Reproductive and developmental toxicity of aluminum: A review

Neurotoxicology and Teratology, Vol. 17, No. 4, pp. 515-521, 1995 Copyright 0 1995 Elsevier Science Ltd Printed in the USA. All rights reserved 0892-0362/95 $9.50 + .@I

Pergamon 0892-0362(95)00002-X

MINI REVIEW

Reproductive and Developmental Toxicity of Aluminum: A Review JOSE

L. DOMINGO

Laboratory of Toxicology and Biochemistry, School of Medicine, “Rovira i Virgili” University, 43201 Reus, Spain Received

9 May 1994; Accepted

21 December

1994

DOMINGO, J. L. Reproductive and developmental toxicity of aluminum: A review. NEUROTOXICOL TERATOL 17(4) 5 15-521, 1995. -It is well known that aluminum is a developmental toxicant when administered parenterally. However, until recently, there was little concern about embryo/fetal consequences of aluminum ingestion because bioavailability was considered low. The importance of the route of exposure and the chemical form of the aluminum compound on the developmental toxicity of this element are now well established. Although no evidence of maternal and embryo/fetal toxicity was observed when high doses of aluminum hydroxide were given orally to pregnant rats and mice during organogenesis, signs of maternal and developmental toxicity were found in mice when aluminum hydroxide was given concurrently with citric or lactic acids. On the other hand, studies in rabbits have shown that aluminum-induced behavioral toxicity is greater in adult and aged animals than in young adults. However, maternal dietary exposure to excess Al during gestation and lactation which did not produce maternal toxicity would be capable of causing permanent neurobehavioral deficits in weanling mice and rats. Adverse effects of parenteral aluminum administration on the mouse male reproductive system have also been reported. The embryo/ fetal toxicity of aluminum administration, the potential reproductive toxicology of aluminum exposure, and the neurodevelopmental effects of aluminum are here reviewed.

Aluminum

Reproductive toxicology

Fetotoxicity

Embryotoxicity

Neurobehavioral effects

Most foods contain small but variable amounts of Al (3 1). It has been reported that 2 to 3 mg of Al daily is probably the lower limit of Al naturally present in western diets (19,31). However, the amount of Al in the diet is small compared to the amount of Al in many antacid products and some buffered analgesics. Some people consume as much as an additional 5 g of Al daily from these compounds (19,31,34). Aluminumcontaining antacids are widely used nonprescription medications which have been administered for many years for the treatment of various gastrointestinal disorders, particularly peptic disorders, because of their acid-neutralizing and local protective properties. It is now well established that small amounts of Al from these antacids are normally absorbed (4SO). Especially outstanding is the intake of large amounts of Al by pregnant women. During pregnancy “dyspepsia” is a common complaint and antacids are used to reduce the dys-

ALUMINUM (Al), the third most common element in the earth’s crust has a significant toxic potential for humans. Although Al toxicity was initially recognized as a neurological and/or skeletal disease which occurred in epidemic proportions in some dialysis populations (1,3,37), it has been demonstrated that concentrations of this element that are toxic to many biochemical processes are also found in a number of neurodegenerative disorders affecting nonuremic and nondialyzed individuals (24,38,39,47). Until recently, there was little concern about toxic consequences of Al ingestion because it was assumed that Al was not orally bioavailable (2,31). However, in recent years, it has been shown that although the gastrointestinal tract normally represents a major barrier to Al absorption, under some circumstances this barrier can be breached (2,4). Consequently, individuals ingesting large amounts of Al compounds do absorb a definite amount of Al (1,2,4).

