Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2 Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants (1984) / Chapter Skim
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3. Psychochemicals
3. Psychochemicals
Pages 47-100
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From page 47... ...
Research Report Concerning the Use of Volunteers in Chemical Agent Research.
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From page 48... ...
In addition, there was a great deal of preselection, in that all the subjects were soldiera -- healthy enough and functioning well enough to meet the criteria for entry into the Army. A detailed set of guidelines, most completely spelled out in a document dated August I2, 196B, described a standard operas ing procedure in the clinical research department (Appendix A, part 2)
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so is In ~ a · ~ o o ~ of so o ~ lo ~ A, 1 lo e ~ 0 ~ 0 0 v a aC CJ O o Al ~ O lo.
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The criteria described in the standard operas ing procedure appear deco be those used either consciously or deliberately in many civilian laboratories that conduct research with psychoactive drugs with normal volunteers. It appears that the subjects actually given paychochemicals in these experiments were selected from an optimal pool of mentally and physically hea lthy persons .
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Particularly in later studies based on earlier observations, interventions were made with assumed antidotes or antagonista; for example, drugs that increased blood pressure were given in conjunction with or after dimethy~heptylpyran to investigate the intriguing and important posture' hypotension. The protocols appeared to be flexible and generally conservative, with variatlone often following up preliminary observations.
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The one subject used was unreeponsive to sensory stimuli, although corneal reflexes were intact. Blood pressure was slightly increased.
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Subjects appeared Slow to think and Slow to make declaiona and reported a subjective slowing don of time. The subjective effects peaked at about 2-4 h after oral administration and, after the 10-mg dose, were still present to a slight degree at 13-14 h.
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min/m3, one sub ject developed visual disturbances and lightheadednese in 7 min and perioral and distal paresthesias within 10 min. Inadvertent exposures by inhalation have been reported-.
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SNB. Receptor sites specific for binding SNB have been found in rat brain aM other organe.66 The greatest specific birthing was found in the cerbral cortex and the corpus striatum.
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Chronic adminlatratlon of SNA altered the distribution of ~ 3H] SNB and its metabolizes in the central nervous system; radioactivity in the cortex was 7-31% ie88 than that in the whole brain.
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Death usually occurred in less than 15 min in the guinea pig, rabbit, and cat; in I-3 h in the mouse; and in 5 min to 24 h in the dog. At 3-5 mg/kg intravenously, SNA caused a decrease in blood pressure, a decrease in heart rate, and mluor cardiac irregularities in cats.
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Plasma binding Volume of distribution Total clearance Renal clearance Apparent terminal half-life Renal excretion ( 10-d collection) Fecal excretion (10-d collection)
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~ ~4 ^ to en ~ e so ~ ~ so :r: X CJ in o At cn o r~ ~ 1 ~1 ~ Q J ~ C)
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More recent studies .8, 9, i2 at dosages that Droduce behavioral changes, have shown that chronic intr~acular or intraperitoneal administration of SNA results in development of tolerance to several test situations in several animal species. Tolerance to roughly 2-4 times as much SNA as initially given was evident in the behavioral effects of SNA in these species.
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From page 61... ...
in 5-HT.58 No effects on aromatic amino acid decarbosylase and monoamine oxidase, wo enzymes 1~,ro1ved in 5-HT formation and destruction, were obeer~red SNA has been shown to reduce the concentration of the 5-HT precursor tryptophan. The uptake of 5-HT into rat brain preparations is vitro and into the brain stem in viva is somewhat inhibited.
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From page 62... ...
The ef fects of SNA on the acetylcholine (ACh) system have been less well studied.36 It has been claimed to raise rat brain ACh content slightly and transiently when given intravenoualy;47 how ever, other studies reported no effects on rat brain ACh content concentrations when it was given tntraperitoneally.23 SNA does not release brain ACh.
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From page 63... ...
