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Few teratogenic studies in animals have been performed simulating marihuana smoking in man. An inhalation marihuana teratology study was conducted in albino rabbits utilizing a modified automatic smoking machine originally developed for rats and mice. Appropriate numbers of dams were exposed to 4 puffs (0.14 mg/kg), 8 puffs (0.72 mg/kg), or 16 puffs (1.44 mg/kg) once daily during gestation Days 6 to 18, and sacrificed on Day 28. Control dams were exposed to 12 puffs of placebo cigarettes or sham-treated for a similar duration in the absence of any smoke. Consistency of smoke was monitored by cigarette weights, total particulate matter, concentrations of carbon monoxide (CO), and tetrahydrocannibinol (THC) in smoke, carboxyhemoglobin levels, and plasma THC levels. Except for a transient decrease in dam respiration rates, other gross toxic signs were absent. Reproductive parameters of mothers were generally normal except for a dose-related embryotoxicity predominantly associated with early resorptions. Despite twice the number of embryo/fetal deaths, there were no marihuana soft tissue or skeletal defects. A correlation between dam demises and CO levels among placebo-exposed animals was related to greater quantities of CO being generated during placebo combustion. It has been shown in the rabbit that marihuana is embryotoxic and not a teratogen at plasma THC levels found in human females.

With increasing clinical use of L-alpha-acetylmethadol.HCl (LAAM), findings of a carcinogenic bioassay could be useful in risk assessment. Initial studies provided a sex-related oral LD50 in B6C3F1 mice, 126 mg/kg for males and 71 mg/kg for females, and changes after treatment with mean doses of 8, 18, and 33 mg/kg for 90 days which included hyperactivity and unchanged growth rate, food intake, and morphology. Twenty-four-month oral doses were 7.6 and 30.1 mg/kg for mice, 3.1 and 9.7 mg/kg for male rats, and 5.7 and 16.6 mg/kg for female rats. LAAM was lethal in high-dose male mice (40% survival) whereas survival rates of 74-78% were similar in other treated and control groups. An 80-90% survival rate was seen for rats. Deaths related to aging and concomitant morphologic changes occurred randomly in all groups. The causes of LAAM-induced deaths were not established. Central nervous system stimulation and fighting were more common to male rodents. A dose-related inhibition of growth was also common but food intake was stimulated in male mice and both sexes of rats. An increase in liver neoplastic nodules was dose related and drug related in rats. Some nonneoplastic lesions may have been drug related. Terminal plasma LAAM and metabolite levels were generally dose related.

The extensive clinical use of methadone encouraged the performance of a carcinogenesis bioassay to support risk assessment in man. An oral LD50 of 178 mg/kg was obtained in B6C3F1 mice. Physiologic changes induced by mean oral doses of 15, 30, and 60 mg/kg for 90 days included dose-related central nervous system (CNS) stimulation, fighting, tolerance development, sex-related alteration of food consumption, and no drug-related pathology. In the chronic study dosages were 15 and 60 mg/kg for mice, 16 and 28 mg/kg for male rats, and 46 and 88 mg/kg for female rats. Survival incidences for treated and control rodents were 72-86% for mice and 80-90% for rats. Deaths related to morphologic changes of aging occurred in all groups. CNS stimulation and fighting were more common to male rodents. Growth rates were unchanged for mice but a dose-related inhibition occurred for rats. Higher doses stimulated food intake in both species. Neither the type nor incidence of neoplasia was drug related but a few nonneoplastic lesions may have been. Preliminary plasma methadone levels at necropsy were dose related in the rat.

Because of a projected pilot study with EDHPA in Cooley's anemia patients, animal studies with emphasis on reversibility of potential toxic signs were performed. Young dogs were treated iv with 6-18 mg/kg or orally with 30-240 mg/kg for 14 days followed by a 16-day recovery period. Drug-induced emesis, elevated BUN changes in kidney, spleen, and thymus weights diminished during recovery. One deceased dog exhibited nephrotoxicity consisting of tubular necrosis and deposition of the iron-EDHPA complex. The latter was observed in the excreta of survivors but kidney damage was not evident. Atrophy of the spleen and thymus in the deceased dog was consistent with less intense organ weight changes in recovered survivors. In the absence of morphologic changes after recovery, the precise effect on the immune system is unknown. The iv LD50 was 53 mg/kg for rats and mice. No rodent deaths occurred at an oral dose of 6000 mg/kg. An elevated BUN and changes in kidney, spleen, and thymus weights were confirmed in rodents given iv doses of 5-20 mg/kg or oral doses of 150-600 mg/kg for 5 days. It is cautioned that during the use of EDHPA derivatives that the functions of the renal and immune systems be monitored.