Requests for reprints should be addressed to Jose L. Domingo, Laboratory of Toxicology and Biochemistry, School of Medicine, San Lorenzo 21, E-43201 Reus, Spain. 515

516

DOMINGO

pectic symptoms. According to the results of a small trial performed to assess whether Al containing antacids were safe during pregnancy, it was suggested that high-dose antacids should not be consumed during gestation (51). However, very little attention has been paid to the effects of Al on possible human embryo/fetal toxicity. The purpose of this article was to review the reproductive and developmental toxicity of Al in mammals. REPRODUCTIVE

TOXICITY

OF ALUMINUM

Although the knowledge of Al toxicity has markedly improved in recent years, information concerning the reproductive toxicity of this element is still very limited. Kamboj and Kar (32) investigated in rats and mice the effects on the testis of 32 water-soluble salts of metals and rare earths, including Al sulfate. A single intratesticular injection of 4.3 mg Al/kg (as Al sulfate) to rats caused focal necrosis of the testes within two days after injection, whereas this dose also destroyed all the spermatozoa within 7 days. A single SC injection of Al sulfate (4.3 mg Al/kg) had no effect on the weight of the testis in rats, but daily administration of this compound significantly reduced the weight of the testis in mice, although no necrotic changes were seen in the testes of these animals. A single SC injection of 4.3 mg Al/kg (as Al sulfate) did not alter the histology of the rat testis. Nevertheless, daily SC administration of the same dose caused shrinkage of the tubules and spermatogenic arrest at the primary spermatocyte or spermatogonial stages without affecting the interstitium (32). In another study, Al chloride was given orally at doses of 6, 17, and 50 mg Al/kg to rats and guinea pigs, and at doses of 3, 9, and 27 mg Al/kg to rabbits, for 20-30 days (short-term exposure). Aluminum chloride was also given orally at 0.0025, 0.25, and 2.5 mg Al/kg to rats for 6 months (chronic exposure). Short-term Al administration caused slight toxicity to the gonads. The gonadotoxic effect of Al was also weak following chronic exposure. Spermatozoa were only affected at the highest dose of Al as shown by changes in their number and in their motility. At that dose, there also was a substantial proliferation of interstitial cells (Leydig cells) (33). In a recent study performed in our laboratory (35), adult male mice were exposed IP to Al nitrate nonahydrate at doses of 50, 100, and 200 mg/kg/day (3.6, 7.2, and 14.4 mg Al/ kg/day) for 4 weeks before mating with untreated females. Reduced body weight was seen in all Al-treated groups of male mice, whereas decreased pregnancy rate was observed in the females mated with males previously exposed to Al nitrate (100 or 200 mg/kg). Necrosis of spermatocytes/spermatids were observed in the testes of mice exposed to 100 and 200 mg/kg of Al nitrate, whereas decreased testicular and epididyma1 weights, significant decreases in testicular and spermatid counts, and significant decreases in epididymal sperm counts were also noted at 200 mg/kg. The “no observable adverse effect level” (NOAEL) was 50 mg/kg/day (3.6 mg Al/kg/ day). Taking into account that most of the Al ingested is excreted into urine in individuals with normal renal function, it was concluded that there would be a remarkable safety margin for any adverse reproductive effect in man due to Al ingestion under the intended conditions of use. MATERNAL

AND DEVELOPMENTAL

TOXICITY

OF ALUMINUM

There is relatively little information regarding the embryotoxic and teratogenic potential of Al. Benett and associates (5) administered Al chloride IP to pregnant rats at doses of 75, 100, and 200 mg/kg (15, 20, and 40 mg Al/kg) on either