In addition, the -results of in vitro experiments cannot be easily extrapolated to the in vitro situation, because the high concentrations necessary to produce in vitro effects are not accumulated by the brain is living organisms. However, the main objection to extrapolating these data to man might well be that all studies use healthy, undisturbed rats, whereas, as is well known, SNA produces its most serious effects in people who are emotionally labile, have had psychiatric problems, or are polydrug users.
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SNA has multiple effects on several neural systems, but evidence is increasing that at least some of its effects are mediated aria interaction with a specific brain receptor. Nero laboratories65~72 have independently identified SNA binding sites in rat brain mom branes.
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SNA heat been given experimentally to known achizophre~ce, who were forms to be very senalti.'re to the induction of long-1 asking psychotic symptoms bar the drug. It is not known whether single doses of SNA can produce long-lasting pag~chotic behavior in normal persons or whether this can occur only in persons with pre-esisting mental disorders.42 Chronic c users of large doses of the street drug PCP containing SNA have been reported to undergo personality changes, cognitive impairment, ami Slurred speech for 6-12 mo after stopping the drug.
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Teratogenic-Reproductive Ef facts Walker and Selg67 reported two ciu8ter8 of agates, limbreduction defects and liveborn triploid infants born to parents involved in the drug culture. Retro spective investigation suggested that the mothers had ingested street drugs controlling SNA during the early first tri - ster of pregnancy.
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From page 67... ...
Therefore, its use can provide clinical information about undesired effects of single doses of the phencyclidine series. ~ number of possible long-term or delayed effects of SNA can be listed on the basis of esperles~ce witch adverse reactions in drug abusers and ire anesthesiology patients.
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In the amounts given to the experimental sub jects at Edgewood, i is highly unlikely that ma jor chronic organic brain syndrome developed, inasmuch as no status eplleptlcus or cerebral hemorrhage —68—
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However, the development of more subtle neuropaychologic impairment, such as difficulties in cognitive func tiering and the impairment of complex psychomotor skills, cannot be ruled out, because these were not evaluated. Residual tram ire Connection with the Intoxicated State The behavioral toxicity that can accompany SNA intoxication can lead to head and other injuries and perhaps leave permanent residue.
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From page 70... ...
These are transient and do not leave permanent residue, except after a cerebral hemorrhage. At the dosages used at Edgewood, it is not expected or likely that any long-term or delayed effects have occurred or will occur, because immediate prolonged mental or cardiovascular ef fects did not take place within a week of drug administration.
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The SNA research going on throughout the world at about the time of the Edgewood studies is relevant to this study. lathe experiments at Edgewood were not unusual and did not involve extraordinary doses (see Table 3-1)
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Blood pressure increased, respiratory minute volume increased, and heart rate increased with no evidence of arrhythmia. At moderate doses, reflex activity was not impaired.
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From page 73... ...
National Institute on Drug Abuse, Rockville, Md. NIDA Research Monograph 21, 19 7B, p .
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: Hi~torical add Current Perspectives. Ann Arbor, MI.: NPP Books, 1981.
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From page 75... ...
: Historical and Current Perspectives, Ann Arbor, MI .: NPP Books .
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National Institute on Drug Abuse, Rockville, Md. NIDA Research Monograph 21, 197B, p.
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National Institute on Drug Abuse, Rockville, Md. NIDA Research Monograph 21, 1978.
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From page 78... ...
M., and Lazdunski, ~I. Interaction of phencyclidine ~ "angel dust" ~ with a specif ic receptor in rat brain membrar~es.
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From page 79... ...
: Historical and Current Perspectives. Ann Arbor, MI.: NPP Books.
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From page 80... ...
44 Rapid onset of such Signs as ataxia, mydriasis, generalized weakness, nystagmus, and ptosis was seen with this route. With ore' administration, fatigue, thirst, headache, postural hypotension, temporary blurring or loss of vision, and pronounced psychomotor activity were observed in h''ma~.
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- ~ 1 I=\ ~1 1 ~ a3~ I A-9-tetrahydrocannabinol 83, AH CHOW ~ ~ GY ~{SH11 CH3 ~ eN3 Congener of I H - [H _ tS~lI ~ H ~ ~ ~ C5N H3 3 - . 1V a-6a, lOa-Dimethylheptylpyran (DIP)
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The investigators concluded that the tissue distribution of total radioactivity (from both DEEP and its metabolizes) is similar to that of THC.
