Abstracts

Introduction

Mercury is a heavy metal considered as the most toxic non-radioactive element in the world. It is ubiquitous, indestructible and exists in three forms in nature: inorganic, metallic and organic ¹1. Contreras C, Vásquez N, Díaz L. Intoxicación acidental com mercúrio elemental. Acta Med Per 2017; 30:26-30.. It is released to the atmosphere from four different sources: (i) primary natural (e.g. volcanic and geothermal activities), responsible for 10%; (ii) primary anthropogenic (e.g. mining and fossil fuel extraction, including oil, gas and coal); (iii) secondary anthropogenic (mercury-dependent artisanal and small scale gold mining sector [ASGM], several industrial processes including chlor-alkali industry), both anthropogenic responsible for 30%; and (iv) remobilization and re-emissions (wildfires, forest clearing, biomass burning), responsible for 60% ²2. United Nations Environment Programme. The global mercury modelling: update of modelling results in the Global Mercury Assessment 2013. Geneva: United Nations Environment Programme; 2015.. Because it is a widespread environmental toxicant, humans are unable to avoid exposure to its forms ³3. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metals toxicity and the environment. EXS 2012; 101:133-64. and the main sources are: fish and shellfish consumption, outgassing from dental amalgam, vaccines containing thiomersal and occupational exposure (agricultural products, industry and gold mining) ⁴4. Clarkson TW. The three modern faces of mercury. Environ Health Perspect 2002; 110 Suppl 1:11-23.. Specifically in relation to the latter, ASGM is considered the number one anthropogenic mercury pollutant in the world, responsible for 37% (410 to 1,400 tones/year) of its emissions to air and water worldwide. It poses a risk not only to miners, estimated at 10 to 19 million workers, of which 5 million are women and children, in more than 70 countries, but also to the environment and general population by water and air ²2. United Nations Environment Programme. The global mercury modelling: update of modelling results in the Global Mercury Assessment 2013. Geneva: United Nations Environment Programme; 2015.^,55. Esdaile LJ, Chalker JM. The mercury problem in artisanal and small-scale gold mining. Chemistry 2018; 24:6905-16.. Such large variation of human exposure to mercury makes it a very important issue from the public health perspective ⁶6. Hong YS, Kim YM, Lee KE. Methylmercury exposure and health effects. J Prev Med Public Health 2012; 45:353-63.^,77. Hacon S, Barrocas PRG, Vasconcellos ACS, Barcellos C, Wasserman JC, Campos RC, et al. An overview of mercury contamination research in the Amazon basin with emphasis on Brazil. Cad Saúde Pública 2008; 24:1479-92..

All forms of mercury could poison cellular function by altering the tertiary and quaternary structure of proteins and membrane permeability due to its affinity for sulfhydryl and selenohydryl groups. As a consequence it can potentially impair function of any organ ⁸8. Bernhoft RA. Mercury toxicity and treatment: a review of the literature. J Environ Public Health 2012; 2012:460508.^,99. Rice KM, Walker EM, Wu M, Gillette C, Blough ER. Environmental mercury and its toxic effects. J Prev Med Public Health 2014; 47:74-83.. Its adverse effects on human health may induce over 250 symptoms. The main ones are from nervous, renal, cardiovascular, respiratory systems, and skin, but any organ may be a target, such as the bone marrow ⁹9. Rice KM, Walker EM, Wu M, Gillette C, Blough ER. Environmental mercury and its toxic effects. J Prev Med Public Health 2014; 47:74-83.. The hematological system, due to its intense cellular proliferation, is quite sensitive to the action of a variety of substances, such as benzene ¹⁰10. McHale CM, Zhang L, Smith MT. Current understanding of the mechanism of benzene-induced leukemia in humans: implications for risk assessment. Carcinogenesis 2012; 33:240-52.. However, there is sparse information and research about mercury’s hematotoxicity on humans, despite its wide exposure ¹¹11. Priya N, Nagaprabhu VN, Kurian G, Seethalakshmi N, Rao GG, Unni VN. Aplastic anemia and membranous nephropathy induced by intravenous mercury. Indian J Nephrol 2012; 22:451-4.. Most of them come from occupational settings ¹²12. Queiroz MLS, Dantas DCM. B lymphocytes in mercury-exposed workers. Pharmacol Toxicol 1997; 81:130-3.^,1313. Zavariz C, Glina DMR. Efeitos da exposição ocupacional ao mercúrio em trabalhadores de uma indústria de lâmpadas elétricas localizada em Santo Amaro, São Paulo, Brasil. Cad Saúde Pública 1993; 9:117-29., in vitro ¹⁴14. Zolla L, Lupidib GL, Bellellic A, Amiconicet G. Effect of mercuric ions on human erythrocytes. Relationships between hypotonic swelling and cell aggregation. Biochim Biophys Acta 1997; 1328:273-80.^,1515. Suwalsky M, Ungerer B, Villena F, Cuevas F, Sotomayor CP. HgCl2 disrupts the structure of the human erythrocyte membrane and model phospholipid bilayers. J Inorg Biochem 2000; 81:267-73. and animals studies ¹⁶16. Deem SL, Norton TM, Mitchell M, Segars A, Alleman AR, Cray C, et al. Comparison of blood values in foraging, nesting, and stranded loggerhead turtles (Caretta caretta) along the coast of Georgia, USA. J Wildl Dis 2009; 45:41-56.^,1717. Seriani R, França JG, Lombardi JV, Brito JM, Ranzani-Paiva MJ. Hematological changes and cytogenotoxicity in the tilapia Oreochromis niloticus caused by sub-chronic exposures to mercury and selenium. Fish Physiol Biochem 2015; 41:311-22..

The aim of this systematic review was to assess the available evidence on human exposure to mercury and its hematological effects.

Methods

This systematic review followed the precepts established by the PRISMA model ¹⁸18. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009; 62:e1-e34. and had a PROSPERO register: CRD42018086389.

