.............is the single leading global cause of health loss (defined as morbidity and premature death).
......................... are the leading causes of death in developed countries
Ischemic heart disease and cerebrovascular disease
In developed countries the main risk factors associated with loss of healthy life are .............
smoking, high blood pressure, obesity, high cholesterol, and alcohol abuse.
In developing countries, infectious diseases constitute 5 of the 10 leading causes of death: ............................................
respiratory infections,HIV/AIDS, diarrheal diseases, tuberculosis, and malaria.
About 70% of all child deaths are attributed to only five conditions, all of them preventable: .............
pneumonia, diarrheal diseases, malaria, measles, and perinatal/neonatal problems (mostly prematurity and neonatal infections).
What are the Emerging infectious diseases (EIDs)?
(1) diseases caused by newly evolved strains or organisms, such as rifampin/isoniazid-resistant and multidrug-resistant (XDR) tuberculosis, chloroquine-resistant malaria, and methicillin-resistant Staphylococcus aureus;
(2) diseases caused by pathogens endemic in other species (e.g., wild mammals and birds) that recently entered human populations, such as HIV and severe acute respiratory syndrome (SARS);
(3) diseases caused by pathogens that have been present in human populations but show a recent increase in incidence, such as dengue fever
.......................... caused approximately 54% of worldwide emerging infectious diseases during the last 60 years
Bacteria and rickettsia
What are the The causes of global climate change?
Human activity is a major contributor, through increases of carbon dioxide (CO2), methane, and ozone, the main agents of the greenhouse effect. These gases (along with water vapor) act like a blanket by absorbing energy radiated from the earth's surface that would otherwise be lost into space.
Recent increases in levels of greenhouse gases, particularly CO2 and ozone produced by the combustion of hydrocarbons in automobiles and energy plants, are strongly correlated with warming of the earth
Also contributing to the increase in atmospheric CO2 is large-scale deforestationwhich decreases carbon sequestration by trees.
Beyond certain levels of warming of the land and seas, it is predicted that positive-feedback loops will amplify the process further.
Examples include increases in heat absorption due to the loss of reflective snow and ice; increases in water vapor in the atmosphere due to greater evaporation from bodies of water and transpiration from trees; large releases of stored CO2 and methane from thawing arctic tundra; and decreased sequestration of CO2 in the oceans, due to diminished growth of diatoms, which serve as an important CO2 sink
How will climate change impact human health by increasing the incidence of several diseases?
Cardiovascular, cerebrovascular, and respiratory diseases, caused by heat waves and air pollution
Gastroenteritis and infectious disease epidemics, caused by water and food contamination as a consequence of floods, and disruption of clean water supplies and sewage treatment, after heavy rains and other environmental disasters
Vector-borne infectious diseases, such as dengue fever, malaria, West Nile virus infection, and hantavirus pulmonary syndrome, as a consequence of changes in vector number and geographic distribution caused by increased temperatures, crop failures, and more frequent El Nino climate cycles
Malnutrition, caused by disruption of crops, mostly in tropical locations in which average temperatures are near or above crop tolerance levels
Xenobiotics are ...............................
exogenous chemicals in the environment in air, water, food, and soil that may be absorbed into the body through inhalation, ingestion, and skin contact
True or False: Most solvents and drugs are lipophilic, which facilitates their transport in the blood by lipoproteins and their penetration through the plasma membrane into cells
True or False: most solvents, drugs, and xenobiotics are metabolized to form inactive water-soluble products(detoxification), or are activated to form toxic metabolites
What are the phase one and two reactions?
In phase I reactions, chemicals undergo hydrolysis, oxidation, or reduction.
Products of phase I reactions are often metabolized into water-soluble compounds through phase II reactions, which include glucuronidation, sulfation, methylation, and conjugation with glutathione. Water-soluble compounds are readily excreted
The most important catalyst of phase I reactions is.......................... located primarily in the .............................
the cytochrome P-450 enzyme system (abbreviated as CYP)/ endoplasmic reticulum of the liver
What are the functions of CYPs?
CYPs are heme-containing enzymes with preferential affinity toward different substrates.
The system catalyzes reactions that either detoxify xenobiotics or activate xenobiotics into active compounds that cause cellular injury.
