Running title: Human milk, environmental toxins and pollution of our infants

	ABSTRACT
	INTRODUCTION
	MATERIALAS AND METHODS
	RESULTS
	DISCUSSION
	REFERENCES

	ABSTRACT

	INTRODUCTION

Despite the significant decline (up to 90%) of most carcinogenic and teratogenic en¬vironmental toxins, like polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), in habitants of developed countries during the past two decades [1], primarily as the result of their prohibi¬tion in in¬dustrial manufacturing, all those organochlorine compounds (OC) are still present in our biosphere. Their persistence and long half-life is because of their chemical stabil¬ity and absence of metabolizing enzymes that can catalyze reactions leading to breakdown or conjugation in mammalian organisms. They still add to our food-chain, are transmitted from mother to foetus, and mother’s milk due to its high lipid content as compared with serum and extra-cellular fluid at all is an exceptional ac¬cumula¬tion pathway. A woman elimi¬nates up to 10 % of her body pol¬lution with PCBs during lactation [2], and these OC are then ingested by and stored in her offspring. So, an ex¬clusively breast-fed infant accumulates 3 to 5 % of his life-long body burden with these OC during the first 6 months of his life, which could be demonstrated in serum as well as in fat tissue [3,4]. Therefore, breast-feeding has been held re¬sponsible for elevated con¬cen¬trations of these OC as well as for different harmful effects in chil¬dren later in life by many studies, as growth re¬tardation in girls (but not in boys, de¬pendent on DDE, but not PCB concentrations) [5], atopic manifestations, including asthma [6], and neu¬ro¬logical impairment [4,7,8]. Indeed, great deal of attention has been paid to the vul¬nerabil¬ity of the embryo and the foetus and the breast-fed infant to OC and other possibly harmful agents. Because the embryo and the child are growing and their tissues and organs are differentiating, deleterious effects may oc¬cur at lower expo¬sures to some chemicals, drugs, and physical agents and produce more severe ef¬fects than those seen in adults [9]. On the other hand, it is important to note that chil¬dren and adoles¬cents have better recuperative capacities than adults for many toxic agents, and, similarly, appropriate drug dosages may be lower or higher on a mg / kg or surface area basis in children than in adults to attain effective thera¬peutic blood levels or to avoid toxicity [10]. In addition, effects produced by OC are not always deleterious or irreversible. This means that for some exposures, the young can re¬cover from some effects more rapidly and completely than adults [9]. This explains, why, in contrast to the studies cited above, other investigators could demonstrate, for example, benefi¬cial effects of breast-feeding on neurodevelopment [11], or even heavier and more fre¬quent cases of gastroenteritis or otitis media in bottle-fed than in breast-fed infants [12]. This reveals the fundamental complexity of the appraisal whether OC and other envi¬ronmental toxicants may have detrimental effects to our children, and whether breast-feeding, as a proven source of a high body pollution with OC should be generally recommended for all children throughout the world, thereby having additionally in mind the availability of infant formulas in dif¬ferent countries throughout the world.
Nevertheless, the mechanisms of toxicity and harmful effects later in life following exposure to environmental pollutants prenatally or during infancy are widely not com¬pletely understood. Growth retardation may be a general indicator of toxicity and suggests that specific organ systems could be affected. Although DDE is a hormon¬ally active agent, a plausible biological mechanism for an effect on growth is not readily apparent [13]. In case of wheezing and asthma, two pathways – immunologi¬cal and/or hormonal – could be involved in the relationship between pollution with OC and these disorders. The immunologic effects of OC exposure have been suggested by many studies, although its mechanism remains unclear until now [14]. Possible explanations are changes in immune cells, immunoglobulins, and cytokines. OC in¬terfere with hormonal receptors and mimic estrogen activity, which might modulate immunologic responses (15). Nevertheless, sexual hormones have been related to asthma by routes other than immunomodulation by unknown mechanisms [16]. The effect of OC on brain growth and possible later neurodevelopmental impairment is still an important issue of concern [17]. Because multiple variables play important roles in the development of the human brain, it is difficult, if not impossible, to eluci¬date the interactions and relations between all variables. Neurotoxic exposures that affect subtle brain functioning manifest themselves only, when this functioning is needed, and, therefore, might be never detected [18]. The effects of OC on health are most often subtle, because they usually occur at concentrations that are not ex¬pected to result in acute toxic symptoms, but these probable small effects at an indi¬vidual level might have a large impact at the population level [19].
Recently, significantly elevated HCB and DDE concentrations in breast-fed infants could be demonstrated at 1 year of age [20], but, unfortunately, the lactational uptake of harmful OC has not been investigated during the first six months of life until now, the time span, most mothers breast-fed their infants and finish breast-feeding. It was the aim of the pre¬sent study to determine the lactational uptake of PCBs, HCB, and DDE (1,1-di¬chloro-2,2-bis(p-chlorophenyl)-ethyl¬ene), the main metabolite of DDT in mam¬mals, in breast-fed vs. bottle-fed human infants at the age of 6 weeks and 6 months, respec¬tively. As early as at the age of six weeks of life, breast-fed infants had accu¬mulated about 90% more OC than their bottle-fed peers, as could be dem¬onstrated in a pre¬liminary evaluation of our study’s results obtained at that time [21]. Here, we now present the results of our study at the age of six months of life, and the further course of up¬take of these harmful OC in the same study population of infants in comparison with the results previously published [21].

