Atenolol: pharmacokinetic/dynamic aspects of comparative developmental toxicity

Reproducti e Toxicology ELSEVIER

Reproductive Toxicology 16 (2002) 1-7

www.elsevier.com/locate/reprotox

Review

Atenolol: pharmacokinetic/dynamic aspects of comparative developmental toxicitytr Sonia A. Tabacovaa·*, Carole A. Kimmelb "National Center for Toxicological Research, US Food and Drug Administration, Rockville, MD, USA bNational Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, Washington, DC, USA

Keywords: Antihypertensive drug; Beta-adrenoreceptor antagonist; Atenolol; Pharmacokinetics; Pharmacodynamics; Developmental toxicity; Animal-human comparisons

1. Introduction Atenolol is a cardioselective {3-adrenoreceptor blocking agent, used for treatment of hypertension, including hyper­ tension in pregnancy. Beta-adrenoreceptor antagonists have been implicated in the production of intrauterine growth retardation and a considerable range of neonatal problems including hypoglycemia, bradycardia, respiratory depres­ sion and death [1,2]. The relationship between these com­ plications and drug administration is often difficult to eval­ uate because of the anecdotal or retrospective nature of observations. In addition, since {3-blockers are used in preg­ nancies having a major complication (e.g. severe hyperten­ sion), it can be very difficult to differentiate drug effects on the fetus from those caused by the underlying maternal disease. This paper reviews pharmacokinetic and pharmacody­ namic issues relevant to atenolol prenatal toxicity in humans and in experimental animal species with the aim of better . understanding the origin of adverse developmental out­ comes that have been associated with atenolol exposures in pregnancy.

* The views expressed in this paper are those ofthe authors, and do not necessarily represent the views or policies of the US Environmental Pro­ tection Agency or the Food, and Drug Administration. *Corresponding author. Tel.: + 1-301-827-6697; fax: + l-301-4433019. E-mail address: [email protected] (S. Tabacova).

2. Pharmacokinetic aspects 2.1. General Chemically, atenolol is a phenylacetamide [(4-2'-hy­ droxy-3'-isopropyl-aminopropoxy) phenylacetamide]. lt is a relatively polar, hydrophilic compound. In adult nonpreg­ nant subjects, the disposition ofatenolol has been studied in humans and in several animal species: rats, mice, rabbits, dogs, and rhesus monkeys [3,4]. The absorption of the drug upon oral administration in humans and most laboratory animal species is rapid but incomplete. Due to incomplete intestinal absorption, the systemic bioavailability is about 50% to 60% in the human [5] as well as in the rat, mouse, rabbit, and monkey [6]. ln contrast, in the dog, absorption from the gut is almost complete-98% of the total dose [3]. This striking differ­ ence in the intestinal absorption has been attributed to in­ terspecies differences in the intestinal luminal pH values. lt has been shown that atenolol is well absorbed at pH values above 7.5, and the normal pH of the dog ileum is 7.8 to 8.0, whereas in the rat and human it lies between 7.2 and 7.6 [6]. Peak plasma levels are attained rapidly-2 to 4 h after oral administration in humans, as well as in dogs and mice, and slightly later in the rat. In the human and in animal species, plasma levels are proportional to dose over the ranges stud­ ied. Following absorption, atenolol is widely distributed to most body tissues in humans [4,5] and in animal (rodent) species [3,7]. However, only a small proportion of the administered dose reaches the brain in both humans [8] and animals [3,7]. The brain tissue:blood concentration ratio in the human is about 0.2:1 compared to a much larger pro­ portion (33:1) for another widely used drug of the same class, propranolol [8]. Atenolol shows little-less than

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S.A. Tabacova, C.A. Kimmel I Reproductive Toxicology 16 (2002) 1-7

