Environmental & Nutritional Disease

Environmental & Nutritional Disease Pathology I – May 2014

Cause-of-death statistics help health authorities determine their focus for public health actions. A country where deaths from heart disease and diabetes rapidly rise over a period of a few years, for example, has a strong interest in starting a vigorous programme to encourage lifestyles to help prevent these illnesses. Similarly, if a country recognizes that many children are dying of malaria, but only a small portion of the health budget is dedicated to providing effective treatment, it can increase spending in this area. • High-income countries have systems in place for collecting information on causes of death in the population. Many low- and middle-income countries do not have such systems, and the numbers of deaths from specific causes have to be estimated from incomplete data. Improvements in producing high quality cause-of-death data are crucial for improving health and reducing preventable deaths in these countries.

Global Burden of Disease • The WHO global burden of disease (GBD) measures burden of disease using the disability-adjusted-life-year (DALY). This time-based measure combines years of life lost due to premature mortality and years of life lost due to time lived in states of less than full health. The DALY metric was developed in the original GBD 1990 study to assess the burden of disease consistently across diseases, risk factors and regions.

Disability-Adjusted Life Year • DALYs for a disease or health condition are calculated as the sum of the Years of Life Lost (YLL) due to premature mortality in the population and the Years Lost due to Disability (YLD) for people living with the health condition or its consequences: • Calculation • DALY = YLL + YLD • This calculation (DALY) provides health information about acute and chronic diseases in different regions of the world.

GENERAL MECHANISMS OF TOXICITY • ENVIRONMENTAL POLLUTION • EFFECTS OF TOBACCO • EFFECTS OF ALCOHOL • INJURY BY THERAPEUTIC DRUGS AND DRUGS OF ABUSE • INJURY BY PHYSICAL AGENTS • NUTRITIONAL DISEASES

ENVIRNOMENTAL DISEASE • The term environmental diseases refers to lesions and diseases caused by exposure to chemical or physical agents in the ambient, workplace, and personal environments, including diseases of nutritional origin.

Toxicology is defined as the science of poisons • Xenobiotics - These are exogenous chemicals present in air, water, soil, and food. • Enter the body through skin, inhalation, and ingestion • Some xenobiotcs form inactive water soluble products called detoxification

Mechanisms of Toxicity • Threshold effect • Absorption at portals of entry • ingestion • inhalation • skin contact • Distribution within the body • Metabolism and Excretion • Toxic effects

Xenobiotic Mechanisms • Phase I Reactions (Smooth ER), makes them less lipophilic by adding a direct polar group (Hydrolysis, oxidation, reduction) • Cytochrome P-450-dependent monooxygenase system • Flavin-containing monooxygenase system • Peroxidase-dependent co-oxidation • Phase II Reactions, combines them with other polar substances • Glucuronidation • Biomethylation • Sulfation • Glutathione conjugation

The most important catalyst in phase 1 is • Cytochrome P-450 enzyme they detoxify or activate the xenophyte to cause cellular injury. • The oxidative reactions release oxygen free radicals which cause cellular damage. • Metabolic activation seen in carbon tetrachloride in the liver, also benzopyrene carcinogen in cigarette smoke • Peroxidase dependant co-oxidation in 2-Naphthyalamine metabolism which cause bladder cancer.

CommonExposures • Outdoor Air Pollution • Indoor Air Pollution • Metals • Industrial Exposures • Agricultural Hazards • Natural Toxins • Radiation Injury • Physical Injury

OZONE (O3) • Environmental pollution • “Good” Ozone - Stratosphere • Ozone depleting substances such as CFCs (chlorofluorocarbons) in coolants, pesticides, and aerosol propellants • “Bad” Ozone - Lower atmosphere • Chemical reaction between oxides of Nitrogen and volatile organic compounds (VOCs) in the presence of sunlight • Ozone – Injury to respiratory and alveoli (Type 1 alveolar cells) results in URTI and inflammation mainly in asthmatics, emphysema • The reaction air way hyperactivity and NEUTROPHILIA • Also damages vegatation and ecosystem

The ozone hole reached its biggest extent for the year on 26 September, 2013 Photograph: NOAA

