Chronic Marijuana Smoke Exposure in the Rhesus Monkey I. Plasma Cannabinoid and Blood Carboxyhemoglobin Concentrations and Clinical Chemistry Parameters

Chronic Marijuana Smoke Exposure in the Rhesus Monkey I. PlasmaCannabinoid and Blood Carbxyhemoglobin Concentrations and ClinicalChemistry Parameters SLIKKER, W., JR., PAULE, M. G., ALI, S.F., SCALLET, A. C., AND BAILEY, J. R (1991). Fundam. Appl Toxicol17, 321–334. This report is the first in a series abouta large multidisciplinary study designed to determine whetherchronic marijuana (MJ) smoke exposure results in residual behavioraland/or neuropathological alterations in the rhesus monkey. Priorto the initiation of a year of chronic MJ smoke exposure, 64periadolescent male rhesus monkeys were trained for 1 year toperform five operant behavioral tasks and then divided, accordingto their performance in these tasks, into four exposure groups(n=15–16/group): (1) a high dose (HI) group, exposed 7days/week to the smoke of one standard MJ cigarette; (2) a lowd m (LO) group, exposed on weekend days only to the smoke ofa standard MJ cigarate; (3) an extracted MJ cigarette (EX) group,exposed 7 days/week to the smoke of one ethanol-extracted MJcigarette; and (4) a sham group (SH), exposed 7 days/week tosham exposure conditions. Daily exposures for 1 year were accomplishedusing a mask that covered the subjects' nose and mouth. Averagebody weights (initially 3.7?0.5 kg, mean?SD) and rates of weightgain (approximately 0.1 kg/month) were the same for all groupsthroughout the entire experiment. During the first week of expsure,plasma concentrations of -9-tetrahydrocannabinol and 11-nor-9-carboxy-THCin the HI group were 59?7 (mean?SE) and 5.5?1.5 ng/ml, respectively,45 min after MJ smoke administration and did not change significantlyat similar times after exposure throughout the remainder ofthe year. Whole blood carboxyhemoglobin levels increased toapproximately 13% 1 min after expsure to smoke in either theMJ or the EX groups. Comparison of blood chemistry and hematologyvalues before, during, and after exposure indicated no differencesfor most parameters. During exposure, lymphocytes, alkalinephosphatase and -glutamyl transferase were depressed in theHI group compared to in the SH group. During exposure, aspartateaminotransferase was elevatd for both the HI and EX groups,suggesting a general effect of smoke exposure. Because theseeffects were transient and remained within the range of reportednormal values, these data indicate that long-term, experimentalexperimental exposure to MJ smoke is feasible and does not compromisethe general health of the rhesus monkey.     

Postnatal Toxicity following Prenatal Reserpine Exposure in Rats: Effects of Dose and Dosing Schedule

Postnatal Toxicity following Prenatal Reserpine Exposure inRats: Effects of Dose and Dosing Schedule. BUELKE-SAM, J., KIMMEL,G. L., WEBB, P. J., SUKKER, W., JR., NEWPORT, G. D., NELSON,C. J., AND KIMMEL, C. A. (1984). Fundam. Appl. Toxicol. 4, 983–991.Pregnant CD rats were treated subcutaneously with 0, 0.1, 0.33,or 1.0 mg reserpine/kg/day either on Days 12–15 or onDays 16–19 of gestation. Dams were allowed to deliverand litters (4 ± 1 of each sex) were weighed weekly andheld to 21 days of age. Basal ornithine decarboxylase (ODC)activity and neurocheraical determinations were made on heartsand brains, respectively, from pups culled from litters on postnatalDay 1, and from two males and two females/litter at 21 daysof age. Following both treatment schedules, the high dose ofreserpine resulted in maternal weight loss during dosing, increasedstillborn pups, reduced pup weight at birth, retarded postnatalgrowth, and decreased survival to 21 days of age. Basal cardiacODC activity was reduced to 33% of control levels only on PostnatalDay 1 in both high-dose groups, while absolute heart weightdecreased and relative heart weight increased in these pups.Whole-brain concentrations of two neurotransmitter metabolites,3–4-dihydroxy-phenylacctic acid (DOPAC) and 5-hydroxyindoleaceticacid (5-HIAA), were increased only at Postnatal Day 1 in thehigh dose group treated on Days 12–15 of gestation. Noother changes were found in concentrations of these metabolitesor in the transmitters dopamine and serotonin. The only effectfound following administration of 0.33 mg/kg reserpine was areduction in maternal weight gained during both dosing periods.No signs of toxicity were observed following low-dose exposureon either schedule. Most previously reported postnatal functionalstudies following reserpine exposure have used mid- to late-gestationaltreatment with 1.0 mg/kg, a dose shown here to result in markedovert maternal and fetal toxicity. Such overt toxicity raisesthe question of whetheT the functional effects of reserpineare primary or may be secondary to general toxic effects. Suchquestions must be considered when interpreting postnatal functionaldata and in the design of further studies.     