5%-binding to plasma protein in the human [9]. In ro­ dents, atenolol is evenly distributed between red blood cells and plasma [6]. Metabolism and excretion: Only about 10% of the ab­ sorbed amount is metabolized in animals and humans; the rest is excreted unchanged. The major route of excretion is through the urine in humans as well as in the animal species studied (rats, mice, rabbits, dogs, and rhesus monkeys) [3,4]. Since 80-90% of [14C]atenolol is excreted un­ changed, there is little biotransformation. Two minor me­ tabolites have been identified in urine from healthy human subjects. The chief component is an unconjugated metabo­ lite that arises as a result of hydroxylation in the liver of the methylene carbon of the acetamide moiety; the other is a glucuronide of atenolol and comprises less than 2% of the total [14C]labelled atenolol excreted. The chief metabolite is identical in humans and experimental animals (rats and dogs) and has about one tenth of the /3-blocking activity of atenolol. When given i.v., atenolol is almost completely excreted in the urine. Upon oral administration, between 40% and 50% of the unchanged compound is recovered in the urine, and 50% is recovered unchanged in feces due to incomplete intestinal absorption in the human and in most experimental species, except for the dog. There is no evidence that there is an alternative biliary route for excretion in either humans or experimental animals [6,10]. The elimination half life (t112) after oral administration is 4-7 h in mice and 6.5 h in dogs, which is comparable to the t112 in the human-between 6 and 8 h; in contrast, the t112 in rats is 24-35 h [3,5,11,12]. No change in human t 112 is seen upon repeated oral administration of atenolol at a dose of 200 mg/day for eight days [10]. Excretion in healthy sub­ jects is essentially complete 48 h after a single dose [4], but following longer-term treatment of patients with hyperten­ sion, detectable blood levels persist for several days [13]. Because atenolol clearance is dependent on glomerular fil­ tration, the elimination half-life is longer in cases of renal impairment. In patients with renal disease, the t 112 of ateno­ lol is prolonged in proportion to the reduction in renal clearance [14], implying that in cases of pregnancy compli­ cations that involve renal impairment (such as preeclamp­ sia, chronic hypertension of renal origin, or other renal disease), atenolol clearance is likely to be decreased. 2.2. Pharmacokinetic aspects in pregnancy 1n pregnancy, atenolol is mainly used for treatment of pre-existing or pregnancy-associated hypertensive disor­ ders. These conditions are known to be among the most frequent complications of pregnancy. Upon oral adminis­ tration of the drug to pregnant women in the last month of gestation for a minimum of 4 days at a dose of 100 mg/day, the peak concentration in the maternal blood (0.59 p,g/mL) is reached 3 h after administration, and the area under the curve over the dosing interval is 7.1 p,g/mL-h. The reported

half-life of atenolol in maternal blood after a 100 mg oral dose is 8 h, and the 24-h urinary excretion is 52 ± 9 mg, indicating approximately 50% absorption [15]. These val­ ues all lie within the normal range for nonpregnant subjects, suggesting that gestation by itself induces no changes in the pharmacokinetics of this drug [5,11]. lt should be noted that the available pharmacokinetic studies in pregnancy have been performed on patients suffering from pregnancy-in­ duced hypertension, and not on healthy subjects. Placental transfer in the human has been shown for most of the /3-blocking agents used in pregnancy, including atenolol [16]. However, following administration of 14 [ C]labeled atenolol to pregnant rats, only trace levels were found in fetal tissues at 1 and 24 h after dosing, in contrast to the widespread distribution of radioactivity in the mater­ nal organs [3].1n experimental animals (ewes), a correlation has been found between the lipid solubility of f3-adrenore­ ceptor blockers and permeability of the placenta [17]. Al­ though atenolol has very low lipid solubility, it readily crosses the human placenta [15,18]. A strong correlation between the maternal and umbilical cord blood plasma levels has been observed [18,19]. lt has been suggested that factors other than lipid solubility may be important for atenolol transplacental passage, such as the low level of plasma protein binding of this drug in the human. Atenolol is less than 5% bound in human plasma as compared to 80-90% binding of another widely used /3-adrenoreceptor blocker, propranolol [9]. After oral administration of ateno­ lol at doses of 50 or 100 mg/day to pregnant women for at least 6 days before delivery, the drug was detected at ap­ proximately equal concentrations in maternal and umbilical cord blood immediately after delivery. The mean maternal­ umbilical serum ratio was 1.13 [20]. This ratio has been confirmed in another study [15] with similar exposure (100 mg/day for a minimum of 4 consecutive days); that study reported a mean maternal-fetal concentration ratio of 1.11 (average maternal and cord blood concentrations 0.26 and 0.22 p,g/mL respectively). In both studies, the blood sam­ ples used for atenolol determination were obtained during steady-state conditions, so that it was reasonable to assume that atenolol penetrates the placental barrier, and that during steady-state conditions the blood levels in mother and fetus are approximately equal [20]. As atenolol disappears rapidly from maternal and fetal blood after withdrawal, it is likely that fetal accumulation does not occur [20]. Atenolol is excreted in neonatal urine after maternal exposure to the drug in the perinatal period and puerperium [21]. After birth, the newborn eliminates the drug generally slower than does an older child or adult; the plasma halflives can be 2 or 3 times higher in the early postnatal life [16]. Atenolol accumulates in human breast milk, in accor­ dance with the findings that drugs that are weak bases accumulate in breast milk due to pH differences between plasma and milk [18]. The mean AUC in milk was reported to be 4.5 times greater than in the serum [18]. ln another

