1 Human-driven global nutrient imbalances increase risks to health 2 3 Josep Penuelas1,2,* and Jordi Sardans1,2 4 5 1 CSIC, Global Ecology Unit CREAF‐CSIC‐UAB, 08193 Bellaterra, Barcelona, Catalonia, Spain 2 6 CREAF, 08193 Cerdanyola del Vallès, Barcelona, Catalonia, Spain 7 8 * Corresponding author 9 Emails:Josep.penuelas@uab.cat 10 11 12 Abstract 13 Human-induced inputs of nitrogen (N) and phosphorus (P) into the biosphere have reached unprecedented 14 levels, particularly N, leading to an escalating global anthropogenic N:P ratio. This ratio has emerged as a 15 significant driver of environmental change, impacting organisms, ecosystems, and global food security. 16 However, the implications of this ratio for human health have been largely overlooked and remain 17 uncertain. This article aims to fill this knowledge gap by exploring the potential effects of N:P ratios on 18 both non-infectious and infectious diseases. Preliminary data emphasize the importance of investigating the 19 influence of N:P ratios on human health, suggesting a potential role in the rise of non-infectious diseases, 20 such as cancer, as well as the proliferation of infectious diseases, including Zika and malaria. These findings 21 highlight the urgent need for increased attention from the scientific community and policymakers regarding 22 the complex impacts of the human-induced biospheric N:P ratio. It is crucial to investigate and understand 23 the underlying mechanisms and drivers behind these effects. Furthermore, there is significant potential for 24 improving human health through the manipulation of N:P ratios and the availability of N and P. This applies 25 not only to medical treatments but also to innovative fertilizer management strategies. These avenues 26 present promising opportunities to address the challenges associated with human health in an ever-changing 27 world. 28 29 Keywords: Nitrogen; Phosphorus; N:P ratio; Non-infectious diseases; Infectious diseases; 30 Medicaltreatments 31 32 1. Human impacts on nitrogen and phosphorus cycles 33 In recent decades, human activities have had a profound impact on the nitrogen (N) and phosphorus (P) 34 cycles, leading to unprecedented releases of N into the environment and resulting in a nutrient imbalance 35 between N and P in the biosphere 1. Anthropogenic inputs of reactive N to the biosphere, driven by fossil 36 fuel combustion and fertilizer use, have increased significantly, contributing to annual N releases of 25–33 37 Tg N and >150 Tg N, respectively. Additionally, leguminous crops and rice fix approximately 90 Tg N per 38 year from atmospheric N2. Some regions have also experienced N eutrophication 2. On the other hand, 39 anthropogenic releases of P have remained relatively stable and lower compared to N, primarily originating 40 from fertilizer use (22–26 Tg P per year) and animal feed. However, these human-induced P fluxes, 1 41 although comparable to natural global fluxes 3, have been shown to cause regional soil and water 42 eutrophication, influencing the global biogeological P cycle. 43 The difference in the anthropogenic release of reactive N and P has led to an overall increase in the 44 global mean N:P ratio, which now stands at approximately 30 on a molar basis for anthropogenic inputs, 45 while values for principal ecosystem components range from 16 (ocean water, plankton) to 22 (soils). 46 However, at local-regional scales, the imbalance in N and P inputs may be even greater due to uneven 47 distribution and differences in environmental mobility. P tends to have low water solubility and 48 volatilization, often adsorbing and precipitating in the soil as salt minerals or being buried in sediments 49 near emission sources. In contrast, N is more water-soluble and volatile, spreading over larger distances 50 from its sources 4. 51 P enrichment is common in agricultural soils, as it has low solubility and a tendency to precipitate and 52 become immobilized. This has led to declines in N:P ratios in several parts of the world 4,5, particularly in 53 regions with high livestock density where manure waste exhibits very low N:P ratios 6. While most 54 continental and coastal areas have experienced increased N:P ratios due to N spreading capacity, cropland 55 soils and adjacent habitats receiving untreated or diffuse wastes and leachates have witnessed decreased 56 N:P ratios. 57 The N:P ratio plays a crucial role in determining community structure and function, especially when 58 concentrations of both N and P are not limiting. Plankton’s protein synthesis rate, for instance, is dependent 59 on the amount of P-rich RNA produced, leading to a negative correlation between cellular N/P ratio and 60 protein synthesis rate, resulting in faster growth rates of plankton with lower N/P ratios 7. This negative 61 correlation has ecological consequences for the structure and functioning of ecosystems, as observed in 62 various ecosystem types 4. 63 In addition to N and P imbalances, human activities have also caused imbalances among other 64 elements, such as carbon (C), N, iron, zinc, calcium, and potassium, in plant tissues 8,9 . Increasing 65 atmospheric CO2 concentrations are likely drivers of increased C concentrations in plants, consequently 66 reducing the concentrations of these other elements 8,9. 