Chapter 9: Environmental and Nutritional Diseases Flashcards
Sources of CO2 causing climate change
Burning of fossil fuels, ozone, methane–these gases along with water vapor produce the green house effect by absorbing/re-emitting infrared energy; also increased by deforestation, increase n surface heat absorption due to loss of ice, increase in water vapor due to greater evaporation, decreased sequestration of CO2 in oceans due to reduced organisms, increased heat energy in oceans and atmosphere
A quantatitative concept of a poison strictly depends on?
Dosage
Exogenous chemicals in the environment in air, water, food and soil that may be absorbed into the body through inhalation, ingestion and skin contact
Xenobiotics
Most solvents and drugs are ____philic which facilitates their transport in the blood by _____ and their penetration through the plasma membrane into cells
Lipo
Lipoproteins
_____ estimates the burden imposed by environmental disease, including communicable disease, and nutritional diseases by applying a metric called DALY (disability adjusted life year)–Sum of years of life lost due to premature mortality and years of life lost to disability in a population
GBD–Global Burden of Disease, a world health organization project
Most solvents and drugs absorbed by the body go one of either two paths. They can be detoxified by obtaining _____ properties or they can be activated to form toxic metabolites
Water soluble
Phases that occurs in metabolism
Phase I: chemicals undergo hydrolysis, oxidation or reduction
Phase II: products of phase I become conjugated onto something (this makes them water soluble–examples are glucoronidation, sulfation, methylation, and conjugation with glutathione
Most important catalyst of phase I reactions
CYP (cytochrome P 450 enzyme system)
Where is P-450 located?
Primarily in endoplasmic reticulum in liver but also present in skin, lungs, and GI mucosa and other organs
The P-450 system catalyzes reactions that either detoxify cenobitic so or less commonly covert xenobiotics into active compounds that cause cellular injury. Which one causes ROS?
Both may produce ROS as byproduct
In the United States, the environmental protection agency monitors and sets allowable upper limits for what six pollutants?
Sulfur dioxide Carbon monoxide Ground level ozone Nitrogen dioxide Lead Particulate matter
Which ozone is the good one and which is the bad?
Good=O3
Bad=ground level ozone
What does O3 do? What does ground level ozone do?
Ozone (O3) is produced by interaction of UV radiation and oxygen in the stratosphere and protects life on earth by absorbing the most dangerous UV radiation emitted by the sun
It is a gas formed by the reaction of nitrogen and volatile organic compounds (industrial and motor vehicle exhaust) in the presence. It’s toxicity is mediated by the production of free radicals, which injure epithelial cells along the respiratory tract and type I alveolar cells
Conditions caused by exposure to chemical or physical agents in the ambient, workplace and personal environment including diseases of nutritional origin. Diseaase related to environmental exposures mostly comes to publics attention after dramatic events
Environmental disease
Single leading global cause of health loss
Undernutrition
Leading causes of death in developed nations
Undernutrition
Major risk factors of coronary and cerebrovascular diseases
Obesity, smoking and high cholesterol
5 of the top 10 causes of death in developing countries are what?
Infectious diseases–respiratory infection, HIV, diarrheal disease, TB, malaria
Malnutrition increases the risk of?
Infection
50% of all death in children younger than 5 are attributable to what 3 conditions (all preventable)
Pneumonia, diarrheal diseases, and malaria
Type of diseases constitute almost 1/3 of newly emerging infections and in many cases can be linked to environmental changes including global warming?
Vector borne diseases
How has worldwide mortality of under 5 yo children changed since 1980?
27% decline but does not meet UN goals yet. Under 5 year old mortality in central and west Africa has not declined
3 examples of emerging infectious diseases
- Newly evolved strains of organisms (MRSA, XDF TB, chloroquine-resistant malaria)
- Endemic in other species that have recently entered human population (HIV and SARS)
- Present in human populations but show a recent increase in incidence (dengue fever)
4 aspects of health and disease affected by global warming
- Increase in vector borne disease (dengue fever, west Nile, hanavirus pulmonary syndrome)
- Malnutrition: due to disrupted crops
- Gastroenteritis and infectious disease epidemics–due to contamination after natural disasters
- Cardiovascular, cerebrovascular, respiratory disease–heat waves and air pollution
Most solvents are drugs are of what chemical category?
Lipophilic, facilitating transport in blood by lipoproteins and penetration through PM into cells
2 phases of bio transformation of xenobiotics
Phase I–P450 (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 I reactions that is harmful to cells?
ROS
Example: trichloromethyl free radical from CCl4, DNA binding metabolite from Benzo-a-pyrene in cigarette smoke
Inducers of CYP
Environmental chemicals, drugs, smoking a, EtOH and hormones
What decreases CYP activity?
Fasting or starvation
Mechanism of inducers of CYP
- Bind nuclear receptors
- Heterodimerize with retinoic X receptor
- Form transcriptional activation complex in 5’ flanking region of CYP genes
What nuclear receptors participate in CYP induction?