I S.A. Tahacova, C.A. Kimmell Reproductive Toxicology 16 (2002) 1-7

study [21], the mean plasma:milk ratio was 1.3:1, with a wide range (0.1 to 4.7) between and within subjects. The observed variations were attributed to factors other than the physicochemical properties of the drug. Possible factors of importance for breast milk excretion of the drug were con­ sidered to be the fat and protein content of the milk and the time of collection in relation to feeding [21]. Two hours after a single oral dose of 100 mg/day given during the puerperium to five breastfeeding mothers, the mean sys­ temic maternal blood level of atenolol was 630 p.g/liter and the mean milk level, 710 p.g/liter. In summary, the animal/human comparison of atenolol pharmacokinetics suggests that, due to marked differences in intestinal absorption of the drug in the dog, the internal rather than the ingested dose should be considered with this experimental model for predicting human effects upon oral exposures. Other commonly used experimental species (rats, mice, rabbits, and rhesus monkeys) handle the drug in a way similar to that in the human, except for the slower elimination of atenolol in the rat in comparison to the human. In pregnancy, the transplacental passage of atenolol is greater in the human in comparison to the rat, a fact that could be due to the very low binding of the drug to human plasma.

3. Pharmacodynamic aspects 3.1. General Atenolol is a cardioselective beta 1-adrenoreceptor block­ ing agent without intrinsic sympathomimetic activity. It has a markedly greater effect on cardiac than bronchial or vas­ cular adrenoreceptors [22,23] and reduces blood pressure mainly by reducing cardiac output, in contrast to the non­ selective {3-blockers that reduce blood pressure mainly by decreasing the peripheral vascular resistance [24]. Atenolol main!y causes its hypotensive effect by decreasing heart rate and cardiac contractility in both humans and experimental animals [25]. It has been shown that in humans, a plasma level of 1 p.g/mL atenolol is associated with a 30% reduc­ tion of exercise-accelerated heart rate and that a clear linear relationship could be obtained between log plasma concen­ tration and percentage reduction in heart rate [5]. However, while in humans atenolol reduces blood pressure in normal as well as in hypertensive subjects [26,27], this is not always the case with experimental animals. The hypoten­ sive effect in experimental hypertension models depends on the model used, as well as on the dose and timing of administration. Thus, atenolol is ineffective against experi­ mental hypertension induced in rats and dogs by application of deoxycorticosterone acetate/sodium chloride in drinking water [6].In genetically hypertensive rats, atenolol has only a transient effect on the elevated blood pressure at doses of 50 and 100 mg/kg (much higher than the maximal human therapeutic dose), and a dose of 200 mg/kg is required to

