Toxicity of PCP

Based on the dramatic changes in volume of distribution and the free fraction of PCP found in serum, we predict that this form of therapy has the potential to rapidly reverse the toxicity of PCP, if sufficient Fab can be administered relative to the dose of PCP, The most practical method for making large quantities of antibodies with reproducible properties is through monoclonal... 

The solubility of sodium and potassium pentachlo-rophenate in water is pH dependent it increases from 79 mg/L at pH 5.0 to >4 g/L at pH 8.0 (Bevenue and Beckman 1967). But the differential toxicity of PCP in solution is primarily attributable to variations in uptake as a function... 

Data are scarce on the toxicity of PCP to mammalian wildlife, but studies with livestock and small laboratory animals show that the chemical is rapidly excreted. However, there is great variability between species in their ability to depurate PCP, as well as in their overall sensitivity. Acute oral LD50 values in laboratory animals were 27 to 300 mg/kg BW. Tissue residues were elevated at dietary levels as low as 0.05 mg/kg feed and at air levels >0.1 mg/m3. Histopathology, reproductive impairment, and retarded growth were evident at doses of 0.2 to 1.25 mg/kg BW, and when the diets fed contained >30 mg PCP/kg. 

Technical-grade PCP was related to decreased body weight and feed conversion efficiency, anemia, enlarged liver and lungs, decreased thymus weight, and lesions in urinary bladder mucosa. Holsteins exposed to analytical grade PCP were comparable to controls. The toxicity of PCP in cattle seems to be due to its contamination with toxic impurities, especially dioxins (McConnell etal. 1980 Parker etal. 1980)... 

Commercial PCP preparations often contain variable amounts of chlorophenols, hexachloroben-zene, phenoxyphenols, dioxins, dibenzofurans, chlorinated diphenyl ethers, dihydroxybiphenyls, anisoles, catechols, and other chlorinated dibenzodioxin and dibenzofuran isomers. These contaminants contribute to the toxicity of PCP — sometimes significantly — although the full extent of their interactions with PCP and with each other in PCP formulations are unknown. Unless these contaminants are removed or sharply reduced in existing technical- and commercial-grade PCP formulations, efforts to establish sound PCP criteria for protection of natural resources may be hindered. 

Fisher, S.W. 1986. Effects of temperature on the acute toxicity of PCP in the midge Chironomus riparius Meigen. Bull. Environ. Contam. Toxicol. 36 744-748. 

PCP presents a different picture from that of the lower chlorophenols and their derivatives. The corresponding dioxin shows much more stability to light than does TCDD, enough to permit its prolonged existence at low concentrations in a photoreactor. As a phenol it can directly yield dioxins, a process favored by its normal mode of application as the sodium salt. Although octachlorodibenzo-p-dioxin has much lower mammalian toxicity than TCDD (6), its formation, properties, and effects demand additional investigation. Technical preparations of PCP are frequently mixtures of tetra- and pentachlorophenols consequently, hepta-and possibly hexachlorodibenzo-p-dioxins might be expected as photolysis products in addition to the octachloro derivative. 

OWENS has prepared antibodies to PCP in goats. When administered to mice the PCP levels in blood rose tenfold as an antibody-bound form that was readily excreted in urine. BROWNE tested the selfadministration by rats of 1,000 compounds related (and not related) to PCP, some of which produced PCP-like effects. One compound that was self-administered prevented the entrance of PCP into brain. BALSTER gave a general review of the effects produced by PCP in laboratory animals and showed that some effects were similar to those produced by amphetamine, some to barbiturates, and some to antipsychotics. This response profile makes PCP a unique drug that stands alone in its complex effects and toxicity. 

FIGURE 6. Histograms depicting doses of PCP and related compounds which produced (A) maximal disruption of rotarod performance (B) loss of righting reflex (C) clonic and/or toxic convulsions and (D) lethality in rats (n=6) given cumulative intravenous doses... 

In addition to having a high affinity, the amount of antibody administered must be sufficient to reduce the body burden of PCP below that of toxic levels. Therefore, the effectiveness of a given dose of Fab fragments depends on its affinity and the amount of antibody administered relative to the dose of PCP. Since the affinity of the Fab fragments in the present study was so high... 

We have viewed these withdrawal effects on behavior as evidence of behavioral dependence on PCP. Behavioral signs have also been reported in human users of PCP during withdrawal (Tennant et al. 1981) however, these instances appear to be relatively rare. Nonetheless, the relative ease with which a dependence phenomenon can be produced in monkeys suggests that PCP has a potential for producing dependence in PCP users, particularly those who use the drug very frequently. Behavioral sequelae seen in chronic PCP abusers might be examined as possible manifestations of dependence as well as of cumulative toxicity. 

Uni 1ke other drugs of abuse, the diagnosis of PCP intoxication is often difficult because of the wide spectrum of clinical findings that occurs with this drug. PCP toxicity sometimes can be mistaken for delirium tremens, acute psychiatric illness, sedative/ hypnotic overdosage, amphetamine intoxication, or sedative/ hypnotic withdrawal syndromes. 

In adult patients, the manifestations of PCP use can be grouped into nine clinical patterns of intoxication. Four of these are called major patterns because they may be associated with severe toxicity and often necessitate hospitalization. Patients with major patterns are usually unpredictable symptoms wax and wane, and the patient may abruptly change from one pattern of intoxication to another. Five other symptom complexes are designated as minor patterns since toxicity is usually mild and of short duration. Major Patterns consist of coma, catatonic syndrome, toxic psychosis, and acute brain syndrome. Minor Patterns are lethargy, bizarre behavior, violent behavior, agitation, and euphoria (McCarron et al. 1981b). 

Patients with the lethargy pattern of PCP toxicity may be clinically indistinguishable from patient with mild sedative/hypnotic intoxication, although hypertension and grand mal seizures which may occur with PCP intoxication, are not expected with sedative/ hypnotic overdose. The remaining minor patterns are differentiated as follows. 

Urine concentrations of PCP determined by enzyme immunoassay did not correlate with the state of intoxication at the time the urine sample was taken. The test was negative in 15 percent of 1,000 patients with clinical evidence of PCP toxicity, many of whom admitted taking PCP (McCarron et al. 1981a). Several of these negative urines were analyzed for PCP analogues none were found. 

McCarron s paper (this volume) describes the behaviors of 1,000 adults admitted to an inpatient service with acute symptoms of PCP intoxication. She states that some of the patients have appropriate behavior while many have mute and staring episodes, bizarre facial grimacing, localized dystonic reactions, rigidity, tremors, coarse jerky movements, and nystagmus. Thus, there is similarity between the acutely intoxicated adult s behavior and that of the newborn with a positive urine toxic screen for PCP. 

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