67 While the environmental impact of human-driven N and P inputs on managed and semi-natural 68 ecosystems and food security is well-documented 1-4 , their direct effects on human health are less 69 understood. This article aims to review current research on the potential impacts of N:P ratios on human 70 health (Fig. 1), shedding light on this important yet understudied aspect. 71 72 2. Impact of nutrient imbalances on human health 73 2.1. Growth 74 Humans, like other species, are profoundly influenced by elemental and stoichiometric changes in their 75 environment. The impact of anthropogenic shifts in the input of N and P into the biosphere, and the resulting 76 changes in N:P ratios, have cascading effects on the human food chain 10,11. In the past, the excessive use 77 of N fertilizer in economically advanced countries has led to food overproduction, while low levels of 78 fertilizer use in economically developing countries have helped prevent malnutrition 12. These disparities 79 in fertilizer use have contributed to variations in human growth and development. Notably, variations in 80 per capita intake of N and P, as well as the associated balance in the N:P ratio, correlate with differences in 2 81 the average height of men born in high-income countries. This correlation is even more significant than 82 socioeconomic or sanitary variables such as GDP, the human development index, and birth weight, as 83 indicated by integrated analyses of data from FAO (2006), OECD (2022), and WHO 10. 84 85 2.2. Non-infectious diseases 86 2.2.1 Nitrogen immunological and oncological effects 87 The positive effects of increased N and P intake on human growth and development are accompanied by 88 potential risks to the triggers of non-infectious diseases. For instance, the global annual N fertilization of 89 wheat has significantly increased from 9.8 to 93.8 kg/ha between 1961 and 2010 13, reflecting the overall 90 rise in N fertilizers across different types of farmland (11.3–107.6 Tg) 14. This escalation in N fertilization 91 has raised concerns about the potential increase in the risk of health disorders, including coeliac disease, 92 due to the elevated content of allergenic proteins 15, such as gluten 16,17, particularly the gliadin fraction 18- 20 93 , which is known to trigger and sustain this disease 21-23 . Notably, a higher availability of N has been 94 associated with increased expression of gliadin genes . 20 95 Anthropogenic increases in N, particularly in its active/reactive forms such as nitrate and ammonium, 96 and exposure to atmospheric nitrogen dioxide in occupational and domestic settings, can have adverse 97 effects on human health. However, the pervasive presence of environmental pollutants derived from 98 reactive N complicates the interdisciplinary assessment of their harmful effects on human health 24. 99 The increasing concentrations of nitrates (NO 3-) in groundwater resulting from surface leaching of 100 fertilizers, as well as industrial, animal, and human waste, pose health risks when consumed in drinking 101 water, especially for children under five years old 25. For example, the leaching of livestock waste from 102 cropland has led to high levels of water pollution in aquifers in Europe, China, India, Reunion Island, and 103 various regions of the USA, Canada, and Australia 26-33 . Nitrates and nitrites are also used in processed 104 meats as additives in meat curing 34 and their intake has been related to breast and prostate cancer risk in 105 humans 35. 106 107 2.2.2 Phosphate and cancer 108 High dietary consumption of phosphate (PO4) has been found to stimulate the growth of lung and skin 109 tumours in experimental animals, potentially due to increased growth-promoting cell signaling, 110 neovascularization, and chromosome instability in the presence of excessive phosphate 36. 111 Tumour cells are known to exhibit higher expression levels of phosphate cotransporters and 112 accumulate larger quantities of inorganic phosphate compared to healthy cells 36,37. For example, lung and 113 colon tumours have been found to contain approximately double the amount of P and RNA concentration 114 compared to healthy tissue, resulting in lower N:P ratios 38,39 . Elser et al.38-40 analyzed the elemental 115 composition of normal and tumour tissues from the lung, colon, liver, and kidney. Consistent with the 116 Growth Rate Hypothesis (GRH), they observed that lung and colon tumours exhibited significantly higher 117 P and RNA concentrations (as a fraction of dry weight) and lower N:P ratios compared to their respective 118 normal tissue. However, they did not find significant differences in %P and %RNA between malignant and 119 normal tissues in the liver and kidney tumour tissues. Moreover, the P present in RNA accounted for a 120 significantly larger fraction of the total biomass P in malignant tissues than in normal tissues. These findings 3 121 support the GRH, which suggests that under conditions where neither N nor P is limiting, a low N:P ratio 122 is associated with a high growth rate, as P-rich RNA becomes the limiting factor for synthesizing amino 123 acids and building proteins. 