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Metabolism of t14C] D~P was studied in vitro with 9000 ~ liver supernatant fractions obtained from rabbits, mice, rats, guinea pigs, or dogs and in vitro in rats and rabbits.32 Incubation for ~ h with the supe' Blatant fractions in the presence of an NADPH-generating system resulted in metabolism of the following percentages of the total amount of DEEP: rabbi t, 68; mouse, 63; rat, 44; guinea pig, 41; arid dog, 34.
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was suspected ire early studies of the effects of DIP and DIP acetate on human volunteers, because such signs and symptoms as sluggishness, inability to concentrate, dimness and blurring of vision, and orthostatic hypotension occurred up to 48 h after drug administration.44 At high doses of DIP, cats "lay in plastic-like poses for hours or dais against the side of the container in which they were placed e" DIP in plasma appears to have a half-lif e of 20 h in both rat and rabbit;32 the half-life of total radioactivity ~ [14C] D~P plus C-labeled metabolites)
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ANIMAL 'TOXICOLOGY The ar~imal-toxicity data in this section, taken from several source; ,1B, 20, 35, 36, 40, 44 show that the compounds most studied in animals and h''m~s were DMHP and DMHP acetate (more light- and airstable than DMHP)
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In dogs, repeated intravenous doses at 0.1 and 1.0 mg/kg-d were given to mongrel dogs (three per dosage) for 10 daily injections during a 2-wk period.
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Repeated intravenous administrations of DAMP acetate at 0.01, 0.1, and 1. 0 mg/kg~ to male albino rats ( 10 per dosage ~ were carried out for 20 daily injections during a 4-wk period.
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The perceptual changes may be associated with panic reactions. Pulse rate is increased in a dose-related manner; blood pressure decreases, particularly on standing (orthostatic hypotension)
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From page 89... ...
DELAYED AND LONG-TERt1 EFFECTS DMHP and a series of optical isomers of DRIP acetate, studied at Edgewood in humans, produce similar symptoms, but vary greatly in potency. The more potent isomers appear to produce postural hypotension and fewer psychologic effects than equivalent doses of THC.
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From page 90... ...
The cardiovascular effects are postural hypotension and tachycardia. These are tranaltory and leave no permanent residue.
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From page 91... ...
At 1 and 2.5 me per 70 kg, postural hypotension was common, and faintness on standing was observed often. Blood pressure in a supine or prone position was normal or slightly increased.
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From page 92... ...
As the studies progressed and the relationship between dose and orthostatic hypoter~sion was better appreciated, this ef feet was less likely to occur . In general, oral doses produced changes ire heart rate and blood pressure at 1 or 2 h and peak ef fects at 6-10 h.
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From page 93... ...
Intravenous doses of l-2 me of isomer 2 produced fairly intense tachycardia and orthostatic hypotension in the volunteers, an already described. The postural hypotension was marked, increases in heart rate were present but less intense, and feelings of impaired cognition and concentration and altered mood were present and dosedependent .
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From page 94... ...
National Institute on Drug Abuse. NIDA Research Monograph 2l, 1978.
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From page 95... ...
U.S. A`=y Chemical Research and Development Laboratories, Army Chemical Center, Md .
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From page 96... ...
R Marihuana smoking and intraocular pressure.
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From page 97... ...
Edgewood Arsenal Technical Memorandum EATM 114-5.
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From page 98... ...
The Search for Toxic Chemical Agents. Edgewood Arsenal Technical Report EATR 4210.
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From page 99... ...
Evaluation of the toxicity literature and the Edgewood studies led the Cocci thee to conclude that at the doses and frequencies of administra~cion of phencyclidine and dibenzopyrans used at Edgewood i t is not likely that detec table long-term or delayed ef fee ts have occurred or will occur. Specific information to support this conclusion is, however, lacking.
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