J. Dairy Sci. 106:2213–2229 https://doi.org/10.3168/jds.2022-22599 © 2023, The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Invited review: Iodine level in dairy products—A feed-to-fork overview G. Niero,1 G. Visentin,2 S. Censi,3 F. Righi,4 C. L. Manuelian,1 A. Formigoni,2 C. Mian,3 J. Bérard,5 M. Cassandro,1,6 M. Penasa,1 S. Moore,1 A. Costa,2* and M. De Marchi1 1 Department of Agronomy, Food, Natural Resources, Animals and Environment, University of Padova, Viale dell’Università 16, 35020 Legnaro, Italy 2 Department of Veterinary Medical Sciences, Alma Mater Studiorum, University of Bologna, Via Tolara di Sopra 50, 40064 Ozzano dell’Emilia, Italy 3 Department of Medicine, Endocrinology Unit, University of Padova, 35121 Padova, Italy 4 Department of Veterinary Science, University of Parma, Via del Taglio 10, 43126 Parma, Italy 5 Agroscope, Division Animal Production Systems and Animal Health, 1725 Posieux, Switzerland 6 Italian Holstein, Brown and Jersey Association, Via Bergamo 292, 26100 Cremona, Italy ABSTRACT INTRODUCTION The theme of iodine in the dairy sector is of particu- The milk matrix contains mineral elements of great lar interest due to the involvement and the interconnec- importance in terms of quality and quantity. Calcium, tion of several stakeholders along the dairy food chain. potassium, magnesium, sodium, and phosphorus are Iodine plays a fundamental role in animal nutrition and the major minerals, present at relatively high con- physiology, and in cattle it is an essential micronutri- centration (Cashman, 2006). For decades, these milk ent during lactation and for fetal development and the components have been studied for their relevance at calf’s growth. Its correct use in food supplementation both nutritional and manufacturing levels. On the is crucial to guarantee the animal’s recommended daily other hand, iodine is one of the trace elements of milk requirement to avoid excess intake and long-term toxic- and therefore present in low amounts (Cashman, 2006). ity. Milk iodine is fundamental for public health, being In addition to iodized salt and seafood, milk and dairy one of the major sources of iodine in Mediterranean products are the main source of iodine in the human and Western diets. Public authorities and the scientific diet (Herrick et al., 2018; Censi et al., 2020). This min- community have made great efforts to address how and eral is fundamental to maintain the functionality of the to what extent different drivers may affect milk iodine thyroid gland and to sustain physiologic and metabolic concentration. The scientific literature concurs that the processes regulated by thyroid hormones; thus, iodine amount of iodine administered through animal feed intake and availability are important for human health and mineral supplements is the most important fac- to ensure certain physiological functions. Proper iodine tor affecting its concentration in milk of most common supplementation strategies in dairy species can guaran- dairy species. Additionally, farming practices related tee animal health, together with the consumer’s iodine to milking (e.g., use of iodized teat sanitizers), herd prophylaxis. management (e.g., pasture vs. confinement), and other Iodine level in milk is affected by numerous factors environmental factors (e.g., seasonality) have been along the entire dairy food chain, on a feed-to-fork per- identified as sources of variation of milk iodine concen- spective. The main driver is the level of iodine in the tration. Overall, the aim of this review is to provide a feed administered to lactating animals, which has been multilevel overview on the mechanisms that contribute demonstrated to be linearly associated with the final to the iodine concentration of milk and dairy products. milk iodine concentration. Such a relationship is well Key words: consumer health, dairy industry, farming, documented in literature (Moschini et al., 2010; Weiss et iodine, milk al., 2015; Antaya et al., 2019), even if the dose-response effect is far from being standardized due to several hur- dles, including high analytical costs for the determina- tion of this mineral in feed and milk, and the presence of iodine antagonists in several ingredients included in the animals’ rations (Bath and Rayman, 2016). Some of the factors potentially influencing the milk iodine con- tent, such as season and farming system, can be largely Received July 29, 2022. Accepted November 21, 2022. traced back to the effect of diet composition (Nerhus *Corresponding author: angela.costa2@​unibo​.it et al., 2018; Stevenson et al., 2018). The adoption of 2213 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2214 iodized teat sanitizers has been identified as a further and (5) the analytical methods used for quantification. factor able to increase milk iodine concentration. This The studies were conducted in 14 countries, with Italy happens due to the presence of disinfectant in the teat (8 papers) and the United States (6 papers) ranking canal after postdipping and to the local absorption of first in the number of publications. Few studies consid- iodine at the epithelial level, followed by a release of ered species other than bovine and breeds other than this mineral into the secreted milk (French et al., 2016). Holstein. The most common analytical method for de- The scientific literature demonstrates that milk iodine termination of iodine concentration was the inductively concentration also has a genetic component in cattle, coupled plasma mass spectrometry (24 papers), which meaning that there is genetic variability for this trait is indeed considered the reference method for several as the populations diverge in terms of estimated breed- minerals including iodine. Only a few papers used al- ing value for milk iodine concentration (Denholm et ternative analytical approaches (9 papers), including al., 2019; Costa et al., 2021). Different studies have direct quantification methods (ion exchange chroma- described the importance of milk and dairy products in tography), indirect quantification methods (colorimet- respect to iodine prophylaxis in humans (Herrick et al., ric assays and enzyme-linked immunosorbent assays), 2018; Censi et al., 2020). and predictive methods (mid-infrared spectroscopy). In this scenario, the aim of this review is to update the scientific community on the latest findings concern- ANIMAL PHYSIOLOGY AND NUTRITION ing (1) the most recent recommendations in terms of iodine requirements and adequate intake in dairy cows; Iodine in Cattle Physiology (2) the major factors affecting the variability of iodine in milk and dairy products—namely, animal feeding, According to the US National Academies of Sciences, farm management, and processing at the dairy indus- Engineering, and Medicine (NASEM, 2021), iodine is try level; (3) the key role of iodine in human nutrition the principal constituent of thyroid hormones, includ- and health. The importance of milk and dairy foods as ing thyroxine (T4) and triiodothyronine (T3). Iodine sources of iodine in humans perceived by the scientific is mostly present in the thyroid gland, which stores community was also investigated through a posteriori about 80% of the total iodine circulating in the or- analysis of bibliographic data. ganism. Secretion of thyroid hormones is regulated by other hormones: thyrotropin-releasing hormone, formed REVIEW METHODOLOGY by the hypothalamus, activates the anterior pituitary gland for the release of thyroid-stimulating hormone, Papers included in this review article were retrieved which in turn induces T4 formation from thyroglobulin from different databases, including Scopus (www​.scopus​ and T4 release (Meschy, 2010). A negative feedback .com), ISI Web of Science (www​.webofknowledge​ mechanism is in charge of regulating formation of T4 .com), and Google Scholar (www​.scholar​.google​.com), and T3. In cattle, the main site of absorption of this el- for the period between January 2010 and December ement is the rumen, from where it is transported