gestation days (CD) 9-13 or 14-18. A high incidence of maternal death occurred following treatment with 200 mg/kg of Al chloride, while maternal weight gain during the entire gestational period was less in treated animals, compared to controls. The offspring of dams treated with 100 mg/kg of Al chloride on GDs 14-18 showed significant growth retardation as well as fetal abnormalities (e.g., wavy and missing ribs, abnormal digits). In addition, the incidence of fetal deaths and resorptions was significantly increased in the Al-treated groups (5). In another study, Al chloride was fed to rats as 0.1% in diet (1000 ppm) throughout gestation; no embryotoxicity, teratology, or growth retardation was observed (36). However, 0.1 ml of Al chloride hexahydrate 50 mM (4.2 mg Al/kg), administered IV to mice on day 8 of pregnancy caused an increased frequency of fetal internal hemorrhages and interfered with fetal skeletal ossification (52). Also, in utero exposure of mice to Al chloride at levels which did not cause maternal toxicity (20, 30, or 40 mg Al/ kg/day IP, and 40 or 60 mg Al/kg/day PO) resulted in decreased fetal weight and increased incidence of fetal resorptions. Total fetal Al content was significantly increased compared to maternal Al content following both IP and PO routes of maternal exposure, although changes were greater with IP dosing (13). No maternal mortality or reduction in food intake was observed in mouse dams following SC exposure to Al lactate at 10, 20, or 40 mg Al/kg on GDs 3, 5, 7, 9, 12, 13, and 15. Although fetal crown-rump lengths were significantly lower in the 20 mg Al/kg group, no major malformations were noted in any fetuses. Fetal and placental weight showed no indication of treatment effects (25). In contrast to those studies, oral administration of Al nitrate nonahydrate (13, 26, and 62 mg Al/kg/day) to pregnant rats on GDs 6-14 resulted in decreased fetal body weight and increased incidence and types of external, visceral, and skeletal abnormalities in all the Al-treated groups. It was concluded that although embryolethality was not induced in rats by oral Al nitrate administration, teratogenic effects might result at extraordinarily high doses (45). The importance of the route of administration in the developmental toxicity of Al has been clearly shown by the above studies, whereas the solubility of the Al compounds may also play an essential role in the maternal and embryo/fetal toxic effects of Al. Thus, it has been shown that Al hydroxide is neither embryotoxic nor teratogenic when given orally at extraordinarily high doses to mice (23, 46, and 92 mg Al/kg/ day) (16) or rats (66.5, 133, and 266 mg Al/kg/day) (29) during organogenesis. In addition, the maternal-placental Al concentrations were not significantly different between control and Al-treated rats. Aluminum could not be detected in the whole fetuses in any of the groups (29). These results indicated that Al from Al hydroxide would be very poorly absorbed and would not reach the fetus at levels which might create a developmental hazard. Although environmental and/or therapeutic exposure to Al-containing compounds (including Al hydroxide, probably the Al compound most frequently used therapeutically in large quantities as an antacid) may be high, the low solubility of Al at the pH of the intestine renders most orally ingested Al-containing compounds unabsorbable (44). However, in recent years several chemicals present in the diet have been found to inhibit Al precipitation by forming Al complexes which are soluble at the pH of the intestine (44). It has been demonstrated that ingestion of Al hydroxide concurrently

REPRODUCTIVE

AND

DEVELOPMENTAL

517

TOXICITY

of potassium Al sulfate added to the stock diet compared with that of the controls. Observations were made covering four generations and no other influences of Al addition were noted. Aluminum nitrate nonahydrate was tested for its effects on reproduction, gestation, and lactation in rats at doses of 13, 26, and 52 mg Al/kg/day. Male rats were orally treated for 60 days prior to mating with virgin female rats, which were treated for 14 days prior to mating. Treatment continued throughout mating, gestation, parturition, and weaning of the litters. Although no adverse effects on fertility or general reproductive parameters were noted, the survival ratios were higher for the control group. A dose-dependent delay in the growth of the living young could also be observed in all Altreated groups (14). The same doses were administered PO to pregnant rats from the 14th day of gestation through 21 days of lactation. Administration of Al nitrate (52 mg Al/kg/day) did not produce overt fetotoxic effects, but the growth of the offspring was significantly delayed (body weight, body length, tail length) from birth throughout lactation (15). On the other hand, when Al as Al chloride was administered to weanling rabbits at 2.52 mg Al/kg/day for 28 days by means of a SC implanted osmotic pump, no effect on weight gain or hematocrit, or obvious changes in behavior were noted (23). All tissues, with the exception of brain grey matter, showed elevated Al concentrations. The bone showed the greatest accumulation. The Al content of the testes of the treated rabbits was 16 times that of the controls (23). In another study, female rats received IP injections of Al chloride (10 mg Al/kg/day) during the first 12 days after parturition. This treatment led to a reduction in food intake associated with a reduction in body weight. Pups of the treated dams showed a growth retardation after postnatal day 7. One day after treatment, the female rats exposed to Al had a considerably higher level of Al in milk that controls. However, the Al concentrations in plasma, liver, spleen, and kidneys of