Both types of reactions may produce, as a byproduct,ROS, which can cause cellular damage.
Examples of metabolic activation of chemicals through CYPs are the production of the toxic trichloromethyl free radical from carbon tetrachloride in the liver, and the generation of a DNA-binding metabolite from benzo[a]pyrene, a carcinogen present in cigarette smoke.
What is the mcc of variation in the activity of CYPs among individuals?
exposure to drugs or chemicals that induce or diminish CYP activity
What are some activator and inducers of CYP?
Known CYP inducers include environmental chemicals, drugs, smoking, alcohol, and hormones.
In contrast, fasting or starvation can decrease CYP activity.
What are some examples of Oxidations, P450 dependent?
Drugs that are metabolized to products that irreversibly inhibit the metabolizing enzyme.
Include ethinyl estradiol, norethindrone, spironolactone, secobarbital, allopurinol, and PTU
What is the mechanism of CYP induction?
Inducers of CYP do so by binding to nuclear receptors, which then heterodimerize with the retinoic X receptor (RXR) to form a transcriptional activation complex that associates with promoter elements located in the 5′-flanking region of CYP genes.
Nuclear receptors participating in CYP induction responses include the aryl hydrocarbon receptor, the peroxisome proliferator–activated receptors (PPAR), and two orphan nuclear receptors, constitutive androstane receptor (CAR), and pregnane X receptor (PXR)
What are some important genetic factors regarding metabolism of drugs?
Succinylcholine is an ester that is hydrolyzed in a phase I reaction by plasma cholinesterase ("pseudocholinesterase" or butyrylcholinesterase)--> decreased activity of the enzyme causes prolonged paralysis
Isoniazid and some other amines such as hydralazine and procainamide are metabolized in a phase II reaction by N-acetylation--> slow acetylator (AR) increase toxicity
In the United States the Environmental Protection Agency monitors and sets allowable upper limits for six pollutants: ......
What are the effects of particulate matter on health?
Children: Increased respiratory infections
Individuals with chronic lung or heart disease: Decreased lung function
Asthmatics: Excess mortality, Increased attacks
What are the functions of stratospheric ozone?
The interaction of ultraviolet (UV) radiation and oxygen (O2) in the stratosphere leads to the formation of ozone (O3), which accumulates in the so-called ozone layer 10 to 30 miles above the earth's surface.
This layer protects life on earth by absorbing the most dangerous UV radiation emitted by the sun.
During the last 30 years, the stratospheric ozone layer decreased in both thickness and extent due to the widespread use of aerosols, which drift up into the upper atmosphere and participate in chemical reactions that destroy ozone.
The resulting depletion has been most profound over polar regions, particularly Antarctica, during the winter months.
Recognition of the problem led to the ban of chlorofluorocarbons as aerosol propellants and their replacement by hydrofluoroalkanes, resulting in a decrease in the extent of stratospheric ozone “holes
What are the effect of ground level ozone on health?
In contrast to the “good” ozone in the stratosphere, ozone that accumulates in the lower atmosphere (ground-level ozone) is one of the most pernicious air pollutants .
Ground-level ozone is a gas formed by the reaction of nitrogen oxides and volatile organic compounds in the presence of sunlight. These chemicals are released by industrial emissions and motor vehicle exhaust.
Ozone toxicity is in large part mediated by the production of free radicals, which injure epithelial cells along the respiratory tract and type I alveolar cells, and cause the release of inflammatory mediators.
Healthy individuals exposed to ozone experience upper respiratory tract inflammation and mild symptoms (decreased lung function and chest discomfort), but exposure is much more dangerous for people with asthma or emphysema.
Ozone-induced asthma is associated with airway hyper-reactivity and neutrophilia
Even low levels of ozone may be detrimental to the lung function of normal individuals when combined with other air pollutants.
How is ground level ozone formed?
By the reaction of nitrogen oxides and volatile organic compounds in the presence of sunlight. These chemicals are released by industrial emissions and motor vehicle exhaust
What is the mechanism of ozone toxicity?
Ozone toxicity is in large part mediated by the production of free radicals, which injure epithelial cells along the respiratory tract and type I alveolar cells, and cause the release of inflammatory mediators.