in the 2021. However, previous relevant papers dealing with organism through specific binding with plasma proteins historical information, pilot research, regulations, and (Meschy, 2010). important knowledge related to the topic of the current The impact of different iodine levels on cows’ health review were also included. Therefore, the actual propor- and performance and identification of requirements tion of the papers published before 2010 is about the have been investigated by administration of iodine- 16% of the total cited articles considered in the present deficient diets. A compendium of symptoms related to review. Key words used in the literature search were iodine deficiency in dairy cattle has been summarized “bovine,” “cattle,” “cheese,” “cheese making,” “dairy,” by Anderson et al. (2007), who monitored 12 farms “dairy cows,” “dairy products,” “diet,” “farm,” “feed,” located in the Manawatu District (New Zealand). High “food,” “fortification,” “goiter,” “health,” “integration,” iodine intake also causes goiter, which translates into an “intake,” “iodine,” “metabolism,” “milk,” “mineral,” “re- augmented production of thyroid-stimulating hormone quirement,” “salt,” “species,” “supplementation,” and produced by the pituitary gland. Other than visible “thyroid.” Appropriate combinations of the aforemen- goiter formation, clinical signs of deficit include silent tioned key words were also searched. Table 1 displays estrus, low first service conception rate, and stillbirths, the descriptive information of the reviewed literature, all associated with subphysiological T4 concentrations such as (1) the country where the trials were conducted; in blood (<45 nmol/L; Anderson et al., 2007). On the (2) the food, feed, or biological substrates analyzed for other hand, Iannaccone et al. (2019) reported a bet- iodine concentration; (3) the species (and the breed) of ter immunological activation in dairy cattle receiving animals involved in the study; (4) the number of herds; short-term feed iodine administration, as milk SCC Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2215 Table 1. Reviewed studies on iodine concentration in animal feed, milk, dairy products, and other biological matrices from 2010 to 20211 Reference Country2 Matrix Species (breed)3 Herds,4 n Analytical method5 Moschini et al. (2010) ITA Feed, raw milk, cheese Cow (HO) 1 ICP-MS Borucki Castro et al. (2011) CA Feed, raw milk Cow 60 ICP-MS Borucki Castro et al. (2012) CA Feed, raw milk Cow (HO) 1 ICP-MS Conneely et al. (2014) IRE Feed, raw milk Cow (HO, CR) 1 IE chromatography Antaya et al. (2015) USA Feed, raw milk Cow (JE) 1 ICP-MS Nazeri et al. (2015) IRN Feed, raw milk Cow (HO) 1 Colorimetric Weiss et al. (2015) USA Feed, raw milk, serum Cow 1 Colorimetric Bath and Rayman (2016) GB Feed, raw milk Cow NA — Chaves Lopez et al. (2016) ITA Feed, raw milk Cow (HO) 1 ICP-MS da Silva et al. (2016) BRA Whey protein isolates Cow NA ICP-MS French et al. (2016) USA Raw milk Cow (HO, CR) 1 ICP-MS Sorge et al. (2016) USA Feed, raw milk, serum, tears Cow (HO) 1 — Nerhus et al. (2018) NOR Retail milk, dairy products Cow and goat NA ICP-MS O’Kane et al. (2018) GB Retail milk Cow NA ICP-MS Ovadia et al. (2018) ISR Raw milk Goat 1 ICP-MS Stevenson et al. (2018) GB Retail milk Cow NA ICP-MS van der Reijden et al. (2018) CH, ITA Raw milk Cow (BS, HO, SI, 32 ICP-MS ARP) Walther et al. (2018) CH Raw milk, retail milk Cow NA ICP-MS Antaya et al. (2019) USA Feed, raw milk Cow (JE) 1 ICP-MS Denholm et al. (2019) GB Raw milk Cow (HO) 1 ICP-MS Iannaccone et al. (2019) ITA Feed, raw milk Cow (HO) 22 ICP-MS Konečný et al. (2019) CZ Raw milk Cow 78 ICP-MS Niero et al. (2019) ITA Raw milk, retail milk Buffalo, cow, donkey, NA ICP-MS goat, sheep van de Kamp et al. (2019) NED Retail milk Cow NA ICP-MS van der Reijden et al. (2019) CH, ITA Feed, raw milk, cheeses Cow (HO, ARP) 1 ICP-MS Arrizabalaga et al. (2020) SP Retail milk Cow NA HPLC Coneyworth et al. (2020) GB Feed, raw milk Cow 99 ICP-MS McKernan et al. (2020) IRE Soil, feed, raw milk Cow 185 ICP-MS Miseikiene et al. (2020) LT Raw milk Cow 5 ICP-AES Niero et al. (2020) ITA Raw milk Cow (HO) 4 ICP-MS Roseland et al. (2020) USA Retail milk Cow NA ICP-MS Costa et al. (2021) ITA Raw milk Cow (HO) 221 MIRS Rezaei Ahvanooei et al. (2021) IRN Feed, raw milk, serum, urine Cow (HO) 1 ELISA 1 References are listed by year of publication and, within year, by first author surname. 2 BRA = Brazil; CA = Canada; CH = Switzerland; CZ = Czech Republic; GB = United Kingdom; IRE = Ireland; IRN = Iran; ISR = Israel; ITA = Italy; LT = Lithuania; NED = the Netherlands; NOR = Norway; SP = Spain; USA = United States of America. 3 ARP = Aosta Red Pied; BS = Brown Swiss; CR = crossbreed; HO = Holstein; JE = Jersey; SI = Simmental. 4 NA = not available. 5 ICP-AES = inductively coupled plasma atomic emission spectrometry; ICP-MS = inductively coupled plasma mass spectrometry; IE = ion exchange; MIRS = mid-infrared spectroscopy. was significantly lower in iodine than control cows At the same time, this suggests that extra supplemen- under bacterial infection. Through RNA sequencing, tations—above the minimum recommended value—do these authors demonstrated that 525 genes related to not increase milk production. Similar conclusions were immune response and oxidative stress were differently drawn from an older study conducted on grazing cows expressed in the 2 groups. by Grace and Waghorn (2005). In their trial, feed iodine There is no consensus on the effect of iodine supple- concentration had a low range of variation, with an mentation on the productivity of dairy cows, and a average of 0.24 mg/kg DM, and cows subjected to mul- favorable effect has been defined as “largely anecdotal” tiple iodine injections at 100-d intervals did not present (Cook and Green, 2010). In the study of Shand (1952), changes in their productivity. In particular, milk yield dietary iodine deficiency was claimed to be the factor did not significantly differ between control (3,976 L/ responsible for a reduced milk production, whereas Ian- lactation) and iodine-supplemented animals (3,923 L/ naccone et al. (2019) did not find differences in milk lactation). On the other hand, injections were able to yield when administering 2 different iodine doses (20 increase the milk iodine concentration, from the basal and 85 mg/d). However, both the tested doses exceeded level of <20 μg/L before treatment to a concentration the minimum recommended intake (Iannaccone et al., 3 to 10 times greater, 98 and 55 d after the treatment, 2019), making iodine a nonlimiting factor in this case. respectively (Grace and Waghorn, 2005). Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2216 The review of Hidiroglou (1979) summarized several is below the physiological threshold of 45 nmol/L experiments aimed at evaluating health problems due (Anderson et al., 2007). to deficiency of major and trace minerals in ruminants. As in humans and other mammals, iodine deficiency Iodine in Animal Nutrition is reported to negatively affect cows’ reproductive performance. In fact, fertility disorders are secondary Scant and dated information is available to deter- manifestations of thyroid dysfunctions and include an- mine the average iodine requirement of cattle, and estrus or irregular estrus, retained placenta, abortion, adequate intakes rather than actual requirements are and stillbirth. The administration of iodine-poor diets usually provided (NASEM, 2021). Given this, the term to dairy cows results in reversible anovulatory estrus “adequate intake” is adopted throughout this review for and cystic ovaries, whereas thyroidectomized heifers consistency. demonstrate irregular estrus. Due to the impaired According to the recent guidelines reported in fetal thyroid functions, cows deficient in iodine during NASEM (2021), for the maintenance purposes of dairy pregnancy are prone to abort (Hidiroglou, 1979). cows, the adequate intake of iodine can be calculated With regard to the young stock, the beneficial effect as follows: of iodine supplementation in calves has been described by several authors. Guyot et al. (2011) demonstrated Adequate intake, mg/d = that there is a long-term effect of iodine deficiency observable in calves born from dams subjected to (0.216 × BW0.528) + (0.1 × MY), different levels of supplementations below the recom- mended allowance of 0.5 mg/kg DM. In particular, 2 where BW is the animal body weight (kg) and MY is different levels of supplementation, low (0.45 mg/kg the daily milk yield (kg/d). The calculation is valid iodine and 0.15 mg/kg selenium) and high (5.45 mg/ for all categories of cattle (lactating and nonlactating), kg iodine and 0.45 mg/kg selenium), were evaluated calves excluded, with MY assuming a value of 0 for for a period of 120 d on open cows, pregnant cows, nonlactating cows. The adequate intake for calves, as and their calves. In the group receiving the high level still functionally nonruminating animals, is estimated of supplementation, the nutritional markers related to on the basis of the requirements for human infants as either iodine (iodine concentration in plasma, urine, 0.8 mg of iodine per kilogram of DMI (NASEM, 2021). colostrum, and fetal fluids) or selenium (selenium Even if the diet is apparently balanced in terms of concentration in plasma) improved in both dams and minerals and the intake of iodine seems adequate, the calves. real amount of iodine absorbed may not be. In fact, the In a field trial, Gamsjäger et al. (2020) studied the amount of iodine absorbed is “overestimated” in the efficacy of the therapeutic oral administration of so- presence of goitrogens such as canola meal. Goitrogens dium iodide (20 mg/kg DM) in preventing respiratory are organic compounds that interfere with the synthesis disease in preweaned dairy calves. Although such an and secretion of thyroid hormones either by hampering administration led to a greater concentration of iodine iodine transport across the thyroid cell membrane (and in both serum and nasal fluid of calves, it was not ultimately reducing iodine retention) or by inhibiting effective in preventing the occurrence of bovine re- thyroperoxidase (and ultimately preventing the biosyn- spiratory diseases (Gamsjäger et al., 2020). In calves, thesis of monoiodotyrosine and diiodotyrosine). It has goiter (diagnosed as diffuse thyroid hyperplasia and been reported that diets with canola meal decreased significantly increased thyroid size and weight) was transfer of iodine into milk by 50% (NASEM, 2021). observed in 16% of the 44 stillborn calves retrieved Assuming that the synthesis of thyroid hormones from a pool of New Zealand dairy farms suspected is decreased to a similar extent, the adequate intake of being iodine deficient (Anderson et al., 2007). In would be twice that previously estimated (NASEM, that study, the aim was to define potential and useful 2021). Given a typical dry cow (700 kg BW; 13.5 kg indicators to monitor the iodine status at herd level DMI) and lactating cow (650 kg BW; 35 kg/d MY; 21 in field conditions. Results demonstrated that calves kg DMI), such cattle categories would need to be fed, suffering from iodine deficiency were characterized by respectively, with 0.51 and 0.48 mg of iodine per kg thyroid hyperplasia and by suboptimal serum T4 con- DM in the presence of goitrogen-free diets (NASEM, centrations (80 nmol/L). Adult cows sampled within 2021). Such values become 1.02 and 0.96 mg/kg DM, the study of Anderson et al. (2007) presented an aver- respectively, if goitrogenic compounds are also included age T4 plasma concentration of 42.8 nmol/L, which (NASEM, 2021). Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2217 Table 2. Average iodine concentration of baleage, concentrates, hay, mineral supplements, silages, and TMR (mg/kg of DM) Feed ingredient References Mean SD Baleage Grass Antaya et al. (2015), Schöne et al. (2017), van der Reijden et al. (2018), Antaya et al. 0.29 0.15 (2019) Legume Antaya et al. (2015) 0.20 — Concentrate Antaya et al. (2015), Chaves Lopez et al. (2016), van der Reijden et al. (2018), Antaya et 1.95 1.09 al. (2019) Hay Borucki Castro et al. (2011), van der Reijden et al. (2018) 0.11 0.04 Mineral supplement Ascophyllum nodosum meal Antaya et al. (2015), Sorge et al. (2016), Antaya et al. (2019) 763.67 49.52 Mineral premix van der Reijden et al. (2018), Rezaei Ahvanooei et al. (2021) 81.50 26.16 Silage Corn Borucki Castro et al. (2011), Schöne et al. (2017), van der Reijden et al. (2018) 0.10 0.04 Grass van der Reijden et al. (2018) 0.10 — Mixed Borucki Castro et al. (2011), McKernan et al. (2020) 0.25 0.12 Sugar beet van der Reijden et al. (2018) 0.21 — TMR Moschini et al. (2010), Conneely et al. (2014), Antaya et al. (2015), Chaves Lopez et al. 1.27 0.64 (2016), French et al. (2016), Sorge et al. (2016), Antaya et al. (2019), Iannaccone et al. (2019), Rezaei Ahvanooei et al. (2021) ANIMAL FEEDING, MANAGEMENT, AND GENETICS ingredients, hay, corn silage, and grass silage present the lowest iodine concentration per kilogram of DM Iodine Concentration in Animal Feeds (Table 2). Table 2 summarizes the average iodine concentration Iodine Supplementation of baleage, concentrates, hay, mineral supplements, silages, and TMR based on data retrieved from the Iodine content of feed ingredients reflects the passive literature. As expected, mineral supplements had the uptake of crops and vegetables from soil and water. greatest iodine concentration, with Ascophillum nodo- This, however, is generally not sufficient to cover the sum meal and mineral premix accounting for 763.67 adequate intake of a dairy cow, and inclusion of iodine and 81.50 mg of iodine per kilogram of DM, respec- supplements in the diet is fundamental to fulfill the tively. Concentrates exhibited an average concentration adequate intake and support body maintenance, milk of 1.95 mg of iodine per kilogram of DM. Still, it is production, and fetal development. Type and amount worth noting that concentrates were characterized by of iodine supplementation in the daily ration is the a relatively high iodine variability, being the standard major source of variation of milk iodine. In fact, the deviation equal to 1.09 mg of iodine per kilogram of correlation between iodine supplementation and milk DM and the coefficient of variation 56%. This indicates iodine concentration portrayed (Figure 1A) is linear that we are far from a standardization of this mineral and is characterized by different dose-response effects, in complex matrixes like concentrates. Iodine concen- as demonstrated by the slopes (Figure 1B). Regressions tration in TMR averaged 1.27 mg/kg DM, which is obtained from single studies, together with Figure 1A greater than the recommended concentration of about and 1B, are intended to facilitate the comparison be- 0.5 mg/kg DM (NASEM, 2021), but far below the up- tween different trials and to present the response dose per tolerable limit (5 mg/kg DM; EU, 2005). Similarly, effect and the recovery rate of iodine from feed to milk wide standard deviation (0.64 mg/kg DM) and large in a synthetic manner. The linear regression obtained coefficient of variation (51%) are reported for iodine using all the data from the considered studies (Figure concentration. Overall, this may be attributed to differ- 1C) allows one to infer milk iodine concentration in the ent types and levels of supplementations, which in turn presence of a known feed iodine concentration. are related to different nutritional requirements of cat- Weiss et al. (2015) studied the effect of 2 levels of tle categories, specific feeding programs, and different iodine supplementation (i.e., 0.59 and 1.34 mg/kg DM) farm management practices. Grass and legume baleage on midlactation Holstein cows by administering eth- were characterized by relatively low iodine concentra- ylenediamine dihydroiodide. Results showed a sharp tion, averaging 0.29 and 0.20 mg/kg DM, respectively. increase in milk iodine level (from 358 to 733 µg/L) Similar iodine concentrations were observed for mixed and