Editing Nickel (section)

==Toxicity==
{{Further|Nickel allergy}}
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The major source of nickel exposure is oral consumption, as nickel is essential to plants.<ref>{{cite journal |doi=10.1016/j.yrtph.2017.03.011 |pmid=28300623 |title=Derivation of an oral toxicity reference value for nickel |journal=[[Regulatory Toxicology and Pharmacology]] |volume=87 |pages=S1–S18 |year=2017 |last1=Haber |first1=Lynne T |last2=Bates |first2=Hudson K |last3=Allen |first3=Bruce C |last4=Vincent |first4=Melissa J |last5=Oller |first5=Adriana R |doi-access=free }}</ref> Typical background concentrations of nickel do not exceed 20&nbsp;ng/m{{sup|3}} in air, 100&nbsp;mg/kg in soil, 10&nbsp;mg/kg in vegetation, 10&nbsp;μg/L in freshwater and 1&nbsp;μg/L in seawater.<ref>{{Cite book|last=Rieuwerts|first=John|url=https://www.worldcat.org/oclc/886492996|title=The Elements of Environmental Pollution|publisher=Earthscan Routledge|year=2015|isbn=978-0-415-85919-6|location=London and New York|pages=255|oclc=886492996}}</ref> Environmental concentrations may be increased by human [[pollution]]. For example, nickel-plated [[faucet]]s may contaminate water and soil; [[mining]] and smelting may dump nickel into [[wastewater]]; nickel–steel [[alloy]] cookware and nickel-pigmented dishes may release nickel into food. Air may be polluted by nickel ore refining and [[fossil fuel]] combustion. Humans may absorb nickel directly from [[tobacco smoke]] and skin contact with jewelry, [[shampoo]]s, detergents, and [[coin]]s. A less common form of chronic exposure is through [[hemodialysis]] as traces of nickel ions may be absorbed into the plasma from the [[chelating]] action of [[albumin]].{{Citation needed|date=January 2021}}

The average daily exposure is not a threat to human health. Most nickel absorbed by humans is removed by the kidneys and passed out of the body through urine or is eliminated through the gastrointestinal tract without being absorbed. Nickel is not a cumulative poison, but larger doses or chronic inhalation exposure may be toxic, even [[carcinogen]]ic, and constitute an [[occupational hazard]].<ref>{{cite book|last1 = Butticè|first1 = Claudio|editor1-last = Colditz|editor1-first = Graham A.|title = The SAGE Encyclopedia of Cancer and Society|date = 2015|publisher = SAGE Publications, Inc.|location = Thousand Oaks|isbn = 9781483345734|pages = 828–831|edition = Second|chapter = Nickel Compounds}}</ref>

Nickel compounds are classified as human carcinogens<ref name="Nickel and nickel compounds">IARC (2012). [https://monographs.iarc.fr/ENG/Monographs/vol100C/mono100C-10.pdf "Nickel and nickel compounds"] {{Webarchive|url=https://web.archive.org/web/20170920044638/https://monographs.iarc.fr/ENG/Monographs/vol100C/mono100C-10.pdf |date=September 20, 2017 }} in ''IARC Monogr Eval Carcinog Risks Hum''. Volume 100C. pp. 169–218.</ref><ref name="Reg 1272/2008">Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on Classification, Labelling and Packaging of Substances and Mixtures, Amending and Repealing Directives 67/548/EEC and 1999/45/EC and amending Regulation (EC) No 1907/2006 [OJ L 353, 31.12.2008, p. 1]. [http://www.eur-lex.europa.eu/legal-content/en/TXT/?uri=CELEX%3A32008R1272 Annex VI] {{Webarchive|url=https://web.archive.org/web/20190314212328/https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32008R1272 |date=March 14, 2019 }}. Accessed July 13, 2017.</ref><ref name="GHS">[https://www.unece.org/fileadmin/DAM/trans/danger/publi/ghs/ghs_rev05/English/ST-SG-AC10-30-REv5e.pdf Globally Harmonised System of Classification and Labelling of Chemicals (GHS)] {{Webarchive|url=https://web.archive.org/web/20170829031509/http://www.unece.org/fileadmin/DAM/trans/danger/publi/ghs/ghs_rev05/English/ST-SG-AC10-30-Rev5e.pdf |date=August 29, 2017 }}, 5th ed., United Nations, New York and Geneva, 2013.