ENVIRONMENTALPATHOLOGYChemical and Physical AgentsNutritiondr. Al Munawir, M.Kes., Ph.D.Laboratorium Patologi AnatomiFakultas Kedokteran Universitas Jember

Environmental PathologyMagnitude of the Problem in US600,000 cancer cases/year related to chemical carcinogens (est)400,000 deaths related to smokingReported Chemical Exposures2.4 million reported chemical exp/yr (2005)80% accidentalChildren

US Government Agencies Regulate Environmental HazardsEnvironmental Protection AgencyFood and Drug AdministrationOccupational Safety and Health AdministrationConsumer Products Safety Commission

Sources of ExposureEnvironmentalMan-madeIntentional (Hg, Minimata, Japan)Accidentalmethyl isocyanate, Bhopal, Indiaradiation, ChernobylNatural (H2S/CO/CO2, Cameroon)Occupational (mining, dye, chemical)Iatrogenic (drugs)Self-administered (substance abuse, suicide)

Mechanisms of Toxicity

Mechanisms of ToxicityCorrosive, tissue destruction (acids, alkali)desiccationprotein destructiondenaturationhydrolysisfat saponificationInhibition of enzyme activitycyanide: cytochrome oxidase

Cyanide Poisoning

Mechanisms of ToxicityAlternate metabolic pathwaysethanol: NAD/NADHDisturbances of homeostasissteroids: immune systemaspirin: acidosisMutagenesisCarcinogenesis

Clinical FindingsSymptoms-patient complaintsSigns-what you observeClinicopathologic correlationrelated to mechanism and tissue localizationAcute vs chronic-the signs and symptoms may differ

Lung Injury Related to Air PollutionAcute and chronic inflammationdirect cell injuryEmphysema-enhanced proteolysisAsthma-allergic or irritant effectHypersensitivity pneumonitisimmunologic injury related to organic dustsPneumoconiosis-cytokinesNeoplasiamutagenic/promoting effects

Main Constituents of SmogSO2respiratory irritant (acid rain)NO2*, NOrespiratory irritant (xs O2)COcarboxyhemoglobin ( O2)O3*respiratory irritantPbbinds sulfhydryl groups*Oxidant pollutantsMostly produced by combustion of fossil fuels

Inhalation Toxins Related toMining and Similar Occupations Pneumoconiosis, characterized by cytokine-mediated, progressive fibrotic scarringcoal dust (anthracosis)silica (silicosis)asbestos (asbestosis), Ca/Mg silicatepleural plaques, mesothelioma,bronchogenic caberyllium (berylliosis)Macrophages produce cytokinesSize matters-0.5 to 5

Normal Lung

Pulmonary Fibrosis

Inhalation Toxins Related to FarmingOrganic dusts (hypersensitivity pneumonitis)moldy hay (Farmers Lung)bird droppings (bird breeders lung)Pesticidesorganophosphate (acetycholine esterase inhibitors)organochlorine (DDT, chlordane)Herbicides (paraquat, diquat, dioxin)Fertilizer (ammonia)

Tobacco Smoking400,000 deaths/yr (21% of all deaths in US)50 Million smokers in USSmoke compositioncarcinogens (polycyclic HC, b-naphthylamine, nitrosamines)Irritants and toxinsammonia, formaldehyde, oxides of nitrogenCONicotine

Relative Disease RisksAssociated with SmokingMaleFemaleLung Ca death 22 12Mouth Ca 27 6Larynx Ca 10 18Esophogus Ca 8 10CAD >35 yo 3 2Cerebro VD >35 yo 4 5 COPD 10 10Ill health effects of smoking partially reversible

Heavy Metal Toxic AgentsMercury (HgCl2 , ATN; org Hg, CNS function)Lead ( inhibits heme synthesis, CNS function, kidneys, GI)2-11% of children in US exceed 10 g/dLArsenicIron

Lead Lines

Basophilic Stippling

Normal Kidney

Acute Tubular Necrosis

Organic AlcoholsEthanol1/3 of Americans characterized as heavy drinkersCNS depressantlegally intoxicated >100 mg/dLNearly 50% of fatal MVAMethanol (toxic metabolites inhibit hexokinase, may cause blindness)Ethylene glycol (antifreeze, ATN)

Fatty Change in Liver

Normal Liver

Fatty Change in Liver

Alcoholic HepatitisMallory Body

Alcoholic Cirrhosis

Alcoholic CirrhosisRegeneratingNodulesBands of Fibrosis

Adverse Drug EventsAdverse Drug Reactions +Therapeutic Misadventures

Adverse Drug Events3-6% of all medical admissions160,000 deaths/yrShapiro et al. JAMA 1971; 216: 467-472.Most common adverse event in hosp ptsLeape et al. NEJM 1991;324: 377-384.6.5 ADE/100 admissions, 1% fatalBates et al. JAMA 1995; 274: 29-34.

