21. Occupational intoxications with nitro- and amino-benzenes - etiology, pathogenesis, clinical manifestations, diagnosis, treatment, medical expertise.

Introduction

This topic covers occupational poisoning by aromatic nitro-compounds and aromatic amines, mainly aniline, naphthylamines, nitrobenzene and trinitrotoluene (TNT). The key exam themes are methaemoglobinaemia with haemolysis, the chronic TNT triad, and bladder carcinogenesis, together with treatment with methylene blue and the medico-legal assessment of occupational disease.

Definition and classification

Aromatic nitro- and amino-compounds are benzene derivatives in which a nitro group (-NO2) or an amino group (-NH2) is attached to the ring. Their toxicity depends mainly on the metabolites formed in the liver, not on the parent compound. They are absorbed through intact skin as well as through the lungs, so occupational exposure is often under-recognised.

Etiology and sources of exposure

• Industrial solvents and intermediates used in chemical synthesis
• Dyes and pigments, including azo-dye production
• Explosives manufacture and munitions handling (TNT)
• Rubber, plastics and polyurethane production, pharmaceuticals and pesticides
• Cosmetics, especially hair dyes containing aminophenols and diamines

Pathogenesis

The central mechanism is the oxidation of haemoglobin iron. Metabolites such as phenylhydroxylamine oxidise the ferrous iron of haemoglobin to the ferric state, producing methaemoglobin that cannot carry oxygen. Redox cycling of these metabolites also generates reactive oxygen species that damage red-cell membranes and cause Heinz body formation and haemolysis.

1. Absorption through the lungs and the skin, and to a lesser degree by ingestion
2. Hepatic metabolism (N-hydroxylation and ring hydroxylation) to toxic intermediates
3. Oxidation of haemoglobin iron, forming methaemoglobin
4. Tissue hypoxia despite normal arterial pressure of oxygen, with cyanosis
5. Haemolysis through oxidative damage, more marked in glucose-6-phosphate dehydrogenase (G6PD) deficiency

Aromatic amines, especially alpha- and beta-naphthylamine, are carcinogens of the urinary bladder. The carcinogenic metabolites are excreted in urine and act on the bladder epithelium after a long latency period, often of many years.