Benefit and Risk Assessment of Breastmilk for Infant Health in Norway.

The present benefit and risk assessment of breastmilk and contaminants in breastmilk was initiated by the Norwegian Scientific Committee for Food Safety (VKM). The overall objective is to provide a balanced assessment of the benefits of breastmilk against the possible risks from exposure to contaminants in breastmilk with focus on Norwegian conditions. The aim is to contribute to a foundation for decision-makers when providing recommendations on the length of exclusive and partial breastfeeding. The composition of breastmilk is tailored for the needs of the newborn. Provided that the nutritional needs of the mother are met during pregnancy and breastfeeding, breastmilk covers all the nutritional requirements of the infant the first months of life, with the exception of vitamin D. Breastmilk also contains a number of specialised components, including growth factors, factors with anti-microbial and anti-inflammatory properties and selected immunological components which boost the maturation of the infant’s immune system. Infant formula fulfils the infant’s established nutritional needs, but does not provide the specific protective factors which are present only in breastmilk. However, studies over the last four decades have shown that polluting chemicals have accumulated in the environment, biomagnified in the food chain, are in our bodies, and consequently in breastmilk. The levels of lipid-soluble persistent contaminants in the foetus, the newborn child and in breastmilk largely reflect the amount of these in the mother’s body. Thus, breastmilk contains nutrients and protective immunological factors which have a positive effect on infant health, but may also contain contaminants. Particularly lipid-soluble and persistent contaminants accumulate in the infant during breastfeeding. This has contributed to a debate among experts agreeing that breastfeeding is beneficial, but discussing the advisable length of breastfeeding. Breastfeeding in Norway Breastfeeding prevalence is higher in Norway than in most European countries. 80% of the infants are breastfed at 6 months of age and 46% at 12 months. Mean breastfeeding duration is about 10 months. Norwegian health authorities recommend that infants are exclusively breastfed for 6 months with a total duration of at least 12 months. However, only a minority of Norwegian mothers breastfeed exclusively for the recommended 6 months. The prevalence of exclusive breastfeeding declines rapidly from 3 months onwards with only 9% being exclusively breastfed at 6 months. Mean breastmilk consumption in exclusively breastfed infants increases from approximately 700 ml/day at age 1 month to 850 ml/day at age 6 months. The amount of breastmilk provided to the child is not very different between the partially and exclusively breastfed infants during the first 4 months. From 7 months, breastmilk consumption in partially breastfed infants may be about 500 ml/day. There are a few conditions where breastfeeding is contraindicated. Among these are some metabolic disorders, infections and use of certain pharmaceuticals. Nutrients and Immunological Components in Breastmilk The positive health effects of breastmilk relates to nutritious as well as immunological properties. An infant who is exclusively breastfed for the first 6 months of life has, provided adequate nutrition of the mother, all the nutritional needs covered with the exception of vitamin D. Therefore, worldwide, the recommended daily intake of nutrients for infants is derived from the nutrient concentrations in breastmilk multiplied with the average intake of breastmilk. The composition of nutrients in breastmilk varies by stage of lactation, the time of day and during a given feeding. The concentration of some nutrients also varies according to the mother’s diet. The energy content of breastmilk varies, but has been estimated to be about 700 kcal/L. The content of proteins and carbohydrates is relatively stable, while the fat content has large variations. The fatty acid composition and concentrations of most vitamins reflect the maternal intake, while the concentrations of most minerals are not affected by the maternal diet, except for selenium and iodine. Breastmilk has protective properties. It contains a number of specialised components, including factors with anti-microbial and anti-inflammatory properties as well as constituents boosting the maturation of the infant’s immune system. This benefits health in childhood and most likely also later in life. The milk antibodies are targeted against potential pathogens and other antigens to which the mother has been exposed. Moreover, maturation of the infant’s immune system is influenced by contact with the immune-modulating factors in breastmilk as well as dietary and microbial constituents in the infant’s gut. Different components in breastmilk facilitate the establishment of a beneficial intestinal microbiota, which is important for induction of a balanced