Effects Signs and symptoms Toxicants
Irritation Solvents (skin)
Inflammation of the skin and mucous membranes of nose, eyes, mouth and upper respiratory tract.
Related to the solubility of the substance onto skin or moist surfaces
Chlorine, ammonia, nitrogen dioxide and phosgene (mucous membranes)
Corrosiveness Irreversible damage to tissue on contact Hydrochloric, sulfuric and nitric acids and sodium hydroxide
Asphyxiation A reduction in the concentration of oxygen in inspired air by physical displacement (simple asphyxiation) leading to hypoxia
Irritation, corrosive or allergic reactions Any corrosive, irritating or skin allergenic chemicals The skin contains fairly high levels of fatty
tissue and therefore chemicals which can dissolve fat will cause defatting, which can lead to drying of the skin, cracking and possibly dermatitis
Irritation of the airways, sneezing, nose bleeds, wheezing, coughing, obstruction of airway passages and sinusitis
Sulfur dioxide
Bronchoconstriction and epithelial injury Ammonia
Asthma (reversible bronchoconstriction) Isocyanates, formaldehyde
Increase in secretion of mucous Sulfur dioxide, tobacco smoke
Damage to cellular components of airways and
alveoli Hydrogen chloride,
phosgene Eye damage (ocular
toxicity) Ocular irritation, lacrimation, conjunctival irritation/ conjunctivitis, corneal damage and iritis
Gastric irritation, nausea, diarrhoea, abdominal
pain, colic Ingestion of pesticides,
chlorinated hydrocarbons, food allergens and metal salts
■ teratogens are chemicals that affect the development of the organism
■ carcinogens are chemicals that cause cancer
■ genotoxicants are chemicals that affect genetic material (also called mutagens).
This is one convenient way of splitting the toxic properties of chemicals into manageable and meaningful subunits. Furthermore, this has a useful purpose clinically in that specific organ dysfunction is most likely to be seen at clinical presentation. In conjunction with a good occupational history, it should be possible to determine if the injury is related to workplace exposure to a chemical. However, chemical induced organ dysfunction must be differentiated from that due to other causes because each organ has a limited manner in which it can respond to injury. Therefore, detection of the chemical or its biotransformation products in body fluids or tissues at levels associated with toxicity, as well as evidence of toxicity compatible with exposure to the particular xenobiotic, are needed to make a diagnosis of occupational or environmental disease.
The ultimate expression of toxicity at any particular target depends on a variety of factors as discussed in some detail in Chapter 2. These include the nature of the chemical
itself, the route of exposure, the disposition of the chemical, including any biotransformation, and the sensitivity of the exposed organ or tissue.
Any organ of the body is a potential target for injurious effects from chemicals, but some are more susceptible to adverse effects than others. In the workplace setting, the skin and respiratory tract are the two systems most commonly affected since exposure is often by direct contact with the skin or by inhalation. Since the liver is an important organ for metabolism and excretion of absorbed chemicals, and the kidney is the major organ of excretion, individual chapters have been devoted to these organs. The occupational toxicology of the nervous and reproductive systems and developmental toxicity are also addressed in separate chapters as these systems have specific issues to be covered. Another potential target for chemicals is genetic material. Interaction of xenobiotics with DNA may result in cancer, a major concern with workplace chemicals.
Therefore, two chapters are devoted to this very important aspect of occupational toxicology.
This chapter provides an overview of the systemic toxicology of the haematopoietic, immune, cardiovascular and gastrointestinal systems. Clearly, each of these is a topic in its own right. For a more detailed coverage of these (and other) target organs the reader is referred to texts such as the Target Organ Toxicology Series (Dixon), Casarett and Doull’s Toxicology (Klaassen 2001), Handbook of Toxicologic Pathology (Haschek et al.
2002), or specific references used in subsequent sections.
Gastrointestinal system (W.M.Haschek)
Introduction
Although many industrial chemicals cause gastrointestinal symptoms and even tissue injury, little information is available regarding their specific toxic effects and even less regarding their mechanism of action. This may be due to the generally held view that the gastrointestinal tract is not an important site of action for toxic chemicals except when exposure is to corrosive agents and carcinogens.
