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Toxic agents 

Toxic agents
Toxic agents

Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

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date: 16 May 2022

Drug-induced lung disease: clinical presentations


A vast number of drugs can damage the respiratory system, from nose to alveoli (see Box 48.1). The most up-to-date, complete, useful, and recommended list (plus references) is kept at Toxic agents and can be queried by either drug (or drug type) or nearly 20 different clinical/radiological presentations; all agents have equal prominence but are coded with a star rating to indicate likely prevalence. This chapter describes the commoner drugs that produce respiratory problems. Often the clinical problem is to differentiate drug toxicity from other causes of ILD.

Drug-induced lung disease: examples


Iodinated benzofuran used to suppress supra- and ventricular tachycardias. Lung toxicity correlates loosely with total dose and therefore usually occurs after a variable number of months. Seen in 10% of subjects on >400mg/day. Rare if <300mg/day.

Risk factors

  • Daily dose >400mg

  • Increasing age of patient

  • Use for >2 months

  • Pre-existing lung disease (although not a contraindication to its use)

  • Recent surgical intervention or lung infection.


is usually one of exclusion and response to cessation of drug (which can take months). Infiltrative lung disease varying from acute respiratory distress (rare) through to COP (cough, pleuritic pain, fever, dyspnoea, asymmetric patchy infiltrates, effusion), and the most indolent—chronic interstitial pneumonitis (cough, dyspnoea, weight loss, diffuse, and/or focal opacities).

On CT, the liver, thyroid, and lungs will usually show increased attenuation, indicating a significant amiodarone load. A baseline CXR is useful.

Lung biopsies

exclude other diagnoses and provide compatible findings, but there is dissent as to how diagnostic they are (except for the finding of foamy macrophages in the airspaces, filled with amiodarone–phospholipid complexes, but may occur in absence of lung toxicity). Mechanisms of toxicity are unclear, and there are features to suggest hypersensitivity and direct toxic damage.


Steroids are effective and required in severe disease. The half-life of amiodarone in the tissues is in excess of a month, and response to stopping the drug may be slow. Prognosis is good in the majority.

Anti-TNF agents

(infliximab and etanercept) represent a large step forward in the treatment of RA and Crohn’s disease. However, there is a small, but important, risk of reactivating TB, commonly extrapulmonary (see Toxic agents pp. [link][link]). Pneumonia and development of antibodies are also more common; SLE develops only rarely.


Extensively used as an immunosuppressant but has remarkably little pulmonary toxicity other than via opportunistic lung infection. Case reports of pneumonitis only.


DNA-damaging glycopeptide used in the treatment of lymphomas, germ cell tumours, squamous carcinomas (cervix, head, neck, and oesophagus). Pulmonary fibrosis occurs in about 10%.

Risk factors

  • Older age

  • Those receiving total dose of >300, 000IU (1, 000IU (or 1 old/USB unit) = 1.5–2.0mg)

  • Increased FiO2, probably via increased superoxide/free radical formation. Pneumonitis may be precipitated by supplementary O2 for some time after drug administration—warn anaesthetist if surgery planned in patients who have received bleomycin in previous 6–12 months

  • Pulmonary irradiation, not just in the irradiated field

  • Renal failure decreases drug elimination and thus toxicity

  • Associated use of cyclophosphamide.


(cough, dyspnoea, chest pain, fever) develop 1–6 months after bleomycin. There is hypoxia and a restrictive defect. Progressive basal subpleural shadowing, small lungs, and blunting of costophrenic angles.


shows a dominant subpleural distribution of damage and repair with fibrosis; this appearance is non-diagnostic and common to many drugs/disorders. Toxicity is probably due to DNA damage or oxidative injury, with inter-individual variation occurring due to differing activity of the enzyme bleomycin hydrolase; only low levels of this enzyme exist in the lung (and skin). A rare acute hypersensitivity form comes on within days of administration. Other unusual presentations include pulmonary nodules or OP.


  • Bleomycin must be stopped on suspicion of damage, and some units use lung function tests (kCO) to detect early damage

  • Steroids are used, but there is little evidence they alter long-term prognosis (in the acute hypersensitivity subgroup, there is a clear beneficial effect)

  • Use the minimum FiO2 to maintain an adequate SaO2 (85–90%)

  • Over 50% may experience a relentless decline in lung function.


