OLGA MUNAR BAUSA, M.D., DPSP

1. ENVIRONMENTAL PATHOLOGY OLGA MUNAR BAUSA, M.D., DPSP

2. MECHANISMS OF TOXICITY • toxicology - detection, effects & mecha- • nisms of action of poisons & toxic chemicals • toxicity – relative phenomenon that de- • pends on structure & properties of chemical • & on its dose

5. BASIC PRINCIPLES OF XENOBIOTIC METABOLISM • most xenobiotics are lipophilic • lipophilic toxicants are metabolized to hydro- • philic metabolites • phase I rx: hydrolysis • : reduction • : oxidation

6. phase II rxn: glucuronidation • : sulfation • : methylation • : conjugation • genetic variations in level of activity of • xenobiotic metabolizing enzymes • CYP1A1 : lung CA • GSTM1 deficiency : lung, bladder & colon • CA

7. multiple pathways involved in metabolism • of a chemical toxicant • endogenous factors (nutritional & hormonal • status) alter enzyme activities • exogenous factors (chemicals,drugs,ethanol, stress) can induce/inhibit enzyme activities

8. PHASE 1 REACTIONS: • Cytochrome P-450-dependent monooxyge- • nase system – activity is highest in the liver - eg: metabolism of benzo[a]pyrene to a secondary metabolite that binds to DNA causing lung and skin tumors • Flavin-containing monooxygenase system - located in the SER of the liver

9. - oxidizes nicotine in cigarette smoke • Peroxidase-dependent cooxidation • high activity in seminal vesicles, kidneys • & urinary bladder. • involved in metabolism of 2-naphthylamine • found in synthetic dyes associated with in- • creased risk of bladder cancer

10. PHASE II REACTIONS: • Glucuronidation – secondary metabolite is • excreted in urine resulting to formation of N- • hydroxy-2-naphthylamine - increased incidence in can- cer of urinary bladder in workers exposed to synthetic dyes

11. Biomethylation – inorganic mercury (HgCl2), • causes necrosis of proximal convoluted tubules • of kidneys - exposure occurs in industries manufacturing germicides, fungicides, electro- nics and plastics • Glutathione conjugation – vinyl chloride used • in the manufacture of plastics, can cause angio- • sarcoma of the liver in exposed workers

12. Common Environmental and Occupational Exposures PERSONAL EXPOSURES Tobacco Use • includes cigarettes, cigars, pipes & snuff • major risk factor for lung Ca • interacts with other environmental and • occupational exposures ( additive/synergistic • effect)

13. eg: increase risk of lung CA in cigarette • smokers exposed to asbestos • mainstream cigarette smoke : - particulate phase: tar w/o H2O or nicotine - gas phase • 43 known carcinogens in mainstream smoke • carcinogenic metals – arsenic, nickel, cadmium & • chromium • potential promoters – acetaldehyde & phenol

14. irritants - nitrogen dioxide, formaldehyde • cilia toxins – hydrogen cyanide

15. ORGAN CARCINOGEN Lung, larynx polycyclic aromatic hydrocarbons 4-methynitrosoamino-1-3-pyridyl -1-butanone (NNK) polonium 210 Esophagus N’-nitrosonornicotine (NNN) Pancreas NNK Bladder 4-Aminobiphenyl,2-naphthylamine Oral cavity (smoking) polycyclic aromatic hydrocarbon, NNK, NNN Oral cavity (snuff) NNK, NNN, polonium 210

16. carbon monoxide – colorless, odorless gas; • 200x higher affinity for Hgb than O2 - impairs release of O2 from Hgb decreases delivery of oxygen to the peripheral tissues • nicotine – important constituent of cigarette • smoke - crosses blood brain barrier ;stimulates nicotine receptors in brain

17. - responsible for acute effects me- diated by catecholamines ( increased heart rate/BP, increased coronary blood flow, in- creased contractility & cardiac output and mobilization of FFA - also responsible for tobacco addiction