What are the sources and effects of sulfur dioxide?
Sulfur dioxide is produced by power plants burning coal and oil, from copper smelting, and as a byproduct of paper mills.
Released into the air, it may be converted into sulfuric acid and sulfuric trioxide, which cause a burning sensation in the nose and throat, difficulty in breathing, and asthma attacks in susceptible individuals
What is the significance of Particulate matter (known as “soot”) ?
emitted by coal- and oil-fired power plants, by industrial processes burning these fuels, and by diesel exhaust
fine or ultrafine particles that are less than 10 μm in diameter are the most harmful
They are readily inhaled into the alveoli, where they are phagocytosed by macrophages and neutrophils, which release inflammatory mediators such as macrophage inflammatory protein 1α and endothelin.
Acute exposure to diesel exhaust that contains fine particles may cause irritation to the eyes, throat, and lungs, induce asthma attacks, and promote myocardial ischemia.
In contrast, exposure to particles that are greater than 10 μm in diameter is of lesser consequence, because these particles are generally removed in the nose, or trapped by the mucociliary epithelium of the airways
What is the mechanism of particulate matter induced damage?
fine or ultrafine particles that are less than 10 μm in diameter are the most harmful.
They are readily inhaled into the alveoli, where they are phagocytosed by macrophages and neutrophils, which release inflammatory mediators such as macrophage inflammatory protein 1α and endothelin
What are the sources and features of CO?
Carbon monoxide (CO). CO is a nonirritating, colorless, tasteless, odorless gas produced by the incomplete oxidation of carbonaceous materials.
Its sources include automotive engines, industrial processes using fossil fuels, wood and charcoal burning with an inadequate supply of oxygen, and cigarette smoke
What are the health consequences of CO?
The low levels often found in ambient air may contribute to impaired respiratory function, but of themselves they are not life-threatening.
However, chronic poisoning can occur in individuals working in confined environments with high exposure to fumes, such as tunnels, underground garages, and in highway toll workers.
CO is a systemic asphyxiant that kills by inducing CNS depression, which appears so insidiously that victims are often unaware of their plight and fail to help themselves.
Hemoglobin has 200-fold greater affinity for CO than for oxygen, and the resultant carboxyhemoglobin does not carry oxygen. Systemic hypoxia develops when the hemoglobin is 20% to 30% saturated with CO; unconsciousness and death are likely with 60% to 70% saturation
What are the features of chronic CO poisoning?
Chronic poisoning by CO develops because carboxyhemoglobin, once formed, is remarkably stable.
Even with low-level, but persistent, exposure to CO, carboxyhemoglobin may rise to life-threatening levels in the blood.
The slowly developing hypoxia can insidiously evoke widespread ischemic changes in the CNS; these are particularly marked in the basal ganglia and lenticular nuclei.
With cessation of exposure to CO, the patient usually recovers, but often there are permanent neurologic sequelae such as impairment of memory, vision, hearing, and speech. The diagnosis is made by measuring carboxyhemoglobin levels in the blood
What are the characteristic CNS changes in CO poisoning?
Ischemia of BG and lenticular nuclei
What are the symptoms of acute CO poisoning?
Generally a consequence of accidental exposure or suicide attempt.
In light-skinned individuals, acute poisoning is marked by a characteristic generalized cherry-red color of the skin and mucous membranes, which result from high levels of carboxyhemoglobin.
If death occurs rapidly morphologic changes may not be present; with longer survival the brain may be slightly edematous, with punctate hemorrhages and hypoxia-induced neuronal changes. The morphologic changes are not specific and stem from systemic hypoxia
CO kills by...............
True or False: Standard pulse oximetry (Sp02) CANNOT screen for CO exposure, as it does not differentiate carboxyhemoglobin from oxyhemoglobin
The commonest indoor pollutant is ........................
What are other indoor pollutants?
CO, nitrogen dioxide, asbestos
What is the importance of wood smoke?
Predisposes to lung infections
Contain carcinogenic polycyclic hydrocarbons
What are bioaerosols?
Bioaerosols range from microbiologic agents capable of causing infectious diseases such as Legionnaires' disease, viral pneumonia, and the common cold, to less threatening but nonetheless distressing allergens derived from pet dander, dust mites, and fungi and molds responsible for rhinitis, eye irritation, and asthma
What is the significance of Radon?
