We searched literature from 2010 to 2023 regarding epidemiological and experimental evidence related to the health outcomes of POPs and MPs when ingested during the first stages of life through breast milk or infant formula, as follow:
Search strings used for studies measuring POPs in human milk
Pubmed: ("human milk" [All Fields] OR "breast milk" [All Fields]) AND ("chemicals" [All Fields]OR "pesticides" [All Fields] OR "volatile organic compounds" [All Fields] OR "brominated flame retardant" [All Fields] OR "DDE" [All Fields] OR "DDT" [All Fields] OR "dieldrin" [All Fields] OR "dioxin" [All Fields] OR "organophosphate" [All Fields] OR "PCB" [All Fields] OR "perfluorinated chemicals" [All Fields] OR "polybrominated diphenyl ether" [All Fields] OR "contaminants" [All Fields] OR "pollutants" [All Fields] OR "toxicants" [All Fields]).
Search strings used for studies measuring POPs in infant formula
- Pubmed: ("Infant formula" [All Fields] OR "baby formula" [All Fields]) AND ("chemicals" [All Fields] OR "pesticides" [All Fields] OR "volatile organic compounds" [All Fields] OR "brominated flame retardant" [All Fields] OR "DDE" [All Fields] OR "DDT" [All Fields]OR "dieldrin" [All Fields] OR "dioxin" [All Fields] OR "furan" [All Fields] OR "organophosphate" [All Fields] OR "PCB" [All Fields] OR "perfluorinated chemicals" [All Fields] OR "polybrominated diphenyl ether" [All Fields] OR "contaminants" [All Fields] OR "pollutants" [All Fields] OR "toxicants" [All Fields]).
Search strings used for studies measuring microplastics in human milk and in infant formula
- PubMed: ((infant formula) OR (human milk)) AND (microplastics)
The search queries were from 2010 to 2023, for POPs the search resulted in 1,044 results for human milk, 261 results for infant formula and 17 results for microplastics in both human milk and human milk substitutes. Data was analyzed by both authors and the most representative results were used.
Defining the Problem: POPs and MPs
POPs are a group of chemicals related to the fast growing industrial and agricultural sectors. In 2001, the Stockholm Convention agreed with more than 90 countries for a treaty aiming for the restriction or elimination of the initial twelve “dirty dozen” POPs that included nine organochlorine pesticides (OCPs) and three industry-specific chemicals; Recent evidence added 17 additional chemicals (Guo et al. 2019). POPs display a carbon based skeleton with stable chemical structures and halogenated (chlorine/fluorine/bromine) moieties which give them enhanced resistance to chemical, biological or photolytic degradation and in many cases with lipophilic properties; these chemicals have long half-lives and bioaccumulative properties specially in fatty tissue, thus concentrating while passing through food chains (Govaerts et al. 2018; Guo et al. 2019). Accordingly, POPs can be divided into 1) OCPs, 2) Industrial specific chemicals and 3) Unintentional industrial byproducts. OCPs integrate to the hexachlorocyclohexanes (HCH) or dichlorodiphenyltrichloroetane (DDT) and metabolites-related compounds including α-HCH, γ-HCH, δ-HCH and β-HCH, normally expressed as ΣHCH, whereas the DDT-related metabolites include o,p’-DDT, p,p’-DDT, o,p’-DDD, p,p’-DDD, and the major p,p’-DDE, which consistently are expressed as ΣDDT. The Industrial-specific chemicals are many and include polychlorinated biphenyls (PCBs), brominated flame retardants (BFR) such as polybrominated diphenyl ethers (PBDEs) and per and poly fluoroakyl substances (PFAS) with multiple highly stable fluorine and carbon bonds such as perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA). Finally, the unintentional industrial byproducts include polycyclic aromatic hydrocarbons (PAHs), polychlorinated naphthalenes (PCN), hexachlorobenzene (HCB), hexachlorobutadiene (HCBDs) or dioxin-like compounds such as polychlorinated dibenzofurans or dioxins (PCDD/PCDFs) that will be referred to as dioxins or furans (UNEP 2019; Guo et al. 2019).
