Desarrollo del proyecto

The CNS presents a challenge to direct evaluation, since invasive diagnostic pro- cedures involving the brain and spinal

cord may be life threatening. Indirect ex- aminations provide information about neurological function, and the following are helpful in CNS and PNS toxicity di- agnoses: (1) patient history, (2) mental status (e.g., memory), (3) deficits in cra- nial nerve function (e.g., auditory nerve function in hearing and balance), (4) sen- sory neuron function (e.g., pain, tempera- ture), and (5) motor neuron function (e.g., coordination, gait, muscle strength, re- flexes, tremors).

Other information related to neurologi- cal structure and function may be obtained from x rays, computerized axial tomogra- phy (CAT scans), magnetic resonance imaging (MRI), electromyography (EMG), electroencephalography (EEG), peripheral nerve conduction velocity, and cerebros- pinal fluid (CSF).

Dermatotoxicity

Introduction

Dermatotoxicity describes the adverse ef- fects produced by toxicants in the skin. Re- call that skin is composed of the epidermis, dermis, and subcutaneous fatty tissue. Hair follicles, oil and sweat glands, blood ves- sels, and sensory neurons are present. Skin is more than a protective covering. It func- tions to limit water loss, reduce the harm- ful effects of ultraviolet radiation, prevent the entrance of microorganisms, regulate body temperature, and also biotransform and eliminate toxicants. Skin, with all its related functions, is vulnerable to toxicity, because skin is often the first part of the body to come into contact with a toxicant during handling.

Toxicity Mechanisms

Toxic skin reactions are diverse and may involve any one or a number of combina- tions of skin components. Irritant contact dermatitis results when toxicants elicit an inflammatory response in skin. Depend- ing on the exposure site, this form of dermatotoxicity is manifest in the accu- mulation of watery fluid (edema), an in- crease in the amount of blood (hyper- emia), or, if serious, the loss of tissue (ul- ceration and necrosis). Although irritant contact dermatitis is usually confined to the site of contact, prolonged exposure may result in systemic toxicity.

Some individuals show little or no re- sponse on exposure to a chemical; how- ever, on exposure at a later time they may exhibit a delayed hypersensitivity reaction, sometimes severe, termed allergic contact dermatitis. This delayed sensitivity to toxicants involves the immune system, and it may take from a few days to many years for individuals to become sensitized. Spe- cifically, the initial exposure sensitizes the immune system (T lymphocytes) to “rec- ognize” the toxicant on later exposure. Again, the delayed dermatotoxicity or hy- persensitivity reaction may result in edema, hyperemia, or ulceration.

Phototoxicity, a form of light-induced dermatotoxicity, results when skin is over- exposed to ultraviolet light or from the combination of exposure to specific wave- lengths of light and a phototoxic sub- stance. Symptoms associated with phototoxicity include erythema (sunburn), hyperpigmentation, premature skin aging, and cancer. Hyperpigmentation and hypopigmentation symptoms result from changes in melanocytes, the cells located

Target Organ Toxicity 97 in the epidermis responsible for the pro-

duction of melanin (a pigment that gives color to skin and hair).

Dermatotoxic responses may occur in hair, and in sebaceous and sweat glands. The cells responsible for hair production have some of the highest mitotic (cellular division) rates in the body. Toxicants, in- cluding chemotherapeutic agents, that in- terrupt cellular division typically will in- duce hair loss. Some dermatotoxins stimu- late a proliferation of the epithelium sur- rounding sebaceous glands. Proliferating epithelial cells plug the pilosebaceous (L.

pilus, hair; L. sebaceus, oily) orifices, pro-

ducing chloracne, a condition similar to acne vulgaris experienced by adolescents.

Examples

Irritant contact dermatitis (e.g., edema, erythema) may result from exposure to a variety of agents, including organic sol- vents, acids (pH less than 5.5), bases, plants (orange peel, nettles), detergents, and even water. Chronic exposure to ce- ment and chrome can result in serious ul- cerative conditions accompanied by ne- crosis.

Allergic contact dermatitis has been linked to exposure to antibiotics (e.g., peni- cillin), antihistamines (e.g., diphenhy- dramine), anesthetics, plants (e.g., poison ivy), tanning agents, metal compounds (e.g., chromates), numerous industrial agents, and rubber antioxidants. The lat- ter are commonly used in the manufacture of gloves, shoes, and undergarments.

Phototoxicity can result from acute and chronic exposure to ultraviolet radiation (e.g., “sunbathing”). Exposure to certain wavelengths of light coupled with simul-

taneous exposure to phototoxicants, such as drugs (e.g., tetracycline), perfumes, poly cyclic aromatic hydrocarbons, and dyes, can result in dermatotoxicity.

Sunlight, coal tar compounds, petro- leum oils, and heavy metals (e.g., arsenic, mercury) are known to produce hyperpigmentation. Of therapeutic inter- est in the treatment of hypopigmentation are the psoralens (e.g., 8- methoxypsoralen). Vitiligo (white patches of skin caused by an absence or decrease in melanin production) is often successfully treated with PUVA (psoralen and ultravio- let-A) therapy. Together the phototoxicant and UV-A produce hyperpigmentation.

A decrease in melanin production, or hypopigmentation, can be produced as a result of burns, chronic dermatitis, and dermatotoxicants such as p-tertiary butyl phenol. The mechanism by which p-terti- ary butyl phenol functions as a depigmenting agent (i.e., melanotoxicant) is probably related to its structural like- ness to L-tyrosine, one of two amino acid precursor molecules involved in melanin biosynthesis. The resulting decrease in melanin is likely due to the biosynthesis of a nonfunctional “melanin-like” mol- ecule, or as a result of a reduction of the enzymes that normally catalyze the reac- tion of L-tyrosine into melanin. The en- zymes are depleted or inhibited during attempts to catalyze p-tertiary butyl phe- nol, and hence are unavailable to catalyze the normal L-tyrosine to melanin reaction (Figure 7–3).

Acne-like conditions may be produced by a number of dermatotoxicants, includ- ing coal tar, greases, oils, and even cosmet- ics. However, a few specific halogenated aromatic compounds are responsible for

producing chloracne (Figure 7–4). Among the more active chloracne-producing chemicals are polyhalogenated biphenyls, dibenzofurans, dioxins, and naphthalenes. These halogenated chemicals induce epi- thelial hyperplasia (i.e., increase the num- ber of epithelial cells), which blocks the opening to sebaceous glands.