DNA alkylating, myelosuppressive agent mainly used to treat chronic myeloid leukaemia and prior to bone marrow transplantation, with a low rate of lung toxicity (4–10%) due to fibrosis.

Risk factors

  • Cumulative doses >500mg (mostly over 120 days)

  • Concurrent administration of other alkylating agents

  • Pulmonary irradiation.

Presents with cough and progressive SOB, often years after exposure (usually about 4y). CXR is typically unremarkable. Reduced kCO and restrictive defect. Diagnosis is usually by exclusion. The place of steroids is unproven.


DNA alkylating agent mainly used to treat CLL, lymphomas, and ovarian cancer. It has additional immunosuppressive actions and is also used in conditions such as RA. Low risk (1%) of pulmonary toxicity and confined to those who have received >2g. Similarly to busulfan, presentation may be many years later. Presents with cough, dyspnoea, weight loss, and basal crackles. CXR shows diffuse basal reticular shadowing. Non-specific histology. On suspicion, chlorambucil should be stopped; use of steroids is unproven. Prognosis is poor (50% fatal).


DNA alkylating agent mainly used to treat CLL, SCLC, and other solid tumours. Particularly useful as an immunosuppressive agent in certain vasculitides and nephropathies. Lung toxicity is rare.

Risk factors

  • Pulmonary irradiation

  • O2 therapy

  • Concurrent drugs causing pulmonary toxicity, e.g. bleomycin.

Clinical presentation

is usually within 6 months, with a short duration of fever, cough, and fatigue. Reticular shadowing with ground-glass appearance on CT. Later-onset progressive pulmonary fibrosis can also develop insidiously in those on therapy for many months with progressive SOB and dry cough. The histology of the more acute type can be similar to any of the acute interstitial pneumonias (e.g. COP, diffuse alveolar damage), whereas the more chronic form is indistinguishable from UIP. Cyclophosphamide is not itself toxic to the lung, but its metabolites are. There appears to be genetic variation to susceptibility, as there is no obvious dose-response relationship. Cessation of drug and steroid therapy is used successfully in the acute form, but the chronic form seems to progress inexorably, in a similar manner to UIP. Lung transplantation is an option. Note increased risk of PCP whilst taking cyclophosphamide.


Used in RA, >500mg cumulative dose can produce pneumonitis (possibly COP, obliterative bronchiolitis), with cough, dyspnoea, and basal crackles. Rare (1%) but associated with certain HLA types and distinctive histological feature of alveolar septal inflammation. Good prognosis following drug cessation; poor evidence for steroids.


Folic acid derivative, inhibiting cell division by blocking dihydrofolate reductase and nucleic acid production. Mainly used in leukaemia and as an immunosuppressive, e.g. RA and psoriasis. Commonly (4–10%) causes a variety of lung pathologies, not associated with folic acid deficiency.

Risk factors

  • Hypoalbuminaemia

  • Diabetes

  • Previous use of drugs that modify disease progress in rheumatoid

  • Rheumatoid or other lung/pleural disease

  • Not particularly dose-related; can occur at doses of <20mg/week

  • Daily, rather than intermittent (weekly), therapy

  • >60y.


both acutely (interstitial pneumonitis, fever, and eosinophilia) and over very long time periods; however, the subacute form (within a year, dyspnoea, fever, cough, hypoxia, basal crackles, restrictive defect, and reduced kCO) is commoner. Bilateral diffuse pulmonary infiltrates or mixed pattern with alveolar shadowing on CXR, occasional effusions.


More useful than in other drug toxicities, shows alveolitis, interstitial pneumonitis, epithelial cell hyperplasia, eosinophilic infiltration, and granuloma formation in the more acute hypersensitivity form and more UIP-like changes in indolent form. Mechanism of damage unknown but likely to be multifactorial.


consists of drug withdrawal and unproven use of steroids. Anecdotal reports support use of steroids in the more acute hypersensitivity form. Other methotrexate-related lung diseases include opportunistic lung infection (including PCP) and non-Hodgkin’s B-cell lymphoma, which may regress with drug withdrawal and may be associated with EBV.