Plastics are materials with high polymer contents and added chemicals for increased performance such as stabilizers, flame retardants, plasticizers, fillers and pigments (Hirt and Body-Malapel 2020). While the characterization of plastics identities as a source of pollution are still a major caveat for researchers, classical chemical structures can be identified to polyethylene (PE), high density polyethylene (HDPE), polyamide (PA), polyvinyl chloride (PVC), polyethylene terephthalate (PET), polypropylene (PP), polyurethane (PU), poly(ethylene-co-vynil acetate) (PEVA), poly methylmethacrylate (PMMA), polyethyl methacrylate (PEMA), polyester (PES), polystyrene (PS) and polycarbonate (PC) as major contributors in every industry (Hirt and Body-Malapel 2020). Resembling to the POPs accumulation, plastics display lipophilic nature (Ragusa et al. 2022) and bioaccumulative features with poor biodegradability properties leading them to fragmentation, resulting in MPs (<5mm) that share the same physicochemical properties than the fragmentation source (Xu et al. 2020). Smaller nanoplastics (<100nm) can also be formed; however, due to its reduced size are harder to study and therefore less information is available to support their impact on nature and human health (Kutralam-Muniasamy et al. 2020; Hirt and Body-Malapel 2020). Among the causes of MP fragmentation are UV radiation, physical abrasion (Bläsing and Amelung 2018), and photo- and thermo-oxidative degradation (Xu et al. 2020). The gut microbiome of earthworms (Huerta Lwanga et al. 2018) and of other soil inhabitants also contribute to the formation of MPs and nanoplatics (Xu et al. 2020). The most common shapes for MPs are fragments, followed by fibers, film and lastly foam, while whereas the MPs found in human intended foods are PE and PP followed by PS, PVC, PET and PA. Acrylic related compounds and PMMA can also be found but at lower concentrations (Koelmans et al. 2019; Hirt and Body-Malapel 2020). Alarming scenarios have confirmed that even cosmetic products containing microbeads such as exfoliating agents or toothpastes containing microparticles can be internalized or end in municipal water drains (Cheung and Fok 2017; Liu et al. 2022a).
The growing demand together with defective recycling programs for plastics leads to fragmentation processes and MPs accumulation has become a notorious problem in nature and potentially for human health (Bläsing and Amelung 2018; Tong et al. 2020; Xu et al. 2020; Hirt and Body-Malapel 2020). We next describe the detrimental effect of POPs and MPs accumulation in world ecosystems and in human breast milk.
How does contamination of POPs and MPs in nature occur?
POPs and MPs are present in virtually all ecosystems and show bioaccumulative features, affecting living organisms including plants, animals and ultimately humans. Despite their hydrophobicity, POPs remain in stable configuration in nature and remain tied to aquatic sediments where they can build up as a “reservoir”, allowing their reintroduction into the trophic chains when sediment disturbances occur (US EPA 2014). This new ecosystem might provide them a common route of entering to the water cycle, remaining suspended in liquid droplets and reaching distant areas such as the polar regions (Peeken et al. 2018; Dudarev and Odland 2022). In fact, although their production ceased decades ago (Hu et al. 2021), POPs are still widely distributed and inevitably accumulated in the ecosystems, including in water and agriculture-dependent food products (Guo et al. 2019). Similarly, metabolites from banned insecticides from the “dirty dozen ” such as aldrin or DDT can still be widely found in soil and accumulated in food products (Schafer and Kegley 2002; Raza and Kim 2018; Guo et al. 2019). Alarming scenarios have been identified in developing countries where the use of banned POPs production and environmental regulations has not improved (Alharbi et al. 2018). Together, human anthropogenic activities have provided POPs diversification, which accumulate in nature and ecosystems reaching human destined water and food chain suppliers.