Radon, a radioactive gas derived from uranium widely present in soil and in homes, can cause lung cancer in uranium miners.
However, it does not seem that low-level chronic exposures in the home increase lung cancer risk, at least for nonsmokers
What is the health importance of formaldehyade?
Manufacture of building materials (cabinetry, furniture, adhesives, etc.)
Refugees from environmental disasters living in poorly ventilated trailers
Many of these cases occurred in trailers occupied by families displaced from their homes after Hurricane Katrina, which hit the southeastern United States in 2005.
At concentrations of 0.1 ppm or higher, it causes breathing difficulties and a burning sensation in the eyes and throat, and can trigger asthma attacks.
What are the two old resource of lead?
residential paints, and leaded gasoline
What are the occupations associated with lead poisoning?
mining, foundries, batteries, and spray painting
manufacturing of batteries, pigments, car radiators, and tin cans
...................... pose major hazards of lead poisoning to youngsters, and ingestion of up to 200 mg/day can occur
flaking lead paint in older houses and soil contamination
What is the importance of lead <10 microgram/dl?
Subclinical lead poisoning may occur in children exposed to levels of lead below 10 μg/dL, causing low intellectual capacity, behavioral problems such as hyperactivity, and poor organizational skills
What are the symptoms of lead poisoning?
What is the major reservoir of lead in human?
Most of the absorbed lead (80% to 85%) is incorporated into bone and developing teeth, where it competes with calcium; its half-life in bone is 20 to 30 years
What are the neurological symptoms of lead poisoning?
High levels of lead cause disturbances in the CNS in adults and children, but peripheral neuropathies predominate in adults
Why are children more susceptible to lead CNS effect?
Children absorb more than 50% of ingested lead (as compared with ≤15% in adults); the higher intestinal absorption and the more permeable blood-brain barrier of children create a high susceptibility to brain damage
The neurotoxic effects of lead are attributed to .................................
the inhibition of neurotransmitters caused by the disruption of calcium homeostasis
what is the mechanism of lead induced bone disease?
Lead interferes with the normal remodeling of cartilage and primary bone trabeculae in the epiphyses in children.
This causes increased bone density detected as radiodense “lead lines”.
Lead inhibits the healing of fractures by increasing chondrogenesis and delaying cartilage mineralization
What is the mechanism of lead induced anemia?
Lead inhibits the activity of two enzymes involved in heme synthesis, δ-aminolevulinic acid dehydratase and ferrochelatase.
Ferrochelatase catalyzes the incorporation of iron into protoporphyrin, and its inhibition causes a rise in protoporphyrin levels. The resulting heme deficiency causes microcytic, hypochromic anemia stemming from the suppression of hemoglobin synthesis
How is lead poisoning suspected and diagnosed?
In children it may be suspected on the basis of neurologic and behavioral changes, or by unexplained anemia with basophilic stippling in red cells.
Definitive diagnosis requires the detection of elevated blood levels of lead and free (or zinc-bound) red cell protoporphyrin
The major anatomic targets of lead toxicity are the ........................
bone marrow and blood, nervous system, gastrointestinal tract, and kidneys
What is the morphology of lead poisoning in blood ?
Blood and marrow changes occur fairly early and are characteristic.
The inhibition of ferrochelatase by lead results in the appearance of scattered ringed sideroblasts, red cell precursors with iron-laden mitochondria that are detected with a Prussian blue stain.
In the peripheral blood the defect in hemoglobin synthesis appears as a microcytic, hypochromic anemia that is often accompanied by mild hemolysis.
Even more distinctive is a punctate basophilic stippling of the red cells
What is the morphology of nervous system damage in lead poisoning?
Brain damage is prone to occur in children. It can be very subtle, producing mild dysfunction, or it can be massive and lethal.
In young children, sensory, motor, intellectual, and psychologic impairments have been described, including reduced IQ, learning disabilities, retarded psychomotor development, blindness, and, in more severe cases, psychoses, seizures, and coma.
Lead toxicity in the mother may impair brain development in the prenatal infant.