124 Considering the growing evidence linking phosphate and N:P ratios to certain cancer incidences in 125 humans, it is crucial to consider the human-driven impacts on global P and N cycles 3,41 and their potential 126 consequences on P concentrations and N:P ratios in food. Accumulation of P in some cropland soils has 127 been reported, leading to increased P uptake by crops and potentially influencing food composition by 128 elevating P concentrations 42-44 . Although studies have shown high levels of P uptake in both crops and 129 non-crop plants under conditions of high soil P concentrations, the global-scale link between P 130 accumulation in crop soils, P concentrations in food, and the resulting implications for human health 131 remains unknown. Further research is needed to explore the effects of increased dietary P intake, as 132 excessive P intake has been inconsistently linked to health problems such as bone health, cancer risk, and 133 heart failure associated with the augmented use of P additives in foods 45-47. 134 Several reports have highlighted the links between cancer incidence and phosphate levels in the human 135 body. Chromosome instability, a characteristic of cancer cells, has been positively associated with high 136 phosphate concentrations. For example, hyperphosphatemia has been shown to increase the risk of 137 chromosome aberrations in the parathyroid glands of patients with hyperparathyroidism 48, and high levels 138 of dietary phosphate have been linked to increases in lymphocyte genotoxicity 49 . A 24-year monitoring 139 study as part of the Health Professionals Follow-Up Study revealed that high levels of dietary phosphate 140 are independently associated with lethal and high-grade prostate cancer 50 . Milk and dairy products 141 contribute the highest percentage of phosphate intake in the American diet 51 . Newmark and Heaney 142 proposed that phosphate from dairy products is a risk factor correlated with prostate cancer in 143 epidemiological studies of American male physicians and Swedish males 52. In Swedish women, cancer 144 (all types) mortality increased by 44% (hazard ratio 1.44; 95% confidence interval 1.23–1.69) when 145 consuming three glasses of milk per day compared to one glass 53. In a clinical study of 9,686 adults aged 146 20–80, with analyses adjusted for demographics, cardiovascular risk factors, kidney function, and energy 147 intake, higher phosphorus intake was associated with higher all-cause mortality in individuals, with this 148 association being particularly significant among individuals with a daily phosphorus intake exceeding 1,400 149 mg/d 54. 150 These findings emphasize the complex relationship between phosphate levels, dietary intake, and 151 cancer incidence. Tumour cells exhibit altered phosphate accumulation and metabolism, which can 152 contribute to their growth and proliferation. Furthermore, the accumulation of phosphorus in certain 153 cropland soils and its subsequent uptake by crops raise concerns about elevated phosphorus concentrations 154 in food. However, the direct implications of these changes on human health are still not fully understood. 155 Further research is needed to explore the specific mechanisms underlying the association between 156 phosphate levels and cancer development. Additionally, investigating the global-scale link between 157 phosphorus accumulation in crop soils, phosphorus concentrations in food, and their impact on human 158 health is crucial. Understanding the effects of excessive dietary phosphorus intake and the use of 159 phosphorus additives in food production will help to elucidate potential health risks and guide strategies 160 for maintaining a balanced and healthy diet. 4 161 In conclusion, medical studies have underscored the role of phosphate toxicity as a pathophysiological 162 determinant in cancer cell growth, with tumour cells exhibiting higher expression levels of phosphate 163 cotransporters and storing larger amounts of inorganic phosphate compared to normal cells. Disruption of 164 phosphate homeostasis has been associated with the development of various human tumours 36. 165 166 2.2.2 Therapies for cancer 167 Chemotherapy typically results in a significant reduction in tumour populations, often by a factor of a 168 thousand, before resistance emerges. However, complete eradication of the tumour population is essential 169 to prevent tumour recurrence, as the extracellular conditions following chemotherapy can stimulate the 170 proliferation of surviving tumour cells due to the release of substantial amounts of phosphate and other 171 cellular material upon tumour cell death 55 . Therefore, integrating stoichiometric theory into cancer 172 treatment strategies may enhance the efficacy of chemotherapy. For example, post-chemotherapy dialysis, 173 which selectively removes circulating phosphate from the blood plasma, could be considered to minimize 174 the proliferation of surviving tumour cells and facilitate improved immune system management 40. 175 However, it is not only phosphate itself that plays a critical role; the N:P ratios may also be crucial in 176 enhancing the effectiveness of cancer therapies. One promising approach in combating cancer growth 177 involves targeting the p53 tumour suppressor gene. The successful application of this therapy relies on the 178 specific delivery of the p53 gene to cancer cells. The protein carriers involved in the process possess 179 structures—such as morphology, size, and surface charges—that are highly influenced by the N:P ratio (the 180 ratio of nitrogen to phosphate groups). It has been observed that the N/P ratio significantly impacts the 181 efficiency of gene transfection, a process that involves introducing nucleic acids into eukaryotic cells using 182 nonviral methods. Thus, the N:P ratio can be precisely adjusted to achieve desired levels of protein 183 expression and apoptosis. The notable advantage of this proposed system lies in the use of N/P ratios as a 184 customizable parameter that not only modulates vector properties but also controls the extent of plasmid 185 DNA delivery, protein production, and, consequently, the efficacy of p53-mediated cancer therapy 56,57 . 