aluminum, perinatal toxicity
P Nayak. Perinatal Toxicity Of Aluminum. The Internet Journal of Toxicology. 2005 Volume 3 Number 1.
In the modern life, the exposure to aluminum is inevitable. Though the toxicity of aluminum was noticed long back, it was not well established. Conclusive evidences about aluminum induced pathologies or pathological consequences linked with aluminum exposure are limited. However, extensive researches on every aspect of aluminum toxicity for the last 35 years proved that the metal should not be taken as safe. In spite of persistent arguments, it is well accepted that aluminum is a potent neurotoxicant. The risk is more at the perinatal age, because of more vulnerability of neuronal tissues. Thus, in this review, the available reports on perinatal aluminum toxicity are accumulated and an imperative aspect of aluminum toxicity is discussed as — why aluminum should be regarded as significant toxicant at perinatal age group, how perinates are exposed to aluminum, distribution of aluminum between the pregnant or lactating mother and prenatal or postnatal age groups, impairment of overall growth or development, alteration in other important trace elements and finally the impact on the neurobehavioral development with special emphasis.
Severity of aluminum as perinatal toxicant
Potentially noxious substances may act as fetal teratogens at levels far lower than those required producing detectable effects in adults; further, behavioural teratogenicity may occur at levels lower than those which produce morphological teratogenesis. Aluminum is a potential neurotoxin in adults and it is well accepted that it is capable of inducing neurobehavioral deficit even without altering the morphology. Due to lower bioavailability, the reproductive toxicity of aluminum is rarely assessed ( 1 ). Only in 1990s, aluminum is paid attention on its reproductive toxicity and it took nearly end of the last century to concern about embryo/fetal consequences of aluminum ingestion. Since pregnant women may be exposed to untoward levels of aluminum compounds under certain conditions ( 2 ), therefore aluminum toxicity may be of particular concern to the developing fetus. Very few studies on humans are available in this regard. However, a number of studies on animal model are presenting conflicting observations (3 ).
At the perinatal age, aluminum is highly neurotoxic ( 4 ) and inhibits prenatal and postnatal brain development ( 5 ). In addition, maternal dietary exposure to excess aluminum during gestation and lactation which did not produce maternal toxicity would be capable of causing permanent neurobehavioral deficits in weanling mice and rats ( 6 ). Over and above of these facts, the route and chemical form of aluminum exposure are two important determinants of the impacts of aluminum at this crucial age of neurodevelopment. It is well known that aluminum is a developmental toxicant specifically when administered parenterally. 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 ( 6 ). So the future of life is being worsened even before birth, adding up the impact throughout life. However, the impacts are dependent upon the time of exposure, duration of exposure, route of exposure as well as form of exposure. As a result, the number of children in clinical populations that are at risk of aluminum toxicity is not known and needs to be determined.
Inevitable exposure to aluminum
In the earth's crust, the most abundant metallic element is aluminum. Despite its ubiquity, evolution has not conferred essentiality or utility as far as known in biological systems ( 7 ). Aluminum was being considered as nontoxic, nonabsorbable and harmless element for long; as a result it has been exempted from testing for safety by the Food and Drug Administration (FDA) under a convoluted logic wherein it is classified as GRAS (Generally Regarded As Safe). It has never been tested by the FDA on its safety and there are no restrictions whatever on the amount or use of aluminum. Therefore, the light weight, shiny metal is being used extensively in our contemporary life. Aluminum has only recently been considered a problem mineral. Though it is not very toxic in normal levels, neither has it been found to be essential (http://www.bodychem.co.uk/ body_aliminum.html).
Because aluminum permeates our air, water, and soil, environmental exposure to aluminum in the present day life is inevitable ( 7 ). Small amounts of aluminum are present in our foods, besides, food additives, foils and cooking utensils of aluminum-make are adding further aluminum to it. The concentration of aluminum in natural waters can vary significantly depending on various physicochemical and mineralogical factors. Aluminum levels in drinking-water vary according to the levels found in the source water and whether aluminum is used during water treatment ( 8 ). Aluminum salts are widely used in water treatment as coagulants to reduce organic matter, color, turbidity, and microorganism levels. Such use may lead to increased concentrations of aluminum in finished water ( 9 ). Iatrogenic exposure to aluminum is also adding to the increasing body aluminum burden ( 7 ). Moreover, children may ingest aluminum from dirt from unwashed hands or when playing in contaminated soils, vitamin/mineral supplements, and from consumer products not normally ingested by adults (e.g., toothpaste) ( 6 , 10). Dust from talcum powder, baby powder, cement, asphalt mixes, tobacco smoke and ashes contain aluminosilicates ( 11 ), thus may be of high concern of passive exposure to aluminum (Table I).
