Implicit and explicit affective associations towards cannabis use in patients with recent-onset schizophrenia and healthy controls.

BACKGROUND: Cannabis use is common in patients with recent-onset schizophrenia and this is associated with poor disease outcome. More insight in the cognitive-motivational processes related to cannabis use in schizophrenia may inform treatment strategies. The present study is the first known to compare implicit and explicit cannabis associations in individuals with and without psychotic disorder. METHOD: Participants consisted of 70 patients with recent-onset psychotic disorder and 61 healthy controls with various levels of cannabis use. Three Single-Category Implicit Association Tests (SC-IAT) were used to assess 'relaxed', 'active' and 'negative' implicit associations towards cannabis use. Explicit expectancies of cannabis use were assessed with a questionnaire using the same words as the SC-IAT. RESULTS: There were no differences in implicit associations between patients and controls; however, patients scored significantly higher on explicit negative affect expectancies than controls. Both groups demonstrated strong negative implicit associations towards cannabis use. Explicit relaxed expectancies were the strongest predictors of cannabis use and craving. There was a trend for implicit active associations to predict craving. CONCLUSIONS: The findings indicate that patients suffering from schizophrenia have associations towards cannabis similar to controls, but they have stronger negative explicit cannabis associations. The strong negative implicit associations towards cannabis could imply that users of cannabis engage in a behaviour they do not implicitly like. Explicit relaxing expectancies of cannabis might be an important mediator in the continuation of cannabis use in patients and controls.

Development of behavioral tests for the assessment of neurologic effects of lead in sheep.

Reports of neurologic impairment of children following recovery from acute lead encephalopathy have raised questions concerning the effects of chronic low-level lead exposure on the central nervous system. Behavioral toxicologic techniques have been employed to assess the effects of lead on the central nervous system in sheep. Mature sheep receiving daily doses of 100 mg lead/kg showed a significant decrease in performance on an auditory signal detection task. Daily oral doses of 120 and 230 mg lead/sheep for 27 weeks did not alter the performance of mature sheep on a fixed-interval schedule of reinforcement behavioral task. Prenatal exposure to maternal blood lead levels of 16 or 34 mug/100 ml during gestation and postnatal daily ingestion of 16, 8, 4, or 2 mg lead/kg did not alter performance of lambs on a closed-field maze task. Slowed learning was demonstrated in lambs prenatally exposed to maternal blood lead levels of 34 mug/100 ml during gestation when tested on nonspatial, two-choice visual discrimination problems at 10-15 months of age.

Review of risk assessments on 1,3-butadiene (1985-1991).

During the past decade, several assessments have estimated the carcinogenic risk of inhaled 1,3-butadiene (BD) to the general population as well as for occupational exposures. Although most of the risk assessments have been based on inhalation bioassays in mice, some of the assessments have included the 2-year inhalation bioassay in rats. Because of the marked species differences in the carcinogenic response to butadiene, estimates of risk vary over nine orders of magnitude going from the most sensitive target organ in female mice to less sensitive male rats. An important tool in determining which estimate is most relevant for extrapolation to humans is to ascertain consistency with human experience. Estimated workplace cancer risks which are based on the assumption that humans are as responsive as the mouse suggest added risks of 200 or more out of 1000 workers (1 in 5) exposed to 2 ppm butadiene (assume 40 years of exposure). This estimate is clearly inconsistent with what has been seen and this would not have been missed in epidemiology studies. Risk assessments based on the growing understanding of the mechanisms of toxicity and the importance of various tissues ability to produce and maintain reactive epoxide metabolites demonstrate why rats are much less susceptible than the mouse. By developing a mechanistic understanding of humans, it is possible to refine the traditional approach to risk assessment, whereby better risk assessments can be made. This paper presents a summary of eight risk assessments that have been developed to date for butadiene.

Effect of vitamin E and other amelioratory agents on the fenvalerate-mediated skin sensation.

Previous investigations have demonstrated that dermal exposure to fenvalerate or other synthetic pyrethroid insecticides can produce a skin sensory response characterized by an itching/tingling sensation in humans and animals. The objective of this investigation performed in guinea pigs was to establish treatments which would be effective against pyrethroid-mediated skin sensation. Two classes of agents were tested. Barrier agents, which block penetration of substances through the skin, did not significantly reduce the fenvalerate-mediated skin sensations. Post-treatments with steroidal Dermolate, antihistamine Delamine or anti-inflammatory aspirin did not significantly reduce the pyrethroid-mediated skin sensation. However, Bicozene (a local anesthetic cream) and Tashan (a vitamin A, D, and E-containing cream) were effective in reducing the pyrethroid-mediated skin sensations. Prior (30 min and 5h) dermal application of vitamin E was found to be effective in significantly reducing the fenvalerate-mediated skin sensation; even when applied 29 h prior to fenvalerate exposure, there appeared to be a reduced skin response. Piperonyl butoxide (PBO), a pesticide synergist, reduced the fenvalerate skin sensations when applied either directly to the skin or in conjunction with the pyrethroid.

Deldrin toxicity and successive discrimation reversal in squirrel monkeys (Saimiri sciureus).

Seven squirrel monkeys were systematically exposed to dieldrin (C12H10DC16) at two oral doses: 0.10 and 0.01 mg/kg-day. Two zero-dose controls were included. After 55 days of exposure dose assignments were shifted and continued for an additional 54 days. The higher dose group was shifted to zero exposure and lower dose group was shifted to high-dose exposure. Controls continued at zero exposure. The monkeys were presented with a visual nonspatial successive discrimination reversal task. During the first 55 days (preshift), control and low-dose monkeys learned the task; high-dose monkeys did not (p less than 0.001). During the subsequent 54 days (postshift), all groups performances remained at the approximate level achieved at the end of the preshift period. It was concluded that the high dose disrupted learning acquisition. This effect is speculated to be attributed to disruption of hippocampal activity. The low dose had no effect on task acquisition or maintenance.

Subchronic feeding study of decarboxyfenvalerate in rats.

Groups of 30 male and 30 female Fischer-344 rats were fed dietary concentrations of 0, 30, 100, 300, 3000, or 10,000 ppm decarboxyfenvalerate (DC-FEN) for up to 13 wk. An interim kill of 10 rats/sex X group was performed at 7 wk. Following 7 or 13 wk of dietary treatment, groups of rats were necropsied, which included evaluation of hemocellular, hemochemical, and uretic parameters, selected absolute and relative organ weights, and macroscopic and microscopic observations. DC-FEN did not affect mortality. Body weight was decreased in male rats fed 10,000 ppm DC-FEN. Statistically and toxicologically significant differences in clinicopathologic parameters were observed at either the highest or two highest exposure levels. Some statistically significant differences were noted in some hemocellular and/or hemochemical parameters at either 100 or 300 ppm. These subtle changes were either not dose-related, inconsistent, or not of sufficient difference to be determined to have biological significance. Absolute and relative liver weights of male and female rats fed greater than or equal to 300 ppm DC-FEN were all higher than control values except for absolute weights in female rats (300 ppm) at the interim kill. Consistent significant increases in absolute or relative kidney weights were observed in male and female rats fed 3000 or 10,000 ppm DC-FEN. Other statistically significant differences in absolute and/or relative organ weights were seen primarily where the higher doses had caused decreased carcass weight. Macroscopic treatment-related liver enlargement (hepatomegaly) was observed in male and female rats fed 3000 or 10,000 ppm DC-FEN. Only one female rat fed 300 ppm DC-FEN had hepatomegaly at the terminal kill. Significant treatment-related microscopic effects were limited to glomerulonephrosis in male and female rats fed 10,000 ppm and hepatocellular hypertrophy and other associated liver changes in male and female rats fed 3000 or 10,000 ppm DC-FEN. Liver effects at doses less than 3000 ppm were indicative of a physiologic adaptive response and were not toxicologically significant. Therefore, the biologically significant no-effect level was 300 ppm.

Neuropharmacologic and neuropathologic effect of fenvalerate in mice and rats.

B6C3F1 mice and Sprague-Dawley rats displayed the characteristic signs of pyrethroid intoxication following single oral doses ranging from 56 to 320 and 133 to 1000 mg/kg fenvalerate, respectively. The LD50s for mice and rats were 180 and 776 mg/kg, respectively, with corn oil as the vehicle. Signs of neurologic deficit such as splayed gait, tremors, ataxia, and hind limb incoordination were observed at doses of greater than or equal to 100 mg/kg (mice) and greater than or equal to 133 mg/kg (rats) within 1-8 hr after dosing. These signs had disappeared in most animals within 72 hr. Slight peripheral nerve fiber damage was detected in surviving mice and rats sacrificed 10 days after dosing. The incidence and severity were dose related at doses greater than or equal to 56 and greater than or equal to 180 mg/kg; however, even at lethal doses, evidence was lacking for the presence of nerve lesions in several animals. Thus two distinct neurologic effects were observed: a reversible ataxia/incoordination and a neuropathologic effect manifested as sparse axonal damage in peripheral nerve.

National Cooperative Gallstone Study: nonprimate toxicology of chenodeoxycholic acid.

A program involving acute, subacute, and chronic toxicity as well as reproduction studies was performed to evaluate the potential toxicity of chenodeoxycholic acid in rats, hamsters, and dogs. Acute oral toxicity studies showed that there were some species differences and that female hamsters were more sensitive to toxic doses than male hamsters. Subacute and chronic studies in hamsters showed the toxicity to be limited to effects on the liver, including proliferation of intrahepatic bile ducts in portal areas with elevations of serum glutamic-pyruvic transaminase and glutamic-oxaloacetic transaminase. No tumorigenic effect was observed. A series of reproduction studies showed no adverse effect on fertility, gestation, live birth indices, or skeletal or visceral development of fetuses. A dominant lethal study detected no biologically significant increases in proportions of embryo deaths. The changes in the animals were rather similar bile duct reduplications. The data suggest that at high doses in sensitive animals inflammation and scarring may develop. No other significant organ pathology was observed. The mechanism of toxicity of chenodeoxycholic acid remains speculative. Some chenodeoxycholic acid may be converted to lithocholic acid by bacteria in the large bowel. The lithocholic acid may be resorbed and cause lesions such as bile duct proliferation. This liver toxicity might not be expected in humans since lithocholic acid is sulfated to a large extent.

Chronic toxicity and carcinogenicity evaluation of fenvalerate in rats.

Groups of 93 male and 93 female Sprague-Dawley rats were fed diets containing 1, 5, 25, and 250 ppm fenvalerate for up to 2 yr. The control group consisted of 183 males and 183 females. Approximately 10 treatment and 20 control rats/sex . group were killed at intervals of 3, 6, 12, and 18 mo. When body weights, food consumption, hematology, clinical chemistry and organ weights did not reveal a treatment effect, two additional groups of 50 males and 50 female rats were placed on 0 or 1000 ppm fenvalerate diets and maintained for 2 yr. Body weight was decreased and organ/body weight ratios were increased in brain, liver, spleen, kidneys (females), heart (females), and testes (males) in the 1000 ppm group. Mammary and pituitary tumors were commonly observed, along with a variety of other tumors occurring randomly among all control and treatment groups. No statistically significant differences in the number and type of neoplasms were observed except for mammary tumors in females in the main study. These effects were judged not to be toxicologically significant, since mammary tumor incidences did not exceed expected incidences in aged female Sprague-Dawley rats, time to tumor appearance was unchanged, and no shift in percent benign versus malignant tumors occurred. Sarcomas identified in the subcutis and dermis in 5/51 1000-ppm-treated males were also identified in 2% (1/50), 2% (2/102), and 0-6% of concurrent, original, and historical controls, respectively. Microscopic examination did not reveal any treatment-related lesions. The no-observable-effect level was determined to be 250 ppm.

Six-month feeding study of fenvalerate in dogs.

Groups of six male and six female Beagle dogs were fed diets containing 0, 250, 500, or 1000 ppm fenvalerate for a period of 6 months. Prominent in-life observations related to treatment were emesis, head shaking, biting of the extremities, ataxia, and tremors. One high-dose male dog was sacrificed in extremis during the study period. Mean body weights of 1000-ppm female dogs were significantly lower than those of controls. Red blood cell counts and hematocrit and hemoglobin values in high-dose male and female dogs were significantly lower than those of controls at most sampling intervals. Serum cholesterol and alkaline phosphatase levels were also increased primarily in the high-dose group. Ophthalmic examination revealed changes in retinal vessel tortuosity in some mid- and high-dose dogs. Hepatic multifocal microgranulomata were observed in control and treated dogs microscopically. These changes increased in incidence and severity with dose and were considered to be related to treatment. Histiocytic cell infiltrate in mesenteric lymph nodes in some 500- and 1000-ppm female and 1000-ppm male dogs was the only other treatment-related microscopic effect.

Pyrethroid-mediated skin sensory stimulation characterized by a new behavioral paradigm.

Occupational exposures to pyrethroids have been associated with skin sensory effects characterized by transient itching/tingling sensations. This effect had not been detected in "Draize" skin irritation tests and exists in the absence of visible skin irritation. The objective of this investigation was to develop an animal model to study this phenomenon. Guinea pigs were treated with pyrethroid solutions on one side of their shaved back and control substances on the other side. The animals responded by licking, rubbing, scratching, or biting the test sites and activity was quantified by counting the number of times the animals responded to pyrethroid or control treated sites. Animals responded to pyrethroid more than to control substances and this behavioral activity was apparently maximum during the first hour and essentially over by the fourth hour after treatment. The sensory response did not directly correlate with overt visible signs of skin irritation. However, a chemical irritant (oil of mustard) was able to restimulate the behavioral activity when applied within 24 hr after pyrethroid application. Skin sensory stimulation produced by cyano-containing synthetic pyrethroids was significantly greater than that produced by a non-cyano-containing pyrethroid. This behavioral model provides a quantitative means to evaluate pyrethroid nonerythematous skin sensory stimulation.

Oncogenic evaluation of tetrachlorvinphos in the B6C3F1 mouse.

Groups of 80 male and 80 female B6C3F1 mice were fed diets containing 17.5, 64, 320, 1600, 8000, and 16000 ppm tetrachlorvinphos (TCVP) for up to 103 weeks. Another group of 80 male and 80 female mice were fed TCVP (16000 ppm) that was used in a previous bioassay. One hundred-sixty male and 160 female mice served as the control group. Ten treated and 20 control mice/sex/group were killed at 6, 12, and 18 months. It was estimated that the study maximum-tolerated dose was exceeded by three- and sixfold in the 8000- and 16000-ppm dose groups, respectively. Consequently, these exposures produced excessive cytotoxicity and regenerative changes in the liver and kidneys which were associated with sex-hormonal imbalance and metabolic overload in liver. A significant decrease (15-40%) in body weight was observed in mice fed 8000 and 16000 ppm TCVP. These treated mice did not gain weight during the study. Reduced food consumption and caloric intake throughout the study were probably responsible for the increased survival and the decreased incidence of spontaneous neoplasia in mice fed 8000 and 16000 ppm TCVP. Classification of pathologic lesions observed in these high-dose groups differed among study and consulting pathologists. The consultant and Shell pathologists concluded that the liver and kidney changes were causally related to excessive toxicity which was manifest primarily by hepatocellular hyperplasia and renal tubular adenoma. Study pathologist in accordance with his classification found statistically significant increases in hepatocellular carcinoma, hepatocellular adenoma or carcinoma, and renal tubular carcinoma in male mice fed 16000 ppm TCVP. The incidence of hepatic neoplasms as evaluated by the study pathologist in female mice fed 8000 and 16000 ppm TCVP although statistically significant was of questionable biologic significance when compared with historical female controls. The only statistically significant finding observed by the consulting pathologist was an increased incidence of renal tubular adenoma and renal tubular adenoma or carcinoma in male mice fed 16000 ppm TCVP. Use of results from these high-dose groups is contraindicated due to the many compromising factors affecting mice fed 8000 and 16000 ppm TCVP. TCVP was found not to be oncogenic in B6C3F1 mice at dose levels not exceeding the maximum tolerated dose.