Rayo hydrocarbon receptor, peroxisome proliferator-activated receptors and two orphan nuclear receptors (androstane receptor and pregnant X receptor)
6 pollutants in outdoor air
- Ozone
- Sulfur dioxide
- Nitrogen dioxide
- Carbon monoxide
- Lead
- Particulate matter
Health effects of ozone exposure
Damage 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 ozone exposure
Damage 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 ultra fine particles less than 10um in diameter are most harmful. Inhaled into alveoli leading to release of 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—leads to impaired memory, vision, hearing and speech
Symptoms of acute CO poisoning
Characteristic generalized cherry-red color of skin and MM brain edema, punctate hemorrhages, hypoxia–induced neuro changes
8 examples of indoor air pollutants
- Tobacco smoke
- CO
- NO2
- Asbestos
- Wood smoke
- Bio aerosols
- Radon
- Formaldehyde
Health effects of bioaerosol exposure
Microbes causing legionnaires disease, viral pneumonia, cold allergens from pet dander, dust mites, and fungi/molds–>rhinitis, eye irritation, and asthma
Health effects of radon exposure
Lung cancer
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
- Lead
- Mercury
- Arsenic
- Cadmium
Health problems associated with sub clinical 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 erythrocytes protoporphyrin, decreased vitamin D metabolism, and decreased calcium homeostasis
At about 4x the max allowed level of lead, what problems occur?
Decreased hemoglobin synthesis
At about 10x the max allowed level of lead, what health problems 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% vs. less than 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 epiphysis, causing radio dense lead lines of increased bone density–also appears in gums
Inhibits healing of function by increasing chondrogenesis and delaying cartilage mineralization
Hematopoietic consequences of lead poisoning in children
Inhibits delta aminoelvulinic acid dehydratase and ferrocene latest–>microcytic hypochromic anemia
What is used to diagnose lead poisoning?
Detection of elevated blood levels of lead and free (or zinc bound) red cell protoporphyrin
Morphological changes in lead poisoning
- Ringed sideroblasts (iron-laden mitochondria) in marrow
- Microcytic hypochromic anemia with mild hemolysis
- Punctate basophilic stippling of RBCs
CNS and PNS changes in lead poisioning
CNS: brain edema, demyelination of cortical neurons, diffuse astrocytic proliferation
PNS: peripheral demyelinating neuropathy in motor nerves of most commonly used muscles–wrist drop and foot drop
GI and renal changes in lead poisoning
GI: lead colic
Renal: proximal tubular damage, interstitial fibrosis, renal failure, saturnine gout
Which organ 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 treat what disease?
Relapsing acute promo elocution leukemia
three most toxic forms of arsenic
- Arsenic trioxide
- Sodium arsenite
- 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 cancer in almost all tissues, particularly lungs and skin
Skin changes in arsenic exposure
Hyper pigmentation and hyperkeratosis–>basal and squamous cell carcinoma. Appears on palms and soles (unlike skin tumors induced by sunlight)
Mechanism of cadmium toxicity
- Obstructive lung disease, due to necrosis of Alvolar macrophages
- Kidney damage, due to tubular damage progressing to ESRD
- Skeletal problems, due to calcium loss. (Osteoporosis and osteomalacia)
- Elevated risk of lung cancer due to ROS causing DNA damage
Vinyl chloride associated disease
Liver angiosarcoma
Poly chlorinated biphenyls, dioxins, and herbicides: associated diseases
Folliculitis and acneiform dermatosis
Benzene and 1,3-butadiene: associated disease
Leukemia
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 cancer
Napthylamines, 4-amino biphenyl, Benzedine, rubber products
Chemicals associated with peripheral neuropathies
Solvents, acrylamide, methyl chloride, Mercury, lead, arsenic
Chemical associated with ataxic gait
DDT
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 respirator irritation
Ammonia, sulfur oxides, formaldehyde
Chemicals associated with respiratory hypersensitivity
Beryllium, isocyanates
Chemicals associated with COPD
Grain dust, coal dust, cadmium
Chemicals associated with lung cancer
Radon, asbestos, silica, bis (chloromethyl) ether, nickel, arsenic, chromium, mustard gas, uranium
chemicals associated with nasal cancer
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 cancer
Examples of organochlorides
- Endocrinopathies, having anti-estrogen or anti androgen effects
- Folliculitis and chloracne dermatosis
- 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), CO, nicotine, formaldehyde and nitrogen oxides (toxic to cilia)
What two drugs interact in forming laryngeal cancer
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 Cancer
Allelic variation of what enzyme affects 50% of Asians?
ALDH–very low ALDH activity due to base substitution (ALDH2x2) of one allele
People who cannot oxidize acetaldehyde have what abnormal enzyme?
Homozygous for ALDH*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 intestinal flora respond to alcohol?
Release of endotoxin (LPS) to stimulate TNF production and cytokines from macrophages and Kuppffer cells–>hepatic injury
Gastric changes in acute alcholism
Gastritis and ulceration
CNS changes in acute alcoholism
Depressant, first affecting su cortical 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 and HTN
EtOH is most harmful during which trimester of pregnancy?
First
Mechanism of EtOH induced laryngeal and esophageal cancer?
Acetaldehyde-DNA adducts
People with this allele who drink alcohol are at higher risk of developing esophageal cancer
One copy of ALDH2*2 allele
What compound in red wine may have protective effects against CV disease?
Resveratrol activates protein deacetylases of the sir2 family, including histones deacetylases
Estrogen therapy alone is only used in these pateints
Hysterectomized women increased risk of uterine cancer in other patients
Findings by the WHI in 2002
Combined therapy caused a reduction in function but increased risk of breast cancer and thromboembolism; no effect in preventing CV disease in patients over 60. 10 million drop in therapy in 5 year
HRT: Risk highest and latency times shorter for developing these cancers:
Lobular carcinomas and ductal-lobular carcinoma
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
- Thromboembolism: due to generation of acute phase response with increase in CRP and coagulation factors and reduction in anticoagulants
- Reduce incidence of endometrial and ovarian cancer and small increase of breast cancer