Data sources, search strategy and study selection

The selection criteria were based on PICOS’ acronymous ¹⁹19. Galvão TF, Pereira GM. Revisões sistemáticas da literatura: passos para sua elaboração. Epidemiol Serv Saúde 2014; 23:183-4.: “Does human exposure to mercury lead to hematological effects?” and included all studies (except textbook, author’s opinion and review) regarding human exposure to mercury and hematological effects, published between 1950 and February 2018. Hematological effects were considered as any blood cell alteration concerning number ²⁰20. Bauer KA. Maternal adaptations to pregnancy: hematologic changes. UpToDate 2018; 27 apr. https://www.uptodate.com/contents/maternal-adaptations-to-pregnancy-hematologic-changes (accessed on 28/Apr/2018).
https://www.uptodate.com/contents/matern... and the normal values of mercury on biological matrices were those presented by the authors.

We developed a search strategy including key terms (MeSH, text word and equivalents) for querying four different electronic databases (BVS/LILACS; MEDLINE/PubMed; Scopus; and TOXLINE/NIH) and two Master dissertation/PhD thesis databases (Fiocruz/ARCA and University of São Paulo). There were four search strategies containing the descriptors according to database and repositories. For BVS/LILACS: “mercúrio” AND “anemia” OR “leucopenia” OR “basopenia” OR “eosinopenia” OR “neutropenia” OR “linfopenia” OR “monocitopenia” OR “trombocitopenia” OR “policitemia” OR “leucocitose” OR “basofilia” OR “eosinofilia” OR “neutrofilia” OR “linfocitose” OR “monocitose” OR “trombocitose” OR “hemograma completo”. For MEDLINE/PubMed: “anemia” OR “leukopenia” OR “thrombocytopenia” OR “eosinopenia” OR “basopenia” OR “monocytopenia” OR “polycythemia” OR “leukocytosis” OR “thrombocytosis” OR “eosinophilia” OR “basophilia” OR “neutrophilia” OR “monocytosis” OR “blood cell count” AND “mercury”. For TOXLINE/NIH, the search was made in a binary way: anemia and mercury/leukopenia and mercury. For the two repositories: “mercúrio” and “efeitos hematológicos”. Reference lists were also searched for relevant studies. No restrictions were applied concerning language and translation was done whenever necessary. Both authors (A.S.V. and E.P.M.) followed the same schedule independently: first they reviewed the title, then the available abstract, soon after the analysis of full text, and finally the search for reference. Any discrepancy in the search results not solved between A.S.V. and E.P.M. was planned to be discussed with a third author (C.I.R.F.A.). In order of priority, we excluded: non-human studies; without mercury exposure; lacking hematological effect; textbook, author’s opinion and review papers (type of study); and those published before 1950. To determine agreement between the two raters, Cohen’s kappa statistic was used for each step.

Data extraction

The extraction process was also done independently and included: author, year, place, journal, data base, type of study, substance, exposure (local and duration), population (number, exposed versus non exposed, age, sex), hematological outcome (primary or secondary), death, blood cell count, bone marrow biopsy, mercury (sample, level, method) and statistical analysis. Once more, Cohen’s kappa statistic was used to evaluate an inter-rater agreement.

Study quality assessment

To assess the quality/bias risk of the selected studies, we chose a tool known as Effective Public Health Practice Project (EPHPP) ²¹21. Effective Public Health Practice Project. Quality assessment tool for quantitative studies. https://merst.ca/ephpp/ (accessed on 21/Apr/2018).
https://merst.ca/ephpp/... . This quality assessment tool for quantitative studies has eight components ratings: (a) selection bias; (b) study design; (c) confounders; (d) blinding; (e) data collection methods; (f) withdrawals and drop-outs; (g) intervention integrity; and (h) analyses. Items from “a” to “f” are rated as strong (1), moderate (2) or weak (3). There is a dictionary to correctly rate each section. These six items are included in global rating, ranked as follows: strong must not have no weak ratings; moderate may have one weak rating, and weak may have two or more weak ratings. At the end there is an item for discrepancy between both reviewers that indicate the reason for discrepancy: oversight, differences in interpretation of criteria and differences in interpretation of study. That will lead to a final decision of both reviewers.

The results were summarized in a descriptive manner for occupational and non-occupational exposure data, due to toxicological differences between them.

Results

The search yielded 1,297 citations as of February 14th 2018, 323 from BVS/LILACS, 142 from MEDLINE/PubMed, 525 from Scopus, 110 from TOXLINE/NIH, 197 from Fiocruz/ARCA and none from the University of São Paulo. After 78 duplicates were removed, 1,219 records were screened based on review of titles and abstracts. Thereafter 63 full texts of articles were assessed for eligibility. The search to identify any missed report or citations resulted in selection of 80 articles: 61 from electronic databases search and 19 from reference lists. The reasons for 1,158 articles exclusion were: no mercury (457), without hematological effect (381), non-human (215), study type (104) and year of study (1) (Figure 1).

The Cohen’s kappa statistic was considered as almost perfect (0.98, 95%CI: 0.91; 1.0, p < 0.001) during screening title and abstract and substantial (0.76, 95%CI: 0.54; 0.98, p < 0.001) during extraction process. There was no more disagreement at other steps.

All were observational studies comprising 48 case reports (42 comprising one person/52.5%), 24 cross-sectional (12 containing control group), six case series and two cohorts. The study design was reported according to authors’ description. They were published between 1950 and 2018, with an increasing pattern in the last three decades (1950: 4 studies; 1960: 5; 1970: 7; 1980: 10; 1990: 15; 2000: 19; and 2010: 20). They were done in 34 different countries (14 in the USA) on the five continents and the main language was English (63). However, hematological effect was the primary outcome only in 14 studies (17.5%).

A total of 9,284 people were evaluated: 6,601 from non-occupational (60 studies) and 2,605 from occupational (23 studies) exposure. There was no report on 78 times. Three articles had both types, so there was a split between persons, according to it.

There were differences of age and sex distribution between exposure: at non-occupational, children and teenagers were the majority (4,982/75.47%) while at occupational, adults were (1,752/67.26%). According to sex: women were predominant (3,640/55.14%) at non-occupational and men were at occupational settings (1,402/53.84%).

