Editing Heavy water (section)

==Effect on biological systems==
Different isotopes of chemical elements have slightly different chemical behaviors, but for most elements the differences are far too small to have a biological effect. In the case of hydrogen, larger differences in chemical properties among protium, deuterium, and tritium occur because chemical bond energy depends on the [[reduced mass]] of the nucleus–electron system; this is altered in heavy-hydrogen compounds (hydrogen-deuterium oxide is the most common) more than for heavy-isotope substitution involving other chemical elements. The isotope effects are especially relevant in biological systems, which are very sensitive to even the smaller changes, due to isotopically influenced properties of water when it acts as a [[solvent]].

To perform their tasks, [[enzyme]]s rely on their finely tuned networks of [[hydrogen bond]]s, both in the active center with their substrates and outside the active center, to stabilize their [[tertiary structure]]s. As a hydrogen bond with deuterium is slightly stronger<ref>Katz, J. J. (1965). "Chemical and biological studies with deuterium".
39th Annual Priestly Lecture, Pennsylvania State University,
University Park, Pennsylvania. pp. 1–110, August 2008.</ref> than one involving ordinary hydrogen, in a highly deuterated environment, some normal reactions in cells are disrupted.

Particularly hard-hit by heavy water are the delicate assemblies of [[mitotic spindle]] formations necessary for [[mitosis|cell division]] in [[eukaryote]]s. Plants stop growing and seeds do not germinate when given only heavy water, because heavy water stops eukaryotic cell division.<ref>{{cite journal | last1 = Bild | first1 = W. | last2 = Năstasă | first2 = V. | last3 = Haulică | year = 2004 | title = In Vivo and in Vitro Research on the Biological Effects of Deuterium-depleted water: Influence of Deuterium-depleted water on Cultured Cell Growth | journal = Romanian Journal of Physiology | volume = 41 | issue = 1–2| pages = 53–67 | pmid = 15984656 }}</ref> Tobacco does not germinate, but wheat does.<ref>{{Cite journal |last=Urey |first=Harold C. |date=1935 |title=Heavy Water |url=https://www.jstor.org/stable/24999142 |journal=Scientific American |volume=152 |issue=6 |pages=300–302 |doi=10.1038/scientificamerican0635-300 |jstor=24999142 |bibcode=1935SciAm.152..300U |issn=0036-8733}}</ref> The deuterium cell is larger and is a modification of the direction of division.<ref>Crespi, H., Conrad, S., Uphaus, R., Katz, J. (1960). "Cultivation of Microorganisms in Heavy Water". ''Annals of the New York Academy of Sciences, Deuterium Isotopes in Chemistry and Biology'', pp. 648–666.</ref><ref>Mosin, O. V., I. Ignatov, I. (2013). "Microbiological Synthesis of 2H-Labeled Phenylalanine, Alanine, Valine, and Leucine/Isoleucine with Different Degrees of Deuterium Enrichment by the Gram-Positive Facultative Methylotrophic Bacterium Вrevibacterium Methylicum". ''International Journal of Biomedicine'' Vol. 3, N 2, pp. 132–138.</ref> The cell membrane also changes, and it reacts first to the impact of heavy water. In 1972, it was demonstrated that an increase in the percentage of deuterium in water reduces plant growth.<ref>{{cite journal | last1 = Katz | first1 = J. | last2 = Crespy | first2 = H. L. | year = 1972| title = Biologically important isotope hybrid compounds in nmr: 1H Fourier transform nmr at unnatural abundance| doi = 10.1351/pac197232010221 | pmid = 4343107 | journal = Pure and Applied Chemistry | volume = 32 | issue = 1–4| pages = 221–250 | doi-access = free }}</ref> Research conducted on the growth of [[prokaryote]] microorganisms in artificial conditions of a heavy hydrogen environment showed that in this environment, all the hydrogen atoms of water could be replaced with deuterium.<ref>{{cite journal | last1 = Mosin | first1 = O. B. | last2 = Skladnev | first2 = D. A. | last3 = Egorova | first3 = T. A. | last4 = Shvets | first4 = V. I. | year = 1996 | title = Biological Effects of Heavy Water | journal = Bioorganic Chemistry | volume = 22 | issue = 10–11| pages = 861–874 }}</ref><ref>Mosin, O. V., Shvez, V. I, Skladnev, D. A., Ignatov, I. (2012). "Studying of Microbic Synthesis of Deuterium Labeled L-Phenylalanin by Methylotrophic Bacterium Brevibacterium Methylicum on Media with Different Content of Heavy Water". ''Russian Journal of Biopharmaceuticals'', No. 1, Vol. 4, No 1, pp. 11–22.</ref> Experiments showed that bacteria can live in 98% heavy water.<ref>Skladnev D. A., Mosin O. V., Egorova T. A., Eremin S. V., Shvets V. I. (1996). "Methylotrophic Bacteria as Sources of 2H-and 13C-amino Acids". ''Biotechnology'', pp. 14–22.</ref> Concentrations over 50% are lethal to multicellular organisms, but a few exceptions are known: plant species such as switchgrass (''[[Panicum virgatum]]'') which is able to grow on 50% D<sub>2</sub>O;<ref>{{cite journal | last1 = Evans | first1 = B. R. | display-authors = etal | year = 2015 | title = Production of deuterated switchgrass by hydroponic cultivation | journal = Planta | volume = 242 | issue = 1 | pages = 215–222 | doi=10.1007/s00425-015-2298-0 | pmid = 25896375 | bibcode = 2015Plant.242..215E | osti = 1185899 | s2cid = 18477008 }}</ref> ''[[Arabidopsis thaliana]]'' (70% D{{sub|2}}O);<ref>{{cite journal | last1 = Bhatia | first1 = C. R. | display-authors = etal | year = 1968 | title = Adaptation and growth response of ''Arabidopsis thaliana'' to deuterium |journal=Planta | volume=80 | issue = 2 | pages = 176–184 | doi=10.1007/BF00385593 | bibcode = 1968Plant..80..176B | s2cid = 19662801 }}</ref> ''[[Vesicularia dubyana]]'' (85% D<sub>2</sub>O);<ref>{{cite journal | last1 = Kutyshenko | first1 = V. P. | display-authors = etal | year = 2015 | title = 'In-plant' NMR: Analysis of the Intact Plant ''Vesicularia dubyana'' by High Resolution NMR Spectroscopy |journal=Molecules | volume = 20 | issue = 3 | pages = 4359–4368 | doi=10.3390/molecules20034359 | doi-access = free | s2cid = 19662801 }}</ref> ''[[Funaria hygrometrica]]'' (90% D{{sub|2}}O);<ref>{{cite journal | last1 = Vergara | first1 = F. | display-authors = etal | year = 2018 | title = ''Funaria hygrometrica'' Hedw. elevated tolerance to D<sub>2</sub>O: its use for the production of highly deuterated metabolites | journal = Planta | volume = 247 | issue = 2 | pages = 405–412 | doi=10.1007/s00425-017-2794-5 | pmid = 29030693 | bibcode = 2018Plant.247..405V | s2cid = 11302702 }}</ref> and the [[anhydrobiotic]] species of [[nematode]] ''[[Panagrolaimus superbus]]'' (nearly 100% D{{sub|2}}O).<ref name="An animal able to tolerate D">{{cite journal | last1 = de Carli | first1 = G. J. | display-authors = etal | year = 2020 | title = An animal able to tolerate D<sub>2</sub>O | journal = ChemBioChem | volume = 22 | issue = 6 | pages = 988–991 | doi=10.1002/cbic.202000642 | pmid = 33125805 | s2cid = 226218470 }}</ref>

