Pathogenesis of injury by

Pathogenesis of injury by

Chemical agents

Session 19: Pathogenesis of Injury by Chemical Agents

Pathology — CMT/CDT NTA Level 4

Kolandoto College of Health Sciences Mwanza

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Learning tasks

Learning tasks

At the end of this session, students are expected to be able to:

Explain the general mechanisms of chemical injury.

Differentiate between directly acting and indirectly acting chemical agents.

Explain injury caused by environmental and occupational chemicals.

Explain injury caused by therapeutic drugs.

Explain injury caused by social drugs — alcohol and tobacco.

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Introduction

Introduction

Chemical agents are an important cause of cell injury in both community and hospital practice. Almost any chemical substance can cause injury if the dose is sufficient.

Chemicals reach the body through ingestion, inhalation, absorption through the skin, or by injection.

The effect produced depends on the nature of the chemical, the dose, the route of exposure, the duration of exposure, and the susceptibility of the individual.

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Factors influencing chemical injury

Factors influencing chemical injury

The chemical nature and concentration of the agent.

Dose and duration of exposure — the fundamental principle is that the dose makes the poison.

Route of entry into the body.

Rate of absorption, distribution and excretion.

The capacity of the individual to metabolise and detoxify the agent.

Age, nutritional status, existing liver or kidney disease, and genetic variation in metabolising enzymes.

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Mechanisms of chemical injury

Mechanisms of chemical injury

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Mechanisms of chemical injury

Mechanisms of chemical injury

Direct injury — the chemical combines directly with a critical molecular component or cellular organelle.

Indirect injury — the chemical is converted to a reactive toxic metabolite that then damages the cell.

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Direct injury

Direct injury

Directly acting chemicals

These chemicals injure the cell without requiring metabolic conversion. The cells with the greatest damage are usually those at the site of contact, or those that concentrate or excrete the chemical.

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Examples of directly acting chemicals

Examples of directly acting chemicals

Corrosive substances — strong acids and strong alkalis produce coagulative and liquefactive necrosis at the site of contact.

Mercuric chloride binds to sulphydryl groups of cell membrane proteins, causing increased permeability and inhibition of ATPase-dependent transport; the gastrointestinal tract and kidney are most affected.

Cyanide binds to and inactivates mitochondrial cytochrome oxidase, blocking cellular respiration.

Cancer chemotherapeutic agents and some antibiotics damage cells by direct cytotoxic effects.

Hypertonic solutions of glucose and salt injure cells by causing osmotic derangement.

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Indirect injury

Indirect injury

Indirectly acting chemicals

These chemicals are not intrinsically toxic. They must first be converted, mainly by the cytochrome P-450 mixed function oxidase system of the smooth endoplasmic reticulum of the liver, into reactive toxic metabolites — usually free radicals.

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Free radical mechanism of injury

Free radical mechanism of injury

The toxic metabolite is usually a highly reactive free radical.

Free radicals attack cellular constituents by three main routes

Lipid peroxidation of membranes — destroying the plasma membrane and organelle membranes.

Oxidative modification of proteins — inactivating enzymes and structural proteins.

Damage to DNA — causing mutations that may lead to neoplasia.

Because these metabolites are formed in the liver, hepatocytes are frequently the principal target of indirectly acting chemicals.

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Classical examples of indirect injury

Classical examples of indirect injury

Carbon tetrachloride (CCl4)

Converted by P-450 to the free radical CCl3, causing lipid peroxidation, fatty change and centrilobular hepatic necrosis.

Paracetamol (acetaminophen)

In overdose, glutathione is exhausted and the reactive metabolite NAPQI accumulates, causing centrilobular liver necrosis.

Ethanol

Metabolised to acetaldehyde; causes fatty change, alcoholic hepatitis and cirrhosis.

Aflatoxin B1

Fungal toxin from Aspergillus in poorly stored grain and groundnuts; a potent cause of hepatocellular carcinoma.

Benzopyrene

Present in tobacco smoke; converted to an epoxide that binds DNA and causes lung cancer.

Methanol

Metabolised to formaldehyde and formic acid, causing blindness and severe metabolic acidosis.

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Environmental and occupational chemicals

Environmental and occupational chemicals

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Air pollutants

Air pollutants

Carbon monoxide — a colourless, odourless gas from incomplete combustion; binds haemoglobin with about 200 times the affinity of oxygen to form carboxyhaemoglobin, causing systemic hypoxia.

Cherry-red discolouration of the skin and mucous membranes is characteristic.

The central nervous system is the most vulnerable; death may occur without any morphological change.

Sulphur dioxide, nitrogen dioxide and ozone irritate and injure the respiratory epithelium.

Particulate matter (smoke, dust) is deposited in the alveoli and ingested by macrophages, causing chronic inflammation.

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Heavy metals

Heavy metals

Lead

Sources: batteries, paint, contaminated water. Interferes with haem synthesis causing anaemia with basophilic stippling; also causes encephalopathy, colic, nephropathy and a gingival lead line.

Mercury

Sources: contaminated fish, artisanal gold mining, some skin-lightening creams. Causes CNS damage (tremor, ataxia), renal tubular injury and gingivitis.