mucosal immune system. Through all these mechanisms, breastfeeding represents an ingenious immunologic integration of mother and child. Nutrients in Infant Formula If breastfeeding is not possible or if there is a need for more milk in addition to breastmilk, infant formula is recommended until the child is 12 months of age. Infant formula fulfills the infant´s established nutritional needs, but does not provide maternal antibodies and innate defence factors or immunity-promoting components. The majority of the infant formulas on the Norwegian market are cow’s milk-based. Data from a national dietary survey among infants (Spedkost, 2006) showed that at 6 months of age, 43% of the infants in Norway had been introduced to infant formula, and 36% used it regularly. At 1 year of age, 43% of the infants received infant formula regularly. Infant formulas in Norway are subject to EU regulations that cover the composition, labelling, marketing and distribution of the product. The regulations give minimum and maximum limits for nutrients for infant formulas and include some of the provisions of the WHO Code1. Contaminants and Microbiological Organisms in Breastmilk and Infant Formula Breastmilk, as a reflection of the mother’s body, contains low concentrations of a mixture of different contaminants. Only the most prevalent contaminants in breastmilk have been determined chemically and even fewer have been studied in humans with regard to impact on early life health. The main focus of the present benefit and risk assessment of breastmilk are contaminants which are included in the Stockholm convention on Persistent Organic Pollutants (POPs)2. They can be divided into the three main groups; pesticides (DDT and HCB), other halogenated organic pollutants (dioxins and dioxin-like PCBs, non-dioxin-like PCBs, brominated flame retardants (PBDE), perfluorinated compounds (PFOS/PFOA)) and heavy metals (lead, mercury and cadmium). In the identification and characterisation of negative health effects, combined exposures to multiple contaminants3 from breastmilk have to some extent been taken into consideration, as several of the cohorts have been investigating the impact on health outcomes of PCBs and dioxins in combination with DDT or HCB and some in combination with mercury. Additionally, it should be noted that the contaminants studied may be considered as markers for the combined exposure of multiple contaminants, since their occurrences are often correlated. Metal concentrations in both breastmilk and infant formula (e.g. mercury and lead) are generally low and not at levels associated with concern. Due to national and international restrictions and bans on use, the levels of dioxins, PCBs, and pesticides (like DDTs and HCB) have declined substantially (more than 60%) in the environment and in humans the last three decades. Compared to DDTs, HCB, dioxins and PCBs, the concentration of PBDEs in breastmilk in Norway increased until approximately year 2000, after which a decline has been observed. The fluorinated surfactants PFOS and PFOA have shown a similar time trend as the PBDEs. There are limited Norwegian data on levels of persistent organic pollutants in infant formula, but the levels reported are generally much lower than in breastmilk. Some contaminants which do not accumulate in the food chain may also be relevant in both breastmilk and infant formula. Substances from food packaging materials, e.g. phthalates, may be present in both breastmilk and infant formula, as well as process-generated substances such as acrylamide, PAHs, furan and 3-MDCP. The hormone active substance bisphenol A (BPA) used in plastic has recently been banned in infant feeding bottles in EU and Norway. Occurrence data in breastmilk and infant formula for these substances in Norway are scarce. The main difference between the contaminants in breastmilk and those provided by infant formula or bottle-feeding is that breastmilk generally contains higher levels of persistent organic pollutants, while most of the unwanted substances imposed by infant formula and bottle-feeding have a shorter half-life. Infant formula may contain microbial contamination of concern, which may lead to diarrhea and in severe cases bacteraemia and meningitis. Cronobacter spp. (formerly Enterobacter sakazakii) is a rare cause of invasive infection with high death rates in newborn infants. Possible outbreak from microbiological hazards in infant formula itself or due to contaminated water is an issue in developing countries, but no such outbreaks have been registered in Norway. Methodological Approach to this Benefits and Risk Assessment The benefit assessment is based on positive health effects reported in systematic reviews and meta-analyses published within the last 10 years. This implies that VKM has not conducted its own specific literature search to reveal the epidemiological studies that have examined positive health effects of breastmilk, but summarises and discu

Risk Assessment of Beta-carotene in Food Supplements.