A comprehensive study of heavy water on the fission yeast ''[[Schizosaccharomyces pombe]]'' showed that the cells displayed an altered glucose metabolism and slow growth at high concentrations of heavy water.<ref name="pubs.acs.org">{{Cite journal|last1=Kampmeyer|first1=Caroline|last2=Johansen|first2=Jens V.|last3=Holmberg|first3=Christian|last4=Karlson|first4=Magnus|last5=Gersing|first5=Sarah K.|last6=Bordallo|first6=Heloisa N.|last7=Kragelund|first7=Birthe B.|last8=Lerche|first8=Mathilde H.|last9=Jourdain|first9=Isabelle|last10=Winther|first10=Jakob R.|last11=Hartmann-Petersen|first11=Rasmus|date=17 April 2020|title=Mutations in a Single Signaling Pathway Allow Cell Growth in Heavy Water|url=https://pubs.acs.org/doi/10.1021/acssynbio.9b00376|journal=ACS Synthetic Biology|language=en|volume=9|issue=4|pages=733–748|doi=10.1021/acssynbio.9b00376|pmid=32142608|s2cid=212621576|issn=2161-5063}}</ref> In addition, the cells activated the heat-shock response pathway and the cell integrity pathway, and mutants in the cell integrity pathway displayed increased tolerance to heavy water.<ref name="pubs.acs.org" /> Despite its toxicity at high levels, heavy water has been observed to extend lifespan of certain yeasts by up to 85%, with the hypothesized mechanism being the reduction of reactive oxygen species turnover.<ref>{{cite journal | last1=Li | first1=Xiyan | last2=Snyder | first2=Michael P. | title=Yeast longevity promoted by reversing aging-associated decline in heavy isotope content | journal=npj Aging and Mechanisms of Disease | publisher=Springer Science and Business Media LLC | volume=2 | issue=1 | date=2016-02-18 | pages=16004– | issn=2056-3973 | doi=10.1038/npjamd.2016.4| pmid=28721263 | pmc=5515009 }}</ref>