MPs can accumulate in land soil, oceans, seas, freshwater sources, tap water, barreled water and bottled drinking water (Koelmans et al. 2019; Novotna et al. 2019; Danopoulos et al. 2020; Liu et al. 2022c). Atmospheric suspended MPs such as fragmented fibers were also detected in indoor and outdoor air, turning them as a potential health issue given that they provide a growing surface for pathogens (Hirt and Body-Malapel 2020). POPs such as PAHs can be inhaled, dispersed in the environment, deposited on water or food intended for human consumption (Gasperi et al. 2018; Huerta Lwanga et al. 2018). Human activities such as littering or agricultural practices that include irrigation with wastewater, flooding, compost and/or sewage sludge use or agricultural techniques such as plastic mulching can increase the formation of MPs (Bläsing and Amelung 2018). Another source of MPs are synthetic textiles, through abrasion processes during washing and drying cycles. Water treatment plants use processes aimed at reducing the amount of such unwanted agents, but MPs unfortunately are not eliminated from tap water (Jönsson et al. 2018; Novotna et al. 2019). When MPs are found in the soil, physical, chemical, microbial and enzymatic activities are altered with a negative impact on plant growth (Xu et al. 2020). Presence of PFOS, PAHs, OCPs and PCBs is also reported (Guo et al. 2019). Notoriously, POPs and MPs interaction might exacerbate and consolidate worse outcomes, for instance, depending on their size, shape, color and chemical structure, MPs can absorb and disperse POPs such as DDT and PAHs, PCBs, HCH and/or PFAS that include PFOS and PFOA (Gasperi et al. 2018; Xu et al. 2020; Ragusa et al. 2022). For such increased transfer to organisms, some authors have referred this interaction as “The trojan horse effect” (González-Soto et al. 2022). In relation to modern feeding human habits, industrial food processing and packaging can add additional POPs to the final product (Guo et al. 2019). As examples, MPs sources include table salt specially sea salt, tea bags and kitchen plastics such as tools and vases or plastic food packaging (Senathirajah et al. 2021) in which the simply plastic package opening can leach copious amounts of MPs to the foods (Sobhani et al. 2020). Additional MPs can add up to the finished product when larger transportation processes are required (Zhang et al. 2023), as well as through industrial food processing and packaging (Hirt and Body-Malapel 2020). Daily used plastic based products for food and drinks such as disposable liquid containers or plastic forks will release MPs (Sipe et al. 2022) and disposable paper cups with hydrophobic films such as PE or copolymers will also add additional MPs when exposed to hot water (Ranjan et al. 2021)
POPs and MPs interaction with human life
POPs are widely dispersed and in animals, including humans, the main route of entrance is through ingestion. Contaminated POPs sources included water and foods, such as honey, fruits, vegetables and their oils; cereals, rice and other grains; diverse animal meats (pork, chicken, beef) and related products (eggs, dairy products including milk, butter, cheese, cream, yogurt and others) and seafood including fish, mussels, oysters and others (Solomon and Weiss 2002; Schafer and Kegley 2002; Raza and Kim 2018; Guo et al. 2019). Food contaminants vary from source but the most common include OCPs, PCBs, PCDD/Fs, PAHs, HBCDs, PBDEs, and the PFAS including PFOA and PFOS (Guo et al. 2019). Chemical mixtures of POPs are therefore inevitable and little is known about the possible effects of such combinations (Landrigan et al. 2020) as presence, quantities and exposition can vary widely from regions and individuals. Given that PCBs, p,p’-DDE, HCB, dioxins, PBDEs, PFOS and PFOA disturb the endocrine system properties, these POPs can also be referred to as endocrine disruptive chemicals (EDCs showing a sex-dependent effect on health (Guo et al. 2019; Björvang and Mamsen 2022). In some cases, accumulation can occur before birth as such contaminants have been identified in placentas and in fetal tissue (Björvang and Mamsen 2022). Clinical evidence has confirmed that prenatal exposure of dioxin-like PCBs are negatively associated with head circumference, a parameter that can measure delayed brain development (Ouidir et al. 2020; Landrigan et al. 2020) and adverse neurocognitive outcomes have been described for adults (Pessah et al. 2019). PFOA is associated with reduced birth weight (Lenters et al. 2016) and increased risk of small-for-gestational-age (SGA) birth (Govarts et al. 2018); PCB 153 can also increase odds for SGA with a more prominent effect in females than males and HCB can increase odds for SGA in females while reducing it in males (Govarts et al. 2018). PFAS exposure is also related to several health outcomes that include dyslipidemia, decreased immunity, asthma, renal function and puberty development such as age at menarche (Rappazzo et al. 2017). Early exposition of PFOS and β-HCH is linked to attention deficit and hyperactive disorder (ADHD) in school-aged children, with a higher effect on girls (Lenters et al. 2019). PBDEs are associated with negative effects on thyroid function and impaired neurodevelopment (Herbstman et al. 2010; Gibson et al. 2018). Exposure to OCPs mixtures is also associated with reduced head circumference and other fetal measures including abdominal circumference, femur length (Ouidir et al. 2020) and lower birth weight (Lenters et al. 2016, 2019). DDT and DDE is also related to behavioral and neurocognitive effects (van den Berg et al. 2017) and later in life modify fecundity outcomes, as p,p’-DDE showed an increasing effect and p,p’-DDT a decreasing effect (Cohn et al. 2003). Augmented risk of cancer and toxicity to neurons and genes is also documented (Hu et al. 2021). Exposure to PCBs, dioxins, PBDEs, and OCPs can also lead to increased metabolic syndrome, diabetes, cardiovascular conditions such as stroke and heart failure, as well as immune and neurologic defects (Govarts et al. 2018; Landrigan et al. 2020; National Institute of Environmental Health Sciences 2023). Together, this evidence substantially confirms negative effects of POPs and MPs in human health (Fig. 1).