is used commonly for long-term prophylaxis against urinary tract infections (UTIs). Acutely, nitrofurantoin causes a hypersensitivity vasculitis and, much less frequently, a chronic interstitial fibrosis. Most patients are women due to their much higher prevalence of chronic UTIs. The acute form presents abruptly with fever, dyspnoea, dry cough, rash, chest pain, hypoxia, crackles, and eosinophilia within a week or two of starting and is dose-independent. Lower zone diffuse patchy infiltrates and sometimes unilateral effusions on CXR. Lung biopsy reveals vasculitis, eosinophilia, reactive type II pneumocytes, focal haemorrhage, and some interstitial inflammation. Treatment consists of discontinuation, and improvement begins rapidly. Prognosis is good, with or without steroids.


Prolonged 80–100% O2 therapy can provoke lung damage.


Used in the treatment of RA, penicillamine may increase the prevalence of obliterative bronchiolitis. This is dose-related but rare, with a subacute onset (after several months) of dyspnoea and cough. There is a progressive obstructive pattern without bronchodilator response; 50% mortality.


Used extensively in treatment of IBD (mainly ulcerative colitis). Rarely causes side effects but can cause new-onset dyspnoea and pulmonary infiltrates after any period of use. Cough, fever, lung crackles, and blood eosinophilia are the usual presentation. Prior allergy history, rash, and weight loss also seen with eosinophilic pneumonia, the usual pathology. Withdrawal of drugs is usually successful within weeks, and recovery can be hastened by steroids. Rare deaths when the histology is more like usual interstitial pneumonitis and may be more related to the condition requiring sulfasalazine.


is commonly used for pleurodesis (see Toxic agents pp. [link][link]). Talc particles may be small enough to enter the circulation after intrapleural instillation, being found throughout the body at post-mortem. They appear to provoke a systemic reaction with fever, raised inflammatory markers, and hypoxia, suggestive of an ARDS-like pathology. Occasional deaths after talc pleurodesis have been reported. Refined talc with fewer smaller particles seems less toxic.

Paraquat poisoning


(Weedol®, Pathclear®, Gramoxone®) and related bipyridyl compounds are used as contact herbicides. They kill plants by inhibiting NADP reduction during photosynthesis, which involves the production of superoxide radicals. Most of the toxicity of paraquat in animals is also believed to be due to the production of damaging superoxides. Most cases of poisoning are deliberate, and the treatment should be commenced as soon as possible. Serious poisoning is usually by ingestion (although paraquat is absorbed through the skin and mucous membranes, including the conjunctiva and bronchial mucosa).

  • >6g is always fatal

  • <1.5g is rarely fatal

  • Between 1.5 and 6g, the mortality is 60–70%

  • Mouthful of 20% Gramoxone® liquid (10g/50mL) is almost certainly fatal

  • <1 sachet of Weedol® granules (1.4g paraquat/57g sachet) is unlikely to cause death

  • Usually fatal if blood level >0.2mg/mL at 24h.

Clinical features

  • Oral and oesophageal ulceration shortly after contact, with later formation of a pseudomembrane

  • Renal failure (reversible) within a few days, but delayed excretion of paraquat prevents falls in blood levels

  • Pulmonary oedema early on, evolving into ‘ARDS’

  • Hepatic damage, jaundice, and raised transaminases

  • Metabolic acidosis

  • Death usually occurs within 1–2 weeks

  • Pulmonary fibrosis if the patient survives, with varying degrees of recovery.

Radiation-induced pulmonary disease

Manifestations of lung injury following radiotherapy include:

Radiation pneumonitis

  • Often asymptomatic although may cause dyspnoea and chronic ventilatory failure

  • Radiographic abnormalities more common than clinical disease. Characteristically straight margins on CT infiltrate

  • Pathological feature is of diffuse alveolar damage, with vascular intimal fibrosis

  • Typically follows lung radiotherapy

  • Treatment of symptomatic disease is with steroids (1mg/kg daily), although minimal evidence to support their use. Amifostine or pentoxifylline (used in the treatment of extrapulmonary manifestations of radiation-induced tissue damage) may be of benefit although unproven.

Radiation-induced organizing pneumonia

  • Often presents with cough (rather than breathlessness, which is more suggestive of radiation pneumonitis)

  • Characterized by migratory patchy consolidation which always extends beyond radiation field on CT

  • Typically follows breast radiotherapy

  • Treatment is with steroids; often long courses are needed. Macrolides may have a role.