The non-occupational pathways of exposure were: food (5,243), home near gold mining plus food (291), amalgam (454), environmental (82), medicine (54), bringing mercury home (29), suicide attempt (15), school (2), maternal exposure (2), aesthetical (1) and thermometer (1). The occupational pathways were: agriculture (1,274), gold mining (230), chlorine alkali industry (215), lamp factory (209), mix of three places: chlorine alkali industry, lamp factory and dentist’s office (71), dentist’s office (47) thermometer factory (2), research lab (1), fur-cleaning establishment (1) and compressor use (1). The main pathways of exposure among children and teenagers were: food (4,800), environmental (82), home near gold mining plus food (70) and bringing mercury home (14).

Three distinctive groups that are more susceptible to chemical substances, due to physiological characteristics and proportional high exposure levels, received attention on 33 studies: 23 for exposed occupational populations (13 cross-sectional of which seven with exposure and control groups), eight for children and teenagers (six cross-sectional and two cohorts), one for pregnant, neonates and children (cross-sectional) and one for pregnant (cross-sectional).

Chronic exposure was the main type for both, comprising 33 non-occupational (6,127 persons) and 16 occupational (2,041 persons) studies.

Hematological effects were described 2,376 times, in 69 studies comprising 1,914 cases (20.62%): 479 children and teenagers, 476 adults, 13 elderly and 946 not classified. Non-occupational exposure was the most frequent (1,111). Blood cell count was done in all cases and bone marrow biopsy in 13 times. Anemia (875), lymphocytosis (361) and lymphopenia (306) were the top three, although only anemia was the most common in both type of exposures. In fact, there was alteration of all bone marrow cellular series in mercury’s presence (Table 1). In 1,567 of all cases (81.87%), mercury’s exposure biomarker was above the recommended threshold. The blood cell count was normal in 7,250 times, where 6,012 individuals were exposed to mercury (75.85%).

Six out of seven studies reported lymphocytosis related to metallic or inorganic mercury exposure ¹³13. Zavariz C, Glina DMR. Efeitos da exposição ocupacional ao mercúrio em trabalhadores de uma indústria de lâmpadas elétricas localizada em Santo Amaro, São Paulo, Brasil. Cad Saúde Pública 1993; 9:117-29.^,2222. Moszczynski P, Slowinski S. The behaviour of T-cell subpopulations in the blood of workers exposed to mercury. Med Lav 1994; 85:239-41.^,2323. Moszczynski P, Slowinski S, Rutkowski J, Bem S, Jakus-Stoga D. Lymphocytes, T and NK cells, in men occupationally exposed to mercury vapours. Int J Occup Med Environ Health 1995; 8:49-56.^,2424. Soleo L, Colosio C, Alinovi R, Guarnieri D, Russo A, Lovreglio F, et al. Immunological effects of exposure to low exposure to inorganic mercury. Med Lav 2002; 93:225-32.^,2525. Lauwerys R, Bonnier C, Evrad P, Gennart JP, Bernard A. Prenatal and early postnatal intoxication by inorganic mercury resulting from the maternal use of mercury containing soap. Hum Toxicol 1987; 6:253-6.^,2626. Montoya-Cabrera MA, Rubio-Rodríguez S, Velázquez-González E, Avila SM. Intoxicación mercurial causada por un medicamento homeopático. Gac Méd Méx 1991; 127:260-70..

Fifteen studies, of which 14 are case reports ²⁷27. Bender CE, Hoxsey RJ, DeMarsh QB. Neutropenia in a patient treated with a mercurial diuretic and its response to BAL. Ann Intern Med 1950; 33:1285-90.^,2828. Portwich F, Maron H. Fatal allergic thrombopenia after influenza prophylaxis with phenylmercuric borate (merfen). Arztl Wochensch 1959; 14:65-6.^,2929. Wilson DR. Mercurial poisoning and aplastic anaemia. BMJ 1966; 2:1534.^,3030. Johnson KG, Evanger A, van Meter W. Elemental mercury poisoning manifest by acrodynia and neutropenia. Vet Human Toxicol 1978; 20:404-9.^,3131. Murphy MJ, Culliford EJ, Parsons V. A case of poisoning with mercuric chloride. Resuscitation 1979; 7:35-44.^,3232. Slee PH, den Ottolander GJ, de Wolff FA. A case of merbromin (mercurochrome) intoxication possibly resulting in aplastic anemia. Acta Med Scand 1979; 205:463-6.^,3333. Pavithran K. Mercury and aplastic anemia. Natl Med J India 1994; 7:252.^,3434. Alvarado EV, Ramírez JA, Nilsman M, Bonilla R. Intoxicación sistemática por mercurio elemental depositado en el organismo. Medicina Legal 1995; 12:36-40.^,3535. Dada MA, Jogessar V, Ramdial PK. Membranous fat necrosis and aplastic anaemia due to mercury poisoning. J Pathol 1999; 189 Suppl S:22A.^,3636. De Palma G, Mariotti O, Lonati D, Goldoni M, Catalani S, Mutti A, et al. Toxicokinetics and toxicodynamics of elemental mercury following self-administration. Clin Toxicol (Phila) 2008; 46:869-76.^,3737. Yildrim R, Erdem F, Gündogdu M, Bilen Y, Koca E, Yillikoglu Y, et al. Mercury toxicity: a family case report. Turk J Hematol 2012; 29:76-9.^,3838. Ryrie DR, Toghill PJ, Tanna MK, Galan GN. Marrow suppression from mercury poisoning? BMJ 1970; 1:499.^,3939. Fuortes LJ, Weismann DN, Graeff ML, Bale JF, Tannous R, Peters C. Immune thrombocytopenia and elemental mercury poisoning. Clin Toxicol (Phila) 1995; 33:449-55.^,4040. Erkek N, Senel S, Sarac A, Ertan U, Karacan CD. Being alive after a severe inorganic mercury intoxication. Eur J Pediatr 2010; 169:625-8. and one is cross-sectional ⁴¹41. Butt EM, Simonsen DG. Mercury and lead storage in human tissue. Am J Clin Pathol 1950; 20:716-23., comprising 27 cases, reported some severe hematological effects associated to clinical condition, such as: cerebral or gastrointestinal bleeding related to thrombocytopenia (14) or aplastic anemia (2); multiple organ dysfunction syndrome and leukopenia (2) or hemolytic anemia (2) or aplastic anemia (1); renal insufficiency and thrombocytopenia (2) or leukemoid reaction (1); sepsis and aplastic anemia (2) or neutropenia (1). Mercury biomarker was measured 22 times ²⁹29. Wilson DR. Mercurial poisoning and aplastic anaemia. BMJ 1966; 2:1534.^,3030. Johnson KG, Evanger A, van Meter W. Elemental mercury poisoning manifest by acrodynia and neutropenia. Vet Human Toxicol 1978; 20:404-9.^,3131. Murphy MJ, Culliford EJ, Parsons V. A case of poisoning with mercuric chloride. Resuscitation 1979; 7:35-44.^,3232. Slee PH, den Ottolander GJ, de Wolff FA. A case of merbromin (mercurochrome) intoxication possibly resulting in aplastic anemia. Acta Med Scand 1979; 205:463-6.^,3636. De Palma G, Mariotti O, Lonati D, Goldoni M, Catalani S, Mutti A, et al. Toxicokinetics and toxicodynamics of elemental mercury following self-administration. Clin Toxicol (Phila) 2008; 46:869-76.^,3737. Yildrim R, Erdem F, Gündogdu M, Bilen Y, Koca E, Yillikoglu Y, et al. Mercury toxicity: a family case report. Turk J Hematol 2012; 29:76-9.^,3838. Ryrie DR, Toghill PJ, Tanna MK, Galan GN. Marrow suppression from mercury poisoning? BMJ 1970; 1:499.^,3939. Fuortes LJ, Weismann DN, Graeff ML, Bale JF, Tannous R, Peters C. Immune thrombocytopenia and elemental mercury poisoning. Clin Toxicol (Phila) 1995; 33:449-55.^,4040. Erkek N, Senel S, Sarac A, Ertan U, Karacan CD. Being alive after a severe inorganic mercury intoxication. Eur J Pediatr 2010; 169:625-8.^,4141. Butt EM, Simonsen DG. Mercury and lead storage in human tissue. Am J Clin Pathol 1950; 20:716-23. out of 27 and was always high according to values reported by the authors.