Resembling POPs, internalization of MPs in human tissues occurs through dermal contact, inhalation and mostly, by ingestion (Ragusa et al. 2022; Zhang et al. 2023). Contaminated water sources display variable levels of MPs according to the target, for instance, MPs were found in fish, mollusks, crustaceans, sugar, honey, beer, and cow’s milk (Kutralam-Muniasamy et al. 2020; Hirt and Body-Malapel 2020). Ingested MPs could pass through gastrointestinal epithelium through endocytosis or paracellular diffusion, followed by translocation by dendritic cells through lymphatic circulation an thus, reaching the bloodstream (Prata et al. 2020; Ragusa et al. 2022). Inhaled MPs could also enter through the lower respiratory tract and, after paracellular diffusion or cellular uptake, reach the circulatory system (Ragusa et al. 2022). To date, MPs adverse health effects are still under study as conclusive information is still limited (Kutralam-Muniasamy et al. 2020; Ragusa et al. 2022), however, in vitro studies using human cell lines have documented oxidative stress, cytotoxicity and changes in immune response (Danopoulos et al. 2022). Animal studies also confirm MPs accumulation in lung, heart, liver, kidney, brain, spleen, intestines, uterus, and ovaries (Liu et al. 2022c). In humans, MPs have been reported in blood (Leslie et al. 2022), colon (Prata et al. 2020), lungs (Amato-Lourenço et al. 2021) and placenta (Ragusa et al. 2021). Alarmingly, when deposited, MPs cannot be removed by the immune system but interact with tissues thus the possibility of chronic inflammation and risk of neoplasia could occur, at least reported by in situ studies (Prata et al. 2020). Also, MPs ingestion is related to digestive insults, especially in regard to intestinal balance, microbiome and gut permeability (Hirt and Body-Malapel 2020). MPs presence of PET, PC (Zhang et al. 2021) PS and PU are frequently reported in meconium however other MPs such as PTFE, PVC, PE and PP (Liu et al. 2022b) had also been documented. This suggests that maternal internalized MPs can reach the fetus. For infants, PA, PU, PE, PET and PTFE are reported in stool (Liu et al. 2022a) and a recent study comparing MPs presence in the stool of infants with adults found more accumulation of PET and PC in infants (Zhang et al. 2021). It is suggested that infants exposure to MPs is higher than adults due to the use of toys, plastic bottles, teethers and feeding habits (Zhang et al. 2021, 2023). Finally, based on that MPs were found in plastic bottles, World Health Organization guidelines prescribed correct sanitization of infant feeding bottles and selective equipment require hot water (World Health Organization 2007), however recent evidence is confirmed that this practice releases a surprisingly high amount of MPs such as PP (Li et al. 2020; Zhang et al. 2023) that can accumulate in the infants digestive system at stage where the digestive system is still immature and susceptible to infections, and thus could be part of the problem of increased MPs presence in infant stool. Accordingly, MPs accumulation in neonates can make them vulnerable to defective microbial colonization and compromise their capacity to fight infections (Camacho-Morales et al. 2021), or display changes in microbiome (Liu et al. 2022b) (Fig. 1).
Based on this evidence, accumulation of POPs and MPs seems to profoundly affect major physiological settings at the highly susceptible perinatal periods encompassing the first 1000 days of life. This suggest that neonates might become susceptible during breast feeding or infant formula feeding. We next describe POPs and MPs accumulation, first in human breast milk, later in human milk substitutes and discuss possible health outcomes at early stages of life. Also, we will provide a potential perspective to tackle POP and MP accumulation in breast milk.