an average milk iodine recovery of 85%. The linear silages and sugar beet silages, averaging 0.25 and 0.21 regression calculated using the data points provided by mg/kg DM, respectively. Among the considered feed Weiss et al. (2015) is Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2218 y = 500x + 63, milk. This is the greatest dose-response rate observed in literature; however, the regression was estimated us- where y is the iodine concentration in milk (µg/L) and ing just 2 test points with a relatively narrow range of x is the iodine concentration in the diet (mg/kg DM). variation of iodine concentration in the feed (0.75 mg/ The slope of the linear regression indicates that an kg DM). A similar regression can be calculated using increase in iodine per kilogram of DM (1 mg) is pro- data provided by Moschini et al. (2010): portional to an increase of 500 µg of iodine per liter of y = 359x − 360. These authors considered 3 levels of feed iodine supple- mentation (1.69, 2.66, and 3.54 mg/kg DM) adminis- tered by adding water fortified with inorganic iodine to the ration. Still, this equation has to be interpreted with caution due to the great intercept of the model and the limited number of animals (n = 4) per treatment. Results reveal a relatively low transfer in milk (23%), which indicates that there is a certain inefficiency when water is used as a carrier. In a controlled study, Borucki Castro et al. (2012) observed an average iodine recovery of 88% in Holstein cows. The same authors reported in- creasing levels of milk iodine (301, 414, and 482 µg/L) as a direct effect of increased integration of iodine-rich feed (0.3, 0.6, and 0.9 mg/kg DM, respectively) by the introduction of vitamin and mineral mixes. That rela- tionship can be modeled as y = 301x + 218. Considering the very narrow range of supplementa- tion doses (Borucki Castro et al., 2012) and the great intercept of the model, this equation should be used prudently. On the other hand, data provided by Antaya et al. (2015) were obtained on a wide range of iodine supplementation doses (i.e., from 0.95 to 8.33 mg/kg DM), achieved through the addition of Ascophyllum no- dosum meal. In particular, Antaya et al. (2015) tested different levels of iodine supplementation: 2 below the tolerable limit of 5 mg/kg of DM (0.95 and 3.32 mg/kg DM) and 2 exceeding that limit (5.73 and 8.33 mg/kg DM). Their results can be modeled as y = 162x + 47. Overall, Antaya et al. (2015) observed a very low re- covery rate (16%) in terms of the ratio between milk and feed iodine concentration. A similar regression and Figure 1. (A) Relationship between dietary and milk iodine con- average recovery rate (23%) can be calculated starting centration calculated for the different studies; (B) slope of each line; from the data of van der Reijden et al. (2019), who and (C) overall regression based on all the data points given in panel tested 5 levels of iodine supplementation (0, 0.5, 0.7, 1, A. Further details on the iodine sources fed in each study and the iodine levels of the diet are reported in the “Iodine Supplementation” and 2 mg of iodine/kg DM): section. Each colored line in panel A corresponds to a published article labeled in panel B. The equation for overall regression is reported to- y = 145x + 9. gether with its coefficient of determination (R2). Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2219 Given the relationships just described (Antaya et al., cific variety, and the technological processes that the 2015; van der Reijden et al., 2019), it can be estimated crop is subjected to (e.g., extrusion) may alter the an- that milk iodine can increase by 162 and 145 µg/L tagonistic effect of goitrogens. In the former case, it was per each milligram of iodine present in the DM, re- observed that fewer strains of red clover contain cyano- spectively. Lower slopes were calculated in regressions genic glycosides compared with white clover, indicating obtained from recent data published by Antaya et al. that the red variety has lower goitrogenic potential (2019) and Rezaei Ahvanooei et al. (2021): compared with the other (Bath and Rayman, 2016). Concerning the treatments, instead, Ngwa et al. (2004) y = 65x + 79 and y = 43x + 249. reported that ensiling techniques can reduce goitrogens in Acacia sieberiana. Speculations, hypotheses, and dis- To the authors’ knowledge, only Borucki Castro et al. cussions about the antagonistic activity of goitrogenic (2011) proposed a regression equation based on an ob- compounds in respect to milk iodine content have been servational longitudinal study, considering the iodine presented by several authors, but very few of them have level of feed and bulk milk samples collected in 60 com- provided direct quantification of goitrogens in animal mercial farms. The equation, characterized by a coef- feed and have successfully correlated goitrogen iodine ficient of determination (R2) of 0.15, looks like with milk iodine. Antaya et al. (2019) reported GLS concentration to be maximum in the concentrate blend y = 113x + 145. (80.10 mg/kg DM), followed by TMR (58.70 mg/kg DM), and thereafter mixed grass baleage (32.9 mg/kg The low model accuracy calculated for bulk milk sug- DM). The level of GLS in animal feed increased linearly gests that other factors in addition to feed affect the (r = 0.98) with the percentage of canola meal in the transfer of iodine at tank level, such as milking prac- TMR (Weiss et al., 2015). Diets without canola meal tices or animal management. contained on average 3.55 mM of GLS per kilogram of The equation obtained from the overall regression in DM, whereas diets supplemented with 3.9 and 13.9% of Figure 1C is canola contained 3.73 and 5.23 mM GLS per kilogram of DM, respectively (Weiss et al., 2015). Indeed, the y = 93x + 217 (R2 = 0.56). same authors reported a relatively greater amount of GLS in canola meal averaging 8.50 mM/kg DM and In general, although the linear relationship between observed that milk iodine concentration was negatively milk and feed iodine concentration has been well associated with the percentage of canola meal included documented, there is still the need to (1) explore more in the feed, and ultimately to feed GLS levels. In par- thoroughly processes impairing the transfer from feed ticular, cows supplemented with 0.5 mg of iodine per to milk, (2) validate the association using larger sample kilogram of DM transferred 358, 289, and 169 μg of sizes, and (3) conduct observational studies to identify iodine per liter of milk for 0, 3.9, and 13.9% canola on-field practices with a favorable or unfavorable role inclusion in the ration DM, respectively (r = −0.99; in iodine recovery. Weiss et al., 2015). This was confirmed also when cows were exposed to 2.0 mg of iodine per kilogram of DM, Goitrogens and Iodine Antagonists in Animal Feed which led to milk iodine concentrations of 733, 524, and 408 μg/L for 0, 3.9, and 13.9% canola meal treatments, Goitrogenic substances, such as glucosinolates respectively (r = −0.93; Weiss et al., 2015). (GLS), thiocyanates, and nitrates, have been identified In this scenario, there is room to (1) specifically char- and characterized in a variety of plant species, includ- acterize goitrogen content and goitrogenic potential of ing ones in the cruciferous family (rape, canola, and crops and strains included as feed ingredients and (2) kale), soybean, beet pulp, millet, linseed, white clover, assess the relationship between these dietary antago- and sweet potato. Goitrogenic substances and their me- nists and final milk iodine concentration. tabolites can inhibit the sodium iodide symporter, di- minishing iodine uptake by the thyroid and mammary Milking Practices gland (Flachowsky et al., 2014). Consequently, feedstuff containing relatively high amounts of GLS leads to a The use of iodinated sanitizers for udder hygiene low excretion and thereby reduces milk iodine concen- has been recognized as an important factor affecting tration (Flachowsky et al., 2014). Furthermore, it is the concentration