186 Therefore, manipulating N/P ratios through dietary interventions or other strategies represents an additional 187 tool that warrants investigation in the fight against certain types of human non-infectious diseases. 188 189 2.3. Infectious diseases 190 There is emerging evidence that gaining a better understanding of the role of environmental stoichiometry 191 in the structure, organization, and function of human microbial communities can contribute to the 192 management and control of disease vectors. Analysis of stoichioproteomics in different body-site locations 193 has revealed variations in the N content of microbial proteins, with skin and nasal proteins, for example, 194 being particularly nitrogen-rich. These varying proportions of bio-elements in proteins from distinct organ 195 tissues are likely linked to the local environments at different human body sites, including atmospheric 196 exposure and food intake rates 58. Moreover, as atmospheric carbon dioxide levels increase globally due to 197 the burning of fossil fuels, human plant food sources show increased C:N and C:P ratios 59,60 , suggesting 198 that humans are altering the elemental stoichiometry that we provide to our symbiotic gut bacteria. This 199 can have impacts on the species structure of gut microflora, which requires further analysis. 5 200 Nutrient stoichiometry, such as N:P ratios, may influence traits, growth, and the geographical 201 distribution of human parasites, thereby impacting the incidence and severity of vector-borne diseases. 202 Paseka and Grunberg 61 examined 27 macroparasite taxa from four phyla that infect vertebrate and 203 invertebrate hosts in freshwater ecosystems in New Jersey. They observed that the allometric scaling of 204 phosphorus across species supports the Growth Rate Hypothesis, which predicts that smaller taxa require 205 more phosphorus to support their relatively higher growth rates. Across all species, parasite phosphorus 206 concentrations scaled negatively with body size, while C:P ratios scaled positively. Similar relationships 207 between parasite phosphorus concentrations and body size were observed at the phylum level and within 208 individual species. Nitrogen concentrations and C:N ratios were related to the life-cycle stage, with non- 209 reproductive parasite stages having lower nitrogen concentrations and higher C:N ratios than actively 210 reproducing parasites. Organismal stoichiometry was found to be linked to ecological function, and the 211 wide variation in macroparasite stoichiometry likely generates diverse patterns in host-parasite nutrient 212 dynamics, as well as variable relationships between parasitism and nutrient cycling. This suggests how the 213 N:P availability ratio in the environment (water and soil) can affect parasites and, consequently, the 214 performance of several human infectious diseases. 215 Aalto et al. 62 reviewed shifts in host-parasite interactions under changing nutrient ratios and observed 216 that the outcome of infection may depend on the overlap in the stoichiometric requirements of the host and 217 the parasite. The authors further hypothesized that environmental nutrient enrichment alters infectivity 218 dynamics, leading to fluctuating selection dynamics in host-parasite coevolution. Shifts in parasite 219 stoichiometry that result in changes in ecosystem function 61 are likely to drive patterns in host-parasite 220 nutrient dynamics, including nutrient cycling, as well as the transmission and prevalence of vectored 221 diseases. These dynamics may depend on overlaps in stoichiometric requirements between hosts and 222 parasites and could potentially impact host-parasite coevolutionary processes 62. In a long-term chemostat 223 experiment conducted by Larsen et al. 63, the marine cyanobacterium Synechococcus was challenged with 224 a lytic phage while manipulating nutrient stoichiometry. The researchers observed alterations in the stability 225 of host-parasite interactions and the underlying mode of coevolution. Nutrient stoichiometry can affect eco- 226 evolutionary feedbacks in ways that may alter the dynamics and functioning of environmental and host- 227 associated microbial communities. 228 Shifts in environmental N:P ratios are likely to impact globally important human diseases, such as 229 mosquito-vectored malaria, which annually causes an estimated 2 million deaths, with particularly severe 230 effects on children under the age of five 64. Ecosystem processes operating on various spatio-temporal scales 231 drive the diversity and abundance of aquatic mosquito larvae that may carry malaria-causing protist 232 parasites (Plasmodium spp.). For instance, shifts in nutrient stoichiometry can affect aquatic plant 233 communities, which provide protection from mosquito predators and serve as substrate for bacteria 234 consumed by mosquito larvae. These shifts can have consequences for the composition of the mosquito 235 community, including species with varying degrees of vectoring efficiency. Studies conducted in 236 subtropical, P-limited oligotrophic wetlands have demonstrated mechanistic links between nutrient 237 enrichment, wetland vegetation, and vector production. In these wetlands, P-enriched runoff from 238 agricultural land and human settlements has resulted in the replacement of sparse macrophytes (rush) by 239 tall, dense species (cattails), impacting the larval mosquito community 65,66. Similarly, increased N:P ratios 6 240 in a western Mediterranean river basin, attributed to improved wastewater treatment, have led to higher 241 macrophyte density, and consequently to increased abundance, and expansion of populations of the black 242 fly (Simulium erythrocephalum), a vector of several pathogenic microbes 67,68. 