POPs and MPs in Human milk and their effect in newborn physiology
Human milk represents the gold standard in infant nutrition because it has a myriad of nutritive and bioactive components, aiding in the infant’s correct organ development and establishment of the gut microbiome and immunologic programming (Camacho-Morales et al. 2021). During the first six months of life, human milk should be the only food given to the child, providing total hydration and energy through an exquisite of complex proteins, lipids and carbohydrates as well as bioactive components that will secure integral development (Camacho-Morales et al. 2021; North et al. 2022). In addition, human milk exhibits high variability of its components that adapt to the stage of lactation, i.e. colostrum, transitional and mature milk (Camacho-Morales et al. 2021). Chronobiotic variations derived from day and night cycles also modify the expression of human milk hormones, macronutrients and other metabolites, such as endogenous cannabinoids that work as zeitgebers, especially for neonates (Caba-Flores et al. 2022b). Epidemiological evidence confirms that breastfeeding increases an infant’s survival rate, and for <5-year-olds in low- and middle-income countries, decreases the odds of dying from pneumonia and diarrhea, which are the leading causes of dead for the age (North et al. 2022). Finally, breast milk immunological cell components can adapt to meet the infant’s requirements during infectious processes (Caba-Flores et al. 2022a) confirming that human breast milk is a dynamic and nutritive complex with tailored features for the infant health with virtually no additional cost (Fig. 2a). Despite the benefits, globally only 44% of six-month-old children feed exclusively from human milk, with the rest feeding from formula or a mixture of formula and human milk (North et al. 2022).
A person’s nutrition status, body mass index (BMI), emotional support, stress, ethnicity and genes can modify the composition, quantity and quality of breast milk (Acharya et al. 2019; Golan and Assaraf 2020). Similarly, food additives, pharmaceutic products, usage of legal/illegal drugs, personal care products as well as environment contaminants including POPs and MPs found in air, soil, water, food and drinks can find their way to the fetus or to breast milk (Berlin et al. 2002; Lehmann et al. 2018; Ragusa et al. 2022). Accordingly, breast milk can accumulate a lipidic mixture that can leach unwanted components such as low molecular weight POPs (Solomon and Weiss 2002), or lipophilic POPs and MPs (Lehmann et al. 2018; Ragusa et al. 2022). In fact, epidemiological evidence confirmed that higher levels dioxins, furans and PCBs in breast milk correlates with the degree of industrialization in a region (van den Berg et al. 2017).
Another way that PCBs, dioxins and furans can reach breast milk is through geophagia. This practice, where pregnant women consume clay, may put them in contact with contaminated clay and thus, with higher levels of dioxins and furans that can then be ingested by breast-feeding infants through the milk (Reeuwijk et al. 2013). Although dioxins, furans and PCBs show decreasing trends, geophagia should be discouraged specially during pregnancy and breastfeeding. In China, ΣDDT that are related to low birth weight (Lenters et al. 2016, 2019) and ΣHCH whose main metabolite β-HCH is linked to increased risk for ADHD (Lenters et al. 2019) has been reported in human milk (Hu et al. 2021). Both contaminants show a decreasing tendency when compared with sampled milk from previous years in the same region, however the main metabolites p,p’-DDE and β-HCH still remain at higher levels when compared to surrounding countries (Hu et al. 2021). Also, higher levels of ΣDDT in human milk tend to concentrate in tropical countries which historically have used such organochloride pesticide for malaria prevention (van den Berg et al. 2017). It is suggested that although common in human milk, DDTs could have more impact during pregnancy than through breastfeeding (van den Berg et al. 2017). Brominated flame retardants are reported at important levels in breastmilk in USA population, PBDE-47 being one of the most common congeners (Marchitti et al. 2017). The carcinogenic PAHs is another compound identified into human milk; however, it has been documented that Increased BMI can positively correlate with higher expression of carcinogenic PAHs in milk when compared to samples from people with lower BMI (Acharya et al. 2019). PAHs have been described in breast milk samples from Colombia, however its rapid metabolism suggest that the toxic potential is lower than other POPs (Torres-Moreno et al. 2022). Other Latin America study in the northern Mexican state of Sinaloa detected various PBDEs congeners specially BDE 47; the brominated flame retardant α-hexabromocyclododecane (α-HBCD); several congeners of PCB, dioxins, furans, and dioxin like PCBs; p-p’DDE, o-p’-DDT and p-p’-DDT and other OCPS (Martínez et al. 2022). A Norwegian study detected various PCBs and BDE congeners, PFOA, PFOS, HCB and its metabolite β-HCH, p,p′-DDE, p,p′-DDT in human milk. Associations of increased risk for ADHD for β-HCH and PFOS specially for girls were suggested (Lenters et al. 2019). Other studies have linked PFOA with reduced birth weight (Lenters et al. 2016). A Study in Czech Republic found high presence of PFAS specially PFOS and PFOA which display lower incidence of the BFR α-HBCD or Tetrabromobiphenol A in 50 human milk samples (Lankova et al. 2013). Other study in human milk from Japan, Korea and China found high incidence of PFAS such as PFOA, PFNA and PFDA in Japan and China (Fujii et al. 2012). Another Dutch study found decreasing PFOA and PFOS in human milk one and three months after delivery. Protein content was associated with PFOA levels and physiological variations such as older maternal age, first time breastfeeding as well as lower parity were associated with higher PFOS and PFOA levels in human milk (van Beijsterveldt et al. 2022). Recent evidence from an African study found high levels of ΣPCB and dioxins and furans in human milk exceeding toxicological standards considered as safe(Reeuwijk et al. 2013). In the same study, DDT levels were found around or below what is considered healthy and safe levels, however; when the risk of POPs levels is compared with the benefits of breastfeeding, such hazard is greatly outweighed (van den Berg et al. 2017). In this sense, even when POPs are present, breast milk has a myriad of cost effective benefits for the feeding infant and therefore is still recommended (Fig. 2a). This outcome could be potentially different when compared to exclusive infant formula feeders as such products are nutrition-oriented with far less bioactive properties (Fig. 2b).