of this mineral in individual—and worth mentioning that, within the same plant species, thus bulk—milk. How composition of sanitizers (e.g., goitrogen concentration varies depending on the spe- iodized vs. noniodized, concentration of iodine) and Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2220 their application (e.g., predipping vs. postdipping, im- productive traits to fitness and health performances, mersion vs. spraying) influence iodine concentration such as functional morphology, reproductive charac- of milk has been explored in the literature. Although teristics, longevity, and resistance to diseases (Miglior not significant, the application of iodized sanitizer in et al., 2017). In addition, milk technological traits the premilking phase resulted in 16% more milk iodine have been proposed in some countries where cheese (121.1 µg/L) compared with control animals (104.4 production is important (Cassandro et al., 2016). µg/L; Rezaei Ahvanooei et al., 2021). A significantly However, desired characteristics that are not presently greater carryover was observed when postdipping sani- considered in dairy breeding objectives are potentially tizers were applied after milking (334.2 µg/L, +220%). numerous—for example, fine milk quality attributes, Due to dermal absorption, an increase in iodine was including protein composition and mineral fractions. observed even in serum and urine of those animals Although such attributes manifest exploitable genetic (Rezaei Ahvanooei et al., 2021). variation (Visentin et al., 2017, 2019) and are im- Borucki Castro et al. (2012) observed that the ap- portant for the dairy stakeholders (Henchion et al., plication of 1% iodized sanitizer through dipping and 2016), the difficulty of large-scale and cost-effective spraying increased milk iodine concentration of about data collection on fine composition traits is still a lim- +20 and +166%, respectively, compared with the ap- iting factor to be considered when designing ad hoc plication of noniodized disinfectants. Borucki Castro et breeding schemes. For this reason, for instance, genetic al. (2012) also observed that teats dipped in 0.5% io- parameters of milk minerals have been estimated by dized sanitizer presented +54% of milk iodine concen- few authors (Sanchez et al., 2018; Denholm et al., tration compared with not predipped teats. A smaller 2019; Visentin et al., 2019; Zaalberg et al., 2021). In increase was observed when predipping was performed Denholm et al. (2019), genetic parameters of milk with 0.5 and 1% iodine sanitizers followed by complete iodine concentration, quantified through inductively drying before milking (+15 and +33%, respectively). coupled plasma mass spectrometry, were estimated us- Similar increases were reported by McKernan et al. ing a linear mixed repeatability animal model in 267 (2020), who compared postmilking iodine-based teat Scottish Holstein dairy cows. In the aforementioned dips or sprays with non-iodine-based teat treatments, research, heritability (0.22 ± 0.12) and repeatability whereas French et al. (2016) discovered that milk (0.24 ± 0.08) estimates were characterized by rela- iodine concentrations increased from 6 to 20% when tively large standard errors due to the relatively small using iodine-based teat disinfectants compared with sample size. This is a typical characteristic of genetic products free of iodine. Notably, milk iodine increased studies based on data generated from reference (gold- gradually and consistently along the experimental pe- standard) laboratory methodologies that are generally riod (French et al., 2016), suggesting again that iodine costly and time consuming. Such limitations can be transfer is subjected to a carryover effect due to skin overcome by employing large-scale and cost-effective permeability. This has also been demonstrated by Con- assessment techniques such as prediction via mid- rad and Hemken (1978), who observed that one way infrared spectroscopy. Prediction of milk minerals and to increase milk iodine is through skin absorption. Ac- their fractions is still challenging, and the prediction cordingly, Borucki Castro et al. (2010) reported that accuracy at the moment is not sufficient for punctual in-line or hand spraying (which covers a large part of determination. Mid-infrared predicted minerals of milk the mammary gland with iodine) was the application can be used for screening and discrimination; thus, resulting in the greatest level of iodine in milk. These equations are not commercially available yet. Through findings have been—at least partially—confirmed in the prediction model developed by Niero et al. (2020) goat milk. As an example, Ovadia et al. (2018) re- that was characterized by a moderate accuracy (R2 ported an increase of 15% iodine in milk collected from in calibration, cross-validation, and external valida- goats treated with iodized sanitizer compared with tion of 0.69, 0.60, and 0.57, respectively), Costa et animals subjected to an iodine-free disinfectant. How- al. (2021) attempted to estimate genetic parameters ever, such an increase was not significant, likely due to of predicted iodine concentration using milk data of the limited sample size, which reduced the statistical 4,072 Italian Holsteins. Their results indicated that power of the study. iodine concentration is lowly heritable (0.025 ± 0.005) and characterized by an extremely low coefficient of Genetic Variation of Milk Iodine genetic variation (1.72%). These estimates suggest that directly improving iodine concentration in milk Breeding objectives for dairy cattle breeds have through selective breeding is far from being feasible changed in the last century, moving the emphasis from and convenient. However, it is worth highlighting that Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2221 Table 3. Average iodine concentration in dairy products Reference Matrix (dairy species) Samples, n Mean Minimum Maximum Milk, µg/kg Nerhus et al. (2018) Semiskimmed pasteurized milk (cow) 54 149 117 200 O’Kane et al. (2018) Whole pasteurized milk (cow) 24 470 467 473 O’Kane et al. (2018) Semiskimmed UHT milk (cow) 12 489 — — Stevenson et al. (2018) Whole pasteurized milk (cow) 96 3341 1981 5221 Stevenson et al. (2018) Whole UHT milk (cow) 48 3141 2801 3431 Walther et al. (2018) Whole UHT milk (cow) 220 911 351 1511 van de Kamp et al. (2019) Semiskimmed pasteurized milk (cow) 64 159 38 358 Niero et al. (2019) Whole pasteurized milk (cow) 5 254 — — Niero et al. (2019) Semiskimmed pasteurized milk (cow) 5 359 — — Niero et al. (2019) Whole UHT milk (cow) 5 305 — — Niero et al. (2019) Semiskimmed UHT milk (cow) 5 267 — — Arrizabalaga et al. (2020) Whole UHT milk (cow) 489 1901 1061 2721 Cheese, µg/kg Nerhus et al. (2018) Solid cheese (cow) 9 157 140 190 Nerhus et al. (2018) Soft cheese (cow) 6 155 130 180 Nerhus et al. (2018) Soft cheese (goat) 6 300 140 460 Nerhus et al. (2018) Whey cheese (cow) 6 1,200 1,000 1,400 Nerhus et al. (2018) Whey cheese (goat) 3 4,500 — — van der Reijden et al. (2019) Solid cheese (cow) 32 186 0 522 van der Reijden et al. (2019) Soft cheese (cow) 12 78 0 195 Yogurt, µg/kg Nerhus et al. (2018) Yogurt (cow) 6 155 130 180 van der Reijden et al. (2019) Yogurt (cow) 4 72 4 174 Protein concentrate da Silva et al. (2016) Casein concentrates (cow) 1 371 — — da Silva et al. (2016) Whey protein concentrates (cow) 4 4,348 2,530 8,040 Milk whey, µg/kg van der Reijden et al. (2019) Milk whey (cow) 44 75 0 197 1 Data expressed as micrograms per liter. mid-infrared predictions carry a certain prediction IODINE IN DAIRY PRODUCTS error, depending on the accuracy of the developed model. Such a prediction error contributes to increase Iodine Concentration in Dairy Products the residual variance in the animal model and, at the same time, to decrease the amount of variance attrib- Table 3 summarizes average iodine concentration in utable to additive genetic effect. This explains why the dairy products, including retail milk, different types heritability of mid-infrared predicted traits