Radiation-induced chronic eosinophilic pneumonia

  • Possible association; few cases reported.

Inhalational lung injury


Agents damaging the lung and airways through direct toxicity. Much of the acute damage is common to many toxic agents, including pneumonitis/pulmonary oedema, mucosal damage/sloughing/airway debris. 2° infection is common due to breached defences.

Examples of toxic agents, listed alphabetically


(acetaldehyde, formaldehyde)

  • Chemical and plastics industry, used for disinfection

  • Highly irritant to mucosal membranes

  • Acute damage

    • Pneumonitis and pulmonary oedema

  • Chronic effects

    • Rhinitis/asthma.


  • Fertilizer and plastics production, used in many chemical industries

  • Highly irritant to mucosal membranes

  • Acute damage

    • Upper airway obstruction from secretions and mucosal oedema

    • Lung damage and 2° infection

  • Chronic effects

    • Airways obstruction and bronchiectasis described.


  • Extensive use in the chemical industry, bleaching agent

  • Acute damage

    • Overwhelming toxicity, producing rapid hypoxia

    • Pneumonitis and pulmonary oedema

  • Chronic effects (e.g. from repeated accidental exposure)

    • Airways obstruction; sometimes reversible.


(when smoked)

  • Pneumothorax/pneumomediastinum

  • Pulmonary haemorrhage

  • Pulmonary oedema

  • Allergic responses (asthma, pulmonary eosinophilia, HP).

Metals and metal compounds

(as fumes or nebulized solutions)

  • Mainly used in the chemical industry

  • Acute damage

    • Mucosal irritation

    • Pulmonary oedema

  • Chronic effects

    • Pneumoconiosis

  • Some specific effects such as:

    • Sarcoid-like reaction to beryllium

    • Asthma from cobalt, chromium, nickel, vanadium

    • Fibrosing alveolitis from cobalt and zinc fumes.

Methyl isocyanate

(Bhopal disaster: 3,800 dead, 170,000 injured)

  • Chemical industry, carbamate pesticides

  • Acute damage

    • Pneumonitis and pulmonary oedema

    • 2° infection

  • Chronic effects

    • Airways obstruction

    • Bronchiolitis obliterans

    • Pulmonary fibrosis.

Hydrocarbons/mineral oils

  • Used as lubricant and cooling agent

  • Acute damage

    • Pneumonitis

  • Chronic effects

    • Pneumonitis

    • Fibrosis

    • Asthma.

Nitrogen dioxide (NO2)

  • Chemical industry (explosives)

  • Agricultural silos

  • Odourless and therefore high doses inhaled without knowing

  • Acute damage (several hours after exposure)

    • Silo-fillers lung (pneumonitis/pulmonary oedema)

  • Later effects

    • 2° pulmonary oedema 2–8 weeks after exposure

    • Steroid-responsive, needs 2 months therapy after exposure.


  • Bleaching agent

  • Product of welding

  • Similar to NO2

  • Both immediate and late effects of pneumonitis/pulmonary oedema.


  • Chemical warfare, chemical industry, chlorination

  • Released from heated methylene chloride (paint stripper)

  • Acute damage

    • Pneumonitis and pulmonary oedema

    • Produces carboxyhaemoglobin (COHb); breath CO therefore reflects degree of exposure.


  • Most smoke injury is due to heat damage to upper airway

  • Hypoxia, vaporized toxins (e.g. formaldehyde, chlorine), systemic agents (e.g. CO and cyanide)

  • Acute damage

    • Mucosal oedema and sloughing with airway blockage

  • Look out for:

    • Peri-oral burns

    • Black sputum

    • Altered voice

    • Respiratory distress

    • Stridor (rapid inspiration to accentuate)

    • Additional CO and/or cyanide poisoning.

Sulfur dioxide

  • Used as a fumigant, and bleaching agent in the paper industry

  • Very irritant as dissolves to form sulfuric acid

  • Acute damage

    • Sloughing of airway mucosa

    • Pneumonitis and haemorrhagic pulmonary oedema

  • Chronic effects

    • Airways obstruction.