MPs problem is by far less studied than POPs but their presence has also been documented in breastmilk. A recent study found that 26 out of 34 analyzed samples exhibited irregular and sphere-shaped fragments resembling MPs from different polymer matrixes displaying selective accumulation (Ragusa et al. 2022). Authors identified PE, PVC and PP as the major MPs, and also, a low accumulation of polycarbonate, HDPE, PS, PE, PA, PC, nitrocellulose, PEMA and acrylonitrile butadiene styrene. Finally, small number of particles per sample were found; however, such amount could be underestimated as only a small volume of 4.16 ± 1.73 g of milk was exanimated (Ragusa et al. 2022). Additionally, when breastmilk is stored in plastic bags for milk banks, irregular and oval plastic and microplastic fragments of PE, PET and nylon have been reported (Liu et al. 2023), and such scenario can be worsened if milk is provided to the infant in plastic feeding bottles as increasing evidence report copious amounts of MPs leaching through the preparation process (Zhang et al. 2021). Finally, cow milking process has been suggested to contaminate dairy with MPs, however to our knowledge the contamination of human milk with MPs from plastic based breast pumps have not been studied. Given the scenario in which plastic containers leach microfragments to the contained media, and that during heat based sterilization regimens plastic based containers leach copious amounts of MPs, microplastic contamination is then expected (Fig. 1). This evidence suggests that plastic free alternatives for milk extraction, storing and for child feeding should be encouraged.
Together, a comprehensive characterization of POPs and MPs identities in breastmilk and their potential chemical interaction is still mandatory. We conceive that early stages of life are more susceptible to PCBs, potentially affecting birth weight, cognitive performance, psychomotor and immune and endocrine response. Biomonitoring POPs and MPs in breastmilk might provide a rational contextual diagnosis at earlier stages of life for the infant where they become susceptible to environmental insults. This data supports the effect of POPs and MPs on health in the offspring.
Human milk substitutes
Human milk is the gold standard in infant nutrition and should be the only food during the first 6 months of life (de Mendonça Pereira et al. 2020; Camacho-Morales et al. 2021); however, when breast milk production is insufficient, not possible or medically not recommended, infant formulas as human milk substitutes can be used (de Mendonça Pereira et al. 2020). Infant formulas are animal or plant-based preparations for infant feeding available in different presentations. These include powder for reconstitution, concentrated liquid that requires an equal amount of water, or as a ready-to-eat product (Martin et al. 2016). In general, human milk substitutes are formulated for meeting infant’s nutritional requirements until complementary feeding is possible (de Mendonça Pereira et al. 2020). The most common substitute is cow-based as it is nutritious and readily available (Roy et al. 2020); however, raw cow’s milk does not meet infant’s needs, thus for achieving a nutritious profile similar human milk, industrialized processes that include milk dilution, skimming, addition of vegetable oils, vitamins, minerals and iron are required (de Mendonça Pereira et al. 2020). Other industrial processes include pasteurization and homogenization, fractionation, mixing of additives, emulsification, evaporation, spray drying and packaging (Maryniak et al. 2022). As cow’s milk is intended for calves, unfortunately, some infants can develop allergic reaction to one or more of the cow’s milk proteins and therefore, additional processing is required for obtaining a hypoallergenic formula, namely extensive hydrolyzation and, for the most severe cases, a more processed amino acid–based formula. Such formulas are the first choices when cow’s milk protein allergy is present (Maryniak et al. 2022). Other infant formula can be goat based, which can meet infant nutritional requirements after several industrialized processes (Prosser 2021). This type of human milk substitute can be used when an alternative to cow-based milk formula is desired; the protein profile of goat milk is very similar to cow’s milk, however the slight differences could translate to less allergenic activity and gastrointestinal symptoms when compared with cow-based infant formulas (Prosser 2021). However, its use is advised in cases with cow’s milk allergy as allergic cross reactivity has been documented (Prosser 2021; Maryniak et al. 2022). For infants with specific needs, namely lactose intolerance or milk protein allergy, other special formulas adapted for infant feeding such as rice-based formulas can be used. This formula is naturally lactose free and requires amino acid supplementation for reaching required nutritional quality. As rice possess low allergy rates and their vegetable proteins do not exhibit cross allergy with animal proteins (Dupont et al. 2020) it