Environmental and Nutritional Diseases

• Toxicology


  The science of poisons. It studies the distribution, effects, and mechanism of action of toxic agents
• Poison


  A quantitative concept strictly dependent on dosage
• Xenobiotics


  Exogenous chemicals in the environment in air, water, food, and, soil, that may be absorbed into the body via inhalation, ingestion, and skin contact
• Xenobiotic metabolism


  1. Phase I reactions: Chemicals undergo hydrolysis, oxidation, or reduction

  2. Phase II reactions: The activated metabolites of xenobiotics undergo conjugation with glutathione, glucoronidation, sulfation, or methylation to make them water-soluble and be readily excreted
• Outdoor air pollutants monitored and set an allowable limit in the US


  • Sulfur Dioxide
  • Carbon Monoxide
  • Ozone
  • Nitrogen Dioxide
  • Lead
  • Particulate Matter
• Ozone


  • Produced by the interaction of UV radiation and oxygen (O2) in the stratosphere and naturally accumulates in the so-called ozone layer
  • Ground-level ozone is a gas formed by the reaction of nitrogen oxides and volatile organic compounds in the presence of UV
• Sulfur Dioxide


  • Can be converted to sulfuric acid and sulfur trioxide, which causes burning sensation in the nose and throat
• Particulate Matter


  • Fine or ultrafine particles less than 10µm in diameter and are readily inhaled into the alveoli where they can be phagocytosed and elicit an inflammatory reaction
• Carbon Monoxide


  • A systemic asphyxiant which can cause death by inducing CNS depression. Hemoglobin has 200-fold greater affinity for CO than for O2, and the resultant carboxyhemoglobin cannot carry O2
• Indoor air pollutants


  • Tobacco smoke
  • Carbon monoxide
  • Nitrogen dioxide
  • Asbestos
  • Polycyclic aromatic hydrocarbons
  • Bioaerosols
  • Radon
  • Formaldehyde
• Lead


  A readily absorbed heavy metal that binds to sulfhydryl groups in proteins and interferes with calcium metabolism
• Effects of lead


  • Interferes with the normal remodeling of cartilage and primary bone trabeculae in the epiphyses in children, causes increased bone density in radiograph detected as a radiodense lead lines
  • Inhibits the healing of fractures by increasing chondrogenesis and delaying cartilage mineralization
  • Inhibits the activity of 2 enzymes involved in heme synthesis: ∆-aminolevulinic acid dehydratase and ferrochelatase
• Morphologic changes in lead toxicity

  • Blood and marrow changes occur rapidly
  • Inhibition of ferrochelatase result in the appearance of few ring sideroblasts, red cell precursors with iron-laden mitochondria detected with Prussian blue stain
  • In the PBS, there is microcytic hypochromic anemia accompanied by mild hemolysis
  • Even more distinctive is a punctate basophilic stippling of RBCs
• Mercury


  Like lead, it binds to sulfhydryl groups leading to damage in the CNS and the kidneys
• Forms of mercury


  • Metallic mercury (elemental mercury)
  • Inorganic mercury (mostly mercuric chloride)
  • Organic mercury (mostly methyl mercury)
• Arsenic


  Interfere with several aspects of cellular metabolism leading to toxicities that are most prominent in the gastrointestinal tract, nervous system, skin, and heart
• Effects of arsenic


  • Neurologic effects occur 2-8 weeks after exposure and consist of sensorimotor neuropathy causing paresthesia, numbness, and pain
  • Chronic exposure causes skin changes consisting of hyperpigmentation and hyperkeratosis
  • Most serious consequence of chronic exposure is development of cancer in the lungs, bladder, and skin
• Cadmium


  Preferentially toxic to the kidneys and lungs through uncertain mechanisms that may involve increased production of ROS
• Industrial and agricultural exposures

  • Organic solvents
  • Polycyclic hydrocarbons
  • Organochlorines
  • Dioxins and PCBs
  • Mineral dusts
  • Vinyl chloride
  • Bisphenol A (BPA)
• Organic solvents


  • Acute exposure to high levels of vapors can cause dizziness leading to CNS depression and even coma
  • Occupational exposure to benzene and 1,3-butadiene increases risks of leukemia
• Polycyclic hydrocarbons


  • Most potent carcinogens and industrial exposures have been implicated in the development of lung and bladder CA
  • Polycyclic Hydrocarbons most of the time are initiators
• Organochlorines