243 Overlap in parasite-host stoichiometric requirements has been observed, particularly in the case of N:P 244 ratios in a freshwater cyanobacterium host (Planktothrix rubescens), which were positively correlated with 245 experimental N:P ratios. These host responses were mirrored in the N:P stoichiometry and the production 246 of toxic microcystins by the fungal parasite Rhizophydium megarrhizum (Chytridiomycetes), while 247 zoospore size exhibited a negative association with N:P ratios 69 . Consequently, fungal parasites 248 demonstrate a trade-off between zoospore size and production. As zooplankton graze on chytrid zoospores, 249 changes in parasite production, stoichiometry, and zoospore cell size can have implications for aquatic food 250 web dynamics. 251 The GRH provides evidence of how parasite-host relationships are influenced by N:P ratios, as the 252 growth rates of hosts with low C:P-ratio diets are positively associated with levels of viral infections 70 and 253 bacterial infections 71. Although the understanding of this relationship in human pathogenic parasites is 254 limited 72, this association could be of concern for human health in countries where diets are high in P 73. 255 For example, N:P ratios drive the growth of non-pathogenic bacteria and associated blooms in aquatic 256 systems 7,11 , suggesting that shifts in N:P ratios might also influence the growth and proliferation of 257 pathogenic bacteria, such as Vibrio cholerae, the causative agent of cholera, and heterotrophic bacteria in 258 aquatic environments 72. 259 Effects of shifts in environmental stoichiometry on the incidence of vector-borne parasitic diseases in 260 humans may be influenced by their impacts on hosts 74. This is evident from the effects of aquatic ecosystem 261 stoichiometry on the distribution and population dynamics of larval mosquitoes, which in turn affect adult 262 mosquitoes 75,76 . For instance, mosquito larval hosts of Zika virus exhibit accelerated growth and earlier 263 maturation when provided with an N-rich diet featuring high N:P ratios. This results in a shorter 264 transmission period and reduced risk of infection in humans 77. 265 Consequently, the relationship between environmental nutrient enrichment and pathogen abundance 266 is intricate, and it varies depending on factors such as microbe type, host/vector density and distribution, 267 pathogen virulence and toxicity, ecosystem conditions, degree of enrichment, and the life cycles of the 268 parasites involved. Such effects may exacerbate the incidence of diseases caused by generalist parasites 269 with direct or simple life cycles, potentially leading to sustained epidemics or chronic pathology. 270 Understanding the interactions between nutrient enrichment and disease becomes increasingly crucial in 271 tropical and subtropical regions, where nutrient inputs are predicted to rise in pathogen-rich environments, 272 thereby necessitating disease management strategies to mitigate the intensification of global nutrient cycles 78 273 . 274 275 3. Conclusions 276 Anthropogenic inputs of N and P have surpassed the planetary safety threshold, leading to severe 277 consequences for ecosystems and global food security, but also very likely human health. Activities such 278 as fertilizer use, pollution, and dietary changes have likely contributed to the increased prevalence of non- 279 communicable diseases in developed countries, including lung and colon cancers, and coeliac disease. 7 280 Additionally, in developing countries, these inputs have contributed to the spread of vector-borne diseases 281 like malaria and Zika. However, several studies have also highlighted the potential benefits of controlling 282 N, P, and N:P ratios in human intake as a therapeutic approach. This aligns with the observation of high 283 concentrations of phosphorus-rich RNA, elevated P levels, and low N:P ratios in various neoplastic cells. 284 Furthermore, recent research suggests that manipulating molecular N:P ratios can enhance the effectiveness 285 of active molecular medicines, and improved management of N and P shifts holds promise for controlling 286 vector-borne diseases. We advocate for deeper scientific and management consideration of anthropogenic 287 nutrient imbalances in human health science under global change. Furthermore, we assert that the increasing 288 N:P ratio and nutrient imbalances should be recognized as another of the planetary boundaries already 289 crossed by humans (Fig. 2). 