is considered as second option for managing cow’s milk protein allergy (Maryniak et al. 2022). Soy based infant formula is another animal alternative that can be used by full-term infants with specific clinical conditions such as galactosemia or hereditary lactase deficiency (Testa et al. 2018). Naturally present phytates and phytoestrogens still divide the scientific community and health professionals as the potential effects to infants’ health are still controversial (Martin et al. 2016; Maryniak et al. 2022). Cow’s milk protein allergy can be a reason for choosing soy based infant formulas, however protein cross allergy might also occur in some infants, therefore other alternatives such as extensively hydrolyzed formulas, amino acid-based formulas or rice-based formulas should be preferred (Maryniak et al. 2022). Finally, as previously stated animal based formulas pass through a skimming process and later on to a vegetable oils adding process that are formulated for matching the lipidic profile of human milk as this nutrient also has neurodevelopment properties, however, to date no human milk substitute has matched it (González and Visentin 2016). In sum, infant formulas are feeding alternatives to human milk that are nutritive and can be used when the baby has special needs as they are packed and readily available. However, they are expensive and as they are from raw sources that can’t be grown under uncontaminated scenarios that require highly industrialized processes, they can still be contaminated (Fig. 2b).
Prescence of POPs and MPs in human milk substitutes
Infant formulae are designed to feed the infant and meet specific nutritional requirements when human milk is insufficient or not available; however, as they are intended for a highly susceptible stage of life, quality and safety regulations are more strict than other food products as infants will highly or exclusively depend on such food for months (Koletzko et al. 2012; Martin et al. 2016). Even with strict regulations, harmful chemicals can still be found on the finished product. These can be veterinary drugs, mycotoxins, heavy metals, pesticides and other POPs with known health threats that include hepatotoxic, inmunotoxic, carcinogenic, teratogenic and mutagenic properties (Pandelova et al. 2011; Fujii et al. 2012; Lankova et al. 2013; Acharya et al. 2019; de Mendonça Pereira et al. 2020). Recent evidence also demonstrated MPs presence in powdered infant formula (Liu et al. 2022a; Zhang et al. 2023). Contaminants that are found in infant formula may come from raw sources as MPs and POPs are ubiquitous in nature and enhanced through agricultural and other anthropogenic activities, therefore present in water sources, soil, atmosphere and cattle food. For cattle, main route of entrance for MPs and POPs is also through ingestion and for plants, POPs can pass from foliage or roots, subsequently reaching the edible parts. This scenario means that for human milk substitutes, contamination in crops and animals is inevitably and can come from many sources (Raza and Kim 2018; Bläsing and Amelung 2018; Huerta Lwanga et al. 2018; Guo et al. 2019; Xu et al. 2020; Hirt and Body-Malapel 2020). Accordingly, MPs have been reported in cows raw milk (Da Costa Filho et al. 2021) and in processed commercially available cow’s milk products (Kutralam-Muniasamy et al. 2020; Da Costa Filho et al. 2021). Another contamination sources of MPs and POPs can derive from the multiple industrialization process as they typically need production, manufacturing, processing, preparation, treatment and packaging. High heating processes together with the added ingredients for formula preparation can lead to the presence of other unwanted chemicals (de Mendonça Pereira et al. 2020). Additional contamination could occur through leaching from containers when caps or containers contain plastics or when product needs to travel long distances (de Mendonça Pereira et al. 2020; Zhang et al. 2023). Contaminants including POPs and MPs can be added while resuspending infant formula through water as well as from plastic feeding bottles (Lehmann et al. 2018; Koelmans et al. 2019; Danopoulos et al. 2020; Liu et al. 2022a). Additionally, powder for reconstitution is the most accessible and common infant formula available, however as powders cannot be sterilized, disease causing bacteria can be present (de Mendonça Pereira et al. 2020). Finally, contamination in infant foods, even in slight concentrations is of concern as this population is more sensible than adults and thus, more susceptible to brain, reproductive and immune system damage (EFSA Scientific Committee et al. 2017). In this sense, the Food and Agriculture Organization of the United Nations and the World Health Organization have established maximum residue limit (MRL) for contaminants such as pesticides allowed in food and animal feeds that secure good agricultural practice with minimal amount necessary. MRL takes into consideration the acceptable daily intake and establishes toxicologically acceptable levels for foods (FAO/WHO 2018) (Fig. 1).