Major Patterns of ADRsBlood dyscrasias (Chloramphenicol)dose related or idiosyncraticpan or line specificSkin eruptions (Penicillin)Hepatic reactionsfatty change (Tetracycline)cholestasis (Chlorpromazine)hepatitis (INH)massive hepatic necrosis (Halothane)

Major Patterns of ADRsRenal reactionspredictable (aminoglycosides)hypersensitivity (sulfa)Lung reactionscongestionedemahemorrhageinterstitial fibrosis

Major Patterns of ADRsCardiac reactionsarrhythmiascardiomyopathyCNS reactionsrespiratory depressionSystemic reactionsanaphylaxisvasculitishormonal effects (HRT, OC)

Syndromes Related to Drugs of AbusePulmonary complications (edema, septic emboli, absess, opportunistic infections)Granulomas (adulterants)Infectious complicationsKidney diseaseOften related to diluents, cutting agents, and needle sharing

Outdoor Air PollutionSumber utama: Commbution of fosil fuels, photochemical reactions, waste incinerators, etc.Pollutants: Ozone, Nitrogen dioxide, Sulfur dioxide, Acid aerosols, Particulates.Target: Skin, eye, and airway irritations to Respiratory infections.

Indoor Air PollutionSumber utama: Ventilasi jelek.Pollutant: CO, Nitrogen dioxide, Wood smoke, Formaldehide, Radon, Asbestos, mineral fiber, Bioaerosols. Target: Skin, eye, and airway irritations to Respiratory infections.

Industrial ExposuresVolatile organic compounds.Polycyclic aromatic hydrocarbons.Plastics, Rubber, and Polymers.Metals.

Agricultural Hazards.Organochlorine.Organophosphate.Carbamate.

Natural ToxinsPotent toxins and carcinogens.Animal toxins.Poisonous plants.Amanita phalloides mushrooms.

Pathology Laboratory

This is the first report of garlic impaction and garlic-induced esophageal injury.A 60-year-old woman was presented with severe and sustained chest pain after eating sliced raw garlic 12 hours previously.A Case Report on Garlic adverse effectsPathology Laboratory

A and C no changeB elongation, rounded cell (light microscope); apoptotic-fragmented multinuclei and cells with chromatin condensation.Fig. 1-4. Morphological changes of INT-407 cells observed at 24 hr after exposure. Pathology Laboratory

Fig. 1-5. Cycle cell analysis of Fresh Garlic Extract treated on INT-407 Intestinal Epithelial Cells.Pathology Laboratory

Tabel 1-1. Cycle cell analysis of Fresh Garlic Extract treated on INT-407 Intestinal Epithelial Cells.

Increasing percentage cell with hypodiploid----- ApoptosisDecreasing G1 and increasing G2, M-------Cycle ArrestPathology Laboratory

Exposure (20 minute)Cycle cellVehicle alone (PBS)FGE 100 g/mLFGE 300 g/mLBGE 300 g/mL%%%%Hypodiploid2 114 3*6 2*2 1G162 743 5*22 3*66 8S13 39 310 411 3G2, M23 434 5*62 6*21 4

Cytotoxicity of FGE completely blocked by NAC/ scavenger ROSIts mediated by ROS generationFig. 1-6. Pretreatment of NAC protects INT-407 Intestinal Epithelial Cells from cytotoxicity.Pathology Laboratory

Fig.1-1. Cytotoxicity of garlic extracts (fresh or boiled)Fresh garlic extract has cytotoxic effect, not boiled garlicPathology Laboratory

Physical InjuriesMechanical forceabrasionlacerationincisioncontusionGunshot woundsentry woundexit wound

Contusion/22 hours

Laceration with Marginal Abrasion

Incision

Stab Wound

GSW/Contact

GSW/Close Range/Stippling

GSW/Distant and Contact

THERMAL INJURYCutaneous burns.Hyperthermia (heat cramps, heat exhaustion, heat stroke).Hypothermia.

Electrical InjuriesResistence of tissue (dry or wet skin).Intensity.

Injuries Related to Changes in Atmospheric PressureHight-altitude illness.Blast injury.Air or gas embolism.Decompression disease.

Radiation InjuryDirect (target) effect-radiation acts directly on target molecules, such as DNAIndirect effect-free radical intermediaryCell death, mutations, developmental abnormalitiesTissues have differential radiosensitivityOxygen effectWhole body radiation

FIGURE 8-22. Radiation-induced cancers.

Radiation Injury

Radiation Sensitivity of Biological TissueLymphocytesThrombocytesGranulocytesGI liningEndothelial cellsNeural tissueSensitivityCell DivisionMost SensitiveFastest

Least SensitiveSlowest

NUTRITION AND DISEASEFood Safety: Additives and contaminantsNutritional deficiencies (energy, essential amino acids and fatty acids, vitamins and minerals).Obesity.Diet and systemic diseaseChemoprevention and cancer

Nutritional deficienciesIgnorance and poverty.Chronic alcoholism.Acute and chronic illness (burns).Self-imposed dietary restriction (Anorexia nervosa, bulimia).

Protein-Energy MalnutritionMarasmus.Kwashiorkor.