290 291 Declaration of competing interests 292 The authors declare no competing interests at all. 293 Author contributions 294 J.P. and J.S. designed the study, gathered the information and wrote the manuscript 295 Acknowledgments 296 Grants TED2021-132627B-I00 and PID2022-140808NB-I00 funded by MCIN, 297 AEI/10.13039/501100011033 and by the European Union NextGenerationEU/PRTR, and grant 298 CIVP20A6621 from the Fundación Ramón Areces. We thank Rosa Casanovas for her help with the figures. 299 300 References 301 (1) Peñuelas, J.; Sardans, J. The global nitrogen-phosphorus imbalance. Science 2022, 375, 266-267. 302 (2) Melillo, J. M. Disruption of the global nitrogen cycle: A grand challenge for the twenty-first century: This 303 article belongs to Ambio’s 50 th Anniversary Collection. Theme: Eutrophication. Ambio 2021, 50,759-763. 304 (3) Peñuelas, J.; Poulter, B.; Sardans, J.; Ciais, P.; van der Velde, M.; Bopp, L., et al. Human-induced 305 nitrogen-phosphorus imbalances alter natural and managed ecosystems across the globe. Nat. Commun. 2013, 306 4, 2934. DOI: 10.1038/ncomms3934. 307 (4) Peñuelas, J.; Janssens, I. A.; Ciais, P.; Obersteiner, M.; Sardans, J. Anthropogenic global shifts in 308 biospheric N and P concentrations and ratios and their impacts on biodiversity, ecosystem productivity, food 309 security, and human health. Glob. Change Biol. 2020, 26, 1962-1985. 310 (5) Peñuelas, J.; Sardans, J., Rivas-Ubach, A.; Janssens, I. A. The human-induced imbalances between C, N 311 and P in Earth’s life system. Glob. Chance Biol. 2012, 18, 3-6. 312 (6) Oster, M.; Reyer, H.; Ball, E.; Fornara, D.; McKillen, J.; Sorensen, C. U., et al. Bridging gaps in the 313 agricultural phosphorus cycle from an animal husbandry perspective-the case of pigs and poultry. Sustain. 314 2018, 10, 1825. 315 (7) Sterner, R. W.; Elser, J. J. Ecological stoichiometry: The biology of elements from molecules to the 316 biosphere. Princeton, NJ: Princeton University Press. 2002. 317 (8) Meunier, C. L.; Gundale, M. J.; Sánchez, I. S.; Liess, A. Impact of nitrogen deposition on forest and 318 lake food webs in nitrogen-limited environments. Glob. Change Biol. 2016, 22, 164-179. 8 319 (9) Vitousek, P. M.; Naylor, R.; Crews, T.; David, M. B.; Drinkwater, L. E.; Holland, E., et al. Nutrient 320 imbalances in agricultural development. Science 2009, 324, 1519-1520. 321 (10) Peñuelas, J.; Janssens, I. A.; Ciais, P.; Obersteiner, M.; Krisztin, T.; Piao, S., et al. Increasing gap in 322 human height between rich and poor countries associated to their different intakes of N and P. Sci. Rep. 323 2017, 7, 17671. 324 (11) Sardans, J.; Janssens, I.A.; Ciais, P.; Obersteiner, M.; Peñuelas, J. Recent advances in Ecological 325 stoichiometry. Perspect. Plant Ecol. Evol. Syst. 2021, 50, 125611.4003. 326 (12) Smil, V. Nitrogen and food production: Proteins for human diets. Ambio 2002; 31, 126–131. 327 (13) Curtis, B. C. Wheat in the world. Retrieved from http://www.fao. 328 org/3/y4011e/y4011e04.htm#TopOfPage. (Accessed September 5, 2022) 2019. 329 (14) Lu, C.; Tian, H. Global nitrogen and phosphorus fertilizer use for agriculture production in the past 330 half century: Shifted hot spots and nutrient imbalance. Earth Syst. Sci. Data 2017, 9, 181–192. 331 (15) Peñuelas, J.; Gargallo-Garriga, A.; Jannssens, I.; Ciais, P.; Obersteiner, M.; Klem, K., et al. Global 332 intensification of N fertilisation may increase allergenic proteins and spread coeliac pathology. Foods 2020, 333 6, 1602. 334 (16) Litke, L.; Gaile, Z.; Ruza, A. Effect of nitrogen fertilization on winter wheat yield and yield quality. 335 Agron. Res. 2018, 16, 500– 509. 336 (17) Zheng, T.; Qi, P. F.; Cao, Y. L.; Han, Y. N.; Ma, H. L.; Guo, Z. R., et al. Mechanisms of wheat 337 (Triticum aestivum) grain storage proteins in response to nitrogen application and its impacts on processing 338 quality. Sci. Rep. 2018, 8, 11928. 339 (18) Guardia, G.; Sanz-Cobena, A.; Sanchez-Martín, L.; Fuertes-Mendizábal, T.; González-Murua, C.; 340 Álvarez, J. M., et al. Urea based fertilization strategies to reduce yield-scaled N oxides and enhance bread- 341 making quality in a rainfed Mediterranean wheat crop. Agric. Ecosyst. Environ. 2018, 265, 421–431. 342 (19) Kindred, D. R.; Verhoeven, T. M. O.; Weigthman, R. M.; Swaston, J. S.; Agu, R. C.; Brosnan, J. M., 343 et al. Effects of variety and fertiliser nitrogen on alcohol yield, grain yield, starch and protein content, and 344 protein composition of winter wheat. J. Cereal Sci. 2008, 48, 46-57. 345 (20) Shewry, P. R.; Tatham, A. S.; Halford, N. G. Nutritional control of storage protein synthesis in 346 developing grain of wheat and barley. J. Plant Growth Regul. 2001, 34, 105–111. 347 (21) Dubois, B.; Bertin, P.; Hautier, L.; Muhovski, Y.; Escarnot, E.; Mingeot, D. Genetic and environmental 348 factors affecting the expression of a-gliadin canonical epitopes involved in celiac disease in a wide 349 collection of spelt (Triticum aestivum ssp. Spelta) cultivars and landraces. BMC Plant Biol. 2018, 18, 262. 350 (22) Morrell, K.; Melby, M. K. Celiac disease: The evolutionary paradox. Int. J. Celiac Dis. 2017, 5, 86– 351 94. 352 (23) Gil-Humanes, J.; Pistón, F.; Altamirano-Fortoul, R.; Real, A.; Comino, I.; Sousa, C., et al. Reduced- 353 Gliadin wheat bread: An alternative to the gluten-free diet for consumers suffering gluten-related 354 pathologies. PLoS ONE 2014, 9, e90898. 355 (24) Wolfe, A. H.; Patz, J. A. Reactive nitrogen and human health: Acute and log-term implications. Ambio 356 2002, 31, 120-125. 357 (25) Ahada, C. P. S.; Suthar, S. Groundwater nitrate contamination and associated human lealth risk 358 assessment in southern districts of Punjab, India. Environ. Sci. Pollut. Res. 2018, 25, 25336-25347. 