</ref><ref name="Carcinogens">National Toxicology Program. (2016). [https://ntp.niehs.nih.gov/pubhealth/roc/index-1.html "Report on Carcinogens"] {{Webarchive|url=https://web.archive.org/web/20170920044600/https://ntp.niehs.nih.gov/pubhealth/roc/index-1.html |date=September 20, 2017 }}, 14th ed. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service.</ref> based on increased respiratory cancer risks observed in epidemiological studies of sulfidic ore refinery workers.<ref name="Nickel Carcinogenesis in Man">{{cite journal|pmid=2185539|jstor=40965957|year=1990|title=Report of the International Committee on Nickel Carcinogenesis in Man|journal=Scandinavian Journal of Work, Environment & Health|volume=16|issue=1 Spec No|pages=1–82|doi=10.5271/sjweh.1813|doi-access=free}}</ref> This is supported by the positive results of the NTP bioassays with Ni sub-sulfide and Ni oxide in rats and mice.<ref name="Studies of Nickel Subsulfide">{{cite journal|pmid=12594522|year=1996|title=NTP Toxicology and Carcinogenesis Studies of Nickel Subsulfide (CAS No. 12035-72-2) in F344 Rats and B6C3F1 Mice (Inhalation Studies)|journal=National Toxicology Program Technical Report Series|volume=453|pages=1–365|author1=National Toxicology Program}}</ref><ref>{{cite journal|pmid=12594524|year=1996|title=NTP Toxicology and Carcinogenesis Studies of Nickel Oxide (CAS No. 1313-99-1) in F344 Rats and B6C3F1 Mice (Inhalation Studies)|journal=National Toxicology Program Technical Report Series|volume=451|pages=1–381|author1=National Toxicology Program}}</ref> The human and animal data consistently indicate a lack of carcinogenicity via the oral route of exposure and limit the carcinogenicity of nickel compounds to respiratory tumours after inhalation.<ref>{{cite journal|pmid=22158127|pmc=3243677|year=2011|last1=Cogliano|first1=V. J|title=Preventable exposures associated with human cancers|journal=JNCI Journal of the National Cancer Institute|volume=103|issue=24|pages=1827–39|last2=Baan|first2=R|last3=Straif|first3=K|last4=Grosse|first4=Y|last5=Lauby-Secretan|first5=B|last6=El Ghissassi|first6=F|last7=Bouvard|first7=V|last8=Benbrahim-Tallaa|first8=L|last9=Guha|first9=N|last10=Freeman|first10=C|last11=Galichet|first11=L|last12=Wild|first12=C. P|doi=10.1093/jnci/djr483}}</ref><ref>{{cite journal|pmid=17692353|year=2007|last1=Heim|first1=K. E|title=Oral carcinogenicity study with nickel sulfate hexahydrate in Fischer 344 rats|journal=Toxicology and Applied Pharmacology|volume=224|issue=2|pages=126–37|last2=Bates|first2=H. K|last3=Rush|first3=R. E|last4=Oller|first4=A. R|doi=10.1016/j.taap.2007.06.024|bibcode=2007ToxAP.224..126H }}</ref> Nickel metal is classified as a suspect carcinogen;<ref name="Nickel and nickel compounds" /><ref name="Reg 1272/2008" /><ref name="GHS" /> there is consistency between the absence of increased respiratory cancer risks in workers predominantly exposed to metallic nickel<ref name="Nickel Carcinogenesis in Man" /> and the lack of respiratory tumours in a rat lifetime inhalation carcinogenicity study with nickel metal powder.<ref name="Inhalation carcinogenicity">{{cite journal|pmid=18822311|year=2008|last1=Oller|first1=A. R|title=Inhalation carcinogenicity study with nickel metal powder in Wistar rats|journal=Toxicology and Applied Pharmacology|volume=233|issue=2|pages=262–75|last2=Kirkpatrick|first2=D. T|last3=Radovsky|first3=A|last4=Bates|first4=H. K|doi=10.1016/j.taap.2008.08.017|bibcode=2008ToxAP.233..262O }}</ref> In the rodent inhalation studies with various nickel compounds and nickel metal, increased lung inflammations with and without bronchial lymph node hyperplasia or fibrosis were observed.