Death was reported 29 times, most of them at non-occupational settings (26), due to medicine use (19/26). In 19 times, the cause of death was directly related to hematological effect: 16 due to severe bleeding (thrombocytopenia [14] and aplastic anemia [2]) and three due to sepsis (neutropenia [1] and aplastic anemia[2]).

The authors of 38 studies hypothesized that mercury could be responsible for the hematological effect by direct toxicity to bone marrow (13), immunologic/hypersensitivity (9), apoptosis (5), chronic disease (3), immunologic/autoimmunity (3), inflammatory reaction (3), hemolysis (3), loss of blood (3), increased calcium content in cytoplasm (2), idiosyncrasy (2) and increased level of erythropoietin (1).

Statistical analysis concerning mercury exposure and hematological effect was reported in 17 studies as follows: 11 were mean difference (Student’s t-test; Wilcoxon) ¹²12. Queiroz MLS, Dantas DCM. B lymphocytes in mercury-exposed workers. Pharmacol Toxicol 1997; 81:130-3.^,2222. Moszczynski P, Slowinski S. The behaviour of T-cell subpopulations in the blood of workers exposed to mercury. Med Lav 1994; 85:239-41.^,2323. Moszczynski P, Slowinski S, Rutkowski J, Bem S, Jakus-Stoga D. Lymphocytes, T and NK cells, in men occupationally exposed to mercury vapours. Int J Occup Med Environ Health 1995; 8:49-56.^,2424. Soleo L, Colosio C, Alinovi R, Guarnieri D, Russo A, Lovreglio F, et al. Immunological effects of exposure to low exposure to inorganic mercury. Med Lav 2002; 93:225-32.^,4242. Oluwole AF, Asubiojo OI, Adekile AD, Filby RH, Bragg A, Grimm CI. Trace element distribution in the hair of some sickle cell anemia patients and controls. Biol Trace Elem Res 1990; 26-27:479-84.^,4343. Siblerud RL. The relationship between mercury from dental amalgam and the cardiovascular system. Sci Total Environ 1990; 99:23-35.^,4444. Langworth S, Elinder EG, Sundqvist KG. Minor effects of low exposure to inorganic mercury on the human immune system. Scand J Work Environ Health 1993; 19:405-13.^,4545. Zabinski Z, Dabrowski Z, Moszczynski P, Rutowski J. The activity of erythrocyte enzymes and basic indices of peripheral blood erythrocytes from workers chronically exposed to mercury vapours. Toxicol Ind Health 2000; 16:58-64.^,4646. Frisk P, Danersund A, Hudecek R, Lindh U. Changed clinical chemistry pattern in blood after removal of dental amalgam and other metal alloys supported by antioxidant therapy. Biol Trace Elem Res 2007; 120:163-70.^,4747. Brázdová ZD, Pomerleau J, Fiala J, Vorlová L, Müllerová D. Heavy metals in hair samples: a pilot study of anaemic children in Kazakhstan, Kyrgyzstan and Uzbekistan. Cent Eur J Public Health 2014; 22:273-6.^,4848. Mathee A, Naicker N, Kootbodien T, Muluma T, Nkomo P, Naik I, et al. A cross sectional analytical study of geophagia practices and blood metal concentrations in pregnant women in Johannesburg, South Africa. S Afr Med J 2014; 104:568-70.; eight (two data not shown) were correlation coefficient r (Pearson; Spearman) ¹²12. Queiroz MLS, Dantas DCM. B lymphocytes in mercury-exposed workers. Pharmacol Toxicol 1997; 81:130-3.^,2222. Moszczynski P, Slowinski S. The behaviour of T-cell subpopulations in the blood of workers exposed to mercury. Med Lav 1994; 85:239-41.^,2323. Moszczynski P, Slowinski S, Rutkowski J, Bem S, Jakus-Stoga D. Lymphocytes, T and NK cells, in men occupationally exposed to mercury vapours. Int J Occup Med Environ Health 1995; 8:49-56.^,2424. Soleo L, Colosio C, Alinovi R, Guarnieri D, Russo A, Lovreglio F, et al. Immunological effects of exposure to low exposure to inorganic mercury. Med Lav 2002; 93:225-32.^,4343. Siblerud RL. The relationship between mercury from dental amalgam and the cardiovascular system. Sci Total Environ 1990; 99:23-35.^,4444. Langworth S, Elinder EG, Sundqvist KG. Minor effects of low exposure to inorganic mercury on the human immune system. Scand J Work Environ Health 1993; 19:405-13.^,4949. Plante C, Blanchet C, Rochette L, O'Brien HT. Prevalence of anemia among inuit women in Nunavik, Canada. Int J Circumpolar Health 2011; 70:154-65.^,5050. Kim JH, Lee KH, Hong SC, Lee HS, Lee J, Kang JW. Association between serum mercury concentration and leukocyte differential count in children. Pediatr Hematol Oncol 2013; 32:109-14.; three were regression coefficient β (linear models) ⁵¹51. Kim KN, Bae S, Park HY, Kwon HJ, Hong YC. Low-level mercury exposure and risk of asthma in school-age children. Epidemiology 2015; 26:733-9.^,5252. Oulhote Y, Shamim Z, Kielsen K, Weihe P, Grandjean P, Ryder LP, et al. Children's white blood cell counts in relation to developmental exposures to methylmercury and persistente organic pollutants. Reprod Toxicol 2017; 68:207-14.^,5353. Weinhouse C, Ortiz EJ, Berky AJ, Bullins P, Hare-Grogg J, Rogers L, et al. Hair mercury level is associated with anemia and micronutrients status in children living near artisanal ans small-scale gold mining in the Peruvian Amazon. Am J Trop Med Hyg 2017; 97:1886-97.; two (one data not shown) were prevalence ⁴⁹49. Plante C, Blanchet C, Rochette L, O'Brien HT. Prevalence of anemia among inuit women in Nunavik, Canada. Int J Circumpolar Health 2011; 70:154-65.