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maintain normal blood pressure throughout the observation period [28]. This suggests that the hypertension models in these experimental species would be inadequate to predict atenolol effects in the hypertensive human. In addition to cardiac adrenoreceptors, atenolol acts on adrenoreceptors that regulate renin release and metabolic responses. Release of renin from the kidneys is enhanced by beta receptor stimulation and antagonized by atenolol, as demonstrated in vitro in isolated rat kidney slices [29], and in vivo in animal (cat) experiments [30]. Other drugs from the same class (propranolol, metoprolol) have also been shown to decrease plasma renin activity in animal studies [31]. Similarly, in the human, atenolol reduces circulating levels of active renin [32,33] and of angiotensin II [6]. Suppression of renin release decreases production of angio­ tensin II and aldosterone, which is a key factor in minimiz­ ing fluid volume retention. The adrenoreceptors subserving metabolic changes vary with species, but lipolysis is generally regarded as a beta 1mediated response and glycogenolysis as a beta 2-mediated response [6]. Atenolol shows antilipolytic activity in both human and rat adipocytes in vitro [34] as well as in vivo by reducing the circulating levels of free fatty acids in dogs and in humans [6,35]. Studies on the effects of atenolol on glucose homeostasis in normal and diabetic human subjects suggest that atenolol has no significant hypoglycemic effect in humans [36,37]; however, atenolol has a hypoglycemic action in the rat. Atenolol reduces plasma glucose and raises plasma insulin levels in fasted rats, as well as in alloxan­ diabetic rats upon i.v. application of doses (1 and 4 mg/kg, respectively) that are comparable to human therapeutic ones [38]. Hypoglycemic reactions in humans have also been described in both non-diabetic and diabetic patients treated with other {3-blocking drugs [39]. Thus, although the main pharmacodynamic properties of atenolol are generally similar in humans and experimental animals, there are differences with respect to atenolol he­ modynamic effect in hypertensive human subjects and an­ imal hypertension models (dogs, rats), as well as the effect on glucose homeostasis in rats and humans. These differ­ ences might affect the comparability of animal/human de­ velopmental toxicity data, considering the adverse effect of maternal hypertension and the importance of glucose ho­ meostasis in intrauterine development. 3.2. Pharmacodynamic aspests in pregnancy Beta-adrenergic activity during pregnancy is physiolog­ ically important because of the direct effects the sympa­ thetic nervous system has on umbilical blood flow and uterine tone and contractility [40]. In the myometrium, there are adrenergic receptors of the alpha and beta types. Stim­ ulation of the beta receptor results in myometrial relaxation, whereas a-adrenergic stimulation potentiates contractility [41]. Beta-adrenergic tone affects the basal umbilical blood

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S.A. Tabacova, C.A. Kimmel I Reproductive Toxicology 16 (2002) 1-7

flow and a disturbance in sympathetic inputs could be po­ tentially harmful to the developing fetus [40]. The immediate fall in blood pressure after atenolol ad­ ministration is to some extent prevented by the vasocon­ strictor activity mediated through the baroreflex [42]. In long-term treatment, however, the hemodynamic changes take the form of lower vascular tone rather than vasocon­ strictor activity [43]. This effect could be important in pregnancy, considering that long-term application of ateno­ lol is possible in the case of hypertensive disorders of pregnancy. Atenolol has a direct effect on fetal hemodynamics and fetal cardiac function [16]. Significant effects on uteropla­ cental and fetal hemodynamics (although within normal physiologic ranges) have been observed among patients with pregnancy-induced hypertension treated with an ateno­ lol oral dose of 100 mg/day during the third trimester of pregnancy [42,44]. Maternal and fetal hemodynamics were measured before, during, and after the treatment. Atenolol lowered the maternal blood pressure and significantly re­ duced the maternal heart rate; the fetal heart rate was either reduced [42] or unchanged [44]. The most important find­ ings were, however, that the pulsatility index (an indicator of peripheral vascular resistance) increased consistently in the umbilical artery and fetal aorta after atenolo1 treatment. The increased peripheral vascular resistance has been ex­ plained by the reflex vasoconstriction seen when cardiac output is reduced [42]. In the other study, however, the increased resistance to blood flow in the fetoplacental cir­ culation was not associated with changes in fetal heart rate, and was attributed to the fact that atenolol has no intrinsic sympathomimetic (vasodilating) activity [44]. Absent or severely reduced end-diastolic blood flow in the umbilical artery and the descending aorta of the fetus was reported after atenolol treatment throughout pregnancy [45]. Ab­ sence or reversal of umbilical end-diastolic blood flow in the second half of gestation is considered a signal of severe impairment of placental function and is associated with fetal hypoxemia [46]. Indeed, a significant reduction in placental weight was found after maternal atenolol treatment in the second half of pregnancy even in the absence of changes in the birth weight, length, and head circumference [42]. The decreased placental weight, also confirmed by subsequent studies [47], has been attributed to alterations in placental hemodynamics, with atenolol increasing peripheral vascular resistance in the central fetal circulation and reducing blood flow in the umbilical vein [42]. Such an effect was not observed with a different {3-blocker, pindolol, a nonselec­ tive blocker with intrinsic sympathomimetic activity [42, 44]. The higher neonatal and placental weight that has been found with pindolol in comparison to atenolol treatment has been explained by the fact that pindolol, by decreasing (rather than increasing) peripheral vascular resistance, has a favorable effect on uteroplacental blood flow, which pro­ motes fetal growth [48]. The short-term uterine and hemodynamic effects of