Heavy water affects the period of [[circadian rhythm|circadian oscillations]], consistently increasing the length of each cycle. The effect has been demonstrated in unicellular organisms, green plants, isopods, insects, birds, mice, and hamsters. The mechanism is unknown.<ref>{{cite journal |title= A Differential Effect of Heavy Water on Temperature-Dependent and Temperature-Compensated Aspects of the Circadian System of Drosophila pseudoobscura |last1=Pittendrigh |first1=C. S. |last2=Caldarola |first2=P. C. |last3=Cosbey |first3=E. S. |journal= [[Proceedings of the National Academy of Sciences USA]] |volume= 70 |issue= 7 |date=July 1973 |pages= 2037–2041 |pmid= 4516204|doi= 10.1073/pnas.70.7.2037 |pmc= 433660 |bibcode = 1973PNAS...70.2037P |doi-access=free }}</ref>

Like ethanol, heavy water temporarily changes the relative density of cupula relative to the endolymph in the vestibular organ, causing [[Positional alcohol nystagmus|positional nystagmus]], illusions of bodily rotations, dizziness, and nausea. However, the direction of nystagmus is in the opposite direction of ethanol, since it is denser than water, not lighter.<ref name=":0">{{Cite journal |last1=Money |first1=K. E. |last2=Myles |first2=W. S. |date=February 1974 |title=Heavy water nystagmus and effects of alcohol |url=https://www.nature.com/articles/247404a0 |journal=Nature |language=en |volume=247 |issue=5440 |pages=404–405 |doi=10.1038/247404a0 |pmid=4544739 |bibcode=1974Natur.247..404M |issn=1476-4687}}</ref>

===Effect on animals===
Experiments with mice, rats, and dogs<ref name="k">{{cite journal |pmid=10535697 |title=Pharmacological uses and perspectives of heavy water and deuterated compounds |first1=D. J. |last1=Kushner |first2=Alison |last2=Baker |first3=T. G. |last3=Dunstall |journal=Canadian Journal of Physiology and Pharmacology |volume=77 |issue=2 |pages=79–88 |date=1999 |quote=...&nbsp;used in boron neutron capture therapy ... D{{sub|2}}O is more toxic to malignant than normal animal cells ... Protozoa are able to withstand up to 70% D{{sub|2}}O. Algae and bacteria can adapt to grow in 100% D{{sub|2}}O | doi = 10.1139/cjpp-77-2-79}}</ref> have shown that a degree of 25% deuteration prevents [[gamete]]s or [[zygote]]s from developing, causing (sometimes irreversible) sterility. High concentrations of heavy water (90%) rapidly kill fish, [[tadpole]]s, [[flatworm]]s, and ''[[Drosophila]]''. Mice raised from birth with 30% heavy water have 25% deuteration in body fluid and 10% in brains. They are normal except for sterility. Deuteration during pregnancy induces fetal abnormality. Higher deuteration in body fluid causes death.<ref name=":1">{{Cite magazine |last=Katz |first=Joseph J. |date=1960 |title=The Biology of Heavy Water |url=https://www.jstor.org/stable/24940548 |magazine=Scientific American |volume=203 |issue=1 |pages=106–117 |jstor=24940548 |issn=0036-8733}}</ref> Mammals (for example, rats) given heavy water to drink die after a week, at a time when their body water approaches about 50% deuteration.<ref>{{cite journal | last1 = Thomson | first1 = J. F. | year = 1960 | title = Physiological Effects of D{{sub|2}}O in Mammals. Deuterium Isotope Effects in Chemistry and Biology | journal = Annals of the New York Academy of Sciences | volume = 84 | issue = 16| pages = 736–744 | doi=10.1111/j.1749-6632.1960.tb39105.x| pmid = 13776654 |bibcode = 1960NYASA..84..736T | s2cid = 84422613 }}</ref> The mode of death appears to be the same as that in [[cytotoxicity|cytotoxic poisoning]] (such as [[chemotherapy]]) or in acute radiation syndrome (though deuterium is not radioactive), and is caused by deuterium's action in generally inhibiting cell division. It is more toxic to malignant cells than normal cells, but the concentrations needed are too high for regular use.<ref name="k"/> As may occur in chemotherapy, deuterium-poisoned mammals die of a failure of bone marrow (producing bleeding and infections) and of intestinal-barrier functions (producing [[diarrhea]] and [[fluid loss|loss of fluids]]).