^,5454. Douine M, Mosnier E, Le Hingrat Q, Charpentier C, Corlin F, Hureau L, et al. Illegal gold miners in French Guiana: a neglected population with poor health. BMC Public Health 2017; 18:1-20. and one was odds ratio (data not shown) ⁴⁸48. Mathee A, Naicker N, Kootbodien T, Muluma T, Nkomo P, Naik I, et al. A cross sectional analytical study of geophagia practices and blood metal concentrations in pregnant women in Johannesburg, South Africa. S Afr Med J 2014; 104:568-70.. The results reported for mean difference were: four studies evaluated anemia and two did not find difference (p = 0.05 and p = 0.183) ⁴²42. Oluwole AF, Asubiojo OI, Adekile AD, Filby RH, Bragg A, Grimm CI. Trace element distribution in the hair of some sickle cell anemia patients and controls. Biol Trace Elem Res 1990; 26-27:479-84.^,4848. Mathee A, Naicker N, Kootbodien T, Muluma T, Nkomo P, Naik I, et al. A cross sectional analytical study of geophagia practices and blood metal concentrations in pregnant women in Johannesburg, South Africa. S Afr Med J 2014; 104:568-70. and other two found it (p = 0.016 and p < 0.05) ⁴³43. Siblerud RL. The relationship between mercury from dental amalgam and the cardiovascular system. Sci Total Environ 1990; 99:23-35.^,4747. Brázdová ZD, Pomerleau J, Fiala J, Vorlová L, Müllerová D. Heavy metals in hair samples: a pilot study of anaemic children in Kazakhstan, Kyrgyzstan and Uzbekistan. Cent Eur J Public Health 2014; 22:273-6.; one study found difference for leukopenia and neutropenia (p < 0.05) ⁴⁶46. Frisk P, Danersund A, Hudecek R, Lindh U. Changed clinical chemistry pattern in blood after removal of dental amalgam and other metal alloys supported by antioxidant therapy. Biol Trace Elem Res 2007; 120:163-70.; five studies analyzed lymphocytes and three did not find difference (p not informed) ²²22. Moszczynski P, Slowinski S. The behaviour of T-cell subpopulations in the blood of workers exposed to mercury. Med Lav 1994; 85:239-41.^,2323. Moszczynski P, Slowinski S, Rutkowski J, Bem S, Jakus-Stoga D. Lymphocytes, T and NK cells, in men occupationally exposed to mercury vapours. Int J Occup Med Environ Health 1995; 8:49-56.^,2424. Soleo L, Colosio C, Alinovi R, Guarnieri D, Russo A, Lovreglio F, et al. Immunological effects of exposure to low exposure to inorganic mercury. Med Lav 2002; 93:225-32. and one did find (p < 0.05) ¹²12. Queiroz MLS, Dantas DCM. B lymphocytes in mercury-exposed workers. Pharmacol Toxicol 1997; 81:130-3.; one study evaluated polycythemia and did find difference (p < 0.05) ⁴⁵45. Zabinski Z, Dabrowski Z, Moszczynski P, Rutowski J. The activity of erythrocyte enzymes and basic indices of peripheral blood erythrocytes from workers chronically exposed to mercury vapours. Toxicol Ind Health 2000; 16:58-64.. For correlation coefficient, two studies evaluated anemia and found moderate negative correlation (r = -0.4208, p = 0.003) ⁴⁴44. Langworth S, Elinder EG, Sundqvist KG. Minor effects of low exposure to inorganic mercury on the human immune system. Scand J Work Environ Health 1993; 19:405-13. and no correlation (r = 0.04, p not informed) ⁴⁹49. Plante C, Blanchet C, Rochette L, O'Brien HT. Prevalence of anemia among inuit women in Nunavik, Canada. Int J Circumpolar Health 2011; 70:154-65.; six studies analyzed lymphocytes and three found no correlation (r = -0.077, p not informed; r not informed; r = -0.11, 0.10, p not informed) ¹²12. Queiroz MLS, Dantas DCM. B lymphocytes in mercury-exposed workers. Pharmacol Toxicol 1997; 81:130-3.^,2323. Moszczynski P, Slowinski S, Rutkowski J, Bem S, Jakus-Stoga D. Lymphocytes, T and NK cells, in men occupationally exposed to mercury vapours. Int J Occup Med Environ Health 1995; 8:49-56.^,4444. Langworth S, Elinder EG, Sundqvist KG. Minor effects of low exposure to inorganic mercury on the human immune system. Scand J Work Environ Health 1993; 19:405-13. and other three found a weak to moderate positive correlation (r = 0.3405, p < 0.05; r = 0.184, p < 0.05; r = 0.121, p = 0.049) ²²22. Moszczynski P, Slowinski S. The behaviour of T-cell subpopulations in the blood of workers exposed to mercury. Med Lav 1994; 85:239-41.^,2424. Soleo L, Colosio C, Alinovi R, Guarnieri D, Russo A, Lovreglio F, et al. Immunological effects of exposure to low exposure to inorganic mercury. Med Lav 2002; 93:225-32.^,5050. Kim JH, Lee KH, Hong SC, Lee HS, Lee J, Kang JW. Association between serum mercury concentration and leukocyte differential count in children. Pediatr Hematol Oncol 2013; 32:109-14.. For regression coefficient, two studies found inverse association for lymphopenia (β = -1.26 [95%CI: -2.61; 0.08]; β = 23% [95%CI: -43; -4]) ⁵¹51. Kim KN, Bae S, Park HY, Kwon HJ, Hong YC. Low-level mercury exposure and risk of asthma in school-age children. Epidemiology 2015; 26:733-9.^,5252. Oulhote Y, Shamim Z, Kielsen K, Weihe P, Grandjean P, Ryder LP, et al. Children's white blood cell counts in relation to developmental exposures to methylmercury and persistente organic pollutants. Reprod Toxicol 2017; 68:207-14. and one for anemia (β = -0.14, p = 0.04) ⁵³53. Weinhouse C, Ortiz EJ, Berky AJ, Bullins P, Hare-Grogg J, Rogers L, et al. Hair mercury level is associated with anemia and micronutrients status in children living near artisanal ans small-scale gold mining in the Peruvian Amazon. Am J Trop Med Hyg 2017; 97:1886-97.. One found positive association for neutrophilia and basophilia (β = 1.38, 95%CI: 0.11; 2.65 and β = 0.04, 95%CI: -0.03; 0.11) ⁵¹51. Kim KN, Bae S, Park HY, Kwon HJ, Hong YC. Low-level mercury exposure and risk of asthma in school-age children. Epidemiology 2015; 26:733-9.. For prevalence, one study reported 22% (95%CI: 18.0; 25.9) for anemia ⁵⁴54. Douine M, Mosnier E, Le Hingrat Q, Charpentier C, Corlin F, Hureau L, et al. Illegal gold miners in French Guiana: a neglected population with poor health. BMC Public Health 2017; 18:1-20..