Arsenic

Sources: contaminated ground water, pesticides. Interferes with oxidative phosphorylation; causes gastrointestinal, skin and nervous system disease and skin and lung cancers.

Cadmium

Sources: batteries, tobacco smoke. Causes renal tubular damage and obstructive lung disease.

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Occupational and agricultural chemicals

Occupational and agricultural chemicals

Organophosphate pesticides inhibit acetylcholinesterase, producing cholinergic crisis — salivation, lacrimation, urination, defecation, bronchospasm and muscle paralysis.

Organic solvents — benzene damages the bone marrow and causes acute myeloid leukaemia; toluene damages the nervous system.

Mineral dusts inhaled over long periods cause the pneumoconioses

Silica → silicosis.

Coal dust → coal workers' pneumoconiosis.

Asbestos → asbestosis, bronchogenic carcinoma and mesothelioma.

Vinyl chloride is associated with angiosarcoma of the liver.

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Injury by therapeutic drugs

Injury by therapeutic drugs

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Adverse drug reactions

Adverse drug reactions

Adverse drug reactions are untoward effects of drugs given in conventional therapeutic doses. They are a common and important cause of disease, and are largely preventable.

Drug toxicity may be predictable and dose-related, or unpredictable (idiosyncratic, allergic or genetically determined).

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Examples of drug-induced injury

Examples of drug-induced injury

Paracetamol overdose — centrilobular hepatic necrosis; treated with N-acetylcysteine which restores glutathione.

Aspirin overdose — respiratory alkalosis followed by metabolic acidosis; gastric erosions and bleeding.

Aminoglycosides (e.g. gentamicin) — nephrotoxicity and ototoxicity.

Chloramphenicol — aplastic anaemia; grey baby syndrome in the newborn.

Anti-tuberculosis drugs — isoniazid and rifampicin cause drug-induced hepatitis.

Antiretroviral drugs — lactic acidosis, lipodystrophy and hepatotoxicity.

Exogenous oestrogens — increased risk of thromboembolism and endometrial carcinoma.

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Injury by social drugs

Injury by social drugs

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Alcohol (ethanol)

Alcohol (ethanol)

Ethanol is metabolised in the liver by alcohol dehydrogenase and by the microsomal ethanol oxidising system to acetaldehyde.

Acetaldehyde and the associated excess of NADH cause accumulation of fat within hepatocytes.

Effects of chronic alcohol use

Liver — fatty change, alcoholic hepatitis, cirrhosis and hepatocellular carcinoma.

Gastrointestinal — gastritis, peptic ulceration, acute and chronic pancreatitis.

Nervous system — peripheral neuropathy, Wernicke-Korsakoff syndrome, cerebral atrophy.

Cardiovascular — dilated cardiomyopathy and hypertension.

Fetus — fetal alcohol syndrome with growth retardation and mental impairment.

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Tobacco

Tobacco

Tobacco smoke contains more than 4000 constituents, including nicotine, carbon monoxide, tar, polycyclic aromatic hydrocarbons and nitrosamines.

Nicotine is responsible for addiction; the carcinogens are responsible for the malignancies.

Effects of tobacco use

Respiratory — chronic bronchitis, emphysema, squamous metaplasia and bronchogenic carcinoma.

Cardiovascular — atherosclerosis, ischaemic heart disease and peripheral vascular disease.

Oral cavity — leukoplakia, periodontal disease and oral squamous cell carcinoma.

Other cancers — larynx, oesophagus, pancreas, urinary bladder and cervix.

Passive (second-hand) smoking carries similar though lesser risks, particularly in children.

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Key points

Key points

Chemical injury may be direct, or indirect through conversion to reactive toxic metabolites.

Indirectly acting chemicals are activated mainly by the cytochrome P-450 system in the liver, so the liver is a frequent target.

Free radicals injure cells by lipid peroxidation, protein oxidation and DNA damage.

Carbon monoxide produces systemic hypoxia by forming carboxyhaemoglobin.

Lead, mercury, arsenic and cadmium are the heavy metals of greatest public health importance.

Alcohol and tobacco are the social drugs responsible for the largest burden of chemically induced disease.

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Review questions

Review questions

Differentiate between directly acting and indirectly acting chemical agents, giving two examples of each.

Explain the mechanism by which carbon tetrachloride causes liver injury.

Explain how carbon monoxide causes cell injury and state its characteristic clinical sign.

List four (4) heavy metals of public health importance and state the main effect of each.

Describe five (5) effects of chronic alcohol consumption on the body.

Explain why the liver is the organ most frequently damaged by indirectly acting chemicals.

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References

References

Kumar V.; Abbas A. K.; Aster J. C.; (2013): Robbins and Cotran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, China. Pg. 269-287.

Mohan H.; (2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India. Pg. 232-242.

Goljan E.; (2007): Rapid Review Pathology (2nd Ed.) Elsevier Saunders, USA. Pg. 110-116.

Bezabeh M.; Tesfaye A.; Ergicho B. et al (2004): General Pathology Lecture Notes for Health Sciences Students. Ethiopia Public Health Training Initiative. Pg. 225-231.

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