FIGURE 8-23. Complications of kwashiorkor.

Nutritional deficienciesVitamin deficiencyMineral deficiency

Vitamin Deficiency

Vitamin

Function

Deficiency State

A

Vision

Immune system

Epithelium

Diet, malabsorption

Night blindness, xerophthalmia, keratomalacia, immune deficiency

D

Blood calcium and phosphate

Diet, malabsorption, inadequate sun, liver and renal disease

Rickets, osteomalacia

Vitamin Deficiency

Vitamin

Function

Deficiency State

E

tocopherols

Antioxidant

Free radical scavenger

Diet, malabsorption

Neuromuscular deficits

K

Clotting factors

II, VII, IX, X

Malabsorption, loss of gut flora, Coumadin therapy

bleeding

Vitamin Deficiency

Vitamin

Function

Deficiency State

Thiamine

(B1)

TPP

Enzyme co-factor, nerve conduction

Diet, EtOH

Polyneuropathy, cardiomyopathy, Wernicke-Korsakoff

Riboflavine

(B2)

FMN, FAD

Enzyme co-factor

Diet, EtOH

Cheilosis, glossitis, dermatitis (atrophy)

Niacin

NAD, NADP

Enzyme co-factor

Diet, EtOH

Pellagra, dermitis, diarrhaea, dementia

Vitamin Deficiency

Vitamin

Function

Deficiency State

Pyridoxine

(B6)

Enzyme co-factor

Drugs (INH), EtOH

Similar to riboflavin and niacin deficiency

C

Hydroxyl-ation of proteins

Antioxidant

Diet, EtOH

Scurvey, weak connective tissue

Bleeding, fractures, gingival swelling, peridontal disease, poor wound healing

Obesity

Diet and systemic disease

Atherogenesis.Hypertension.Diverticulosis.Colon cancer.Calorie restriction.

Chemoprevention and cancer

Consume large quantity of fruit and vegetables.

Pathology Laboratory

Page *Environmental Diseases (ch 8). In Basic Pathology (7th ed). Kumar V, Cotran RS, and Robbins SL. Saunders, Philadelphia, PA, 2003.Page *Data are from the US alone.Many chemical exposures go unreported.Page *Page *CH3-N=C=O methyl isocyanatePage *Page *Super Nail Offfrom MMWRPage *

Page *Page *Cytokines such asMacrophage inflammatory protein 1Endothelin 1Page *Disproportionation of nitrogen dioxide6NO2 2N2O5 + 2 NO

2N2O5 +2H2O 4HNO3

HNO2 = nitrous acidHNO3 = nitric acidN2O = nitrous oxideNO = nitric oxideNO2 = nitrogen dioxidePage *Macrophages producefibrogenic factors, such as TNF, PDGR, IGF-1, and fibronectin,cytokines such as LTB4(leukotriene B4), IL-8, IL-6, TNF, and MIP-1Toxic factors, such as proteases, oxygen free radicalsPage *Page *Page *Organochlorine compounds are nervous system stimulants, may cause seizures.

Herbicides cause pulmonary fibrosis.Page *Page *Page *Inorganic and organic mercury cause different clinical syndromes.Page *Page *Microcytic, hypochromic anemiaBasophilic stippling caused by precipitated ribosomes in reticulocytes.Page *Page *Page *Legal intoxication defined in some states as 80 mg/dL.Page *Page *Page *Page *Page *Page *Page *Page *Not all ADE or ADE-related deaths are due to errors.The % IP ADE is overstated in Robbins (they say 10% on p276, but it is more likely about 1%).These data are c/w the Institute of Medicine report on Errors in Medicine.Page *Page *Page *Page *Page *Page *Pattern may be evidence in criminal assault.Page *Page *Page *Page *Page *Page *Page *Page *Page *Page *Vitamin A def may cause squamous metaplasia.Xerophthalmia = dry eyeskeratomalacia = corneal ulceration w/o inflammation.

Note: Generally have to stop here for 50 min lecture.Page *Vit E deficiency rare in western diets.The major deficits are neuromuscular, including loss of reflexes, weakness, ataxia, loss of proprioception, loss of pain perception, ophthalmoplegia. May inhibit atheroma formation.

Page *Thiamine def: seen mostly in people eating high amount of polished rice, which is thiamine deficient. Polyneuropathy is dry beriberi. Cardiomyopathy is wet beriberi.Wernicke S is ophthalmoplegia, nystagmus, ataxia, altered mental status, and confusion.Korsokoff S is loss of remote and recent memory and confabulation. WKS is really a continuum of CNS deficit seen in thiamine deficiency, including psychosis.Cheilosis = cracks in corner of mouthNiacin def: Pellagra means rough skin. Def of niacin results in atrophy of many epithelial surfaces.Certain diets, such as Maize, are deficient in tryptophan, which is a precursor of niacin.Page *Vit C def: the bleeding is usually in the form of purpura and ecchymoses in the dependent areas of the body, related to capillary fragility secondary to weak connective walls of the small blood vessels.