The characteristics of these studies are summarized in Tables 2 and 3.

The quality assessment for these studies was considered weak (3) according to EPHPP for 75 of them. Almost all component ratings were considered as weak (selection bias, study design, confounders and blinding) or not applicable (withdrawals and dropouts). There was no discrepancy between the two reviewers concerning component ratings.

Discussion

We identified 80 out of 1,219 studies of mercury exposure and hematological outcomes, including environmental studies of children, teenagers, adults and elderly, as well as occupational ones. However, there were only 14 studies that aimed at hematological effect as the primary outcome. All were observational comprising a total of 9,284 studied people, although 42 were case reports of just one person.

It is important to emphasize the growing articles publication involving human exposure to chemical substances over the past decades. This is a consequence of the efforts made by many countries, through their agencies and institutions, in order to improve health by reducing environmental exposure to toxic substances ⁵⁵55. Ferguson A, Penney R, Solo-Gabriele H. A review of the field on children's exposure to environmental contaminants: a risk assessment approach. Int J Environ Res Public Health 2017; 14:E265.^,5656. Carvalho LVB, Costa-Amaral IC, Mattos RCOC, Larentis AL. Exposição ocupacional a substâncias químicas, fatores socioeconômicos e saúde do trabalhador: uma visão integrada. Saúde Debate 2017; 41:321-6.. Mercury is no exception, as in this review, we reported 26 studies published between the 1950s and the 1980s and 54 studies in the last three decades ⁵⁷57. Chen CY, Driscoll CT, Eagles-Smith CA, Eckley CS, Gay DA, Hsun-Kim H, et al. A critical time for mercury science to inform global policy. Environ Sci Technol 2018; 52:9556-61..

Distribution by age and sex presented the results expected in the literature, where children/teenagers and women were more commonly exposed non-occupationally, while adults and men were occupationally exposed. According to the report on human exposure to environmental chemicals (National Health and Nutrition Examination Survey IV - NHANES), women are the most exposed on non-occupational setting ⁸8. Bernhoft RA. Mercury toxicity and treatment: a review of the literature. J Environ Public Health 2012; 2012:460508.. The main exposure pathway for children/teenagers was food consumption, mainly fish and shellfish, although rice may be another methylmercury source for Asians ⁵⁸58. Hong C, Yu X, Liu J, Chen Y, Rothenberg SE. Low-level methylmercury exposure through rice ingestion in a cohort of pregnant mothers in rural China. Environ Res 2016; 150:519-27.. Another concern regarding this group is the fact that this silver liquid metal - found at home, at school and at others sites where it is not adequately stored - is seen by them as an amusing substance to play with, which may cause health problems. Lee et al. ⁵⁹59. Lee R, Middleton D, Caldwell K, Dearwent S, Jones S, Lewis B, et al. A review of events that expose children to elemental mercury in the United States. Environ Health Perspect 2009; 117:871-8. addressed this subject by reviewing the sources of mercury exposures in children, the location and proportion of children affected and also making recommendations to prevent them.

There was a wide range of exposure pathway, from food and medicine intake, suicide attempt to industrial process and gold mining, among others. Many of them are supposed to be prohibited by 2020, according to Minamata Convention, an international treaty signed in 2013 by more than 140 countries, including Brazil, which have committed to eliminate the use of mercury in different products, such as batteries, light bulbs and health equipment ²2. United Nations Environment Programme. The global mercury modelling: update of modelling results in the Global Mercury Assessment 2013. Geneva: United Nations Environment Programme; 2015.. Two of them deserve a special attention: gold mining/ASGM and fish/shellfish consumption, since they play a role in both types of exposure, occupational and non-occupational.

