Toxicity after repeat exposure

Table 3.9.4 Label elements for specific target organ systemic toxicity after repeated exposure...

Two patients with chronic cardiac toxicity after repeated exposure to trichloroethane had a deterioration in cardiac function following halothane anaesthesia. 

Nature of effect Route-to-route extrapolation is only applicable for the evaluation of systemic effects. For the evaluation of local effects after repeated exposure, only results from toxicity studies performed with the route under consideration can be used. 

The response of an organism to a toxic compound may become modified after repeated exposure. For example, tolerance or reduced responsiveness can develop when a compound is repeatedly administered. This may be the result of increasing or decreasing the concentration of a particular enzyme involved or by altering the number of receptors. For example, repeated dosing of animals with phenobarbital leads to tolerance to the pharmacological response as a result of enzyme induction (see chap. 5). Conversely, tolerance to the hepa to toxic effect of a... 

This inhibition involves reaction with the active site of the enzyme, which is often irreversible. Resynthesis of the enzyme is therefore a major factor governing the toxicity. Toxicity only occurs after a certain level of inhibition is achieved (around 50%). The irreversibility of the inhibition allows cumulative toxicity to occur after repeated exposures over an appropriate period of time relative to the enzyme resynthesis rate. 

Doctor, SV, Costa LG, Murphy SD. 1983. Development of tolerance to the antinociceptive effect but not to the toxicity of trimethyltin after repeated exposure. Developments in the Science and Practice of Toxicology 11 587-590. 

Klimisch HJ, Hellwig J, Kaufmann W, et al. 1991. Di-(2-ethylhexyl)phthalate (DEHP) Investigation of inhalation toxicity inrats after repeated exposure (28 d). Human Exp Toxicol 10 68. 

Procedures for toxic materials minimize exposure Toxic effects are either chronic or acute. Chronic effects are seen after repeated exposures or after one long exposure. Acute effects occur within a few hours at most. 

Chronic toxicity studies provide information on the long-term health effects of chemical substances. Adverse health effects in exposed animals and subsequent severe damage are known to occur after repeated exposure to low doses over a period of time. The slow accumulation of mercury or lead in the body or after a long latency period from exposure to chemical carcinogens is an example. Chronic or prolonged periods of exposure to chemical substances may also cause adverse effects on the reproduction and behavior of animals and humans. The symptoms caused after chronic exposure usually differ from those observed in acute poisoning from the same chemical. In fact, when exposed to low concentrations of chemical substances, as is the case with chronic toxicity studies, the industrial worker and common public are unaware of the exposure. 

Other chemicals may after repeated exposure cause more subtle effects on the skin such as allergic reactions. Skin sensitization can be caused by nickel in jewellery or the constituents of some washing powders. Sensitization of the skin leading to allergic, contact dermatitis can be very serious as well as disfiguring and is the most common industrial disease (see Chapter 7). Some natural toxicants, such as nettle sting (formic acid) and the very potent substances in the plant poison ivy, can be skin irritants. 

Acute toxic contact dermatitis may be induced by a single application of a toxic material. One local inflammatory skin reaction is characterized by erythema and oedema. This type of reaction occurs following contact with materials such as acids, alkalis, solvents, and cleansers and is rarely associated with topical application of medicinal or cosmetic products. In contrast, irritant contact dermatitis (a superficial non-immuno-logically based reaction) may occur after repeated exposure to many substances, including topical pharmaceutical agents. The reaction is usually localized to the site of exposure and usually diminishes after the stimulus has been removed. Some materials can stimulate an immune response following an initial topical application. Any future exposure may result in an inflammatory immune reaction, an allergic contact dermatitis, or sensitization. 

No clinical effects or symptoms of toxicity are known to have occurred in humans due to methoprene exposure alone however, some commercial formulations may potentially contain additional ingredients that cause skin or eye irritation, or allergic reactions after repeated exposures. Based on negative results in several genotoxicity studies and the results of the studies of carcinogenicity with methoprene, it is very unlikely that methoprene poses a carcinogenic risk to humans. 

The response of an organism to a toxic compound may become modified after repeated exposure. For... 

In the Green Screen the hazards of a chemical are defined by its potential to cause acute or chronic adverse effects in humans or wildlife, its fate in the environment, and certain physi-cal/chemical properties of concern to human health. Acute mammalian toxicity (lethality) and irritation of the skin or eye are examples of acute adverse effects that can result from inhalation, ingestion, or dermal contact with a chemical. Chronic effects occur after repeated exposures and include cancer and adverse effects to the reproductive, neurological, endocrine, or immune systems. 

Poisons can be acute (with immediate effect, e.g., hydrogen cyanide (HCN)) or chronic (referring to the systemic damage done after repeated exposure to low concentrations over long periods of time, e.g., heavy metals like mercury, lead, cadmium and also vinyl chloride). The chemicals most often associated with chronic toxicity are also carcinogens (e.g., benzene, cadmium compounds), which are problematic because when, if at all, the... 

Acids, alkalis, and phenols are acute toxins (the effect appears rapidly). Acids and alkalis destroy the skin tissue while phenol rapidly attacks internal body organs. Other absorbed materials can affect the body in a chronic way (the effect becomes visible only after repeated exposures). Personal protective equipment (PPE) is the most widely used means of protection against absorption. Gloves, coveralls, and face shields protect the worker from splash contact with toxic chemicals. However, PPE, if it is not donned properly, is useless for protection. 

Chronically toxic chemicals can cause hamn after repeated exposures. 

Acutely toxic chemicals can only cause harm after repeated exposures. 

Agricultural workers may have the greatest exposure rate to the aforementioned compounds, but one must remember that these chemicals can reside on clothing that is brought back into the household and are found in many household exterminator preparations and garden products. Accumulation of these compounds in the skin after repeated exposures sometimes creates reservoirs of pesticide in the stratum corneum that effectively increase their concentration and their irritant capacity, as well as potential toxic effects. A good investigative history will usually help verify a relationship between possible pesticide exposure and dermatitis. 

In low-level chronic exposure, MX sequesters cadmium intracellularly as the cadmium-MT complex and thereby decreases the toxic effects of the metal. By contrast, extracellular cadmium-MX has been shown to be nephrotoxic to experimental animals. Parenteral injection of cadmium in the form of cadmium-MT can cause acute renal damage in rats and mice (Nordberg et al. 1975 Cherian et al. 1976 Squibb et al. 1984 Maitani et al. 1988). These toxic effects were similar to those observed after repeated exposure to cadmium salts but the critical renal concentration of cadmium is much lower after injection of cadmium-MX (10//g/g) than after repeated injections of cadmium salts (200//g/g). The low molecular weight cadmium-MX is freely filtered by the glomerulus and reabsorbed by the proximal convoluted tubules and can cause acute damage to the renal tubular epithelial cells (Cherian et al. 1976 Goyer et al. 1984 Dorian et al. 1992). It has been proposed that the hepatic cadmium-Mt is released and transported to kidney in blood plasma and that the nephrotoxicity occurs at a certain renal concentration of cadmium with chronic exposure (Goyer et al. 1978, 1984 Dudley et al. 1985). In a recent liver transplant experiment, the movement of cadmium-MX form liver to kidney was demonstrated in rats where the liver with cadmium-MX was transplanted to a control rat (Chan et al. 1993). 

---