with either fruit juices or with some common dietary constituents (citrate, ascorbate, lactate, etc.) causes a marked increase in the gastrointestinal absorption of Al in healthy subjects (18,44,48). The concurrent administration of citric acid (62 mg/kg/ day) and Al hydroxide (133 mg Al/kg/day) during organogenesis did not modify the lack of Al embryotoxicity and teratogenicity in rats. However, fetal body weight was reduced and the incidence of skeletal variations (delayed ossification of occipital and sternebrae) was significantly increased in fetuses from these animals. Some signs of maternal toxicity were also observed (30). Although not statistically significant, the number of resorptions and dead fetuses as well as the incidence of skeletal variations were also higher when Al hydroxide (57 mg Al/kg/day) was administered PO to mice on Gds 6-15 concurrently with lactic acid (570 mg/kg/day), than when Al hydroxide was given alone during the same period (11). In contrast, no signs of maternal or developmental toxicity were observed in mice when Al hydroxide was given alone (104 mg Al/kg/day) or concurrently with high doses of ascorbic acid (85 mg/kg/day) on CDs 6-15 (12). A summary of the above studies is shown in Table 1. Although in those studies, Al hydroxide was given at doses higher than those usually consumed by pregnant women, certain dietary constituents including fruits and beverages, may enhance the gastrointestinal absorption of Al from Al hydroxide (17,20,21,44). Thus, to prevent possible maternal and developmental hazards, it would seem advisable to avoid the consumption of high doses of Al-containing compounds during pregnancy. PERINATAL

AND

POSTNATAL

EFFECTS

In 1928, Myers and Mull (43) reported initial growth in rats that received 2 mg/day

OF

ALUMINUM

a slightly greater of Al in the form

TABLE MATERNAI

AND

EMBRYO/FETAL

TOXICITY

Ot

1

ALUMINUM

COMPOUNDS:

A SUMMARY

OF

VARIOUS

STUDIES

DO% Aluminum

Compound

(mg Al/kg/day)

Species

Roure

23, 46, 92 66, 132, 266 1.5, 20,40

Mice Rats Rats

PO PO IP

No adverse effects No adverse effects Maternal deaths (at 40 mg Al/kg/day). Reduced body weight gain

Al chloride

20, 30, 40

Mice

IP

No adverse effects

Al lactate

10, 20, 40

Mice

SC

No adverse effects

13, 26, 52

Rats

PO

Al hydroxide + citric acid (62 m&kg/day)

133

Mice

PO

Reduced body weight gain and food consumption Reduced body weight gain

Al hydroxide + lactic acid (570 mg/kg/day)

57

Mice

PO

Reduced

104

Mice

PO

No adverse

Al hydroxide Al hydroxide Al chloride

Al nitrate

nonahydrate

Al hydroxide + ascorbic acid (85 mg/kg/day)

Maternal

Toxicity

body weight gain

effects

Embryo/Feral

Toriaty

No adverse effects No adverse effects Embryolethality, growth retardation, fetal abnormalities, (at 20 and 40 mg Al/kg/day) Decreased fetal weight, increased number of resorptions Decreased fetal crown-rump lengths (at 20 mg Al/kg/ day) Fetotoxicity including teratogenic effects Reduced fetal body weight, increase in the incidence of skeletal variations Reduced fetal body weight, increase in the incidence of skeletal variations No adverse effects