AIR POLLUTANTS CAUSING MAJOR HEALTH THREATS • Tobacco smoke. • Smoke generated by burning wood  CO • Exhausts from fossil fuels  CO • Chemicals generated in industrial setting. • Dust containing particulate matter (Soot) produced by coal and oil-fired power plants. • Ultrafine particles are most harmful when inhaled • Normal gases present in excessive amounts – Ozone, nitrogen, carbon monoxide, carbon dioxide • Effects: - Eyes, Nose, throat burning sensation, asthma attacks, decreased lung function, chest pain, promotes myocardial ischemia

Carbon Monoxide • Air pollutants, accidental & suicidal death • Automotive engines, industrial, cigarette smoke • Colorless, tasteless, odorless, and non-irritating • At low levels, forms carboxyhemoglobin producing hypoxia (20 % saturation in hemoglobin)  ischema in CNS  death (60 to 70% saturation) • Clinical Manifestation  Headache, nausea, confusion • Acute poisoning  Cherry-red skin color and mucous membranes due to high carboxyhemoglobin • Chronic poisoning  Hypoxia, Ischemic changes in the CNS(Basal ganglia) • Treatment – O2

Sulfur Dioxide • Sources:- Burning charcoal and oil, paper mills, power plants • When it releases into air converts into sulfuric acid • Effects  Irritation in the nose and throat.

Particulate matter (SOOT) • Sources:- Coal and oil fired power plants • Particulate matter soot less than 10 micrometer diameter is most harmful • Clinical features-Inflammation of lung, asthma attacks, irritation of eyes and nose, myocardial ischemia

HOW DO POLLUTANTS DAMAGE THE HUMAN BODY? • Direct effects: – Strong acids and alkali have a corrosive effect on the skin. – Heavy metals, like mercury, have a direct toxic effect on cells of the gastrointestinal tract and renal tubules. • Indirect effects: – Intermediate metabolites that damage cells. – Generation of new antigens, which stimulate the body to produce cytotoxic antibodies. • Late effects: – Cumulative effect seen only after a long period of time. – Mutagenic effects of some chemicals or ultraviolet light become evident only many years after the initial exposure.

Pollutant may produce acute toxicity: – directly through induction of inflammation or necrosis – indirectly through a hypersensitivity immune response • Chronic effects: – like sub clinical forms of chronic inflammation and fibrosis due to ongoing toxic effect, or degenerative changes (chronic lead toxicity)

EXAMPLES OF EFFECTS OF AIR POLLUTANTS ON LUNG • Acute toxicity • Irritate the bronchi • Pulmonary edema • Allergic reaction • Asthmatic attacks • Chronic lung disease • Pneumoconiosis • Cancer

MAIN DETERMINANTS OF TOXICITY OF AIR POLLUTANTS • Air pollutants do not affect all people equally. • Depending on: * Physical and chemical properties: Solubility in water (e.g.. SO2), particle size and airway anatomy (particles =between 1 to 5 µm are most dangerous), and chemical reactivity

Concentration of pollutant. • * Duration of exposure. • * Host’s reaction to the pollutant and host • clearance mechanisms

Indoor Air Pollution • Tobacco smoke • Carbon Monoxide CO • Nitrogen Dioxide NO2 • Wood Smoke • Nitrogen oxides, carbon particulates, polycyclic aromatic hydrocarbons • Formaldehyde • Building materials, poorly vented homes or trailers • Radon • Uranium derived radioactive gas • Manufactured Mineral Fibers • Bioaerosols

Radon • Radon is a radioactive gas and a decay product of uranium • It is widely distributed in the soil and is prevalent in homes (especially in basements) • Radon decay products are alpha emitters • 10% of US homes have levels associated with an increased risk of lung cancer and an estimated 10,000 lung cancers per year in the United States are due to radon • Smoking elevates risk • Proper venting reduces the exposure

Lead • Lead is classified as a heavy metal (others include mercury, arsenic, and cadmium) • Naturally occuring element • Source of exposure • lead paint • lead solder in plumbing (older houses) • lead-glazed ceramics • industrial exposure • Route of exposure • inhalation with industrial exposure • ingestion with household exposure

Lead Distribution and Excretion • Lead is a divalent cation that is taken up by bone and developing teeth in children (80% to 85%) • Half-life of lead in bone is 30 years • Blood accumulates 5% to 10% of lead, but lead is rapidly cleared from the blood • lead in blood indicates recent exposure • blood level does not allow the determination of total body burden • Remainder is distributed in the soft tissues • Excretion is via the kidneys