atenolol, administered as a single i.v. dose of 0.15 mg!kg, were studied in hypertensive women in the third trimester of pregnancy (28 to 40 weeks of gestation) [24]. Effects on uteroplacenta1 and umbilicoplacental vascular resistance, maternal and fetal he p.odynamics, and cardiac function were evaluated before, at the end, and 30 min after the infusion. Atenolol decreased significantly maternal arterial pressure and heart rate immediately and 30 min after the infusion, and affected uteroplacental circulation by signifi­ cantly increasing vascular resistance of placental and non­ placental uterine arteries. Fetal heart rate did not change, but 30 min after infusion the pulsatility index increased signif­ icantly in the umbilical artery (indicating increased umbil­ ical vascular resistance), and the peak systolic velocity de­ creased significantly in the fetal pulmonary trunk. These data are in agreement with the previously reported umbilical and fetal vascular effects of atenolol upon repeated maternal oral application [42,44]. In contrast, vascular resistance was decreased in the fetal renal artery [24], attributed to the stimulating effect of atenolol on vasodepressor prostaglan­ din generation in the kidney, found in experimental studies [49,50]. Postnatally, a decreased heart rate (bradycardia of less than 100 beats/min) has been noticed in newborns exposed in utero to atenolol [42,51-53]. It should be noted that in the early postnatal life, the heart rate of the normal newborn is physiologically at its lowest, however slightly more than IOO beats/min [54]. The transplacental beta blocking drugs potentiate this slow heart rate tendency, thus inducing the appearance of bradycardia [16]. The normalization of the pulse appears spontaneously after 4 or 5 days of life [16]. These observations have been confirmed in experiments that demonstrated a significantly lower heart rate in newborn rat pups during the first 24 h of life after maternal treatment with atenolol at an oral dose of 7.5 mg!kg from the eighth day of pregnancy until delivery [55]. 3.3. Atenolol pharmacodynamics in the pathogenesis of adverse developmental outcomes Decreased birthweight and neonatal bradycardia, hypo­ glycemia, and bronchospasm are the usual adverse effects attributed to beta blockers [19]. Common side effects of {3-blockers on the mother are lassitude, cold extremities, aggravation of bronchospasm, and premature labor [53]. The relative prevalence of these different adverse effects depends on the type of the {3-blocking agent. Beta-blockers have been classified by their degree of cardioselectivity and intrinsic sympathomimetic activity. Atenolol is a cardiose­ lective beta blocker that acts mainly on the beta 1 receptors, most of which are in the myocardium. In contrast, most of the beta2 receptors are in the uterus and bronchial tubes. Therefore, in comparison to {3-2 receptor blockers, atenolol is less likely to act on uterine activity or produce a bron­ chospasm [56]. The presence of adrenoreceptors in the uterus had led to

