Page 1024 - Basic _ Clinical Pharmacology ( PDFDrive )

1010 SECTION IX Toxicology

exposures as low as 2 ppm-years. The pluripotent bone marrow PESTICIDES
stem cells appear to be targets of benzene or its metabolites and
other stem cells may also be targets. Organochlorine Pesticides
Benzene has long been known to be a potent clastogen, ie,
a mutagen that acts by causing chromosomal breakage. Recent These agents are usually classified into four groups: DDT (chloro-
studies have suggested specific chromosome reorganization and phenothane) and its analogs, benzene hexachlorides, cyclodienes,
genomic patterns that are associated with benzene-induced leu- and toxaphenes (Table 56–2). They are aryl, carbocyclic, or het-
kemia. Epidemiologic data confirm a causal association between erocyclic compounds containing chlorine substituents. The indi-
benzene exposure and leukemia and other bone marrow cancers vidual compounds differ widely in their biotransformation and
in workers. IARC classifies benzene as a class 1, known human capacity for storage in tissues; toxicity and storage are not always
carcinogen. Most national and international organizations classify correlated. They can be absorbed through the skin as well as by
benzene as a known human carcinogen. inhalation or oral ingestion. There are, however, important quanti-
Toluene (methylbenzene) does not possess the myelotoxic tative differences between the various derivatives; DDT in solution
properties of benzene, nor has it been associated with leukemia. is poorly absorbed through the skin, whereas dieldrin absorption
It is not carcinogenic and is listed as class 3 by IARC. It is, how- from the skin is very efficient. Organochlorine pesticides have
ever, a CNS depressant and a skin and eye irritant. It is also feto- largely been abandoned because they cause severe environmental
toxic. See Table 56–1 and OSHA Tables Z-1 and Z-2 (http:// damage. They are now known to be endocrine disrupters in
www.osha.gov) for the PELs. Exposure to 800 ppm can lead to animals and humans. DDT continues to have very restricted use
severe fatigue and ataxia; 10,000 ppm can produce rapid loss of for domestic mosquito elimination in malaria-infested areas of
consciousness. Chronic effects of long-term toluene exposure Africa. This use is controversial, but it is very effective and is likely
are unclear because human studies indicating behavioral effects to remain in place for the foreseeable future. Organochlorine pes-
usually concern exposures to several solvents. In limited occu- ticide residues in humans, animals, and the environment present
pational studies, however, metabolic interactions and modifica- long-term problems that are not yet fully understood.
tion of toluene’s effects have not been observed in workers also
exposed to other solvents. Less refined grades of toluene contain 1. Human toxicology—The acute toxic properties of all the
benzene. If technical grade toluene is to be used where there is organochlorine pesticides in humans are qualitatively similar.
human contact or exposure, analysis of the material for benzene These agents interfere with inactivation of the sodium channel
content is advisable. in excitable membranes and cause rapid repetitive firing in most
Xylene (dimethylbenzene) has been substituted for benzene neurons. Calcium ion transport is inhibited. These events affect
in many solvent degreasing operations. Like toluene, the three repolarization and enhance the excitability of neurons. The major
xylenes do not possess the myelotoxic properties of benzene, effect is CNS stimulation. With DDT, tremor may be the first
nor have they been associated with leukemia. Xylene is a CNS manifestation, possibly continuing to convulsions, whereas with
depressant and a skin irritant. Less refined grades of xylene the other compounds convulsions often appear as the first sign of
contain benzene. Estimated TLV–time-weighted average and intoxication. There is no specific treatment for the acute intoxi-
TLV–short-term exposure limit are 100 and 150 ppm, respec- cated state, and management is symptomatic.
tively. The current OSHA PELs may be found at http://www. The potential carcinogenic properties of organochlorine pes-
osha.gov, Table Z-1. ticides have been extensively studied, and results indicate that

TABLE 56–2 Organochlorine pesticides.

Chemical Class Compounds Toxicity Rating 1 ADI 2
DDT and analogs Dichlorodiphenyltrichloroethane (DDT) 4 0.005
Methoxychlor 3 0.1
Tetrachlorodiphenylethane (TDE) 3 —
Benzene hexachlorides Benzene hexachloride (BHC; hexachlorocyclohexane) 4 0.008
Lindane 4 0.008
Cyclodienes Aldrin 5 0.0001
Chlordane 4 0.0005
Dieldrin 5 0.0001
Heptachlor 4 0.0001
Toxaphenes Toxaphene (camphechlor) 4 —
1
Toxicity rating: Probable human oral lethal dosage for class 3 = 500−5000 mg/kg, class 4 = 50−500 mg/kg, and class 5 = 5−50 mg/kg. (See Gosselin et al, 1984.)
2
ADI, acceptable daily intake (mg/kg/d).