<ref name="Carcinogens" /><ref name="Studies of Nickel Subsulfide" /><ref name="Inhalation carcinogenicity" /><ref>{{cite journal|pmid=12587012|year=1996|title=NTP Toxicology and Carcinogenesis Studies of Nickel Sulfate Hexahydrate (CAS No. 10101-97-0) in F344 Rats and B6C3F1 Mice (Inhalation Studies)|journal=National Toxicology Program Technical Report Series|volume=454|pages=1–380|author1=National Toxicology Program}}</ref> In rat studies, oral ingestion of water-soluble nickel salts can trigger perinatal mortality in pregnant animals.<ref>Springborn Laboratories Inc. (2000). "An Oral (Gavage) Two-generation Reproduction Toxicity Study in Sprague-Dawley Rats with Nickel Sulfate Hexahydrate." Final Report. Springborn Laboratories Inc., Spencerville. SLI Study No. 3472.4.</ref> Whether these effects are relevant to humans is unclear as epidemiological studies of highly exposed female workers have not shown adverse developmental toxicity effects.<ref>{{cite journal|pmid=18655106|year=2008|last1=Vaktskjold|first1=A|title=Maternal nickel exposure and congenital musculoskeletal defects|journal=American Journal of Industrial Medicine|volume=51|issue=11|pages=825–33|last2=Talykova|first2=L. V|last3=Chashchin|first3=V. P|last4=Odland|first4=J. O|last5=Nieboer|first5=E|doi=10.1002/ajim.20609}}</ref>

People can be exposed to nickel in the workplace by inhalation, ingestion, and contact with skin or eye. The [[Occupational Safety and Health Administration]] (OSHA) has set the legal limit ([[permissible exposure limit]]) for the workplace at 1&nbsp;mg/m{{sup|3}} per 8-hour workday, excluding nickel carbonyl. The [[National Institute for Occupational Safety and Health]] (NIOSH) sets the [[recommended exposure limit]] (REL) at 0.015&nbsp;mg/m{{sup|3}} per 8-hour workday. At 10&nbsp;mg/m{{sup|3}}, nickel is [[immediately dangerous to life and health]].<ref>{{cite web|title =NIOSH Pocket Guide to Chemical Hazards – Nickel metal and other compounds (as Ni)|url = https://www.cdc.gov/niosh/npg/npgd0445.html|website =CDC|access-date = 2015-11-20|archive-url = https://web.archive.org/web/20170718164956/https://www.cdc.gov/niosh/npg/npgd0445.html|archive-date = July 18, 2017|url-status = live}}</ref> [[Nickel carbonyl]] {{chem2|[Ni(CO)4]}} is an extremely toxic gas. The toxicity of metal carbonyls is a function of both the toxicity of the metal and the off-gassing of [[carbon monoxide]] from the carbonyl functional groups; nickel carbonyl is also explosive in air.<ref>{{cite book|author=Stellman, Jeanne Mager|title=Encyclopaedia of Occupational Health and Safety: Chemical, industries and occupations|url=https://books.google.com/books?id=nDhpLa1rl44C&pg=PT133|access-date=January 9, 2012|date=1998|publisher=International Labour Organization|isbn=978-92-2-109816-4|pages=133–|archive-url=https://web.archive.org/web/20130529043242/http://books.google.com/books?id=nDhpLa1rl44C&pg=PT133|archive-date=May 29, 2013|url-status=live}}</ref><ref>{{cite journal|journal=Clinical Toxicology|date = 1999|volume = 37|issue = 2|pages =239–258| title =Nickel|first1=Donald G.|last1=Barceloux|first2= Donald |last2= Barceloux|doi =10.1081/CLT-100102423|pmid =10382559}}</ref>

[[Sensitization (immunology)|Sensitized]] persons may show a skin contact [[Nickel allergy (nickel allergic contact dermatitis)|allergy to nickel]] known as a contact [[dermatitis]]. Highly sensitized persons may also react to foods with high nickel content.<ref name="aad" /> Patients with [[Dyshidrosis|pompholyx]] may also be sensitive to nickel. Nickel is the top confirmed contact allergen worldwide, partly due to its use in jewelry for [[pierced ear]]s.<ref>{{cite journal |journal=Contact Dermatitis |date=2007 |volume=57 |issue=5 |pages=287–99 |title= The epidemiology of contact allergy in the general population—prevalence and main findings |author=Thyssen J. P. |author2=Linneberg A. |author3=Menné T.