Beta-carotene is a provitamin, i.e. a precursor of vitamin A (retinol), which is classified as an essential nutrient for humans. Beta-carotene is one of many carotenoids found in plants, fungi and bacteria. Carotenoids are therefore predominantly obtained through foods of plant origin or food supplements. Carrots contribute approximately half of the total beta-carotene intake in the Norwegian diet, followed by mixed frozen vegetables, tomatoes, fruits and berries. VKM emphasises that this opinion on upper level (UL) for beta-carotene addresses beta-carotene in food supplements only. Beta-carotene from regular foods such as vegetables and fruits is not considered to be a health concern. In 2002, the Scientific Committee on Food (SCF) established a tolerable upper intake level (UL) for vitamin A (SCF, 2002). However, the SCF opinion covers only retinol compounds (various forms of vitamin A). The bioconversion of carotenoids to vitamin A in the body is well regulated and therefore only intake of vitamin A has been considered relevant for vitamin A toxicity (Blomhoff et al., 2003; EFSA, 2008). The Norwegian Food Safety Authority is considering whether betacarotene should be regulated separately from retinol compounds. Beta-carotene seems to have a carcinogenic effect in smokers. A number of studies have been published where possible mechanisms of this negative health effect are discussed. The suggested mechanisms are either related to effects on cytochrome P450-related activities, altered retinoid signalling or to a pro-oxidant activity of beta-carotene. No UL has been established for beta-carotene. Several risk-assessment bodies have, however, previously attempted to establish safe levels or temporary guidelines, summarised in the following table: Previous reports Conclusion SCF, 2000, EU No dose-response relationship could be derived. Supplementation of 20 mg beta-carotene per day or more is contraindicated for use in current heavy smokers. There is insufficient evidence to set an UL for beta-carotene. IOM, 2000, USA No UL was established for beta-carotene or carotenoids. Beta-carotene supplementation is not recommended in the general population. EVM, 2003, UK The LOAEL was set to 20 mg/day. An uncertainty factor of 3 was applied to extrapolate from LOAEL to a NOAEL. A Safe Upper Level for beta-carotene supplements was set at 7 mg/day (equivalent to 0.11 mg/kg body weight/day for a 60 kg adult). NNR, 2012, Nordic countries No specific beta-carotene recommendation or UL. Rasmussen, 2006, Denmark A Temporary Guidance Level for beta-carotene equal to the average dietary level of 5 mg/day for all age groups was suggested. Seven randomised controlled trials (RCTs) have been included in this VKM opinion, conducted either in Europe or the USA, with almost 47 100 participants in the beta-carotene groups. In six of these RCTs there were no observed increased risk of cancer, but the large Finnish ATBC study found an increased risk of lung cancer in the beta-carotene group. Two prospective studies were included, one Danish and one from the USA, with 125 000 participants all together. The Danish study found that risk of lung cancer increased in smokers with increasing doses of beta-carotene supplements. In addition, eleven meta-analyses were included; one with age-related macular degeneration as endpoint, one with a mixture of cardiovascular disease (CVD) and cancer as endpoints, four on cancer as only endpoint, one on a mixture of CVD and all-cause mortality as endpoints and four on all-cause mortality alone. One of the meta-analyses on all-cause mortality was later excluded. There were no significant findings in the meta-analysis on macula degeneration. One of the two meta-analyses on CVD found a small increased risk in the beta-carotene arm (Vivekananthan et al., 2003). The combined CVD and cancer meta-analysis did not have sufficient statistical power to get significant results, but found a probable increase in lung cancer incidence in high-risk subgroups (smokers and asbestos workers (Fortmann et al., 2013). In the five meta-analyses studying cancer, there were no effect on other cancer forms than lung cancer. The four meta-analyses on all-cause mortality used information from the same RCTs as included in this VKM-opinion. They extracted information on numbers of death in each study and used these numbers to analyse risk of death in the beta-carotene versus placebo groups. Alarmingly, they all found an increased risk of all-cause mortality. These meta-analyses have been discussed thoroughly. To complete the risk characterisation of beta-carotene, VKM has followed the steps 1 – 4 as suggested by SCF in their Guidelines for the development of tolerable upper intake levels for vitamins and minerals (SCF, 2000a). Step 1 and 2. Hazard identification and characterisation Up until two decades ago, beta-carotene was thought to be harmless even in large doses. In the wake of the Finnish ATBC study which found an increased risk of lung cancer and death in male smokers, animal studies have indicated three possible mechanisms for such a detrimental effect. Although conclusive mechanistic explanations for the negative effects have not yet been agreed upon, there is a scientific rationale for the argument that population groups with vulnerable lungs may also have increased risk from beta-carotene supplements. The dose used in the Finnish ATBC study was 20 mg beta-carotene/day. The effect was only observed during the intervention period; in follow-up studies conducted after the active period was finished, the risk declined and was no longer significant. 