Children absorb more than 50% of lead from food, while adults may absorb approximately 15%. A more permeable blood-brain barrier in children creates a high susceptibility to brain damage • During the last 30 years, there is a significant decrease in blood level of lead in preschool children, 15ug/dL to 2ug/dL • In children living in older homes, blood level of lead can exceed 10ug/dL • Lead poisoning effects  Behavior & learning problems, Lower IQ & Hyperactivity, Slowed growth, Hearing problems, Anemia

Lead poisoning also occurs in:- • Painters • Batteries • House paints • Gasoline • Flaking lead paint in older houses • Mines, foundries and spray paints.

Effects of Lead • High affinity for sulfhydryl groups • inhibition of heme synthesis with hypochromic anemia and basophilic stippling of erythrocytes • Competition with calcium ions • As a divalent cation, lead competes with calcium and is stored in bone. • It also interferes with nerve transmission and brain development. • Inhibition of membrane-associated enzymes • Lead inhibits 5'-nucleotidase activity and sodium-potassium ion pumps, leading to decreased survival of red blood cells (hemolysis), renal damage, and hypertension.

Protoporphyrin level raised in lead poisoning - Why? • Lead inhibits 2 enzymes in heme synthesis  Ferrochelatase and delta-aminolevulinic acid dehydrase • Ferrochelatase catalyzes the incorporation of iron to protoporphyrin, when it is inhibited by lead the level of protoporphyrin raises in turn decrease in heme synthesis resulting in microcytic, hypochromic anemia.

Lead has a high affinity for sulfhydryl groups and interferes with enzymes involved in heme synthesis and iron incorporation into heme is impaired, leading to a microcytic, hypochromic anemia • A characteristic finding is basophilic stipplingof erythrocytes. • Clinical  Increased zinc protophyrin in blood

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Excess lead interferes with the normal remodeling of calcified cartilage and primary bone trabeculae in the epiphyses in children, causing increased bone density, which is detected as radiodense"lead lines" on radiographs and lead line on the gums. • Lower intellectual function, • Hyperactive, abdominal pain, decrease healing of bone fracture.

Peripheral demyelinating neuropathy appears, typically involving the motor innervation of the most commonly used muscles. Thus, the extensor muscles of the wrist and fingers are often the first to be affected, followed by paralysis of the peroneal muscles (wristdrop and footdrop)

The GI tract is also a major source of clinical manifestations. Lead "colic" is characterized by extremely severe, poorly localized abdominal pain.

Consequences of lead exposure

Diagnosis • Elevated blood lead and free erythrocyte protoporphyrin levels (>50 μg/dL) or, alternatively, zinc-protoporphyrin levels are required for definitive diagnosis.

WHAT ARE THE SIGNS OF • LEAD POISONING? • Chronic accumulation of lead in the body has • many consequences: • Lead lines on the gums. • Lead lines in the epiphyses of long bones. • Anemia develops due to the inhibition of hematopoiesis (basophilic stippling).

Renal toxicity • Lead damages proximal renal tubules causing aminoaciduria and glycosuria. • Diagnostic intranuclear inclusions are seen in proximal renal tubule.

Mercury Poisoning • Minamata disease (Industrial disaster) • Cererbral palsy, mental retardation, deafness and blindness • It is caused by Mercury Methyl • Exposure to industrial powerplants, cave paintings, dental amalgams, contaminated fish, contaminated rivers and streams. • Intracellular glutathione exhibits protective mechanism against the effects of mercury toxicity with CNS and kidney damage

Arsenic poisoning • Historically “Murder Weapon” (Royal family) • Found in soil and water , also in agricultural products and wood preservatives, herbicides. • Toxic in trivalent forms  Arsenic trioxide, sodium arsenite, and arsenic trichloride • Disruption in oxidative phosphorylation in mitochondria (Replacing ATP phosphates) • It usually causes lung and skin cancer. • Also GI, Cardiovascular & CNS effects (parathesias, numbness & pain) • Chronic exposure causes hyperkeratosis and hyperpigmentation and development of basal and squamous cell carcioma of skin. • Assoicated with nucleotide excision repair that protects against DNA damage

Environmental & Nutritional Disease