18. mortality – lung cancer, IHD and chronic • obstructive lung disease • risk factor with HPN & hypercholesterolemia • for coronary artery ds and arteriosclerosis • risk factor for acute MI and stroke in women • taking oral contraceptives • increases platelet adhesion & aggregation • leading to arrhythmia; causes imbalance in • the demand for O2 & supply to myocardium

19. effects of maternal smoking to the fetus – • 10 cigars per day can cause fetal hypoxia • resulting to low birth weight, prematurity • & spontaneous abortion - serious complications are premature rupture of membranes, placenta previa & abruptio placenta • sidestream smoke – also called passive smo- • king or environmental tobacco smoke (ETS)

20. increases risk of lung cancer, IHD & acute • MI - in infants & young children, causes increased incidence of respiratory, ear infections and asthma attacks Alcohol Abuse - ethanol from alcoholic drinks like beer, wine & distilled spirits

21. - legal definition for drunk driving is blood alcohol concentration of 100 mg/dl - occasional drinkers, 200 mg/dl pro- duces inebriation; coma, death & respiratory arrest at 300-400 mg/dl - habitual drinkers can tolerate levels up to 700 mg/dl; this is due to increased in- duction by cytochrome P-450 xenobiotic me- tabolizing enzyme, CYP2E1.

22. - ethanol is metabolized to acetaldehyde by alcohol dehydrogenase (gastric mucosa and liver) & by cytochrome P-450 & catalase (liver) - acute action is CNS depressant Mechanisms of Disease Caused by Ethanol Abuse Organ System Lesion Mechanism Liver fatty change toxicity acute hepatitis alcoholic cirrhosis

23. Nervous sys Wernicke syndrome thiamine def Korsakoff syndrome toxicity & thiamine def cerebellar degeneration nutritional def peripheral neuropathy thiamine def Cardiovascular cardiomyopathy toxicity system hypertension vasopressor GIT gastritis toxicity pancreatitis toxicity Skeletal muscle rhabdomyolysis toxicity

24. Reproductive testicular atrophy ? system spontaneous abortion ? Fetal alcohol growth retardation toxicity syndrome mental retardation birth defects LIVER - fatty change, acute alcoholic hepatitis & cirrhosis • Fatty Change – acute, reversible - mechanisms:

25. - increase catabolism of fat by pe- • ripheral tissues increase delivery of FFA - metabolism of ethanol & acetalde- hyde converts nicotinamide adenine dinucleo- tide (NAD+) to reduced form, NADH; excess NADH over NAD stimulates lipid synthesis - oxidation of fatty acids by mito- chondria is decreased - acetaldehyde forms adducts with tubulin, impairs function of microtubules decrease transport of lipoproteins from liver

26. Acute Alcoholic Hepatitis - reversible form of liver injury - fever, liver tenderness & jaundice - toxic effect of ethanol is mediated by: • mitochondrial injury • glutathione depletion • c. altered metabolism of methionine & cyto- • kine release from Kupffer cells

27. histo: focal areas of hepatocyte necrosis & • cell injury by fat accumulation & alcoholic • hyalin or mallory bodies; neutrophils accu- • mulate around foci of necrosis

28. Alcoholic Cirrhosis - irreversible liver damage; chronic ethanol use - gross: hard, shrunken liver • histo: formation of micronodules of regenera- • ting hepatocytes surrounded by dense bands • of collagen • fatal ds; weakness, muscle wasting, ascites, • gastrointestinal hemorrhage & coma

29. patients with cirrhosis have depleted liver stores of alpha-tocopherol, increases their • vulnerability to oxidative injury

30. NERVOUS SYSTEM • acute depressive effects & addiction are rela- • ted to fluidization of membrane phospholipids • & altered signal transduction • chronic thiamine deficiency leads to degene- • ration of nerve cells, reactive gliosis & atrophy • of cerebellum & peripheral nerves • ataxia, disturbed cognition, ophthalmoplegia • & nystagmus (Wernicke syndrome)