Welding fumes

  • Many agents released

  • Specific examples:

    • Cadmium—pneumonitis

    • Zinc—’metal fume fever’

    • Several agents may cause airways obstruction/COPD

  • Siderosis (welder’s lung), non-fibrogenic pneumoconiosis

    • Iron deposits in lung, producing small rounded opacities.

Carbon monoxide poisoning

Definition and epidemiology

  • CO is a colourless and odourless gas formed when carbon compounds burn in limited O2

  • It accounts for about 75 deaths per year in the UK, ~10% of which are accidental

  • Accidental poisonings are commoner in the winter when faulty heating systems are in use

  • Non-accidental deaths are mainly from car exhaust fumes

  • Methylene chloride (industrial solvent, paint remover) is converted to CO in the liver and may present as CO poisoning

  • Up to one-third die following acute high-level exposure, and another third may be left with permanent neurological sequelae

  • Chronic low-grade CO exposure may present as non-specific ill health and may affect thousands of individuals.

Pathophysiology and related conditions

  • CO competes avidly with O2 (250 times greater) to bind with the iron in Hb, making it less available for O2 carriage

  • The Hb molecule is also distorted by combination with CO, making it bind more tightly to O2, shifting the O2 dissociation curve to the left. The PaO2 at which the Hb is 50% saturated (P50) moves from about 3.5 down to 2kPa. This further reduces O2 delivery to the tissues: a 50% COHb level is vastly more dangerous than a 50% anaemia

  • CO also binds to extravascular molecules, such as myoglobin and some of the cytochrome chain proteins, interfering with energy production, and, in this respect, is like cyanide

  • Normal levels of COHb can be up to 3%, and up to 15% in heavy smokers

  • Foetal Hb combines even more avidly with CO; thus the foetus is especially vulnerable to CO poisoning of the mother.


  • Methaemoglobin is due to oxidation of Fe2+ to Fe3+ in Hb, thus preventing O2 carriage. This is due either to inherited deficiencies of enzymes (cytochrome b5 reductase) that reduce the Fe3+ back to Fe2+, or toxic agents (e.g. nitrites (in ‘poppers’), chloroquine) that overwhelm this reversal mechanism

  • Methaemoglobin is slightly left-shifted, but a 40% methaemoglobinaemia may be asymptomatic, apart from the typical grey/blue colour of the patient, often mistaken for cyanosis.

Clinical features of CO poisoning


  • Nausea, headache, malaise, weakness, and unsteadiness

  • Loss of consciousness, seizures, cardiac abnormalities (ischaemia, arrhythmias, pulmonary oedema)

  • No cyanosis, healthy-looking ‘cherry red’ colour

  • Suspect if several members of household present with these features.

Delayed (~1–3 weeks, can be longer)

  • Cognitive defects and personality changes

  • Focal neurology and movement abnormalities.


  • Pulse oximetry will appear normal due to COHb having similar absorption spectra to oxyhaemoglobin. Recent developments in multiwave pulse oximetry may allow rapid COHb detection

  • Arterial PaO2 levels may be normal

  • COHb blood levels can be measured on a co-oximeter

  • Breath CO measured with devices used for smoking cessation work well

  • Routine tests to rule out other diagnoses.

Future developments

Isocapnic hyperpnoea may further raise the PaO2. Alkalosis must be avoided though to prevent further left shift of the Hb dissociation curve. Can be done voluntarily with 5% CO2 in O2 or during intubation. Can double rate of CO elimination.

Further information

Blumenthal I. Carbon monoxide poisoning. J R Soc Med 2001;94:270–2.Find this resource:

Buckley NA et al. Cochrane review of hyperbaric O2. Toxic agents

Plymouth Diving Disease Research Centre. Toxic agents (24h helpline and register of hyperbaric chambers) Toxic agents 01752 209999. Email

Harper A, Croft-Baker J. Carbon monoxide poisoning: undetected by both patients and their doctors. Age Ageing 2004;33:105–9.Find this resource:

Kreck TC et al. Isocapnic hyperventilation increases carbon monoxide elimination and O2 delivery. Am J Respir Crit Care Med 2001;163:458–62.Find this resource:

Roth D et al. Accuracy of noninvasive multiwave pulse oximetry compared with carboxyhemoglobin from blood gas analysis in unselected emergency department patients. Ann Emerg Med 2011;58:74–9.Find this resource: