Plasma Nicotine Levels Research Articles

Influence of cigarette smoking on human autonomic function.

Although cigarette smoking is known to lead to widespread augmentation of sympathetic nervous system activity, little is known about the effects of smoking on directly measured human sympathetic activity and its reflex control. We studied the acute effects of smoking two research-grade cigarettes on muscle sympathetic nerve activity and on arterial baroreflex-mediated changes of sympathetic and vagal neural cardiovascular outflows in eight healthy habitual smokers. Measurements were made during frequency-controlled breathing, graded Valsalva maneuvers, and carotid baroreceptor stimulation with ramped sequences of neck pressure and suction. Smoking provoked the following changes: Arterial pressure increased significantly, and RR intervals, RR interval spectral power at the respiratory frequency, and muscle sympathetic nerve activity decreased. Plasma nicotine levels increased significantly, but plasma epinephrine, norepinephrine, and neuropeptide Y levels did not change. Peak sympathetic nerve activity during and systolic pressure overshoots after Valsalva straining increased significantly in proportion to increases of plasma nicotine levels. The average carotid baroreceptor-cardiac reflex relation shifted rightward and downward on arterial pressure and RR interval axes; average gain, operational point, and response range did not change. In habitual smokers, smoking acutely reduces baseline levels of vagal-cardiac nerve activity and completely resets vagally mediated arterial baroreceptor-cardiac reflex responses. Smoking also reduces muscle sympathetic nerve activity but augments increases of sympathetic activity triggered by brief arterial pressure reductions. This pattern of autonomic changes is likely to influence smokers' responses to acute arterial pressure reductions importantly.

Higher levels of nicotine in arterial than in venous blood after cigarette smoking

We examined differences between arterial and venous concentrations of nicotine in human subjects. Shortly after smoking a cigarette, levels of nicotine in arterial plasma were more than double those in venous plasma. The time course of the rise in arterial nicotine levels and the magnitude of the arteriovenous difference varied considerably among subjects. For some subjects, arterial nicotine concentrations after one cigarette were similar to venous concentrations typically observed after 20 cigarettes and were nearly 10 times greater than venous concentrations. Our findings have implications for understanding the high degree of addictiveness and cardiovascular toxicity of smoked forms of drugs.

Smoking induces insulin resistance—a potential link with the insulin resistance syndrome

The acute effect of smoking and snuffing on insulin sensitivity was studied in a group of healthy habitual smokers. The euglycaemic clamp technique was combined with the subcutaneous injection of a bolus (0.1 U kg-1) of fast-acting insulin (Actrapid). Randomized subjects smoked either one cigarette per hour for 6 h, took one bag-packed snuff per hour for 6 h or refrained from nicotine for 48 h before as well as during the clamp. Seven healthy smokers, four females and three males, of normal weight (BMI, mean +/- SEM, 21 +/- 0.7 kg m-2 with a range of 18.6-23.9), aged 31 +/- 2 years (range 24-35 years), who had consumed at least 20 cigarettes per day for at least 5 years were studied. They were recruited through an advertisement in a newspaper. The steady-state plasma nicotine levels were similar during smoking and snuffing. The insulin and glucose levels were also similar during all three clamps. Smoking, but not snuffing, impaired insulin action (P < 0.05) mainly due to a lower peripheral glucose uptake. The mean growth hormone levels during the 6-h study were more than doubled during smoking (P < 0.01) while no significant differences were seen in the other counter-regulatory hormones. Smoking (also in habitual smokers) acutely impairs insulin action and leads to insulin resistance. Thus, smoking can be of importance for the development of the insulin resistance syndrome associated with risk for cardiovascular disease.

Effects of 5-hydroxytryptamine 3 antagonist, ondansetron, on cigarette smoking, smoke exposure, and mood in humans

Recent studies in the animal laboratory indicate that 5-hydroxytryptamine 3 (5-HT 3) antagonists reduce the reinforcing effects of several psychoactive drugs, including nicotine. The purpose of our study was to determine if ondansetron, a selective 5-HT 3 antagonist, affected tobacco cigarette consumption in smokers. In the first experiment, a prospective, crossover, placebo-controlled trial was used in which subjects ( N=7) were exposed in an inpatient research unit to 0, 0.15, 0.3, or 0.45 mg/kg ondansetron in three equally divided given doses given 4 h apart. In the second experiment, seven different subjects were exposed to the same trial except the dose range was reduced to about 10%: 0, 0.01, 0.02, or 0.04 mg/kg. In each experiment, order of dosing conditions was determined by a Latin square design. Dependent measures included number of cigarettes smoked during the 24-h session, biologic exposure levels (carbon monoxide and plasma nicotine levels), and mood. Number of cigarettes smoked and biologic exposure levels did not differ across drug conditions in either experiment. There were also no effects of ondansetron on mood. From our study results, we conclude that acute administration of ondansetron, at doses appropriate for antiemesis or at markedly lower doses, does not alter tobacco consumption or smoke exposure in humans.

Nicotine Absorption after Pulmonary Instillation

Levels of nicotine in plasma were determined by gas chromatography in eight mongrel dogs after instillation of 0.5mg of nicotine in 100 μL of normal saline at three levels of the tracheobronchial tree: the trachea, a subsegmental bronchus of the right middle lobe, and a subpleural location of the right middle lobe (“distal”). An equivalent dose was given intravenously (iv). Peak of nicotine concentrations in plasma were significantly lower after instillation at the trachea (11.5 ± 4.4 ng/mL) and the subsegmental bronchus (18.2 ± 5.0 ng/mL) than after an iv dose (30.3 ± 10.7 ng/mL); p < 0.05 for each comparison. In addition, the peak concentration after instillation at the trachea was significantly lower than that after instillation at the distal site (22.1 ± 6.2 ng/mL, p < 0.05). Time to peak concentration was significantly longer after tracheal instillation (5.3 ± 3.0 min) than after subsegmental instillation (2.0 ± 0.0 min) or iv infusion (2.0 ± 0.0 min); p < 0.05 for each comparison. Total drug absorbed, half-life, and clearance were equivalent from all four sites. This study demonstrated that quantitative absorption of nicotine from the described lung sites is equivalent to that after an iv dose, with slower absorption and lower peak concentrations from the tracheal site.

Induction of pancreatic acinar pathology via inhalation of nicotine.

This study was conducted to determine the effects of nicotine inhalation on the onset, progression, and sequential development of pancreatic lesions. Male Sprague-Dawley rats in groups of five were exposed to saline or nicotine aerosol twice daily for 15, 30, 45, and 60 min for 21 days. After sacrifice, blood samples were analyzed for plasma levels of nicotine, glucose, gastrin, and cholecystokinin. Pancreatic tissues were examined for pathological lesions. While there were no significant differences in plasma levels of glucose, gastrin, and cholecystokinin in all groups, there was a steady increase in plasma levels of nicotine with increased exposures to nicotine. Histopathological examination of pancreatic tissue revealed definitive pancreatic injuries that also appeared to be directly correlated with increased duration of nicotine exposure. The pathological changes of the pancreas were confined only to acinar cells of the exocrine pancreas. Two main types of cellular changes were observed: cellular swelling/vacuolation and nuclear condensation/cellular pyknosis. Both of these changes indicated tissue injuries in the pancreas. Transformation of the glandular acini to solid masses of epithelial cells was also observed. The results from our present study strongly suggest that the exocrine pancreas is very sensitive and susceptible to nicotine toxicity. Our data further indicate that early morphological changes in the pancreas induced by nicotine may occur without functional or metabolic alterations; however, such changes could occur at a later stage, when tissue and cellular changes become more extensive.

Nicotine and the central nervous system: Biobehavioral effects of cigarette smoking

The effects of nicotine, like those of other drugs with potential for abuse and dependence, are centrally mediated. The impact of nicotine on the central nervous system is neuroregulatory in nature, affecting biochemical and physiological functions in a manner that reinforces drug-taking behavior. Dose-dependent neurotransmitter and neuroendocrine effects occur as plasma nicotine levels rise when a cigarette is smoked. Circulating levels of norepinephrine and epinephrine increase, and the bioavailability of dopamine is altered as well. Among the neuroendocrine effects are release of arginine vasopressin, β-endorphin, adrenocorticotropic hormone, and cortisol. Notably, several of these neurochemicals are psychoactive and/or known to modulate behavior. Thus, affective states or cognitive demands may be favorably modified (at least temporarily) by nicotine intake. When nicotine is inhaled, the neuroregulatory effects just described are immediately available and the reinforcing effects of the drug are maximized. On the other hand, nicotine gum and most other nicotine replacement vehicles in current use have a slower onset of action, resulting in less reinforcement value. Recent data suggest that smoking cessation rates may be optimized by tailoring the dose of nicotine replacement (for example, 2 or 4 mg of nicotine gum) to the individual degree of nicotine dependence. In view of the dynamic interactions between the neuroregulatory effects of nicotine and a host of environmental conditions, nicotine replacement therapy is best carried out in combination with behavior modification techniques.

Acute influence of smoking on platelet behaviour, endothelium and plasma lipids and normalization by aspirin

This study was conducted to investigate acute effects of smoking on platelet function, endothelial cells and plasma lipids and to follow these parameters after Aspirin ingestion. Twelve fasting smokers each inhaled the smoke of one cigarette. Blood was drawn before and 10 min after smoking. Plasma nicotine, measured by gas chromatography, increased from 13.48 before smoking to 78.41 nM after smoking. Platelet aggregation to thrombin and ADP increased significantly ( P < 0.001). The platelet aggregate ratio decreased from 0.95 to 0.75 ( P < 0.005). Plasma β-thromboglobulin also increased in post-smoking samples as measured using radioimmunoassay. ‘Circulating endothelial cells’ increased significantly after smoking ( P < 0.005). Triglycerides decreased ( P < 0.005) in plasma and in the VLDL fraction ( P < 0.05). Both post-smoking plasma free fatty acids and free glycerol increased, respectively, as compared with respective values. Lipase activity ascribable to lipoprotein lipase and hepatic lipase, absent in pre-smoking plasma samples, could be detected in post-smoking plasma without heparin injection. At least 1 week later, the subjects returned to follow an identical protocol except that they had ingested Aspirin (650 mg) 10–14 h before blood sampling. The same parameters were measured before and after smoking the same cigarette. Except for plasma nicotine, all the smoking-induced changes were abolished by ingestion of Aspirin. The results of this study indicate an interrelationship between platelet hyperactivity, endothelial injury and plasma lipids. They also demonstrate an inhibition of the major smoking-induced changes by Aspirin in the presence of high plasma nicotine levels. It is concluded that Aspirin may offset several of the deleterious acute effects of smoking. However, our conclusions cannot be, in any way, extended for long-term effects of both smoking and Aspirin treatment. Based on these data, it is suggested that there may be some links between platelet hyperactivity, endothelium injury and plasma lipids.

Pathogenesis of Ischemic Necrosis in Random-Pattern Skin Flaps Induced by Long-Term Low-Dose Nicotine Treatment in the Rat

The objectives of the present experiments were to study the effects of long-term low-dose nicotine treatment on skin hemodynamics, viability, and microvascular morphology in 4 x 10 cm dorsally based acute random-pattern skin flaps in the rat. In addition, the reversibility of the nicotine-induced detrimental effects on skin-flap viability following cessation of nicotine treatment also was investigated. Low-dose nicotine (0.6 mg/kg) administered twice daily and subcutaneously for 24 weeks significantly (p less than 0.05) decreased skin-flap capillary blood flow, distal perfusion, and length and area of skin viability compared with the saline-treated control (n = 15). However, these same parameters in rats (n = 15) whose nicotine treatment had been withheld for 2 weeks prior to skin-flap surgery were not significantly different from the control, thus indicating that the detrimental effects of this long-term, low-dose nicotine treatment were reversible. The mean plasma level of nicotine in the nicotine-treated rats was 8.1 +/- 0.4 micrograms/dl and was within the range of plasma nicotine levels reported for human heavy cigarette smokers. Light and electron microscopic studies did not show evidence of histologic damage to the cutaneous microvasculature in acute random-pattern skin flaps and samples of normal (nonoperated) skin in nicotine-treated rats. It is concluded that long-term plasma levels of nicotine similar to those of heavy cigarette smokers are detrimental to the capillary blood flow and viability of random-pattern skin flaps in the rat. These deleterious effects can be avoided if skin flaps are raised 2 weeks after cessation of nicotine treatment. This low-dose nicotine treatment does not cause histologic damage to the microvasculature. Other pathogenic mechanisms of nicotine-induced skin flap ischemia are discussed.

Effects of spirometric administration of tobacco smoke containing varying amounts of nicotine on physiological measures and subject ratings

A previously developed spirometric methodology of tobacco smoke administration was evaluated by determining the effects of varying nicotine delivery on various physiological and subjective measures. Eight male tobacco smoking subjects were administered 60cc volumes of tobacco smoke drawn from University of Kentucky research cigarettes, or air. Subjects were exposed to four bouts of smoke administration conducted over an 8h day. Each smoking bout was separated by 2h and involved 20 smoke administrations at the rate of one every 30sec. Each smoke administration consisted of 60cc of air or 60cc drawn from 0.3, 1.2 or 2.7mg nicotine yield cigarettes, followed by 1 liter of air which forced the smoke or air deep into the lungs. Carbon monoxide (CO), blood pressure, and heart rate were measured before and after each smoking bout, and subject ratings of smoke effects were completed after each smoking bout. In a separate study, blood samples were collected on two occasions before and after administration of the two highest nicotine yield cigarettes to determine changes in nicotine plasma levels. Data indicated that the spirometric method produced: (1) similar CO boosts across nicotine yields, and (2) changes in heart rate, blood pressure, subject ratings and plasma nicotine levels which were directly related to the nicotine yield of cigarettes.

Comparison of Blood Aldehyde Dehydrogenase Activities in Moist Snuff Users, Cigarette Smokers and Nontobacco Users

The aldehyde dehydrogenase (ALDH; EC 1.2.1.3) activity was determined in samples of whole blood and in isolated erythrocytes and leukocytes from users of Swedish moist snuff, cigarette smokers and non-tobacco-using controls. The mean whole blood ALDH activity of the smokers was reduced by 21% (p less than 0.001) when compared to the controls, while that of the snuff users was reduced by only 8% (not significant). Similar but somewhat less pronounced differences were obtained both in the assays with erythrocytes and leukocytes. In the cigarette smokers, the whole blood activity correlated significantly (r = -0.79, p less than 0.001) with the plasma concentration of cotinine, the major metabolite of nicotine, whereas no correlation was observed for the users of moist snuff. Similar plasma nicotine and cotinine levels were found in smokers and snuff users, which indicates that the reduced blood ALDH activity in smokers is not caused by nicotine or any of its metabolites, but more likely, by components formed during combustion of tobacco. Since a reduced blood ALDH activity has previously been suggested as an indicator of excessive alcohol consumption, the present results show that, in future studies on blood ALDH, the smoking habits should also be taken into account.

The use of transdermal nicotine in smoking cessation

The transdermal administration of nicotine by means of a transdermal nicotine system (TNS) affords a novel way of nicotine replacement to alleviate smoking cessation. The plasma levels of nicotine maintained with the TNS are in the range of the footpoint concentrations observed in smokers. The efficacy of the TNS was investigated in two placebo-controlled double-blind smoking cessation programs with minimal contact and minimal psychological support. A total of 311 smokers were treated for 3 months or 9 weeks. The abstinence rates at the end of the treatment and weaning periods were almost doubled in the TNS groups (36% and 39%) as compared to the placebo groups (23% and 20%) with a significant difference for both studies (p less than 0.05). These data suggest that the TNS can also improve the smoking cessation rates under the conditions of general medical advice, making it suitable for use outside of specialized smoking cessation centers.

Pharmacokinetics of a single transdermal dose of nicotine in healthy smokers

The plasma concentration-time profiles for nicotine and its major metabolite, cotinine, were characterized after a single application of a nicotine user-activated transdermal therapeutic system (UATTS) to the upper forearm of eight healthy smokers. The volunteers abstained from smoking for 12 h prior to, and during the course of the study. A 10cm 2 system (designed to deliver nicotine base at 72 μg/cm 2/h) was applied for 24 h. Serial blood samples were taken at frequent intervals during dosing and after system removal. After a median 6 h lag time, nicotine plasma levels reached an average peak level of 15.2 ng/ml at a median peak time of 24 h. Following removal of the system, nicotine levels remained relatively constant for 1 h and then declined gradually. The half life was estimated as 4.0 h and the AUC(0–34 h) averaged 256.8 ng-h/ml. Prior to system application, the mean cotinine plasma level started at 214.5 ng/ml, and declined during application for 8 h before increasing to 186.7 ng/ml, 30 min after system removal. The average amount of nicotine delivered per system, as estimated by the residual nicotine content in the system, was 15 mg. The in vivo absorption of nicotine, after adjustment for the expected lag time, parallels the in vitro release as estimated by Wagner-Nelson analysis.

A noninvasive method for delivering controlled doses of nicotine via cigarette smoke

A cigarette-smoke delivery system is described in which nicotine dosage was delimited by having the subject inhale a measured amount of smoke to a predetermined depth and duration of inhalation. A plastic syringe was used to “inject” a specified amount of cigarette smoke into the subject’s mouth, and an airbag containing 1 liter of air was used to provide a “chaser” with a fixed volume of inhalation for the smoke. Using plasma nicotine boost as an indicator, dose control was found to be nearly linear for the three dose levels employed; in the high-dose condition, plasma nicotine levels were moderately consistent within subjects over three successive administrations. Between-subject variability was considerably greater than within-subject variability, however, suggesting that each smoker obtained a characteristic nicotine boost that reflected individual differences in nicotine pharmacokinetics in addition to nicotine intake per se.

Caffeine and cigarette smoking: behavioral, cardiovascular, and metabolic interactions.

Coffee drinking and cigarette smoking are strongly correlated behaviors which have been suggested to act synergistically to produce adverse health consequences, particularly coronary heart disease (CHD). We studied in smokers the influence of four days of multiple daily doses of coffee containing different doses or no caffeine on cigarette smoking behavior, nicotine intake from smoking, heart rate and blood pressure, circadian serum glucose, and urinary catecholamine excretion. We observed a tendency toward greater cigarette consumption during caffeine consumption, and a tendency toward higher plasma nicotine levels during low-dose caffeine compared with the no-caffeine condition; however, these effects were small. No caffeine effects on any other of the above parameters were observed. Previously published research has usually studied effects of single doses of caffeine, which does not account for development of tolerance to effects of caffeine. If caffeine does contribute to CHD risk, it is not likely to be related to caffeine effects on smoking behavior, nicotine intake, blood pressure, heart rate, glucose tolerance, or catecholamine release. Adverse effects of long-term caffeine consumption on lipids cannot be excluded.

Effect of smokeless tobacco on the development of the CD-1 mouse fetus.

The objective of this study was to examine the effect of an aqueous extract of smokeless tobacco (ST) on the development of the CD-1 mouse fetus. Three ST dosages were administered three times daily by gastric intubation during gestational days 1-17: 1 X ST equivalent to a dose of 4 mg nicotine/kg body weight, 3 X ST equivalent to 12 mg nicotine, and 5 X ST equivalent to 20 mg nicotine/kg body weight. Maternal plasma nicotine levels were determined 30 minutes after the second daily intubation at five different times during the gestational period. At these ST dosages, the weight gain of ST-treated dams was not significantly affected in comparison to treated controls, though the difference was significant (P less than .05) in comparison to untreated controls. The mean maternal plasma nicotine level for the low dosage (1 X) group was 99.0 ng/ml, which reasonably approximates human consumption levels. The 3 X ST and 5 X ST dosages produced higher nicotine plasma values, 398 ng/ml and 623 ng/ml, respectively, were considerably more toxic to the dams, and resulted in 18% and 31% maternal deaths. Fetal weights were reduced by 7.4% (P less than .001) in the highest ST dosage group (5 X), whereas at the 1 X and 3 X dosages fetal weight differences were not significantly different from treated controls. Resorptions increased in a dose-related manner (P less than .05), ranging from 4.7% in the 1 X, to 6.4% in the 3 X and 8.9% in the 5 X dosage compared to 3.2% in treated controls. External malformations were few and minor in extent. Internal malformations increased in a linear, dose-related manner (P less than .05). Placental weights were unaffected by ST. The results of skeletal examinations were inconclusive. Precocious ossification was seen in 60% and 70% of the parameters measured in the 1 X and 3 X dosage groups, respectively, in comparison to controls. In the 5 X ST group ossification levels were less than in controls for 30% of the parameters measured. Under these experimental conditions the lowest ST dosage (1 X) produced a negligible effect on the CD-1 mouse fetus and the dam. The highest ST dose (5 X) demonstrated embryotoxicity, growth retardation, few malformations, and maternal toxicity. The intermediate dose (3 X) showed a range of effects between the highest and lowest doses to both the fetus and the dam.

Plasma nicotine levels after inhalation of aerosolized nicotine.

Smokers were given 5 mg of aerosolized nicotine over a 5-min period on 3 separate days to determine if this mode of nicotine delivery could produce nicotine levels similar to those reported from cigarette smoking. Our subjects' mean nicotine level increased from a pretrial level of 12 +/- 2 ng/ml to a peak of 32 +/- 7 ng/ml at 2.5 min after completion of the inhalation. Cough was the most prominent side effect and seemed to be related to irritant effects of the aerosol. Seven of the 16 subjects dropped out of the study because of unpleasant side effects. Side effects did not seem to correlate with nicotine blood levels. We conclude that aerosolized nicotine can produce plasma nicotine levels analogous to cigarette smoking. Cough was a limiting side effect and was presumably due to an irritant effect of the aerosol on the upper airway.

Acute effects of nicotine on resting metabolic rate in cigarette smokers

The acute effects of nicotine on resting metabolic rate (RMR) were examined to identify a mechanism that may help explain the inverse association between smoking and body weight. Multiple administrations of two nicotine doses (moderate [15 micrograms/kg body wt] and low [7.5 micrograms/kg body wt]) and a placebo (0 micrograms) were presented to 18 male smokers via nasal-spray solution on three separate occasions while RMR was assessed by computerized open-circuit indirect calorimetry. Plasma nicotine levels confirmed the reliability of dosing. RMR increases of 6% above base line after both moderate and low doses were significantly greater than the 3% increase after the placebo. Subsequent examination of the effects of smoking a nonnicotine cigarette suggested that the small placebo effect was due to acute metabolic consequences of inhalation. These results confirm that intake of nicotine, isolated from tobacco smoke, significantly increases RMR in humans. However, the results also indicate that non-pharmacological, behavioral aspects of smoking may also contribute to acutely increasing RMR in smokers.

Response of plasma arginine vasopressin to nicotine in normal man.

The response of plasma arginine vasopressin (AVP) to nicotine administered by chewing gum (Nicorette, 2 mg) was examined in nine healthy volunteers. Heart rate, mean arterial pressure, serum osmolality, plasma AVP level, and plasma nicotine level were measured at baseline (control) and at 30, 45, and 60 minutes after initial administration of the gum. There were small increases in heart rate (72 +/- 6.3 to 82 +/- 5.1 beats/min, p less than 0.05) and mean arterial pressure (88 +/- 8.2 to 93 +/- 10 mm Hg, p = NS), while the plasma nicotine level increased to a maximum of 16 +/- 2.0 ng/ml (p less than 0.001). No changes were seen in either osmolality (283 +/- 3.4 mOsm/kg) or AVP level (4.3 +/- 2.0 pg/ml) in eight of the nine subjects who remained asymptomatic. In one subject whose hemodynamic and plasma nicotine responses were similar to the others but who became nauseated, the plasma AVP level increased from 4.2 to 26 pg/ml. These data suggest that nicotine at the plasma concentrations achieved in this study is not associated with stimulation of plasma AVP secretion in normal man. Other factors in association with nicotine use, in this case nausea, may be required for AVP stimulation to occur.

Effect of smokeless tobacco on the development of the CD-1 mouse fetus.

The objective of this study was to examine the effect of smokeless tobacco (ST) on the development of the CD-1 mouse fetus. ST was administered continuously via Alzet osmotic minipumps during the critical gestational days 7-14 and 6-13. Two ST dosages were administered, 3.2 mg/ml (Dosage I) and 6.4 mg/ml (Dosage II), which yielded plasma nicotine levels within the range comparable to those of an average ST user or smoker (36.0 ng/ml). Plasma nicotine levels were maintained in the range of 29.4 +/- 4.8 ng/ml to 44.3 +/- 16.0 ng/ml for the Dosage I group of dams, and in the range of 34.6 +/- 10.9 ng/ml of 75.5 +/- 19.9 ng/ml for the Dosage II group of dams. The main effect on the fetus was weight reduction, with Dosage I producing a tendency toward weight reduction (p = .08). Dosage II produced a significant 8.6% weight reduction from normal (p less than .0001) and an increase in fetal deaths (p less than .03). Dosage I produced an increase in the incidence of hemorrhages and supernumerary ribs, and a significant delay (p less than .05) in ossification of the supraoccipital bone, the sacrococcygeal vertebrae, and the bones of the forefoot and hindfoot. There were no significant differences between placental weights. Weights of dams were significantly reduced only at the higher ST exposure levels. We conclude that at plasma nicotine levels comparable to those of an average ST user, ST produces weight reduction, delayed ossification, and increase in hemorrhages and fetolethality in the CD-1 mouse fetus.