The first exposure pathway, gold mining/ASGM, is the main anthropogenic mercury pollutant in the world, affecting not only the miners but also the neighboring population, mainly in Southeast/East Asia, Sub-Saharan and South America ²2. United Nations Environment Programme. The global mercury modelling: update of modelling results in the Global Mercury Assessment 2013. Geneva: United Nations Environment Programme; 2015.. It is impressive that only seven research articles (four occupational and three non-occupational) have addressed hematological effects among people working or living nearby the gold mining sector, as more than 10 million ASGM miners, most of them informally or even illegally ⁵5. Esdaile LJ, Chalker JM. The mercury problem in artisanal and small-scale gold mining. Chemistry 2018; 24:6905-16., are exposed to mercury through both direct inhalation of mercury vapor and consumption of material taken from contaminated areas (e.g. fish). One example addressing this topic was the research, a purposive field sampling, conducted in Indonesia by Ekawanti & Krisnayanti ⁶⁰60. Ekawanti A, Krisnayanti BD. Effect of mercury exposure on renal function and hematological parameters among artisanal and small-scale gold miners at Sekotong, West Lombok, Indonesia. J Health Pollut 2015; 5:25-32. among non-miners (29) and miners (71), who showed lower levels of hemoglobin and hematocrit. In non-occupational situations, houses near gold mining put the surrounding population at risk due to contamination of soil (children playing outdoor), water (fish consumption) and air (amalgamation process or re-burning it at gold shops) ⁵5. Esdaile LJ, Chalker JM. The mercury problem in artisanal and small-scale gold mining. Chemistry 2018; 24:6905-16.. An example of the latter was a study carried out in Poconé, a town in Mato Grosso State/Brazil ⁶¹61. Câmara VM, Silva AP, Pivetta F, Perez MA, Lima MIM, Filhote MIF, et al. Estudo dos níveis de exposição e efeitos à saúde por mercúrio metálico em uma população urbana de Poconé, Mato Grosso, Brasil. Cad Saúde Pública 1996; 12:69-77.. They evaluated the levels of exposure to metallic mercury emissions by gold dealers and its health effects. It was reported higher mercury levels and referred morbidity among downtown residents.

The second route of exposure, consumption of fish and shellfish, is a major concern for regulatory agencies around the world, because although it is an important part of a healthy diet (presence of omega-3 fatty acids and low in saturated fat), it is also cited as the most significant source of methylmercury. One of the agencies is the U.S. Environmental Protective Agency (EPA), who sets a recommendation to limit or avoid certain species of fish and shellfish for general public and for specific groups of people at risk, such as: high consumers of fish (e.g. coastal dwellers, riverside communities), women of childbearing age, pregnant and breastfeeding women and young children. For example, the threshold for tuna consumption, a carnivorous fish, is one can (226-340g) per week for groups of people at risk ⁶²62. Environmental Protective Agency. 2017 EPA-FDA advice about eating fish and shellfish. https://www.epa.gov/fish-tech/2017-epa-fda-advice-about-eating-fish-and-shellfish (accessed on 23/Jul/2017).
https://www.epa.gov/fish-tech/2017-epa-f... . The risk of contamination of this kind of food is usually high (especially for the species at the top of food chain), because of the bioavailability of this metal in the aquatic environment from different sources such as geothermal activities, fossil fuel burning, hazardous waste incineration, industrial processes, gold mining and so forth. The ASGM, despite its decline in Amazon Basin, continues to contribute to an increase in the mercury load, becoming a major risk for indigenous groups and riverside communities, who have fish as their main source of protein ⁶³63. Hacon S, Farias RA, Barrocas P, Campos RC, Wasserman J, Argento R. Avaliação da exposição humana ao mercúrio na região norte de Mato Grosso-Amazônia Legal. Cad Saúde Colet (Rio J.) 2005; 13:837-54.. On other hand, the general urban population has a low fish ingestion as a result of its cultural and social characteristics, in such a way that they do not face significant health effects from this pathway exposure ⁶⁴64. Hacon S, Rochedo ERR, Campos RRR, Lacerda LD. Mercury exposure through fish consumption in the urban area of Alta Floresta in the Amazon Basin. J Geochem Explor 1997; 58:209-16.^,6565. Farias LA, Fávaro DIT, Oliveira PTMS, Braga ES. Mercury and methylmercury in the children hair and fish mostly consumed in Cubatão, São Paulo State, Brazil. Rev Inst Adolfo Lutz 2014; 73:158-68.. However, the fish resources for urban centers may come from a contaminated water body, as reported by Hacon et al. ⁶⁴64. Hacon S, Rochedo ERR, Campos RRR, Lacerda LD. Mercury exposure through fish consumption in the urban area of Alta Floresta in the Amazon Basin. J Geochem Explor 1997; 58:209-16. in a study carried out in Alta Floresta, a town in Mato Grosso State/Brazil. The assessment of the impact of fish and shellfish contamination on the exposure of human beings and on their health through food deserves special attention, specifically, but not only, for those who are large consumers, such as indigenous groups, riverside communities (e.g. Amazon Basin), coastal (e.g. Florida/Puerto Rico) and island dwellers (e.g. Faroe Islands/Denmark). In this review, 3 articles have targeted this population and hematological effects: 1 sectional study with an indigenous group from the Peruvian Amazon near ASGM, that reported anemia among children under 12 years (83 persons) ⁶⁶66. Bose-O'Reilly S, McCarty KM, Steckling N, Lettmeier B. Mercury exposure and children's health. Curr Probl Pediatr Adolesc Health Care 2010; 40:186-215.; 1 cohort with children from Faroe Islands (56 persons), that reported leukopenia and lymphopenia ⁵²52. Oulhote Y, Shamim Z, Kielsen K, Weihe P, Grandjean P, Ryder LP, et al. Children's white blood cell counts in relation to developmental exposures to methylmercury and persistente organic pollutants. Reprod Toxicol 2017; 68:207-14., and other sectional with children from Jeju Island/South Korea (311 persons), that reported lymphocytosis ⁵⁰50. Kim JH, Lee KH, Hong SC, Lee HS, Lee J, Kang JW. Association between serum mercury concentration and leukocyte differential count in children. Pediatr Hematol Oncol 2013; 32:109-14..