tends to be of cheese, yogurt, protein concentrates, and whey. To generally lower than that of reference traits measured date, iodine content has been well profiled in retail using gold-standard analyses (McParland et al., 2015). milk samples, addressing the effect of heat treatment This is clearly evident for milk iodine, if one compares (i.e., pasteurization and UHT), fat content (i.e., whole, the heritability found by Costa et al. (2021; 0.025) and semiskimmed, and skim milk), month and season of Denholm et al. (2019; 0.22). Further genetic investiga- sampling, and farming system (i.e., conventional and tions about milk iodine are advisable and should rely organic). Iodine concentration in retail milk is not sub- on more accurate phenotypes. jected to standardization and is thus extremely vari- In addition to the heritability, Costa et al. (2021) able, from 91 µg/L (Walther et al., 2018) to 489 µg/kg estimated the genetic correlations of milk iodine with (O’Kane et al., 2018). The recommended daily iodine other traits of interest, including milk composition. intake in adult women and men has been established at Infrared-predicted iodine concentration was nega- 150 µg/d (WHO, 2007). Considering the minimum and tively correlated with fat (−0.405) and protein con- maximum milk iodine level retrieved from literature, a tent (−0.169) and positively with milk yield (0.379), glass of milk (125 mL) can provide from 11 to 61 µg whereas the association with both lactose (0.140) and of iodine, which translates into 7 to 41% of the recom- SCS (−0.057) was weak. Whether there will be inter- mended daily intake of adults, respectively. This review est in increasing milk iodine even through breeding, an puts in evidence that a more stable iodine concentra- indirect selection through genetically correlated traits tion in drink milk can be achieved through different can be an effective solution. strategies within the dairy chain (Coneyworth et al., Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2222 2020)—for example, by monitoring iodine intake in As regards heat treatment, significant differences in lactating animals (Arrizabalaga et al., 2020). In fact, iodine concentration were not detected between pas- the high variability of this mineral in retail milk has im- teurized and UHT retail milk (van de Kamp et al., plications for the adequacy of iodine intake in consum- 2019), nor between unpasteurized and pasteurized ers, which could result in more serious consequences retail milk (O’Kane et al., 2018). However, authors for vulnerable groups such as newborns, children, and of both studies acknowledged that the limited sample pregnant women (van de Kamp et al., 2019). size considered could skew the results in relation to Fewer data are available for commercial dairy prod- temperatures used during treatment. To investigate ucts other than milk. Van der Reijden et al. (2019) the influence of heating on milk iodine concentration, reported average iodine concentration in cow cheese Walther et al. (2018) analyzed the same milk samples varying from 78 µg/kg (Tomino) to 186 µg/kg (Fon- before and after the UHT treatment. Iodine concentra- tina), meaning that 30 g of cheese provides between tion of untreated milk averaged 95 ± 23 μg/L, whereas 2.3 and 5.6 µg of iodine (i.e., from 1.5 to 3.7% of the the same samples averaged 95 ± 25 μg of iodine per li- recommended daily intake for adults). Similar concen- ter after UHT treatment, indicating that this treatment trations have been reported for yogurt by both Ner- had no influence on milk iodine concentration. These hus et al. (2018) and van der Reijden et al. (2019), conclusions were likely expected due to the fact that with average iodine concentrations of 155 and 72 µg/ iodine is a mineral element (i.e., inorganic compound) kg, respectively. Drastically greater iodine concentra- and therefore is not subject to deterioration through tions were measured in cow whey cheeses (1,200 µg/ heating. Moreover, at dairy plant level, milk steriliza- kg) and goat whey cheeses (4,500 µg/kg), suggesting tion is commonly performed as a continuous process, that a portion of 30 g contributes 24 and 90% of the without contact with the external environment, and for recommended daily intake, respectively. High iodine a very short period. Given this, any arising differences concentrations were also obtained for different kinds of between iodine concentration in raw and heat-treated whey protein isolates and concentrates, with an average milk can be due to an artifact. In a study aimed at iodine concentration of 4,348 µg/kg (da Silva et al., validating a chromatographic method for iodine quan- 2016). Such results suggest that iodine is likely embed- tification in raw and processed milk, Niero et al. (2019) ded in whey proteins, but specific and dedicated studies concluded that the variation in iodine concentration of are recommended to confirm this empirical speculation. commercial milk was more related to the milk chemical More efforts should be made to define analytical pro- composition than to heat treatments such as pasteuri- tocols for iodine concentration, with particular regard zation or UHT. Moreover, Arrizabalaga et al. (2020) to processed dairy foods. It will be useful to have a observed a similar concentration of iodine along the fat comprehensive overview of iodine concentration vari- gradient found in whole, semiskimmed, and skimmed ability in a broader range of products, including more UHT milk available in the Spanish (187, 189, and 189 industrial-scale products in addition to laboratory or μg/L, respectively) and French (201, 189, and 215 experimental-scale products. μg/L, respectively) markets. Similar conclusions were reported by O’Kane et al. (2018), who observed similar Effect of Heating and Skimming on Retail Milk iodine concentrations in whole (488.5 μg/kg), semis- Iodine Concentration kimmed (466.5 μg/kg), and skim milk (472.6 μg/kg). Due to the solubility of iodine compounds, O’Kane et The effects of heat and skim treatments on milk io- al. (2018) hypothesized that milk iodine is likely to in- dine concentration have been extensively investigated. crease in low-fat milk, which indeed contains a greater However, most of the studies focused on retail milk soluble fraction compared with other milk as a result of samples where no corresponding samples of the same the skimming process (Niero et al., 2019). Nevertheless, batch of milk were analyzed before and after the tech- although this idea sounds reliable and is in line with the nological treatment. A simple comparison of differently aforementioned study, it is fair to point out that this treated commercial samples is not optimal for studying is a mere speculation inferred from a small sample size the influence of processing, because several other fac- that lacks robust statistical support. tors are likely to interfere with the iodine level. There- fore, it is advisable to evaluate the effect of processing Effect of Season and Farming System on Retail Milk on iodine concentration along the processing line. This Iodine Concentration would permit researchers to follow the same batch of milk along the different processing stages (Walther at Scientific literature agrees on the seasonal variation of al., 2018). iodine concentration in bovine milk. In general, greater Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2223 concentrations are usually found in winter milk com- related cheese products; greater iodine concentration of pared with summer milk (O’Kane et al., 2018; van de milk was consistently coupled with higher iodine con- Kamp et al., 2019; Arrizabalaga et al., 2020). Greater centration of the manufactured cheese. Van der Reijden iodine supplementation and fewer iodine antagonists et al. (2019) reported that cheese ripening had a neg- in winter feed are among the main direct explanatory ligible to null effect on cheese iodine concentration. factors of these differences. Also, differences in milk The most recent literature agrees that, during