9 359 (26) Menció, A.; Mas-Pla, J.; Otero, N.; Soler, A. Nitrate as a tracer of groundwater flow in a fractures 360 multilayered aquifer. Hydrol. Sci. J. 2011, 56, 108-122. 361 (27) Margalef-Marti, R.; Llovet, A.; Carrey, R.; Ribas, A.; Domene, X.; Mattana, S., et al. Impact of 362 fertilization with pig slurry on the isotopic composition of nitrate retained in soil and leached to 363 groundwater in agricultural areas. Appl. Geochemistry. 2021, 125, 104832. 364 (28) Wu, J.; Sun, Z. Evaluation of shallow groundwater contamination and association human health risk 365 in an alluvial plain impacted by agricultural and industrial activities, mid-west China. Expo. Health 2016, 366 8, 311-329. 367 (29) Zhai, Y.; Zhao, X.; Teng, Y.; Li, X.; Zhang, J.; Wu, J., et al. Groundwater nitrate pollution and human 368 health risk assessment by using HHRA model in an agricultural area, NE China. Ecotoxicol. Environ. Saf. 369 2017, 137, 130-142. 370 (30) Zhang, Y.; Wu, J.; Xu, B. Human health risk assessment of groundwater nitrogen pollution in Jinghui 371 canal irrigation area of the loess region, northwest China. Environ. Earth Sci. 2018, 77, 273. 372 (31) Dar, J. M.; Dar, I. A.; Dar, M. M. Nitrate contamination: A major challenge to water and human health. 373 Eur. J. Water Qual. 2010, 15, 19-27. 374 (32) Payet, N.; Nicolini, E.; Rogers, K.; Macary, H. S.; Vauclin, M. Evidence of soil pollution by nitrates 375 derived from pig effluent using 18O and 15N isotope analyses. Agron. Sustain. Dev. 2010, 30, 743-751. 376 (33) Sahoo, P. K.; Kim, K.; Powell, M.A. Managing groundwater nitrate contamination from livestock 377 farms: implications for nitrate management guidelines. Curr. Pollut. Rep. 2016, 2, 178–187. 378 (34) Karwowak M., Kononiuk A. 2020. Nitrates/nitrites in food-risk for nitrosative stress and benefits. 379 Antioxidants 2020; 9: 241. 380 (35) Chalezas E., Pierre F., Druesne-Pecollo N., Esseddik, Y., Szabo de Edelenyi, F., Agaesse, C., et al. 381 Nitrites and nitrates from food additives and natural sources and cancer risk: results from the NutriNet- 382 Santé cohort. Inter. J. Epidemiol. 2022; 51: 1106-1119. 383 (36) Brown, R. B.; Razzaque, M. S. Phosphate toxicity and tumorigenesis. Biochim. Biophys. Acta Rev. 384 Cancer 2018, 1869, 303-309. 385 (37) Brown, R. B. Obesity and cancer: potential mediation by dysregulated dietary phosphate. Obesities 386 2022, 2, 64-75. 387 (38) Elser, J. J.; Kyle, M. M.; Smith, M. S.; Nagy, J. D. Biological stoichiometry in human cancer. PLoS 388 ONE 2007, 2, e1028. 389 (39) Elser, J. J.; Kyle, M. M.; Smith, M. S.; Nagy, J. D. Biological stoichiometry of tumors: A test of the 390 growth rate hypothesis using paired biopsy samples of human tumors. Integr. Comp. Biol. 2007, 46, E39– 391 E39. 392 (40) Elser, J. J.; Nagy, J. D.; Kuang, Y. Biological stoichiometry: An ecological perspective on tumor 393 dynamics. BioScience 2003, 53, 1112-1120. 394 (41) Galloway, J. N.; Bleeker, A.; Erisman, J. W. The human creation and use of reactive nitrogen: a global 395 and region al perspective. Annu. Rev. 2021, 46, 255-288. 396 (42) Selles, F.; McConkey, B.G.; Campbell, C.A. Distribution and forms of P under cultivator and zero 397 tillage for continuous and fallow -wheat cropping systems in the semi-arid Canadian prairies. Soil Till. Res. 398 1999; 51, 47-59 1 399 (43) Tóth, G.; Guicharnaud, R. A.; Tóth, B., Hermann, T. Phosphorus levels in croplands of the European 400 Union with implication for P fertilizer use. European J. Arg. 2014; 55, 42-52 401 (44) Gomez, M. I.; Magnitskiy, S.; Rodriguez, L. E. Nitrogen, phosphorus and potassium accumulation and 402 partitioning by the potato group Andigenum in Colombia. Nutr. Cycling Agroecosyst. 2019, 113, 349–363. 403 (45) Takeda, E.; Yamamoto, H.; Yamanaka-Okumura, H.; Taketani, Y. Increasing dietary phosphorus 404 intake from food additives: Potential negative impact on bone health. Adv. Nutr. 2014, 5, 92–97. 405 (46) Wulaningsih, W.; Michaelsson, K.; Garmo, H.; Hammar, N.; Jungner, I.; Walldius, G., et al. Inorganic 406 phosphate and the risk of cancer in the Swedish AMORIS study. BMC Cancer 2013, 13, 257. 407 (47) Cooke, A. Dietary food-additive phosphate and human health outcomes. Compr. Rev. Food Sci. Food 408 Saf. 2017, 16, 906–1021. 409 (48) Chudek, J.; Nagy, A.; Kokot, F.; Podwinski, A.; Wiecek, A.; Ritz, E., et al. Phosphatemia is related to 410 chromosomal aberrations of parathyroid glands in patients with hyperparathyroidism. J. Nephrol 2007, 20, 411 164-172. 412 (49) Yilmaz, S.; Unal, F.; Yuzbasioglu, D.; Celik, M. DNA damage in human lymphocites exposed to four 413 food additives in vitro. Toxicol. Ind. Health. 2014, 30, 926-937. 414 (50) Wilson, K. M.; Shui, I. M.; Mucci, L. A.; Giovannucci, E. Calcium and phosphate intake and prostate 415 cancer risk: a 24-y follow-up study. Am. J. Clin. Nutr. 2015, 101, 173-183. 416 (51) Calvo, M. S.; Moshfegh, A. J.; Tucker, K. L. Assessing the health impacts of phosphorus in food 417 supply: issues and considerations. Adv. Nutr. 2014, 5, 104.113. 418 (52)Newmark, H.L.; Heaney, R.P. Dairy products and prostate cancer risk. Nutr. Cancer 2010; 62, 297- 419 299. 420 (53) Michaelson, M.; Wolk, A.; Langenskold, S.; Basu, S.; Lemming, W.; Melhus, H., L., et al. Milk intake 421 and risk of mortality and fractures in women and men: cohort studies. B.M.J. 2014, 349, g6015. 