Biologically Based, Quantitative Risk Assessment of Neurotoxicants

The need for biologically based, quantitative risk assessmentprocedures for noncancer endpoints such as neurotoxicity hasbeen discussed in reports by the United States Congress (Officeof Technology Assessment, OTA), National Research Council (NRC),and a federal coordinating council. According to OTA, currentattention and resources allocated to health risk assessmentresearch are inadequate and not commensurate with its impacton public health and the economy. Methods to include continuousrather than dichotomous data for neurotoxicity endpoints, biomarkersof exposure and effects, and pharmacokinetic and mechanisticdata have been proposed for neurotoxicity risk assessment butrequire further review and validation before acceptance. Thepurpose of this symposium was to examine procedures to enhancethe risk assessment process for neurotoxicants and to discusstechniques to make the process more quantitative. Accordingly,a review of the currently used safety factor risk assessmentapproach for neurotoxicants is provided along with specificexamples of how this process may be enhanced with the use ofthe benchmark dose approach. The importance of including physiologicallybased pharmacokinetic data in the risk assessment process andspecific examples of this approach is presented for neurotoxicants.The role of biomarkers of exposure and effect and mechanisticinformation in the risk assessment process are also addressed.Finally, quantitative approaches with the use of continuousneurotoxicity data are demonstrated and the outcomes comparedto those generated by currently used risk assessment procedures.     

The Effect of Dideoxycytidine on Lymphocyte Subpopulations in Nonhuman Primates

In the present study, 2',3'-dideoxycytidine (ddC), which hasantiretroviral activity, was given chronically to uninfectednonhuman primates to determine whether it produces adverse immunologicalor hematological effects. Nine healthy adult male rhesus monkeyswere divided into three groups and given the following dosesof ddC in a gelatin vehicle: group A, 0.06, 6.0, 3.0, and 1.5mg/kg; group B, 0.6 mg/kg; group C, 0 mg/kg. Blood samples werecollected for hematologic analysis and flow cytometric analysesof lymphocyte subpopulations. Chronic ddC exposure did not causesignificant changes in the number of red blood cells, monocytes,or reticulocytes. The number of white blood cells and neutrophilsincreased and these changes were observed only in group A animalsat the 1.5 mg/kg dose. The most significant alterations observedwere decreases in the number of T helper cells (CD4) and B cells(CD20). CD4⁺ and CD20⁺ lymphocytes exhibited dose-related shiftsthat were reversible over time and after drug withdrawal. Theresults indicate that ddC has few hematologic effects but itdoes have profound but transient effects on the number of cellsin lymphocyte subpopulations in normal primates.     

Quantitative Plasma Disposition of Retinol and Retinyl Esters after High-Dose Oral Vitamin A Administration in the Cynomolgus Monkey

A solid-phase extraction technique followed by automated high-performanceliquid chromatography sample elution was successfully used toevaluate the effect of three pharmaceutical parameters on theplasma profile of various forms of vitamin A after an oral doseto cynomolgus monkeys. The three parameters evaluated were thechemical form of vitamin A (retinol versus retinyl acetate),the vehicle (acetone/Tween 20/water versus acetone/soybean oil),and the retinol dose (2, 10, and 50 x 10³ retinol equivalents/kg).The form of the administered compound, retinol or retinyl acetate,appeared to have no major effect on the formation of nonpolarretinoids. The ester profile in plasma differed depending onwhether the dose was administered in the water-based or theoil-based vehicle. Irrespective of the vehicle type the predominantretinoid formed was retinyl palmitate/ oleate. However, retinoldoses in the water-based vehicle formed relatively high concentrationsof retinyl laurate and retinyl my-ristate but no retinyl linolenate.The retinol dose in the oil-based vehicle formed consistent,but relatively minor, concentrations of retinyl linolenate,higher relative concentrations of retinyl linoleate, and noretinyl laurate or myristate. The dose of retinol administeredhad an impact on the diversity of the nonpolar retinoid profile.The low dose led to the presence of almost exclusively retinylpalmitate/oleate and retinyl stearate, whereas at higher dosesthe other retinyl esters became major retinol constituents.These findings are consistent with the hypothesis that, at lowdoses, the principle esterification pathway is via lecithin:retinolacyltransferase (LRAT) which produces retinyl palmitate, butat higher doses acyl-CoA:retinol acyltransferase is a prominentesterification enzyme, due to the saturation of the LRAT pathway,producing a more diverse profile of retinyl esters.