At the more severe end of the spectrum are marked brain edema, demyelination of the cerebral and cerebellar white matter, and necrosis of cortical neurons accompanied by diffuse astrocytic proliferation.
In adults the CNS is less often affected, but frequently a peripheral demyelinating neuropathy appears, typically involving the motor nerves of the most commonly used muscles. Thus, the extensor muscles of the wrist and fingers are often the first to be affected (causing wristdrop), followed by paralysis of the peroneal muscles (causing footdrop).
What are ringed sideroblasts?
red cell precursors with iron-laden mitochondria that are detected with a Prussian blue stain
What is the hallmark of lead neuropathy in adults?
1) Peripheral demyelinating neuropathy of motor nerves of the most commonly used muscles.
2)Extensor muscles of the wrist and fingers are often the first to be affected (causing wristdrop), followed by paralysis of the peroneal muscles (causing footdrop).
What is the first symptom of lead peripheral neuropathy in adults?
What is the hallmark of lead poisoning in GI?
Lead “colic” is characterized by extremely severe, poorly localized abdominal pain
What are the kidney pathologies in lead poisoning?
Kidneys may develop proximal tubular damage with intranuclear lead inclusions.
Chronic renal damage leads eventually to interstitial fibrosis and possibly renal failure. Decreases in uric acid excretion can lead to gout (“saturnine gout”).
What are the symptoms of lead poisoning based on level of exposure?
Lowest exposure: Impaired abilities (patients may be asymptomatic): Decreased learning and memory, Decreased verbal ability, Early signs of hyperactivity or ADHD, Lowered IQ, Impaired speech and hearing functions
High exposure: Paresis or paralysis, Encephalopathy (May abruptly lead to seizures, changes in consciousness, coma, and death) Lead line (blue-black) on gingival tissue, Colic (intermittent, severe abdominal cramps)
What should pregnant women avoid regarding fish?
shark, swordfish, king mackerel, or tilefish because they may contain high levels of mercury
Tuna steaks should be limited to 6 ounces per week
Which fish can be eaten by pregnant women?
Commonly eaten fish that are low in mercury include shrimp, canned light tuna, salmon, pollock, and catfish
What are the recommendation regarding avoidance of food borne illness in pregnancy?
Practice good personal hygiene (frequent hand washing)
Consume only meats, fish, and poultry (including eggs) that are fully cooked
Avoid unpasteurized dairy products and fruit/vegetable juices
Thoroughly rinse fresh fruits and vegetables under running water before eating
Avoid eating raw sprouts (including alfalfa, clover, radish, and mung bean). Bacteria can get into sprout seeds through cracks in the shell, these bacteria are nearly impossible to wash out.
Wash hands, food preparation surfaces, cutting boards, dishes, and utensils that come in contact with raw meat, poultry, or fish with hot, soapy water.In addition, countertops can be sanitized by wiping with a solution of one teaspoon liquid chlorine bleach per quart of water and leaving to dry over 10 minutes
What are the three food borne illness that are dangerous in pregnancy?
Toxoplasmosis — Toxoplasmosis is caused by ingestion of undercooked or cured meat or meat, soil-contaminated fruit or vegetables, and contaminated unfiltered water
Listeria monocytogenes — Listeria is a common low-level contaminant of both processed and unprocessed foods of plant and animal origin, but hot cooked foods are not a vehicle of Listeria transmission. It is most commonly associated with processed/delicatessen meats, hot dogs, soft cheeses, smoked seafood, meat spreads, and paté
Brucellosis — Brucellosis is caused by ingestion of contaminated food such as raw milk, cheeses made from unpasteurized (raw) milk, or raw meat
What is the recommendation regarding folic acid in pregnancy?
Folic acid supplement of 0.4 to 0.8 mg per day preconceptionally and during the first trimester.
Higher doses (4 milligrams per day) are recommended for women known to be at increased risk for offspring with neural tube defects (eg, history of a previously affected infant, maternal use of some anticonvulsant medications)
What are the the main sources of exposure to mercury?
contaminated fish (methyl mercury) and mercury vapors released from metallic mercury in dental amalgams, a possible occupational hazard for dental workers
What is the importance of methyl mercury?
Inorganic mercury from the natural degassing of the earth's crust or from industrial contamination is converted to organic compounds such as methyl mercury by bacteria.
