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70 CLASSES OF TOXICANTS: USE CLASSES

5.6SOLVENTS

Although solvents are more a feature of the workplace they are also found in the home. In addition to cutaneous effects, such as defatting and local irritation, many have systemic toxic effects, including effects on the nervous system or, as with benzene, on the blood-formingelements. Commercial solvents are frequently complex mixtures and may include nitrogenorsulfur-containingorganics—gasolineand otheroil-basedproducts are examples of this. The common solvents fall into the following classes:

Aliphatic Hydrocarbons, such as hexane. These may be straight orbranched-chaincompounds and are often present in mixtures.

Halogenated Aliphatic Hydrocarbons. Thebest-knownexamples are methylene dichloride, chloroform, and carbon tetrachloride, although chlorinated ethylenes are also widely used.

Aliphatic Alcohols. Common examples are methanol and ethanol.

Glycols and Glycol Ethers. Ethylene and propylene glycols, for example, in antifreeze give rise to considerable exposure of the general public. Glycol ethers, such as methyl cellosolve, are also widely used.

Aromatic Hydrocarbons. Benzene is probably the one of greatest concern, but others, such as toluene, are also used.

5.7THERAPEUTIC DRUGS

Although the study of the therapeutic properties of chemicals fall within the province of pharmacology, essentially all therapeutic drugs can be toxic, producing deleterious effects at some dose. The danger to the individual depends on several factors, including the nature of the toxic response, the dose necessary to produce the toxic response, and the relationship between the therapeutic dose and the toxic dose. Drug toxicity is affected by all of factors that affect the toxicity of other xenobiotics, including individual (genetic) variation, diet, age, and the presence of other exogenous chemicals.

Even when the risk of toxic side effects from a particular drug has been evaluated, it must be weighed against the expected benefits. The use of a very dangerous drug with only a narrow tolerance between the therapeutic and toxic doses may still be justified if it is the sole treatment for an otherwise fatal disease. However, a relatively safe drug may be inappropriate if safer compounds are available or if the condition being treated is trivial.

The three principal classes of cytotoxic agents used in the treatment of cancer all contain carcinogens, for example, Melphalen, a nitrogen mustard, adriamycin, an antitumor antibiotic, and methotrexate, an antimetabolite. Diethylstilbestrol (DES), a drug formerly widely used, has been associated with cancer of the cervix and vagina in the offspring of treated women.

Other toxic effects of drugs can be associated with almost every organ system. The stiffness of the joints accompanied by damage to the optic nerve (SMON—subacutemyelo-opticneuropathy) that was common in Japan in the 1960s was apparently a toxic side effect of chloroquinol (Enterovioform), an antidiarrhea drug. Teratogenosis

COSMETICS 71

can also be caused by drugs, with thalidomide being the most alarming example. Skin effects (dermatitis) are common side effects of drugs, an example being topically applied corticosteroids.

A number of toxic effects on the blood have been documented, including agranulocytosis caused by chlorpromazine, hemolytic anemia caused by methyldopa, and megaloblastic anemia caused by methotrexate. Toxic effects on the eye have been noted and range from retinotoxicity caused by thioridazine to glaucoma caused by systemic corticosteroids.

5.8DRUGS OF ABUSE

All drugs are toxic at some dose. Drugs of abuse, however, either have no medicinal function or are taken at dose levels higher than would be required for therapy. Although some drugs of abuse may affect only higher nervous functions—mood,reaction time, andcoordination—manyproduce physical dependence and have serious physical effects, with fatal overdoses being a frequent occurrence.

The drugs of abuse include central nervous system depressants such as ethanol, methaqualone (Quaalude), and secobarbital; central nervous system stimulants, such as cocaine, methamphetamine (speed), caffeine, and nicotine; opioids, such as heroin and mependine (demerol); and hallucinogens such as lysergic acid diethylamide (LSD), phencyclidine (PCP), and tetrahydrocannabinol, the most active principal of marijuana. A further complication of toxicological significance is that many drugs of abuse are synthesized in illegal and poorly equipped laboratories with little or no quality control. The resultant products are therefore often contaminated with compounds of unknown, but conceivably dangerous, toxicity. The structures of some of these chemicals are shown in Figure 5.2.

5.9COMBUSTION PRODUCTS

While many air pollutants (see Chapter 4) are the products of natural or anthropomorphic combustion, some of the most important from the point of view of human health are polycyclic aromatic hydrocarbons. Although also found in natural products such as coal and crude oil, they are generally associated with incomplete combustion of organic materials and are found in smoke from wood, coal, oil, and tobacco, for example, as well as in broiled foods. Because some of them are carcinogens, they have been studied intensively from the point of view of metabolic activation, interactions with DNA, and other aspects of chemical carcinogenesis. Some are heterocyclic, containing nitrogen in at least one of the rings. Some representative structures of the most studied polycyclic aromatic hydrocarbons are shown in Figure 5.3.