Reference 16 29 5

13

25

45 30

11

12

518

DOMINGO

pups of treated dams were not different from those of controls. This fact was attributed to two possible causes: (a) a low bioavailability of Al, and (b) a high systemic clearance of Al (41). In recent years, several investigations on the toxicity of Al exposure in rabbits during gestation and lactation have been carried out in Yokel’s laboratory (54-59). To assess Al toxicity to the Al-exposed lactating organism and her suckling offspring, lactating rabbits received 20 SC Al lactate injections (0.68, 2.7, 10.8, or 21.6 mg Al/kg/injection) between days 4 and 29 postpartum. Offspring were weaned day 30 postpartum. Toxic effects were observed in does including weight loss, decreased milk production, a treatment-dependent elevation of tissue Al concentrations, postural changes, and lethality. Little effects were observed in the suckling offspring, which was probably due to the limited distribution of Al into milk and poor gastrointestinal Al absorption (55). This observation was corroborated in a subsequent study, which showed that Al distributes into milk but only to a limited extent. This fact, together with the observation that Al is poorly absorbed following oral ingestion, showed that the risk of Al toxicity in suckling offspring of Al exposed nursing females would be rather low (57). SC Al lactate injection (0.68, 2.7, or 10.8 mg Al/kg/injection) to pregnant rabbits between GDs 2 and 27 resulted in an Al dose-dependent decrease in milk production by the doe and milk consumption by the offspring which had been exposed to Al in utero (56). Specifically, offspring which suckled non-Altreated rabbit does but were born of does receiving 10.8 mg Al during pregnancy averaged 81% of the milk consumption of offspring not exposed to Al during gestation (56). On the other hand, following prolonged SC Al exposure, the adult rabbit demonstrated greater behavioral deficits and accumulation of Al in tissues than did rabbits exposed to Al at any earlier developmental stage. In contrast, the rabbit exposed to Al during the second postnatal month demonstrated the greatest Al-induced toxicity to the skeletal system (58). According to the above results, it seems that high amounts of Al compounds should not be ingested during gestation, including the late period. However, the results of Al exposure

during lactation suggest that there is little risk of Al toxicity in suckling offspring of nursing females exposed to Al. NEURODEVELOPMENTAL

EFFECTS

OF ALUMINUM

Increased horizontal movement in the open field was observed in rats (60 days old) given Al chloride hexahydrate by intubation in varying doses (o-184.5 mg Al/kg bw/day) for 21-28 days (9), whereas there was no evidence for a deleterious effect of Al ingestion on cognitive behavior in rats (22 days old) subjected as weanlings to 60 days of oral administration of Al hydroxide (49). The results of that study suggested that age is an important factor in Al toxicity studies, which is in agreement with previous reports showing that developing animals are more resistant to the neurotoxic effects of Al (46,53). A similar conclusion was also obtained by Yokel (59), who after 20 SC injections of 10.8 mg Al/kg (as Al !actate) to rabbits found that Al-induced behavioral toxicity was greater in adult and aged animals than in young rabbits, whereas aged rabbits were more susceptible to Al induced mortality than adult or young rabbits. Several reports indicated that maternal dietary exposure to Al chloride (160 and 200 mg Al/kg/day) during gestation, or gestation and lactation, could result in developmental alterations in young rats. The surviving pups of rats treated with Al during gestation showed a delay in their neuromotor development, as well as a delay in weight gain during the first postnatal week (6). In subsequent studies by the same group, an increase in postnatal death rate, growth retardation, and alterations in neuromotor maturation (righting reflex, grasping reflex, negative geotaxis, locomotor coordination) of pups from female rats exposed to dietary Al chloride or lactate during pregnancy were also found (7,8,40). Table 2 summarizes the neurodevelopmental effects reported in some of those studies. The effects of gastric intubation of Al lactate (100 and 200 mg Al/kg/day) on brain choline acetyltransferase activity (CAT) and on learning abilities were examined in rats treated from PNDs 5 to 14. At PNDs 50 and 100, the treated rats did not show alterations in their learning abilities in the two tests