cheese iodine concentrations across years and seasons can be manufacturing, milk iodine is mainly found in the whey indirectly related to climatic conditions of specific geo- (75 to 84% of milk iodine; van der Reijden et al., 2019) graphical areas, which regulate the beginning and end rather than in the curd where it has become incorpo- of the grazing period, and to the adoption of calving rated (below 25% of milk iodine; van der Reijden et al., patterns, which lead to synchronous administration of 2019). Such findings harmonize with the relatively low mineral supplements at different levels depending on cheese iodine concentration (Nerhus et al., 2018; van cattle physiological status and needs (Arrizabalaga et der Reijden et al., 2019), and the extremely high iodine al., 2020). Such factors may hide or overlap the proper concentration of whey cheeses and protein concentrates effect of season. In addition, assessing seasonal varia- (da Silva et al., 2016; Nerhus et al., 2018). This is also tions in iodine concentration of retail milk is even more in agreement with recent findings of Niero et al. (2020), difficult in the case of UHT milk. Indeed, there may be who reported a positive correlation (r = 0.22; P < 0.01) a wide variation in the time span between the treat- between iodine and lactose concentration in milk likely ment date and the purchase date, which ultimately due to the solubility of both compounds. According to creates challenges to date back to the actual milking the current knowledge, it is not possible to understand season (Arrizabalaga et al., 2020). the ratio between inorganic iodine (i.e., soluble or free Most studies also agree that conventionally produced iodine) and organic iodine (i.e., iodine associated with milk is characterized by greater iodine concentration organic compounds such as caseins or whey protein) of compared with milk produced under organic systems cow milk. Based on the considerations mentioned here, (Bath et al., 2012; Stevenson et al., 2018; Walther et we can speculate that most of the milk iodine is in solu- al., 2018). Frequent administration of fresh forages with tion or, at the most, in association with whey proteins. relatively great goitrogenic content and the reduced use of iodine supplements coupled with less frequent teat IODINE IN HUMAN HEALTH AND NUTRITION dipping are likely to reduce iodine concentration in organically produced milk (Flachowsky et al., 2014). The function of the thyroid gland is to produce T4 Lower iodine concentrations in organic milk compared and T3 thyroid hormones. These are characterized with conventional milk have been confirmed by Ner- by the presence of 4 and 3 iodine atoms within their hus et al. (2018), although with a less evident trend molecules, representing 65 and 59% of their molecular in comparison to the previously cited literature. In weight, respectively. Thus, in humans the production contrast, the study conducted by van de Kamp et al. of an adequate quantity of thyroid hormones depends (2019) in the Netherlands resulted in no differences in on an adequate intake of iodine, the rate-limiting ele- iodine concentration between conventional and organic ment for the synthesis of thyroid hormones. Iodine can milk; similar results were reported by Qin et al. (2021) be obtained exclusively through the diet or through in conventional and organic milk produced in southern iodine supplements and cannot be replaced by any England. other nutrient (Velasco et al., 2018). Following the current guidelines of the World Health Organization Effects of Milk Processing on Iodine Concentration (WHO, 2007), recommended daily iodine intake is as of Dairy Products follows: 150 μg/d in adults (above 12 yr old); 250 μg/d in pregnant and lactating women, due to the increased So far, the effect of cheese-making protocols on io- thyroid hormone synthesis by the mother and initiation dine concentration in curd, cheese, and whey have been of thyroid hormone production at wk 16 to 18 by the fe- poorly investigated. Studies often show several limita- tus, as well as the mother-to-newborn transfer of iodine tions—for example, limited sample size, laboratory- occurring during breastfeeding; 90 μg/d in preschool scale products, or restricted geographical areas. children (0 to 59 mo old); and 120 μg/d in schoolchil- Van der Reijden et al. (2019) observed a linear dren (6 to 12 yr old). Iodine deficiency causes a wide relationship between milk iodine concentration and range of health side effects. Overall, diseases associated cheese iodine concentration, with R2 from 0.95 (semi- with inadequate thyroid hormone production are col- hard cheeses) to 1.00 (fresh cheeses). Such results were lectively referred to as iodine deficiency disorders. The confirmed regardless of the cheese-making process and consequences observed after enduring iodine deficiency Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2224 depend on its duration and severity. Thyroid hormones still poorly understood and data are conflicting (WHO, are indeed fundamental for appropriate neurological 2007; Lee and Pearce, 2015; Pearce et al., 2016). Recog- development, and the period between conception and nizing the importance of iodine deficiency prevention, the first 2 yr of life (known as the “first 1,000 d”) is in 1991 the WHO established the goal to eliminate fundamental in the long-term brain development of the iodine deficiency, and 2 yr later the United Nations child (Mattei and Pietrobelli, 2019). Thus, severe io- Children’s Fund recommended Universal Salt Iodiza- dine deficiency endured during fetal life creates higher tion as the principal strategy to guarantee an adequate risks of “cretinism,” miscarriage, and infant mortality iodine intake, based on the iodization of the salt used, (Laurberg et al., 2010). The same deficiency in adult including that derived from food industrial processing. life causes hypothyroidism and goiter (Laurberg et al., Since the 1990s, great improvements have been made 2010). However, moderate iodine deficiency can also in the elimination of iodine deficiency–related diseases: have consequences for human health, especially dur- according to WHO data, the number of iodine-deficient ing pregnancy. Although data are still weak, because countries decreased by half, from 110 countries in 1993 they come from observational studies, a growing body to 54 in 2003 (UNICEF, 2008). From 2003 to 2017, of studies have documented how the offspring of moth- the number of iodine-deficient countries in the world ers who experienced mild to moderate iodine deficiency further fell by 64.8%, from 54 countries to 19 (Gizak during pregnancy are more likely to show learning dis- et al., 2017). Although data demonstrate that improve- abilities and poorer verbal intelligence quotient scores ments were achieved through specific campaigns in (Levie et al., 2019), and even more conflicting data the past decades, it is still a long road to reach iodine exist on a possible association with autism (Velasco et adequacy and iodized salt coverage, even in developed al., 2018; Levie et al., 2020). countries and particularly in childbearing-age women However, excessive iodine intake should also be dis- (Gizak et al., 2017). Alternative valid sources of io- couraged. Indeed, iodine intake and thyroid functions dine are represented by milk and dairy products due are subject to hormesis, so their relationship follows to supplementation of iodine in cattle feed (Herrick et a relationship-inverted pattern: not only inadequate al., 2018; Walther et al., 2018). In numerous published intake but also excessive iodine availability are harmful reports, dairy products have demonstrated a significant to correct thyroid function, leading to goiter, thyroid role in contributing to the total iodine intake, especially autoimmunity, hypothyroidism, or hyperthyroidism in children (Censi et al., 2020; Bath et al., 2022). Cow (Laurberg et al., 2009). The quite small range for ade- milk consumption decreases during the lifespan, from quate