing of bridging vessels
long, narrow instrument. Can be penetrating (when it pierces the tissue) or perforating (when traversing a tissue to also create an exit wound)
Factors determining clinical significance of a burn injury
depth of burns, % of body surface involved, internal injuries caused by inhalation of hot and toxic fumes, and promptness/efficacy of therapy
Classification of burns
1. superficial burns (first-degree): confined to epidermis
2. partial thickness burns (second-degree): injury to dermis
3. full-thickness burns (third-degree): extend to subQ or even muscle tissue (fourth-degree)
Greatest threats to life in burn patients
hypovolemic shock, sepsis, and respiratory insufficiency
What develops in heat burns, associated with excess heat loss and an increased need for nutritional support?
Most common opportunistic pathogen during burns
Pseudomonas aeruginosa; also S. aureus and Candida
What has improved mortality from burns?
techniques for early excision and grafting of the burn wound
Long-term consequences of burns
hypertrophic scars and itching
Morphology of burns
grossly, full-thickness burns are white or charred, dry, and anesthetic
Partial-thickness burns are pink or mottled with blisters and painful
Coagulative necrosis, adjacent to vital tissue that accumulates inflammatory cells and marked exudation
What are heat cramps?
loss of electrolytes from sweating
What is heat exhaustion?
sudden onset prostration and collapse, due to hypovolemia from water loss
What is heat stroke?
associated with high temps, high humidity, and exertion.
thermoregulation fails, internal temperature rises above 40 degrees C
Marked vasodilation-->decreased effective circulating blood volume-->hyperkalemia, tachy, arrhythmias, and others.
People with this genetic variation are at increased risk of heat stroke
ryanodine receptor type 1 in skeletal muscle; SR regulating Ca entry into cytoplasm.
Consequence associated with RYR1 in heat stroke
necrosis of the muscles (rhabdomyolysis) and myocardium due to nitroslyation of the RYR1
What exacerbates hypothermia?
high humidity, wet clothing, and dilation of vessels due to EtOH.
Direct effects of hypothermia
mediated by physical disruptions within cells by high salt concentrations due to crystallization of intra- and extracellular water
Indirect effects of hypothermia
slowly developing chilling--vasoconstriction and increased permeability-->edema and hypoxia
sudden, persistent chilling: ischemic injury and degenerative changes in peripheral nerves; gangrene.
Two types of electrical injuries
burns and V fib or cardiac and respiratory center failure
Factors affecting type and severity of electric burns
1. strength (amps)
3. path of current throughout the body
Characteristic of Alternating current
induces tetanic muscle spasms, causing irreversible clutching, which prolongs damage
Ionizing radiation has this chemical property, different from non-ionizing radiation
has sufficient energy to remove tightly bound electrons
Type of particles inducing heavy damage in a restricted area
Types of particles that dissipate energy over a longer, deeper course, producing less damage per unit of tissue
x-rays and gamma rays
Three units of radiation doses
1. Curie--amount of radiation emitted by a source
2. Gray--energy absorbed by target tissue per unit mass
3. Sievert--absorbed dose multiplied by the relative biologic effectiveness of the radiation
Main determinants of the biologic effects of ionizing radiation
1. rate of delivery--divided doses not at severe as cumulative damage
2. field size--high doses delivered in small, carefully shielded fields less lethal than small doses delivered in large fields
3. cell proliferation--rapidly dividing cells more vulnerable than quiescent cells. Gonads, bone marrow, lymphoid tissue, and GI mucosa are extremely vulnerable
4. oxygen effects and hypoxia--ROS important mechanism of DNA damage, so poorly vascularized tissues with low oxygenation are less sensitive to radiation therapy than nonhypoxic cells
5. vascular damage--to endothelial cells-->narrowing or occlusion of vessels-->fibrosis, impaired healing, and chronic ischemic atrophy
Morphology of radiation exposure
1. structural changes in chromosomes and mitotic spindle.
2. nuclear swelling, condensation, and clumping of chromatin
3. giant cells with pleomorphic nuclei, then nuclear pyknosis and lysis
4. cytoplasmic swelling, mitochondrial distortion, and ER degeneration
5. vascular changes and interstitial fibrosis then endothelial cell swelling and vacuolation-->rupture or thrombosis-->collagenous hyalinization and thickening of the media
Acute effects of radiation on hematopoietic and lymphoid systems
marrow aplasia, lymphopenia destroying circulating blood and tissue lymphocytes; death of stem cells-->permanent aplastic anemia
Common change in tissue included in the irradiated field
fibrosis, due to replacing dead parenchymal cells by connective tissue-->scars and adhesions. Common in lungs, salivary glands, and colorectal/pelvic areas
Most troubling damage to DNA by radiation
double stranded breaks-->homologous and non-homologous end joining-->mutations or gross chromosomal aberrations
Types of CA due to low-level radiation
leukemias, thyroid, breast, lung
"second cancers": AML, myelodysplastic syndrome, Hodgkin lymphoma, and solid tumors
Occupational exposures leading to increased risk of CA development
Radon: from spont decay of Uranium has two decay products: polonium 214 and 218-->emit alpha particles
Inhaled radon deposit in lung