Despite the problems of plants and animals in living with too much deuterium, prokaryotic organisms such as bacteria, which do not have the mitotic problems induced by deuterium, may be grown and propagated in fully deuterated conditions, resulting in replacement of all hydrogen atoms in the bacterial proteins and DNA with the deuterium isotope.<ref name="k"/><ref>Trotsenko, Y. A., Khmelenina, V. N., Beschastny, A. P. (1995). "The Ribulose Monophosphate (Quayle) Cycle: News and Views. Microbial Growth on C1 Compounds". Proceedings of the 8th International Symposium on Microbial Growth on C1 Compounds (Lindstrom M.E., Tabita F.R., eds.). San Diego (USA), Boston: Kluwer Academic, pp. 23–26.</ref> This leads to a process of [[bootstrapping]]. With prokaryotes producing fully deuterated glucose, fully deuterated ''[[Escherichia coli]]'' and ''[[Torula]]'' were raised, and they could produce even more complex fully deuterated chemicals. Molds like ''[[Aspergillus]]'' could not replicate under fully deuterated conditions.<ref name=":1" />

In higher organisms, full replacement with heavy isotopes can be accomplished with other non-radioactive heavy isotopes (such as carbon-13, nitrogen-15, and oxygen-18), but this cannot be done for deuterium. This is a consequence of the ratio of nuclear masses between the isotopes of hydrogen, which is much greater than for any other element.<ref name="isotopegeochem">{{cite book|last=Hoefs|first=J.|year=1997|publisher=Springer|title=Stable Isotope Geochemistry|isbn=978-3-540-61126-4|edition=4}}</ref>

Deuterium oxide is used to enhance [[boron neutron capture therapy]], but this effect does not rely on the biological or chemical effects of deuterium, but instead on deuterium's ability to moderate (slow) neutrons without capturing them.<ref name="k" /> 2021 experimental evidence indicates that systemic administration of deuterium oxide (30% drinking water supplementation) suppresses [[tumor]] growth in a standard mouse model of human [[melanoma]], an effect attributed to selective induction of cellular stress signaling and gene expression in tumor cells.<ref>{{cite journal |title= Deuterium Oxide (D2O) Induces Early Stress Response Gene Expression and Impairs Growth and Metastasis of Experimental Malignant Melanoma |last1=Jandova |first1=J. |last2=Hua |first2=A. B. |last3=Fimbres |first3=J. |last4=Wondrak |first4=G. T. |journal= [[Cancers (journal)|Cancers]] |volume= 13 |issue= 4 |date=February 2021 |pages= 605 |pmid= 33546433|doi= 10.3390/cancers13040605  |pmc= 7913703 |doi-access=free }}</ref>

===Toxicity in humans===
Because it would take a very large amount of heavy water to replace 25% to 50% of a human being's body water (water being in turn 50–75% of body weight<ref>{{cite journal | last1 = Watson | first1 = P. E. | display-authors = etal | year = 1980 | title = Total body water volumes for adult males and females estimated from simple anthropometric measurements | journal = The American Journal of Clinical Nutrition | volume = 33 | issue = 1| pages = 27–39 | pmid = 6986753 | doi = 10.1093/ajcn/33.1.27 | s2cid = 4442439 | doi-access = free }}</ref>) with heavy water, accidental or intentional [[poison]]ing with heavy water is unlikely to the point of practical disregard. Poisoning would require that the victim ingest large amounts of heavy water without significant normal water intake for many days to produce any noticeable toxic effects.