  • Halogenated organic compounds are synthetic lipophilic products that resist degradation
  • Importantly used in pesticides: DDT, Lindane, Aldrin, and Dieldrin
  • Most organochlorines disrupt hormonal balance because of antiestrogenic or antiandrogenic activity
• Dioxins and PCBs


  • Can cause skin disorders such as folliculitis and dermatosis known as chloracne characterized by acne, cyst formation, hyperpigmentation, and hyperkeratosis in the face and behind the ears
  • Can also produce toxicities in the liver and CNS
  • PCBs can induce CYPs and can cause abnormal drug metabolism
• Mineral dusts


  • Can cause chronic, non-neoplastic lung diseases such as pneumoconiosis
  • Most common are exposure to coal dust, silica, asbestos, and beryllium
• Vinyl chloride


  • Exposure in the synthesis of poly vinyl resins lead to the development of angiosarcoma of the liver
• Bisphenol A (BPA)


  • Used in the synthesis of polycarbonate food/water containers
  • A potential endocrine disruptor
• Tobacco


  • Smoking is the most readily preventable cause of death
  • 440,000 premature deaths/year in the US: Cancer, CVS, Respiratory, Cerebrovascular diseases
  • $150 billion in health related costs
  • Passive tobacco inhalation can cause lung cancer in non-smokers
  • Both non-small cell and small cell lung carcinomas are linked to cigarette smoking
  • Tobacco causes 70% of lung cancers, and 30% of all cancers
• Pack-years


  The average number of cigarette packs smoked per day multiplied by the number of years smoking
• Chemicals in tobacco and smoke

  • Contains between 2,000 to 4,000 substances, more than 60 of which has been classified as carcinogenic
• Nicotine


  • An alkaloid present in tobacco leaves, is not a direct cause of the tobacco related diseases, but it is strongly addictive
  • It binds to nicotinic Ach receptors in the brain and stimulates the release of catecholamine from sympathetic neurons
• Effects of smoking on the lungs

  • Agents in smoke have direct irritant effect on the tracheobronchial mucosa, producing inflammation and increased mucous production (bronchitis)
  • It also causes recruitment of leukocytes with increased local elastase production resulting to a subsequent injury to the lung parenchyma leading to emphysema
  • Polycyclic hydrocarbons & nitrosamines are potent carcinogens involved in the development of lung CA in humans
  • CYPs and phase II enzymes increase solubility of carcinogens, however some are electrophilic and form DNA adducts
  • Adducts can cause mutations in the proto-oncogenes and TSGs
• Other diseases associated with smoking

  • Cancers of esophagus, pancreas, bladder, kidney, cervix, and bone marrow
  • Emphysema, chronic bronchitis, and COPD
  • Atherosclerosis and Myocardial Infarction
  • Can harm a developing fetus, increasing the risk of spontaneous abortion, preterm births and intrauterine growth retardation
  • Passive smoke inhalation is associated with the same effects that result from active smoking
• Alcohol


  Ethanol consumption in moderate amounts is generally not injurious, but it can cause serious physical and psychological damage in excessive amounts
• Alcohol metabolism


  • Alcohol in the blood is oxidized to acetaldehyde in the liver by three enzyme systems: alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and catalase
• Smoking during pregnancy


  Increases the risk of spontaneous abortion, preterm births and intrauterine growth retardation
• Passive smoke inhalation is associated with the same effects that result from active smoking
• Ethanol consumption


  Moderate amounts are generally not injurious, but it can cause serious physical and psychological damage in excessive amounts
• Alcohol absorption and distribution

  1. Absorbed unaltered in the stomach and small intestine, then distributed to body tissues in direct proportion to blood levels

  2. The amount exhaled is proportional to the blood level and forms the basis of the alcohol breath test
• Blood alcohol levels


  • 200mg/dl can cause drowsiness, 300mg/dl can cause stupor, and coma with possible respiratory arrest at higher levels
  • Chronic alcoholics can tolerate up to 700mg/dl due to 10-fold induction of the liver CYPs
• Alcohol metabolism


  1. Alcohol in the blood is oxidized to acetaldehyde in the liver by 3 enzyme systems: alcohol dehydrogenase, microsomal ethanol-oxidizing enzyme, and catalase

  2. Acetaldehyde is converted to acetate by acetaldehyde dehydrogenase, which is then utilized in the mitochondrial respiratory chain

  3. The microsomal system involves CYP2E1 located in the smooth ER, induction of CYPs by alcohol explains the increased susceptibility of alcoholics to other compounds metabolized by the same enzyme system