422 (54) Chang, A. R.; Lazo, M.; Appel, L. J.; Gutiérrez, O. M.; Grams, M. E. High dietary phosphorus intake 423 is associated with all-cause mortality: results from NHANES III. Am. J. Clin. Nutr. 2013, 105, 1021. 424 (55) Wilson, F.P.; Berns, J.S. Tumor lysis syndrome: new challenges and recent advances. Adv Chronic 425 Kidney 2014; 21, 18-26. 426 (56) Neves, A. R.; Sousa, A.; Faria, R.; Albuquerque, T.; Queiroz, J. A.; Costa, D. Cancer gene therapy 427 mediated by RALA/plasmid DNA vectors: nitrogen to phosphorus groups ratio (N/P) as a tool for tunable 428 transfection efficiency. Colloids Surf. B. Biointerfaces 2020, 185, 110610. 429 (57) Souza A.; Almeida A.M.; Faria R., Konate K.; Boisguerin P.; Queiroz J.A., et al. Optimization of 430 peptide-plasmid DNA vectors formulation form gene delivery in cancer therapy exploring design of 431 experiments. Colloids and Surfaces B: Biointerfaces; 2019, 183, 110417. 432 (58) Vecchio-Pagam, B.; Bewick, S.; Mainali, K.; Karig, D. K.; Fagan, W. F. A stoichiometric analysis of 433 samples from the human microbiome project. Front. Microbiol. 2017, 8, 119. 434 (59) Loladze, I. Rising atmospheric CO2 and human nutrition: toward globally imbalanced plant 435 stoichiometry? Trens Ecol. Evol. 2002; 17, 457-461. 436 (60) Myers, S.; Zanobetti, A.; Kloog, I.; Huybers, P.; Leakey, A. D. B.; Bloom, A. J., et al. Increasing CO2 437 threatens human nutrition. Nature 2014; 510, 139-142. 1 438 (61) Paseka, R. E.; Grunberg, R. L. Allometric and trait-based patterns in parasite stoichiometry. Oikos 439 2019, 108, 102-112. 440 (62) Aalto, S. J.; Decaestecker, E.; Pulkkinen, K. A three-way perspective of stoichiometric changes on 441 host-parasite interactions. Trends Parasitol. 2015, 31, 333-340. 442 (63) Larsen, M. L.; Wilhelm, S. W., Lennon, J. T. Nutrient stoichiometry shapes microbial coevolution. 443 Ecol. Lett. 2019, 22, 1009-1018. 444 (64) World Health Organization. Malaria. https://www.who.int/news-room/fact-sheets/detail/malaria. 445 (Accessed September 10, 2022) 446 (65) Pope, K.; Masuoka, P.; Rejmankova, E.; Grieco, J.; Johnson, S.; Roberts, D. Mosquito habitats, land 447 use, and malaria risk in Belize from satellite imagery. Ecol. Appl. 2005, 15, 1223-1232. 448 (66) Rejmankova, E.; Grieco, J.; Achee, N.; Masuoka, P.; Pope, K.; Roberts, D., et al. Freshwater 449 community interactions and malaria. Pages 90-104 in S. Collinge and C. Ray, editors. Disease ecology: 450 community structure and pathogen dynamics. Oxford University Press, Oxford, UK. 2006. 451 (67) Cid, N. Ecology of the Benthic Macroinvertebrates in the Lower Ebro River: Community 452 Characterization, Population Dynamics and Bioaccumulation of Pollutants in Response to Environmental 453 Factors. Doctoral Thesis. Barcelona Central University. 2010. 454 (68)Ibañez, C.; Penuelas, J. Changing nutrients, changing rivers. Phosphorus removal from freshwater 455 systems has wide-ranging ecological consequences. Science, 2019, 365, 637–638. 456 (69) Frenken, T.; Wierenga, J.; Gsell, A. S.; van Donk, E.; Rohrlack, T.; Van der Waal, D. B. Changes in 457 N:P supply ratios affect the ecological stoichiometry of a toxic cyanobacterium and its fungal parasite. 458 Front. Microbiol. 2017, 8, 1015. 459 (70) Clasen, J. L.; Elser, J. J. The effect of host Chlorella NC64A carbon:phosphorus ratio on the production 460 of Paramecium bursaria Chlorella Virus-1. Freshw. Rev. 2007, 52, 112–122. 461 (71) Frost, P. C.; Ebert, D.; Smith, V. H. Bacterial infection changes elemental composition of Daphnia 462 magna. J. Anim. Ecol. 2008, 77, 1265–1272. 463 (72) Paseka, R. E.; Bratt, A. R.; MacNeill, K.; Burian, A.; See, R.C. Elemental ratios link environmental 464 change and human health. Front. Ecol. Evol. 2019, 7, 378. 465 (73) Razzaque, M. S. Phosphate toxicity: new insights into an old problem. Clin. Sci. 2011, 120, 91–97. 466 (74) Sanders, A. J.; Taylor, B. W. Using ecological stoichiometry to understand and predict infectious 467 diseases. Oikos 2018, 127, 1399–1409. 468 (75) Murrell, E. G.; Damal, K.; Lounibos, L. P.; Juliano, S. A. Distributions of competing Container 469 Mosquitoes Depend on Detritus Types, Nutrient Ratios, and Food availability. Ann. Entomol. Soc. Am. 470 2011, 104, 688–698. 471 (76) Yee, D. A.; Kaufman, M. G.; Ezeakacha, N. F. How diverse detrital environments influence nutrient 472 stoichiometry between males and females of the co-occurring container mosquitoes Aedes albopictus, Ae. 473 aegypti, and Culex quinquefasciatus. PLoS One, 2015, 10, 1–18. 474 (77) Paige, A. S.; Bellamy, S. K.; Alto, B. W.; Dean, C. L.; Yee, D. A. Linking nutrient stoichiometry to 475 Zika virus transmission in a mosquito. Oecologia, 2019, 19, 1–10. 1 476 (78) Johnson, P. T. J.; Townsend, A. R.; Cleveland, C.C.; Glibert, P. M.; Howarth, R. W.; McKenzie, V. 477 J., et al. Linking environmental nutrient enrichment and disease emergence in humans and wildfire. Ecol. 478 Appl. 2010, 20, 16-29. 479 480 Fig. 1 Schematic diagram of the impact of N:P on human food security and health. 481 1 482 483 Fig. 2 Planetary boundaries with additional consideration of the increasing N:P ratio. 484 485 486 487 1 Highlights 1-Unprecedented N:P ratio impacts environment, organisms, food security. 2-N:P ratios may affect non-infectious and infectious diseases. 3-Urgent need to study N:P ratio effects on human health. 4-Potential for improving health through N:P manipulation. 5-N:P ratios offer opportunities for addressing health challenges.