31. alcoholics with poor nutrition develop severe • memory loss (Korsakoff syndrome) • Cardiovascular System • cardiomyopathy, degenerative ds of the heart • muscle • hypertension, secondary to vasopressor effects • of ethanol by increased release of catechol- • amines • one to two drinks/day show protective effect; • increased levels of HDL & decreased platelet • aggregation

32. Gastrointestinal Tract - acute gastritis, acute & chronic pancreatitis Skeletal Muscle • muscle weakness, pain & myoglobin break- • down Reproductive System • testicular atrophy; decreased fertility in men & • women, spontaneous abortion Fetal Alcohol Syndrome • consequence of maternal ethanol consump- • tion at levels of one drink/day

33. growth & developmental defects; growth • retardation, microcephaly, atrial septal de- • fect etc. • pathogenesis: acetaldehyde crosses the pla- • centa & damages fetal brain Ethanol and Cancer • increased incidence of cancer of the oral ca- • vity, pharynx, esophagus, liver & breast

34. Drug Abuse • Sedative-Hypnotics - ethanol:widely abused CNS depressant • barbiturates: illegal drugs ; downers; induce • sedation & decrease anxiety; develops tolerance • causing drug users to increase the dose : chronic use induces cytochrome P-450 activity, increasing metabolism of drugs (dicumarol, tetracycline, digoxin, OC)

35. simultaneous use of ethanol & barbiturates • is lethal, causing coma & CPA • Diazepam (valium): safer sedative, can cause • drowsiness, dizziness & coma but do not in- • duce cytochrome P-450 activity • Psychomotor Stimulants a. cocaine (crack): produces rapid “high” of short duration (euphoria, increased energy and stimulation

36. : chronic use can cause insomnia, in- creased anxiety, paranoia & hallucinations : acute overdose causes seizures, car- diac arrhythmias & respiratory arrest : main mechanism of cocaine action is to block reuptake of dopamine , serotonin & catecholamines (E & NE) in the presynaptic terminals : prolongs dopaminergic effects in brain’s pleasure centers (limbic system) causing intense euphoria

37. CVS effects of cocaine: accumulation of catechol- • amines causes stimulation of alpha & beta-adrenergic • receptors ( increased BP, heart rate with coronary • spasms - increase myocardial O2 demand, dec O2 supply lea- ding to arrhythmias & ischemia causing MI • typical patient with cocaine-induced MI: male in • early 30’s; cigarette smoking compounds the risk • chronic effects: atherosclerosis , cardiomyopathy & • myocarditis

38. - causes fetal hypoxia b. Amphetamines – overdose causes sweating, tremors restlessness & confusion leading to delirium, convul- sions, cardiac arrhythmias, coma & death - molecular basis of addiction is unknown; underlying abnormality in dopamine D4 receptor • Narcotics • relieve pain but can also cause sedation & altered • mood • IV heroin abuse induces suppression of anxiety, seda- • tion, mood changes, nausea & respiratory depression

39. chronic abuse induces tolerance & psychologic de- • pendence • IV users susceptible to infections: 4 sites most com- • monly affected are skin/subcutaneous tissue, heart • valves, liver & lungs - endocarditis, involving right sided heart valves (tri- cuspid); most common organism is S. aureus • viral hepatitis, acquired by casual sharing of dirty • needles; incidence of AIDS also increasing

40. Hallucinogens - mescaline, psilocybin & marijuana • active ingredient in marijuana is tetrahydrocannabi- • nol (THC) • chronic marijuana smoking has similar lung effects • of tobacco smoking, however it is not carcinogenic • Therapeutic Drugs • adverse drug reactions (ADRs) are untoward effects • of drugs that are given in conventional therapeutic • settings

41. Exogenous Estrogens and Oral Contraceptives • estrogens for postmenopausal syndrome may be • given alone & are usually natural estrogens • oral contraceptives contain synthetic estrogens, • always with progesterone Exogenous Estrogens - adverse effects of estrogen therapy: • endometrial carcinoma – estrogen therapy increases the risk threefold to sixfold after 5 years of use & more than tenfold after 10 years