TABLE 2 NEURODEVELOPMENTAL Aluminum Compound

TOXICITY

Dose

OF ALUMINUM

COMPOUNDS:

Species

Route

Al lactate

500, 1000 ppm

Mice

Diet

Al lactate Al lactate

0.5 and 1 mg Al/g diet 1 mg Al/g diet

Mice Mice

Diet Diet

Al lactate

1 mg Al/g diet

Mice

Diet

Al lactate or AI chloride

100-400 mg Al/kg/day

Rats

PO

A SUMMARY

Neurodevelopmental

OF VARIOUS

STUDIES

Effects

Hindlimb paralysis, seizures and death. Altered performance on a neurobehavioral test battery (foot splay, forelimb and hindlimb grip strengths, thermal sensitivity) Reduced motor activity Reduced forelimb grasp strength, impaired negative geotaxis, decreased temperature sensitivity Decreased motor activity, decreased grip strength, decreased startle responsiveness Delay in neuromotor maturation of pups, (righting reflex, grasping reflex, negative geotaxis, locomotor coordination), increase in postnatal death rate, growth retardation

Reference 25

26 21

28 6, 7, 8, 40

REPRODUCTIVE

AND DEVELOPMENTAL

519

TOXICITY

used. These tests were based on different motivations (avoidance of an aversive light vs. alimentary motivation) and different ways of achievement (pressing on a lever VS. running in a maze). At 200 mg Al/kg/day CAT activity was reduced. A low reduction in the general activity, particularly in the radial maze test, was also observed (10). Recent studies have also shown that high maternal Al lactate intake (400 mg Al/kg/day) during gestation could result in altered essential trace element metabolism of fetuses from those dams (42). Although the concentrations of Al, P, Cu, and Zn did not significantly differ betweeen Al-treated and control groups, the fetuses from Al-treated dams had significantly higher levels of Ca and lower levels of Mg than those of the control group. Aluminum lactate administered orally in a purified diet (500 and 1000 ppm Al) to pregnant mice produced striking signs of neurotoxicity in the lactating dam including hindlimb paralysis, seizures, and death. Offspring of these mice were growth retarded and showed some minimal delay in development, although the direct contribution of Al could not be identified due to maternal toxicity (25). In a subsequent study by the same investigators, Al as Al lactate in a purified diet (0.025, 0.50, or 1.0 mg Al/g diet) was fed to mice from conception through weaning. Although no maternal or reproductive toxicity was detected, mouse weanlings exposed to Al via maternal diet had altered performance on some items of a neurobehavioral test battery (foot splay, forelimb and hindlimb grip strengths, and thermal sensitivity). In contrast, no neurobehavioral deficits were detectable in dams (22). These results showed that maternal dietary exposure to excess Al during gestation and lactation, which do not produce maternal toxicity, could result in persistent neurobehavioral deficits in weanling mice. The above findings were corroborated in subsequent studies (26,27,28). When Al lactate in a purified diet was fed to adult mice at 0.50 mg Al/g diet and 1 mg Al/g diet over a 6-week period, no neurotoxic signs were recorded in any group, but a dose dependent increase in localized fur loss was seen. Also, overall activity level was 20% lower in mice fed 1 mg Al/g diet than in controls (0.025 mg Al/g diet), with vertical movement more affected than horizontal movement (26). Golub and associates (27) reported that maternal dietary Al (as lactate) levels of about 250 mg/kg/day in mice produced neurodeveiopmental effects at weaning as reflected in a ‘I-item neurobehavioral test battery known to be sensitive to neurotoxicants in adults. On the other hand, although there were no detrimental effects on weight gain or overt signs of neurotoxicity in mice, excess Al produced a slight acceleration of growth, decreased motor activity, decreased grip strength, and