S.A. Tahacova, C.A. Kimmel I Reproductive Toxicology 16 (2002) 1-7

the fear that {3-adrenoreceptor blockade would induce abor­ tion or a premature labor [57]. There had been suggestions in the past that beta blockers could cause premature labor, since stimulation of uterine beta2 adrenoreceptors sup­ presses uterine activity [58]. Early clinical reports on the use of nonselective {3-adrenoreceptor blocking drugs, e.g. pro­ pranolol, for hypertension during pregnancy suggested an increased tone of the uterus [59,60]. Animal studies indi­ cated however, that this effect of {3-blockade does not occur in the gravid uterus [60]. Untoward uterine contractions have not been observed in association with atenolol use in pregnancy [57], and the use of atenolol for treatment of hypertensive pregnancy complications was actually associ­ ated with a reduction in premature labor [61]. However, atenolol may have a detrimental effect on uteroplacental blood flow, particularly in pregnancies com­ plicated by maternal hypertensive disorders. In fact, back­ ground maternal hypertension can potentiate uteroplacental and fetal hemodynamic effects of atenolol. Pregnancy-in­ duced hypertension is a hyperadrenergic state with aug­ mented response to pressor agents and angiotensin 11 [62, 63]. In hypertensive pregnancies, uteroplacental blood flow is often decreased [64], and one critical point to consider in the treatment is the effect of antihypertensive agent on the uteroplacental perfusion. If uteroplacental and fetal blood flow is compromised before antihypertensive treatment is started, {3-adrenoreceptor blockade could cause a further deterioration of fetal hemodynamics [42]. If fetal hemody­ namics are adversely affected, placental weight and birth weight may be reduced. Both these parameters have been reported to be significantly reduced after treatment with atenolol in pregnancy [47,65]. Placental functional distur­ bances, indicated by falling serum human placental lactogen concentration, have been reported even if placental weight is unaffected [61]. The decrease in placental weight has been significantly correlated with intrauterine growth retar­ dation (IUGR) and lower birth weight independently of gestational age [47], and IUGR has been associated with the duration of atenolol treatment in pregnancy [65]. Although of a similar antihypertensive effect as labetalol (an a-beta­ adrenolytic compound), atenolol seems to be responsible for lower neonatal weights and higher rates of growth retarda­ tion [19]. The more favorable effect of labetalol has been attributed to the a-blocking property of this drug, which may allow maintenance of placental perfusion and fetal oxygenation despite the lowered maternal blood pressure [19]. This also applies to atenolol comparisons with {3-blockers with vasodilating activity (pindolol, acebutolol) [57] and calcium-channel antagonists (verapamil) [53]. An added problem is the effect of the agent on umbili­ coplacental and fetal circulation [24]. The umbilical vessels and the placenta contain numerous {3-adrenergic receptors [66] and it has been shown that beta blockade causes re­ duced umbilical blood flow in humans [24,42,44] and in animal (sheep) models [67,68]. This reduction is more ev­ ident in hypoxemic cases [69]. Animal studies have shown

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that beta blockers interfere with the normal fetal cardiovas­ cular responses to stress [70]. In animals, the fetus responds to beta blockade with an increased adrenaline drive [71]. If a distressed fetus is {3-blocked, it may not be able to respond by increasing adrenaline and this may lead to fetal compro­ mise and death [71]. Although the effects of {3-adrenergic blockade in the unstressed and undisturbed fetus are mini­ mal [72], when the fetus is stressed, stimulation of the beta receptor may provide an important reserve for neonatal adaptation [40]. Poor adaptation to hypoxia ofthe fetus and the newborn of beta blocker-treated mothers has been re­ ported in humans [73], suggesting that these drugs can be potentially more harmful for a stressed fetus. Thus, maternal treatment with {3-blockers can impair the response to fetal stress in both experimental animals and human subjects.

4. Summary and conclusion The comparability of developmental effects of atenolol in humans and in animal models is affected by animal/ human pharmacokinetic/dynamic differences. Because of considerable differences in atenolol gastrointestinal absorp­ tion in dogs versus other animal species and humans, data collected in the dog need to be interpreted with consider­ ation of the internal dose for extrapolation to humans if this experimental model is used for predicting human develop­ mental effects. Although atenolol absorption is similar in humans and rodents, a higher vulnerability of human con­ ceptus is likely, due to the greater passage of the drug across human placenta in comparison to rodents. This is a conse­ quence of the very low binding of atenolol to human plasma proteins so that more free drug is available in the circula­ tion. Maternal hypertension, the main indication for atenolol use in humans, can potentiate the adverse effects of atenolol on placental and fetal circulation. In addition, the renal impairment that accompanies some hypertensive complica­ tions of pregnancy in humans can delay atenolol clearance and prolong its elimination. However, experimental testing for developmental toxicity is performed in healthy animals, and the use of experimental hypertension models is not feasible with atenolol because of differences between the pharmacodynamic action of this drug in hypertensive ani­ mals (rats, dogs) versus hypertensive humans. Additional problems in animal/human comparability may arise because of the differences in the effect of atenolol on glucose ho­ meostasis in the human and in the rat, the most frequently used experimental model in developmental toxicity testing.

Acknowledgments The authors are grateful to Drs. William Slikker, Debo­ rah Hansen, John Young, National Center for Toxicological Research, Jefferson, AR, and Dr Hugh Barton, EPA, Re-

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S.A. Tahacova, C.A. Kimmell Reproductive Toxicology 16 (2002) 1-7

search Triangle Park, NC, who have reviewed an earlier version of this paper.

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