iodine intake was clearly pointed out by a Danish childhood to adolescence and adulthood, paralleling population study, set to prospectively monitor the io- the frequency of adequate iodine intake, which falls ac- dine fortification program. The study showed profound cordingly, demonstrating the importance of cow milk effects of even small differences in iodine intake on the and dairy products as central contributors to iodine prevalence of goiter, nodules, and thyroid dysfunction, adequacy (Witard et al., 2022). with several environmental factors influencing the epide- miology of thyroid disorders, some factors acting via an INTEREST AND AWARENESS interaction with iodine intake and others independent OF SCIENTIFIC COMMUNITY of iodine (Laurberg et al., 2006). The relatively narrow range between deficiency and a more-than-adequate It is inarguable that milk and its derived products intake is particularly evident during infancy: school-age play a key role in facing iodine deficiency, especially children are great milk consumers and are more prone in populations with scarce access to seafood or iodized to an excessive iodine intake (Farebrother et al., 2018; salt (WHO, 2007). Therefore, in some circumstances, Bath et al., 2022). Thus, many societies recommend a the inclusion in the diet of dairy foods naturally rich in lower iodine intake in young children than that of 90 iodine becomes of primary importance to reduce the risk μg/d recommended by WHO (Committee on Medical of thyroidal dysfunctions and guarantee physiological Aspects of Food Policy, 1991). Although many data hormone synthesis (Watutantrige Fernando et al., 2013, showed that even excessive iodine intakes in children 2016). Unfortunately, awareness of the importance of seem to be well tolerated, at least judging based on the iodine intake is still low among the general population, absence of short-term thyroid dysfunctions (Farebrother but also among health care professionals (Combet et et al., 2018), it should nevertheless be avoided, because al., 2015; Kayes et al., 2022), as is the knowledge of data on possible long-term consequences are still lack- how to achieve adequate iodine intake. In particular, ing. Also, pregnant women and their developing fetus, the fact that dairy products are a great source of iodine as well as breastfed infants, may be vulnerable to iodine is largely neglected (Combet et al., 2015; O’Kane et in excess, although the implications of iodine excess are al., 2016). Because a close relationship exists between Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2225 Table 4. Criteria used to explore the interest in milk iodine in Scopus (https:​/​/​www​.scopus​.com/​) Key word combination Location Time period Output “Iodine,” “milk” Title, abstract, or indexed key 2010 to 2021 Total documents, review articles, “Iodine,” “milk,” “human health” words or original articles “Iodine,” “milk,” “dairy” the knowledge of iodine’s role and its proper dietary The interest in milk iodine within and across differ- intake (O’Kane et al., 2016), efforts should be made to ent scientific communities has been explored. For this promote a greater awareness in populations. purpose, target key word combinations were input fol- Promoting the consumption of animal foodstuff has lowing methodologies and criteria summarized in Table become more challenging in the current era, even with 4. In particular, time trends for the period from 2010 the proven and documented beneficial properties that to 2021 were obtained by restricting the time window of come with animal consumption (Henchion et al., 2021). the research, and the final output consisted in number The consumption of animal products rich in saturated of items traced back for each year (Figure 2). Both the fatty acids has been speciously linked to human dis- key word combinations selected show a positive trend eases. According to Nicklas (2003), this was mainly due in the same direction and demonstrate that milk iodine to the misconception that meat and dairy introduced is a popular subject of debate. In detail, the number into the diet, even in small amounts, increases the risk of documents where “milk” and “iodine” are present in of cardiovascular disease and weight gain. The public the most informative locations—namely, title, abstract, should bear in mind that multifactorial disorders and and Scopus indexed key words—progressively increased pathologies such as strokes and hypertension are the across years following a linear trend (Figure 2). result of combined actions—that is, genetic predisposi- tion and lifestyle. In addition, it is important to remark FINAL REMARKS that foods of animal origin are essential to humans, as they are providers of essential nutrients such as miner- This review provides a wide-ranging overview of fac- als, fatty acids, amino acids, and vitamins (Niero et tors that contribute to iodine concentration in milk and al., 2019). Lastly, the dairy chain is currently facing dairy products and is primarily intended to make the hardship on grounds other than health-related issues, scientific community aware of the importance of this and the whole livestock sector is associated with issues mineral in animal and human nutrition. Several studies relating to food-animal welfare and to greenhouse gas have demonstrated that milk iodine concentration is emissions (FAO, 2018). closely associated with its respective concentration in Nevertheless, stakeholders along the whole chain of the feed. The correlation between the iodine concentra- various livestock production systems should identify tion in feed and milk is linear and characterized by the most appropriate and effective strategies to valorize different dose-response effects according to the feed and their products at best. In the case of milk and dairy, presence of supplementation. Goitrogenic substances efforts should specifically aim to increase the audience’s found in certain forage species are antagonists of iodine, recognition and awareness of nutritional deficiencies in and their specific effects on the concentration of iodine humans. Proper advertisement, attractive and informa- in milk remain to be further elucidated in cattle. From tive labeling, and awareness campaigns are the best the present literature review, we also conclude that the tools to spread knowledge on deficiency-related disor- iodine concentration in bovine milk can be affected by ders. These are also useful ways to stimulate—or keep milking practices and industrial processing. In particu- constant—the purchase frequency of dairy (Wesana et lar, the use of iodine-based products for teat cleaning al., 2020). Milk is the primary source of iodine in the is responsible for a notable artificial increase in the United Kingdom, but the popularity of plant-based concentration of iodine in dairy cows. The effect of milk beverages is constantly increasing to such an extent technological treatments had a minor impact on iodine that they have become milk substitutes, especially in concentration. Being strictly management dependent, adults (Dineva et al., 2021). Although most plant-based the milk iodine concentration is expected to be scarcely drinks are fortified in specific nutrients, the concentra- heritable. Moreover, collection of accurate phenotypes tion of iodine is lower compared with bovine milk; this on a large scale is rather difficult, as the predictive inevitably means a reduction in the daily iodine intake performance of mid-infrared spectroscopy is far from in consumers who choose to totally or partly replace considered reliable enough to be implemented on the bovine milk (Dineva et al., 2021). pool of traits routinely measured, representing an issue, Journal of Dairy Science Vol. 106 No. 4, 2023 Niero et al.: INVITED REVIEW: IODINE IN THE DAIRY SECTOR 2226 Figure 2. Overview of publications including the key words “milk” and “iodine” in various locations across years (source: Scopus, https:​/​/​ www​.scopus​.com/​). 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