decreased startle responsiveness at the end of a 90-day feeding period of an excess of Al and a Mn deficient diet (28). The neurobehavioral syndrome seen in adult mice in that study (28) differed markedly from that seen in weanling mice after developmental exposure to Al via the maternal diet (22, 27). Whereas changes in spontaneous activity and startle responsiveness were not detected in the developmental syndrome, decreased activity, decreased startle responsiveness and decreased hindlimbs strength were reported in adults. Elevated brain Al levels were also observed in adults, whereas brain Al concentrations were not elevated in weanlings. These findings would suggest that different mechanisms may be involved in neurobehavioral effects of developmental versus adult Al exposures (28). These results demonstrate that neurodevelopmental effects of high Al exposure can occur with either gestation or lactation exposure. Taking into account that high Al concentrations in formula, diet, parenteral fluids, antacids, and soil are all significant sources of exposure for infants and children (27), the potential health effects of developmental Al exposure should be considered. CONCLUSIONS It

is now well established that Al is a neurotoxicant

and a developmental toxicant when given by parenteral administration. Aluminum, as Al chloride, was found to be embryotoxic and teratogenic when given IP to rats and mice. Although normally very little Al is absorbed from the gastrointestinal tract, when large oral loads of Al are ingested, some of this Al is absorbed. Aluminum absorption from the gastrointestinal tract has been shown to be dependent on the chemical form of the ingested Al. Moreover, in recent years it has been demonstrated that concurrent ingestion of Al compounds and a number of frequent dietary constituents such as citrate, ascorbate, lactate, etc. might cause a significant increase in the gastrointestinal absorption of Al. Thus, although no evidence of embryo/fetal toxicity was observed when high doses of Al hydroxide were given PO to pregnant rats and mice, some signs of maternal toxicity and fetotoxicity were found when Al hydroxide was given to mice concurrently with citric or lactic acids, or when Al was administered orally as Al nitrate, Al lactate or Al chloride to rats and mice. Neurobehavioral effects in offspring of rats, rabbits and mice following Al lactate or Al chloride administration have also been reported. According to a number of studies here reviewed and taking into account that the gastrointestinal absorption of Al may be significantly enhanced by certain dietary constituents, it would seem advisable to avoid the consumption of high doses of Al-containing compounds during gestation and lactation.

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ure. Am. .I. Clin. Nutr. 33:1509-1516; 1980. Alfrey, A. C. Gastrointestinal absorption of aluminum. Clin. Nephrol. 24:S84-S87; 1985. Alfrey, A. C. Dialysis encephalopathy. Kidney Int. 29:853-857; 1986. Alfrey, A. C. Aluminum metabolism. Kidney Int. 29:S8-Sll; 1986. Benett, R. W.; Persaud, T. V. N.; Moore, K. L. Experimental studies on the effects of aluminum on pregnancy and fetal development. Anat. Anz. Bd. 138:365-378; 1975. Bernuzzi, V.; Desor, D.; Lehr, P. R. Effects of prenatal aluminum exposure on neuromotor maturation in the rat. Neurobehav. Toxicol. Teratol. 8:115-l 19; 1986.

7. Bernuzzi, V.; Desor, D.; Lehr, P. R. Developmental alterations in offspring of female rats orally intoxicated by aluminum chloride or lactate during gestation. Teratology 40:21-27; 1989. 8. Bernuzzi, V.; Desor, D.; Lehr, P. R. Effects of postnatal aluminum lactate exposure on neuromotor maturation in the rat. Bull.‘ Environ. Contam. Toxicol. 42:451-455; 1989. 9. Bowdler, N. C.; Beasley, D. S.; Fritze, E. C.; Goulette, A._M.; Hatton, J. D.; Hession, J.; Ostman, D. L.; Rugg, D. J.; Schmittdiel, C. J. Behavioral effects of aluminum ingestion on animal and human subjects. Pharmacol. Biochem. Behav. 10:505-512; 1979. 10. Cherroret, G.; Bernuzzi, V.; Desor, D.; Hutin, M. F.; Burnel, D.; Lehr, P. R. Effects of postnatal aluminum exposure on choline

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