5.10COSMETICS

The most common deleterious effects of modern cosmetics are occasional allergic reactions and contact dermatitis. The highly toxic and/or carcinogenic azo or aromatic

72CLASSES OF TOXICANTS: USE CLASSES

1.CNS Depressants

 

 

 

 

N CH3

 

 

O

 

 

 

 

 

 

 

 

 

C2H5OH

 

 

 

CH3

 

 

CH(CH3)C3H7

 

 

 

 

N

 

 

N

 

Ethanol

 

 

 

 

 

CH2CH

 

 

 

 

CH2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

O

N

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Methaqualone

 

 

 

Secobarbital

 

 

 

2. CNS Stimulants

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CH3

 

 

NHCH3

 

 

 

H3C

O

CH3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

COOCH3

CH2CHCH3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

N

 

 

 

N

 

 

 

 

 

 

 

N

 

 

 

 

N

 

 

 

 

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

OOCC6H5

 

 

 

 

 

 

 

O

N

 

 

 

 

N

CH3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CH3

 

 

 

Cocaine

Methamphetamine

Nicotine

 

 

Caffeine

 

 

3. Opioids

 

 

 

HO

 

 

CH3

 

 

 

 

 

 

N

 

 

 

O

H

 

 

 

C6H5

 

COOC2H5

NCH3

 

 

Meperidine

HO

Morphine

 

 

(Heroine, OHs = OCOCH3)

4. Hallucinogens

N

Phencyclidine

 

 

 

CON(C2H5)2

 

CH3

 

 

 

H

 

 

 

 

 

 

 

N

 

H

OH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CH3

H3C

 

 

 

 

 

 

 

 

 

 

 

 

H

O

 

C5H11

N

 

 

H3C

 

 

 

 

 

9-Tetrahydrocannabinol

Lysergic Acid Diethylamide

 

(LSD)

 

(THC)

 

 

Figure 5.2 Some common drugs of abuse.

amine dyes are no longer in use, nor are the organometallics, used in even earlier times. Bromates, used in some cold-waveneutralizers, may be acutely toxic if ingested, as may the ethanol used as a solvent in hair dyes and perfumes. Thioglycolates and thioglycerol used incold-wavelotion and depilatories and sodium hydroxide used in hair straighteners are also toxic on ingestion. Used as directed, cosmetics appear to

SUGGESTED READING

73

CH3

Pyrene

Benzo(a)pyrene

3-Methylcholanthrene

N

Benzo(e)pyrene

Dibenz(a,h)anthracene

Dibenz(a,h)acridine

Figure 5.3 Some common polycyclic aromatic hydrocarbons.

present little risk of systemic poisoning, due in part to the deletion of ingredients now known to be toxic and in part to the small quantities absorbed.

SUGGESTED READING

General

Hodgson, E., R. B. Mailman, and J. E. Chambers. Dictionary of Toxicology, 2nd ed. Norwalk, CT: Appleton and Lange, 1994.

Klaassen, C. D., ed. Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed. New York: McGraw-Hill, 2001.

Metals

Goyer, R. A., and T. W. Clarkson. Toxic effects of metals. In Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed., C. D. Klaassen, ed. New York:McGraw-Hill,2001, pp.811–867.

Pesticides

Ecobichon, D. J. Toxic Effects of Pesticides. In Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed., C. D. Klaassen, ed. New York:McGraw-Hill,2001.

Krieger, R. Handbook of Pesticide Toxicology. San Diego: Academic Press, 2001.

74 CLASSES OF TOXICANTS: USE CLASSES

Toxins

Burkholder, J. M., and H. B. Glasgow Pfiesteria piscicida and otherPfiesteria-likedinoflagellates: Behavior, impacts, and environmental controls.Limnol. Oceanogr. 42:1052–1075,1997.

Falconer, I., ed. Algal Toxins in Seafood and Drinking Water. New York: Academic Press, 1993.

Kotsonis, F. N., G. A. Burdock, and W. G. Flamm. Food toxicology. In Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed., C. D. Klaassen, ed. New York: McGrawHill, 2001, pp.1049–1088.

Norton, S. Toxic effects of plants. In Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed., C. D. Klaassen, ed. New York: McGraw-Hill, 2001, pp. 965–976.

Russell, F. E. Toxic effects of terrestrial animal venoms and poisons. In Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed., C. D. Klaassen, ed. New York: McGrawHill, 2001, pp.945–964.

Solvents

Bruckner, J. V., and D. A. Warren. Toxic effects of solvents and vapors. In Casarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed., C. D. Klaassen, ed. New York: McGrawHill, 2001, pp.945–964.

Therapeutic Drugs

Hardman, J. G., L. E. Limbird, P. B. Molinoff, R. W. Ruddon, and A. G. Gilman, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York: McGrawHill, 1996.

PART III

TOXICANT PROCESSING IN VIVO