20 mg beta-carotene may thus be considered as a LOAEL. The Danish prospective study found a dose-dependent increase in lung cancer risk with increased intake of supplemental beta-carotene. Unfortunately, the paper does not allow for setting a NOAEL or LOAEL based on the published data. In the four meta-analyses on all-cause mortality, all found a 6-7% increased risk of death. One of the meta-analyses also found an increased risk of CVD in smokers. However, all results were driven, statistically, by the ATBC study. Studies with a more mixed population (both men and women) and with a more typical prevalence of smokers (10–20%), found no such increased risk. Step 2, continued: Derive at a UL, taking into account the scientific uncertainties in the data. ULs may be derived for various life-stage groups within the population VKM found it extraordinary challenging to decide which uncertainty factor to use for beta-carotene. The present SCF guidelines for establishment of tolerable upper intake levels do not give clear guidance/advice in deciding the numeric level of the uncertainty factor. This seems to leave the decision to scientific judgement. If the NOAEL is based on human data, an uncertainty factor of 10 is recommended as a starting point to encompass inter-individual variation and sensitivity. The SCF guidelines state that a small uncertainty factor is to be used if the judgement is that little population variability is expected for the adverse effects, and a larger uncertainty factor (close to 10) may be used if variability is expected to be large. For beta-carotene, a NOAEL is not available, and an uncertainty factor may be applied to account for the uncertainty in deriving a UL from the LOAEL. The size of the uncertainty factor involves a judgement based on the severity and incidence of the observed effect at the LOAEL and the steepness (slope) of the dose response, if this is possible to estimate. For beta-carotene, we have not found the data necessary to make a dose-response curve. In addition, the following considerations were discussed before deciding on an uncertainty factor: · The study which found a negative effect of beta-carotene supplementation (the Finnish ATBC study) was very large (n=29 133) which indicates that it encompasses inter-individual variation and sensitivity. Additionally, the most vulnerable groups, in this case smokers, was an inclusion criteria. Both these factors indicate that the uncertainty factor can be in the lower end. · The meta-analyses for the endpoint “increased risk of all-cause mortality” found an increased risk of death in the beta-carotene groups. This is severe, and indicates that a maximum uncertainty factor should be applied. However, as all results in the all-cause mortality metaanalyses were driven statistically, by the ATBC study on smokers, we choose to use a lower factor. Based on the above considerations, VKM has chosen to use 5 as an uncertainty factor for betacarotene. An UL for beta-carotene cannot be derived, but a tentative upper level (TUL) is set at 4 mg/day, based on a LOAEL of 20 mg and the uncertainty factor of 5. Smokers and anyone else in the population with vulnerable lungs (e.g. asthmatics, COPD patients) should be discouraged from taking beta-carotene containing supplements all together. Step 3. Exposure assessment – evaluates the distribution of usual total daily nutrient intakes among members of the general population In the food survey Småbarnskost 2007, the mean intake of beta-carotene in 2-year-olds was 1.5 mg/day. In Norkost 3, the estimated mean intake in adults was 2.4 mg/day and 6.9 mg/day in the 95th percentile. About 3% of the adults reported use of beta-carotene supplements. The use of tanning pills containing beta-carotene may have been underreported. Beta-carotene from regular foods such as vegetables and fruits is, however, not considered to be of any health concern. Negative health effects from beta-carotene in natural foods have never been reported. On the contrary, the consumption of vegetables and fruits should be increased, and the recommendation of “5 a day” should be achieved in all age groups of the population. Step 4. Risk characterisation – analyses of the conclusions from steps 1 through 3 and characterises the risk. The risk will depend on the fraction of the population