Methyl mercury enters the food chain, and in carnivorous fish such as swordfish, shark, and bluefish, mercury may be concentrated to levels a million-fold higher than in the surrounding water.
Disasters caused by the consumption of fish contaminated by the release of methyl mercury from industrial sources in Minamata Bay and the Agano River in Japan caused widespread mortality and morbidity.
What are the symptoms of minimata disease?
cerebral palsy, deafness, blindness, mental retardation, and major CNS defects in children exposed in utero.
For unclear reasons, the developing brain is extremely sensitive to methyl mercury
What is the mechanism of mercury induced CNS damage?
The lipid solubility of methyl mercury and metallic mercury facilitate their accumulation in the brain, disturbing neuromotor, cognitive, and behavioral functions.
Mercury binds with high affinity to thiol groups, a property that contributes to its toxicity
What is the major defense against mercury induced damage?
Intracellular glutathione, acting as thiol donor, is the main protective mechanism against mercury-induced CNS and kidney damage
What are the sources of arsenic poisoning?
Arsenic is found naturally in soils and water and is used in products such as wood preservers, as well as herbicides and other agricultural products.
It may be released into the environment from mines and smelting industries.
Arsenic is present in Chinese and Indian herbal medicine, and arsenic trioxide is used in the treatment of relapsing acute promyelocytic leukemia.
Large concentrations of inorganic arsenic are present in ground water used for drinking in countries such as Bangladesh, Chile, and China.
Between 35 and 77 million people in Bangladesh drink water contaminated by arsenic, constituting the highest environmental cancer risk ever found
The most toxic forms of arsenic are .......................
the trivalent compounds arsenic trioxide, sodium arsenite, and arsenic trichloride
Pregnant women should avoid eating ....................................due to high mercury levels
What are the symptoms of acute arsenic exposure?
If ingested in large quantities, arsenic causes acute toxic effects consisting of severe disturbances of the gastrointestinal, cardiovascular, and CNS that are often fatal.
These effects may be attributed to interference with mitochondrial oxidative phosphorylation, since trivalent arsenic can replace the phosphates in adenosine triphosphate.
Neurologic effects usually occur 2 to 8 weeks after exposure and consist of a sensorimotor neuropathy that causes paresthesias, numbness, and pain
What are the consequences of chronic exposure to arsenic?
The most serious consequence of chronic exposure is the increased risk for the development of cancers in almost all tissues, but particularly in the lungs and skin.
Chronic exposure to arsenic causes skin changes consisting of hyperpigmentation and hyperkeratosis, which may be followed by the development of basal and squamous cell carcinomas. Arsenic-induced skin tumors differ from those induced by sunlight; they are often multiple and usually appear on the palms and soles. The mechanisms of arsenic carcinogenesis in skin and lung have not been elucidated but may involve defects in nucleotide excision repair mechanisms that protect against DNA damage.
Recent studies suggest that chronic exposure to arsenic in drinking water can also cause non-malignant respiratory disease
Mees' line in arsenic or thallium poisoning
transverse milky white lines
What is the source of Cadmium?
mining, electroplating, and production of nickel-cadmium batteries, which are usually disposed of as household waste.
Cadmium can contaminate the soil and plants directly or through fertilizers and irrigation water.
Food is the most important source of cadmium exposure for the general population
.............is the most important source of cadmium exposure for the general population
What are the symptoms of cadmium exposure?
The toxic effects of excess cadmium consist of obstructive lung disease caused by necrosis of alveolar macrophages, and kidney damage, initially consisting of tubular damage that may progress to end-stage renal disease.
Cadmium exposure can also cause skeletal abnormalities associated with calcium loss.
Cadmium-containing water used to irrigate rice fields in Japan caused a combination of osteoporosis and osteomalacia associated with renal disease.
Cadmium exposure is also associated with elevated risk of lung cancer, which has been demonstrated in workers exposed occupationally and in populations living near zinc smelters.
Cadmium is not directly genotoxic and most likely produces DNA damage through the generation of reactive oxygen species
A recent survey showed that 5% of the US population age 20 years and older have urinary cadmium levels that may produce subtle kidney injury and calcium loss.