	MATERIALS AND METHODS

The study was approved by the Committee on Ethics in Biomedical Research of the Heinrich Heine University, Düsseldorf, Germany. With the written informed consent of the parents, blood samples were taken from each 10 breast-fed and bottle-fed in¬fants, respectively, at the age of six months of life (for further information about blood sam¬pling, especially even at six weeks of age, see ref. 21). Although it was planned to collect blood samples from each 25 breast-fed and bottle-fed infants at four fixed times (6 weeks, 3 months, 6 months, and 12 months), the complete amount of blood samples were only available from each 10 breast-fed and bottle-fed infants at six weeks and six months of age, respectively, due to refusing blood sampling by many parents at 3 months and 6 months of age, whereas the collection of the blood sam¬ples of the 10 infants remaining in the study population at 12 months of age is nearly completed, and serum will be analyzed as soon as the collection has been finished. Three higher chlorinated PCB con¬geners (IUPAC nos. 138, 153, and 180), HCB, and DDE were determined with capillary gas chromatography, as described elsewhere [21]. In addition, reliability was tested with gas chromatography-mass spec¬trometry. The laboratory successfully participated in nationwide interlaboratory quality assess¬ments for OC determinations. Possible correlations of OC with personal data (table) were tested with a standard multivariate re¬gres¬sion model. Differences be¬tween study groups were tested on mean differences with Wilcoxon´s test for inde¬pendent sam¬ples.

RESULTS

There were no differences between the study groups of breast-fed and bottle-fed in¬fants with regard to their personal characteristics (table). All infants were exclusively breast-fed from birth until the time of investigation (six months). They did not become any additional food, with exception of tea in some cases. The serum concentrations of the three PCB congeners 138, 153, and 180 as well as ΣPCB (sum of the three PCB congeners), HCB, and DDE were significantly (p<0.0001) higher in breast-fed than in bottle-fed infants at six weeks of age (table) as well as at six months of age (figure).

DISCUSSIONS

The results of the present study clearly demonstrate a significant in¬creased body pollution of our infants with different harmful OC during lactational pe¬riod. These re¬sults are remarkably as early as at six weeks of age with a further sig¬nificant increase until the age of six months (figure). Thereby, the OC concen¬trations of the bottle-fed infants correspond to the latest reference values of these sub¬stances in full-term neonates even at the age of six months [1], which may be attributed to the estimated daily OC intake of a bottle-fed infant of only 0.1 μg/kg body weight [2]. On the other hand, the OC concentrations of the breast-fed infants are about 90% higher as early as at the age of six weeks when compared with their bottle-fed peers, and over and above nearly doubled further at the age of six months (table; figure). Any possi¬ble confounding fac¬tors, as gestational age , age of the mothers, and smok¬ing be¬haviour of the parents could be excluded, since there were no differ¬ences be¬tween the study groups of breast- and bottle-fed infants with regard to these con¬founders (table) [1,21]. Therefore, an infant, who is breast-fed for six months, today has a body pollu¬tion with OC that is as high as that measured in neonates born in Germany in the mid-1980s [1]. Long-term breast-feeding leads to a dose- and time-dependent in¬crease of PCBs, HCB, and DDE in children’s serum during the first 6 months of life. These disturbing findings make clear that the reduction of OC in our environ¬ment, e.g., a 70 % to 90 % decline in the prenatal uptake of these sub¬stances from the mid-1980s to the begin¬ning of the 21st century [1], as a promising result of the prohi¬bition and restriction of the use of OC in industrialised countries, will be obvi¬ously destroyed or even minimized by breast-feeding, in fact in a time-dependent manner. It, there¬fore, should be recon¬sidered again, if breast-feeding, despite all its advantages and all considerations, which were outlined in the Introduction of this paper, may pos¬sibly endure suf¬fering any so far unknown health risks to our children. Although all Na¬tional and In¬terna¬tional Committees engaged in the consideration of possible risks of breast-feeding due to OC have favoured breast-feeding for many years, future dis¬cussion about the recommendations of breast-feeding should incorporate the results of the present study to definitely answer the question, if the present recom¬menda¬tions for breast-feeding can still be maintained. To do this in a scientifically accept¬able manner, fur¬ther studies with larger study populations are urgently required to make sure, that breast-feeding can be unreservedly be recommended for all children in all countries of our world, i.e., for example, dependent on the availability of infant formulas in Third World countries.
This is of special importance, although – as outlined in the Introduction section – the mechanisms by which the pollution with different environmental pollutants prenatally or during infancy will produce harmful effects later in life, e.g., growth retardation, wheezing and asthma, and neurological impairment, are widely not understood to¬day, because most studies, which were able to demonstrate harmful effects later in life, were performed in the 1960th to 1980th of the last century, the time span, when the body pollution was much higher as at the beginning of the 21st century, but corre¬sponds to those OC-concentrations, which we were able to find in breast-fed infants at six weeks and six months of age in the present study today. Although it remains to be seen, whether the OC-concentrations found in breast-fed infants today will have any toxic effects to our children, the results are alarming, and further studies are ur¬gently required to investigate the complex interaction of different environmental pol¬lutants and the developing human organism [23].

View larger version : [in a new window] Figure: HCB, ∑PCB, and DDE concentrations (μg/L; median [crossbeam], 25th and 75th percentile by rank) of breast-fed (A) and bottle-fed (B) infants at the age of six weeks (1 and 3, respectively) and six months (2 and 4, respectively).

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