Oral doses of heavy water in the range of several grams, as well as [[Oxygen-18|heavy oxygen]] {{sup|18}}O, are routinely used in human metabolic experiments. (See [[doubly labeled water]] testing.) Since one in about every 6,400 hydrogen atoms is deuterium, a {{convert|50|kg|adj=on}} human containing {{convert|32|kg}} of body water would normally contain enough deuterium (about {{convert|1.1|g|disp=or}}) to make {{convert|5.5|g}} of pure heavy water, so roughly this dose is required to double the amount of deuterium in the body.<!--- atomic mass of water, taking into account the three isotopes of hydrogen and the three of oxygen, is 18.01527; 32 kg of water is thus 1776.27 mol. Figuring in the abundances, we get 1.114014 g of deuterium (0.553258 mol); if we mix this with half as many moles of mean oxygen (0.138359 mol × 15.99930457 mol/g), we get 5.54 g of D<sub>2</sub>O --->

A loss of blood pressure may partially explain the reported incidence of dizziness upon ingestion of heavy water. However, it is more likely that this symptom can be attributed to altered [[vestibular system|vestibular function]]. Heavy water, like ethanol, causes a temporary difference in the density of endolymph within the cupula, which confuses the [[Vestibulo-ocular reflex#Nystagmus|vestibulo-ocular reflex]] and causes motion sickness symptoms.<ref>{{cite journal|last1=Money|first1=K. E.|last2=Myles|first2=W. S.|title=Heavy water nystagmus and effects of alcohol|journal=Nature|date=February 1974|volume=247|pages=404–405|doi=10.1038/247404a0|pmid=4544739|bibcode = 1974Natur.247..404M|issue=5440 |s2cid=4166559}}</ref>

===Heavy water radiation contamination confusion===
Although many people associate heavy water primarily with its use in nuclear reactors, pure heavy water is not radioactive. Commercial-grade heavy water is slightly radioactive due to the presence of minute traces of natural tritium, but the same is true of ordinary water. Heavy water that has been used as a coolant in nuclear power plants contains substantially more tritium as a result of neutron bombardment of the deuterium in the heavy water ([[Tritium#Health risks|tritium is a health risk]] when ingested in large quantities).

In 1990, an employee at the [[Point Lepreau Nuclear Generating Station]] in Canada obtained a sample (estimated as about a "half cup") of heavy water from the primary heat transport loop of the [[nuclear reactor]], and loaded it into a cafeteria drink dispenser. Eight employees drank some of the contaminated water. The incident was discovered when employees began leaving [[bioassay]] urine samples with elevated tritium levels. The quantity of heavy water involved was far below levels that could induce heavy water toxicity, but several employees received elevated radiation doses from tritium and neutron-activated chemicals in the water.<ref>{{cite web |url=http://www.ecology.at/nni/site.php?site=Point++Lepreau |title=Point Lepreau in Canada |publisher=NNI (No Nukes Inforesource) |access-date=10 September 2007 |archive-url = https://web.archive.org/web/20070710224724/http://www.ecology.at/nni/site.php?site=Point++Lepreau <!-- Bot retrieved archive --> |archive-date = 10 July 2007}}</ref> This was not an incident of heavy water poisoning, but rather radiation poisoning from other isotopes in the heavy water.

Some news services were not careful to distinguish these points, and some of the public were left with the impression that heavy water is normally radioactive and more severely toxic than it actually is. Even if pure heavy water had been used in the [[water dispenser]] indefinitely, it is not likely the incident would have been detected or caused harm, since no employee would be expected to get much more than 25% of their daily drinking water from such a source.<ref>
{{cite news |date=1990-03-06 |title=Radiation Punch Nuke Plant Worker Charged With Spiking Juice |newspaper=[[Philadelphia Daily News]] |agency=Associated Press |url=http://nl.newsbank.com/nl-search/we/Archives?p_product=DN&s_site=philly&p_multi=PI%7CDN&p_theme=realcities&p_action=search&p_maxdocs=200&p_topdoc=1&p_text_direct-0=0EB29D29C1FD71F6&p_field_direct-0=document_id&p_perpage=10&p_sort=YMD_date:D&s_trackval=GooglePM |url-status=dead |access-date=30 November 2006 |archive-url=https://web.archive.org/web/20121024214618/http://nl.newsbank.com/nl-search/we/Archives?p_product=DN&s_site=philly&p_multi=PI%7CDN&p_theme=realcities&p_action=search&p_maxdocs=200&p_topdoc=1&p_text_direct-0=0EB29D29C1FD71F6&p_field_direct-0=document_id&p_perpage=10&p_sort=YMD_date:D&s_trackval=GooglePM |archive-date=24 October 2012}}
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