Demand for plant based infant formulas is increasing and the reasons behind could be being perceived as a healthier alternative, or better regarding environmental, climate and ethical reasons (Martin et al. 2016). Despite their nature, plant-based infant formulas can also be contaminated as the water, air and soil can have variable concentrations of many contaminants including POPs and MPs (Bläsing and Amelung 2018; Huerta Lwanga et al. 2018; Guo et al. 2019; Xu et al. 2020; Hirt and Body-Malapel 2020). Regarding MPs, negative environmental effects have been documented in physical, chemical, microbial and enzymatic activities in soil, ultimately modifying plant growth (Xu et al. 2020).
POPs including dioxins, furans, PCBs, OCPs were found in baby foods including six market-dominant infant formulas in 22 European Union counties. As commented previously, such contaminants increase SGA birth and several neurocognitive impairments. Analyzed products included starting (up to 3 months) and follow on (4 to 9 months) soy-based and milk-based formulas. For the 26 analytes investigated, only 9 OCPs were not present and with formulas ranging from 9 to 15 OCPs. In general, the concentrations of such contaminants were below the MRL, however starting and follow on hypoallergenic infant formulas that require additional industrialization processes had more PCDD/Fs presence (Pandelova et al. 2011). In Czechia, six milk- and soy-based formulas were tested with no BFRs presence and only some with PFAS traces such as PFOA or PFNA (Lankova et al. 2013). A study on Asian cow based infant formulas from Japan and China showed presence of PFAS such as PFOA, PFOS, PFNA, and perfluorohexane sulfonate (Fujii et al. 2012). Other study in China reported MPs presence of PU following by PMMA, Polytetrafluoroethylene, PET and PE in infant formula (Liu et al. 2022a). Another study of 40 starting and follow up milk-based infant formulas from Nigeria, South Africa, India, Poland, Spain, United States of America, Switzerland, France, Ireland and the Netherlands found several PAHs however at low concentrations that do not present a health risk for the infant (Acharya et al. 2019). A recent Dutch study analyzed PFAS in six milk-based infant formula, five of which were cow-based and one goat-based. Bottled and tap water were used for resuspension and no PFAS were detected (van Beijsterveldt et al. 2022). Finally, to date only one study has documented MPs fragments and fibers in packaged powdered infant formulas (Zhang et al. 2023). Accordingly, boxed milk powder showed higher MPs presence of PE that was demonstrated to leach from the foil packaging made from PE and aluminum than canned milk powder that in addition to PE also reported PET. Presence of PP, PA and PVC MPs was also documented in powders from both types of containers and for canned presentations; other potentially harming contaminants different from POPs could also leach during such interaction (Fig. 1). Additional MPs have documented to add up during the opening process (Sobhani et al. 2020), therefore this should be considered for boxes and other types of commercialized formulas that use plastics in the containers.
Accordingly, human milk is sensitive to external cues, and so might provide biomonitoring of environmental interaction for two main reasons (Lehmann et al. 2018; Acharya et al. 2019). Firstly, human milk is easily obtainable through noninvasive methods and secondly, pollutant concentrations can mirror concentrations found on mothers’ serum, providing then and effective estimative mothers body burden for POPs as well as an estimative for contaminant ingestion by babies. For such reasons, breastmilk monitoring aids in the estimation of POPs daily intake from the breastfeed baby allowing in the establishment of substantial health risks derived from contaminant ingestion (Rev. in Hu et al. 2021 and Lehman et al. 2018) and could also be a media for monitoring MPs ingestion.