Thus, exposure to aluminum is obligatory in the modern life. The irony is that the relative exposure load (in comparison to normal) is higher in the early life when the susceptibility is high ( 12 ).
Tissue level of aluminum
In the perinatal period, mother is the prime source of aluminum exposure. Work in animal models (rats, mice, and rabbits) demonstrates that aluminum is distributed transplacentally and is present in milk ( 6 ).
Upon oral exposure to aluminum lactate during the day 0-19 of gestation causes significantly higher levels of aluminum in plasma, liver, spleen and kidneys of pregnant rats when compared to non-pregnant female rats ( 13). Cutaneous exposure of aluminum chloride throughout the gestation in mice led to an increase of aluminum in maternal serum, organs and amniotic fluid ( 14 ). Placental levels were increased in some studies as well, and were greater than corresponding fetal levels ( 15 ). However, Golub
Aluminum levels were found high in fetal serum and organs after cutaneous exposure to pregnant mothers ( 14 ). However, Muller
Through studies with exclusively breastfed infants, Okolo
Weight gain or growth
Oral aluminum administration during pregnancy, at doses that also lead to reduced maternal weight gain, produces a syndrome including growth retardation, delayed ossification, and malformations in perinates ( 6 ). Gonda and Lehotzky ( 21 ) have reported that subcutaneous injection of aluminum on gestational days 7-15 does not have any effect on either the litter size or the body weight of pups in rats. On the other hand, Misawa and Shigeta ( 22 ) showed that the body weight of treated offspring can differ from that of control rats even if the mothers were treated with single dose of aluminum chloride. However, gestational exposure of aluminum found to significantly lower the postnatal body weight gain in rats ( 21). Prenatal exposure to intraperitoneal injection with aluminum sulfate during the days 10-13 exhibited decreased growth in treated pups in CBA mice ( 23 ). Similarly, exposure to aluminum lactate to pregnant Swiss mice ( 24) and aluminum hydroxide to pregnant Sprague-Dawley rats ( 25 ) during the gestational days 6-15 was found to reduce the fetal body weight significantly. In the contrary, Muller
Alteration in trace elements
High maternal intake of aluminum can result in altered essential trace element metabolism in the offspring ( 31 ). Belles
Perinatal brain development is being inhibited by aluminum exposure ( 5 ). Experimental teratological studies revealed that over-intake of aluminum could lead obvious teratogenic and toxic effects on fetal development in mice. Effects of oral administration of different doses of aluminum during pregnancy on intra uterine fetal development in mice suggests that excessive ingestion of aluminum may be one of the risk factors contributing to congenital neural tube defects ( 29). Teratogenicity of aluminum was clearly identified after per os or iv administration ( 14). Rankin
In the postnatal period, reduced pup weight gain and effects on neuromotor development have been described as a result of developmental exposures ( 6 ). Learning and memory changes were not observed after aluminum treatment of neonatal and immature rabbits ( 39 ). Whereas, the study of Golub
From the detailed study with excitatory postsynaptic potential, long term potentiation, long term depression and population spike in the rat dentate gyrus, Wang
While experimenting with SPRD rat pups treated prenatlly with aluminum lactate to find out whether observational conditioning (social learning) could reverse the behavioral teratogenicity following aluminum treatment, Gonda
The significance of these findings for human health requires better understanding of the amount and bioavailability of aluminum in food, drinking water, and medications as well as sources unique to infants and children such as breast milk, soil ingestion, and medications used specifically by pregnant women and children ( 6 ). In preterm infants, Bishops
The so-called ‘non-toxic' metal aluminum is already well accepted as neurotoxin, however, the argument about the role of aluminum in different neuropathology is continued without a firm conclusion of whether the metal is itself a causative agent or just being accumulated to worsen the pathological consequences. Whatever may be the situation, certain neuropathologies are well associated with the accumulation of aluminum. Again, number of factors, including exposure level, form of aluminum, route of exposure, accompanying chemicals, etc. are determining the accumulation level of metal and in turn the pathological consequences (Figure I). The dominance of higher susceptibility to aluminum toxicity, especially at perinatal age, over other determinants, is highlighted by the findings cited here. Elevated aluminum exposure level at this vulnerable age might produce a lifelong toxicological consequence.