The gastrointestinal tract is the site of entry for ingested chemicals, for inhaled chemicals that are removed from the lung by coughing or expectoration and then swallowed, and those excreted in the bile (Rozman and Klaassen 2001). Gastrointestinal toxicity may occur from ingested chemicals themselves, or secondarily by chemicals reaching the tract through the circulation or from the bile. Susceptibility of the gastrointestinal tract to injury is due to its barrier role, allowing direct contact with ingested chemicals; its marked absorptive capacity; and its high mucosal proliferative and metabolic rate. Protective mechanisms against chemicals include the low pH in the stomach, the mucous surface layer, and the presence of biotransforming enzymes. These enzymes are present both within the lining epithelium and within endogenous lumenal bacteria; they may metabolise chemicals to either reactive or less toxic intermediates.
Reactive metabolites may be directly toxic to the gastrointestinal tract or may be absorbed into the circulation to reach other target organs. The intestines also contain large amounts of inert binding materials that can act as protective adsorbents.
Structure and function of the gastrointestinal tract
The gastrointestinal tract is a tubular organ whose wall consists of a mucosa, a submucosa, smooth muscle, and serosa. The mucosa is the primary site of chemical-induced injury. It consists of an epithelial lining, a lamina propria of vascularised connective tissue, and the muscularis mucosae, a thin layer of muscle that delineates the mucosal boundary. The epithelium that covers the lumenal surface of the mucosa functions as a selectively permeable barrier to substances within the lumen, and facilitates the transport and digestion of food, as well as the absorption of water and digestive products. Abundant lymphoid tissue is also present in the mucosa and submucosa; protection against infection is primarily through immunoglobulin A (IgA) production.
In the stomach, the mucosa is folded into rugae. The major types of epithelial cells are the mucous, parietal, and chief cells, which secrete large amounts of mucous, hydrochloric acid, and pepsinogen and lipase, respectively. The mucous protects the surface from the secreted acid as well as from ingested materials. In the small intestine, the mucosa is folded into villi with crypts present at the base. The crypt epithelial cells are the progenitor cell with a high mitotic rate. They differentiate as they move up the villus into nondividing absorptive cells which line the lumenal surface. The renewal rate for the mucosal epithelium is less than 5 days in humans. The crypt epithelial cells are very sensitive to compounds that interfere with cell division such as radiation and chemotherapeutic agents. Damage to these cells ultimately decreases the availability of absorptive cells, resulting in malabsorption as well as diarrhoea. The absorptive cells are rich in biotransforming enzymes, similar to those present in the liver, and therefore can metabolise chemicals. Resident bacteria can also metabolise ingested chemicals. The large intestine does not have villi, only crypts, with many mucous cells. It is the major site for water absorption from the intestinal contents and for mucous production.
Chemicals that enter the digestive tract may pass straight through and be excreted unchanged in the faeces; may be directly toxic to the mucosa; be absorbed, primarily by passive diffusion, into the epithelial cells; or may be metabolised by bacteria in the lumen. Once within the cell, a chemical may be directly toxic to the cell, metabolised to reactive or less toxic intermediates, or bound to protein before passing into the lymphatics or capillary bed. After passing through the liver, the absorbed chemical can then be excreted in the urine or the bile. Enterohepatic circulation occurs when the chemical excreted in the bile is absorbed from the intestines, re-enters the circulation, and is once more excreted by the liver into the bile. This process may be repeated several times resulting in concentration of the chemical and increased toxicity.
Classification of gastrointestinal toxicity
Classification of gastrointestinal toxicity can be based on the type of injury, as shown in Table 3.2, or on the pathophysiological or clinical response, as shown in Table 3.3. There are four major types of tissue responses to injury (see section on mechanisms below for additional information):
■ ulceration (Rozman and Hanninen 1986)
■ necrosis and inflammation (which often occur together)
■ proliferation, including cancer.