|author4=Johansen J. D. |doi=10.1111/j.1600-0536.2007.01220.x |pmid=17937743 |doi-access=free }}</ref> Nickel allergies affecting pierced ears are often marked by itchy, red skin. Many earrings are now made without nickel or with low-release nickel<ref>[http://www.nipera.org/WorkplaceGuide/ToxicityOfNickelCompounds/NickelAlloys/DermalExposureNickel%20Alloys.aspx Dermal Exposure: Nickel Alloys] {{Webarchive|url=https://web.archive.org/web/20160222055840/http://www.nipera.org/WorkplaceGuide/ToxicityOfNickelCompounds/NickelAlloys/DermalExposureNickel%20Alloys.aspx |date=February 22, 2016 }} Nickel Producers Environmental Research Association (NiPERA), accessed 2016 Feb.11</ref> to address this problem. The amount allowed in products that contact human skin is now regulated by the [[European Union]]. In 2002, researchers found that the nickel released by 1 and 2 euro coins, far exceeded those standards. This is believed to be due to a [[Galvanization|galvanic]] reaction.<ref>{{cite journal|first1 = O.|last1 = Nestle|last2=Speidel|first2=H.|last3=Speidel|first3=M. O.|title = High nickel release from 1- and 2-euro coins|journal=Nature|volume = 419|issue = 6903|page = 132|date = 2002|pmid = 12226655|doi = 10.1038/419132a|bibcode = 2002Natur.419..132N |doi-access = free}}</ref> Nickel was voted [[Allergen of the Year]] in 2008 by the American Contact Dermatitis Society.<ref>{{cite web| url =http://www.nickelallergyinformation.com/2008/06/nickel-named-2008-contact-alle.htm| archive-url =https://web.archive.org/web/20090203033929/http://www.nickelallergyinformation.com/2008/06/nickel-named-2008-contact-alle.htm| archive-date =2009-02-03|title = Nickel Named 2008 Contact Allergen of the Year| date = June 3, 2008|author=Dow, Lea |website=Nickel Allergy Information}}</ref> In August 2015, the [[American Academy of Dermatology]] adopted a position statement on the safety of nickel: "Estimates suggest that contact dermatitis, which includes nickel sensitization, accounts for approximately $1.918&nbsp;billion and affects nearly 72.29&nbsp;million people."<ref name="aad">[https://www.aad.org/Forms/Policies/Uploads/PS/PS-Nickel%20Sensitivity.pdf Position Statement on Nickel Sensitivity] {{Webarchive|url=https://web.archive.org/web/20150908083534/https://www.aad.org/Forms/Policies/Uploads/PS/PS-Nickel%20Sensitivity.pdf |date=September 8, 2015 }}. American Academy of Dermatology(August 22, 2015)</ref>

Reports show that both the nickel-induced activation of hypoxia-inducible factor (HIF-1) and the up-regulation of hypoxia-inducible genes are caused by depletion of intracellular [[ascorbate]]. The addition of ascorbate to the culture medium increased the intracellular ascorbate level and reversed both the metal-induced stabilization of HIF-1- and HIF-1α-dependent gene expression.<ref>{{cite journal|first = k.|last = Salnikow|display-authors=4|author2=Donald, S. P. |author3=Bruick, R. K. |author4=Zhitkovich, A. |author5=Phang, J. M. |author6= Kasprzak, K. S. |title = Depletion of intracellular ascorbate by the carcinogenic metal nickel and cobalt results in the induction of hypoxic stress|journal=Journal of Biological Chemistry |volume = 279|pmid = 15271983|doi=10.1074/jbc.M403057200|issue = 39|pages = 40337–44 |date=September 2004|doi-access=free}}</ref><ref>{{cite journal|first1 = K. K.|last1 = Das|last2= Das |first2=S. N. |last3=Dhundasi|first3=S. A.|title = Nickel, its adverse health effects and oxidative stress|journal=Indian Journal of Medical Research |volume = 128|pages = 117–131|date = 2008|pmid=19106437|url = http://www.icmr.nic.in/ijmr/2008/october/1005.pdf|archive-url = https://web.archive.org/web/20090410090734/http://www.icmr.nic.in/ijmr/2008/october/1005.pdf|url-status = dead|archive-date = 2009-04-10| access-date= August 22, 2011 |issue = 4}}</ref>