42. breast carcinoma – the increased risk is small & not influenced by the addition of progestins • thromboembolism • cardiovascular disease – estrogens tend to elevate level of HDL & reduce level of LDL, which is protec- tive against development of atherosclerosis - progestins counters the es- trogen effect; 40% to 50% decrease in the risk of IHD in women who received postmenopausal estro- gen therapy

43. Oral Contraceptives • combined OCs contain a synthetic estradiol & • variable amounts of progestins; few preparations • contain only progestins • currently prescribed OCs contain smaller amounts of • estrogens (<50 ug/day); associated with fewer side • effects • adverse effects: • breast carcinoma – slight increase in breast CA risk when combined oral contraceptives are used by wo- men younger than 45 yrs, particularly nulliparous women younger than 25 yrs

44. endometrial cancer – no increased risk, OCs exert a protective effect • cervical cancer – increase risk correlated with dura- tion of use • ovarian cancer – OCs protect against ovarian CA; longer they are used, the greater the protection • thromboembolism – containing > 50 ug estrogens are associated with increase risk of venous throm- bosis & pulmonary thromboembolism due to increa- sed hepatic synthesis of coagulation factors & re- duced levels of antithrombin III

45. - <50 ug estrogens, less risk especially in women younger than 35 yrs who do not smoke - 3rd generation OCs (combine low dose estrogens with synthetic progestins) reduces risk of MI but confer higher risk of venous thrombosis than 2nd generation OCs • hypertension – slight increase in BP • cardiovascular disease – approximately 29% increa- sed risk of MI, especially during the first yr of com- bined HRT use.

46. cholecystitis – increased risk of gallbladder disease Acetaminophen • when taken in large doses will cause hepatic necro- • sis; toxic dose is 15-25 gm • nausea, vomiting, diarrhea, shock followed by jaun- • dice • serious overdosage causes liver failure, with centri- • lobular necrosis involving entire lobule • concurrent renal & myocardial damage seen in some • patients

47. Aspirin (Acetylsalicylic Acid) • overdose in children result from accidental ingestion; • in adults, suicidal - toxic dose in children is 2-4 gm; in adults, 10-30 gm • chronic aspirin toxicity (salicylism) develop in persons • who take 3 gm or more daily, dose required to treat • chronic inflammatory conditions : headache, dizziness, ringing in the ears (tinnitus), difficulty in hearing, mental confusion, drowsiness, nausea, vomiting & diarrhea; CNS chan- ges may lead to convulsions & coma

48. : erosive gastritis causes GI bleeding leading to gastric ulceration : bleeding tendency is also associated because aspirin acetylates platelet cyclooxygenase & blocks thromboxane A2, an activator of platelet aggregation • mixtures of aspirin & phenacetin or acetaminophen • when taken for years causes renal papillary necrosis, • referred to as analgesic nephropathy

49. OUTDOOR AIR POLLUTION - major sources of ambient air pollutants are: • combustion of fossil fuels – motor vehicles (complex mixtue of carbon monoxide, oxides of nitrogen, hydro- carbons, diesel exhaust particles, lead oxide • photochemical reactions- oxides of nitrogen & vola- tile hydrocarbons interact in the atmosphere to pro- duce ozone • power plants – release sulfur dioxide

50. Health Effects of Outdoor Air Pollutants POLLUTANT POPULATIONS AT RISK EFFECTS Ozone healthy adults & children decreased lung function increased airway reactivity lung inflammation athletes, outdoor workers decreased exercise capacity asthmatics increased hospitalizations Nitrogen healthy adults increased airway reactivity dioxide asthmatics decreased lung function children increased respiratory infcxn Sulfur healthy adults increased respiratory sx dioxide px with chr lung ds increased mortality increased hospitalization asthmatics decreased lung function