Anemia and less commonly leukopenia, eosinophilia, thrombocytopenia and pancytopenia have been reported due to mercury toxicity ⁶⁷67. Winship KA. Toxicity of mercury and its inorganic salts. Adverse Drug React Acute Poisoning Rev 1985; 4:129-60.. In this review, most exposed people (75.85%) had a normal blood cell count, however, hematological effects were reported 2,376 times, mainly at non-occupational settings, comprising 1,914 cases. All bone marrow cellular series were affected and the most common, for both exposures, was the erythroid series with anemia (875). Out of five studies that addressed this subject using statistical analysis with significant p-value, there was mean difference in two ⁴³43. Siblerud RL. The relationship between mercury from dental amalgam and the cardiovascular system. Sci Total Environ 1990; 99:23-35.^,4747. Brázdová ZD, Pomerleau J, Fiala J, Vorlová L, Müllerová D. Heavy metals in hair samples: a pilot study of anaemic children in Kazakhstan, Kyrgyzstan and Uzbekistan. Cent Eur J Public Health 2014; 22:273-6., none in one study ⁴²42. Oluwole AF, Asubiojo OI, Adekile AD, Filby RH, Bragg A, Grimm CI. Trace element distribution in the hair of some sickle cell anemia patients and controls. Biol Trace Elem Res 1990; 26-27:479-84.; negative correlation ⁴²42. Oluwole AF, Asubiojo OI, Adekile AD, Filby RH, Bragg A, Grimm CI. Trace element distribution in the hair of some sickle cell anemia patients and controls. Biol Trace Elem Res 1990; 26-27:479-84. was reported in one and inverse association ⁵³53. Weinhouse C, Ortiz EJ, Berky AJ, Bullins P, Hare-Grogg J, Rogers L, et al. Hair mercury level is associated with anemia and micronutrients status in children living near artisanal ans small-scale gold mining in the Peruvian Amazon. Am J Trop Med Hyg 2017; 97:1886-97. in another. On the other hand, polycythemia was also reported in the mercury exposure group and a mean difference was found ⁴⁵45. Zabinski Z, Dabrowski Z, Moszczynski P, Rutowski J. The activity of erythrocyte enzymes and basic indices of peripheral blood erythrocytes from workers chronically exposed to mercury vapours. Toxicol Ind Health 2000; 16:58-64.. Other two hematological effects were also reported: lymphocytosis and lymphopenia. For the first outcome, there were three studies that reported a weak to moderate positive correlation ²²22. Moszczynski P, Slowinski S. The behaviour of T-cell subpopulations in the blood of workers exposed to mercury. Med Lav 1994; 85:239-41.^,2424. Soleo L, Colosio C, Alinovi R, Guarnieri D, Russo A, Lovreglio F, et al. Immunological effects of exposure to low exposure to inorganic mercury. Med Lav 2002; 93:225-32.^,5050. Kim JH, Lee KH, Hong SC, Lee HS, Lee J, Kang JW. Association between serum mercury concentration and leukocyte differential count in children. Pediatr Hematol Oncol 2013; 32:109-14. between lymphocytes and mercury. For the latter, one reported mean difference ¹²12. Queiroz MLS, Dantas DCM. B lymphocytes in mercury-exposed workers. Pharmacol Toxicol 1997; 81:130-3. and other two described inverse association between lymphocytes and mercury exposure ⁵¹51. Kim KN, Bae S, Park HY, Kwon HJ, Hong YC. Low-level mercury exposure and risk of asthma in school-age children. Epidemiology 2015; 26:733-9.^,5252. Oulhote Y, Shamim Z, Kielsen K, Weihe P, Grandjean P, Ryder LP, et al. Children's white blood cell counts in relation to developmental exposures to methylmercury and persistente organic pollutants. Reprod Toxicol 2017; 68:207-14.. One of these studies also described an association between mercury exposure and an increased neutrophils and basophils percentage ⁵¹51. Kim KN, Bae S, Park HY, Kwon HJ, Hong YC. Low-level mercury exposure and risk of asthma in school-age children. Epidemiology 2015; 26:733-9.. These results confirm there are relation or association between mercury exposure and hematological effects, especially for anemia, lymphopenia, lymphocytosis, neutrophilia and basophilia. However, none of these studies could determine a causal relationship, as they were not designed for this purpose.

Recently, researches shed some light on the role of heavy metal exposure at anemia, which is estimated by the World Health Organization (WHO) in 1.62 billion cases (95%CI: 1.0; 1.74 billion) ⁴⁷47. Brázdová ZD, Pomerleau J, Fiala J, Vorlová L, Müllerová D. Heavy metals in hair samples: a pilot study of anaemic children in Kazakhstan, Kyrgyzstan and Uzbekistan. Cent Eur J Public Health 2014; 22:273-6.^,4848. Mathee A, Naicker N, Kootbodien T, Muluma T, Nkomo P, Naik I, et al. A cross sectional analytical study of geophagia practices and blood metal concentrations in pregnant women in Johannesburg, South Africa. S Afr Med J 2014; 104:568-70.^,4949. Plante C, Blanchet C, Rochette L, O'Brien HT. Prevalence of anemia among inuit women in Nunavik, Canada. Int J Circumpolar Health 2011; 70:154-65.. More than half of the cases are caused by iron deficit (51%) and current data point to relation between heavy metals, such as lead and mercury, and iron metabolism (positive correlation for mercury and inverse for lead) ⁴⁹49. Plante C, Blanchet C, Rochette L, O'Brien HT. Prevalence of anemia among inuit women in Nunavik, Canada. Int J Circumpolar Health 2011; 70:154-65.^,6868. Bárány E, Bergdahl IA, Bratteby LE, Lundh T, Samuelson G, Skerfying S, et al. Iron status influences trace element levels in human blood and serum. Environ Res 2005; 98:215-23..

There is some scientific debate about mercury effect on lymphocytes. It is suggested that the difference observed (lymphopenia x lymphocytosis) could be explained by mercury’s level and form, in a way those exposed to methylmercury would be prone to lymphopenia and those to metallic or inorganic mercury to lymphocytosis ⁵⁰50. Kim JH, Lee KH, Hong SC, Lee HS, Lee J, Kang JW. Association between serum mercury concentration and leukocyte differential count in children. Pediatr Hematol Oncol 2013; 32:109-14.^,5252. Oulhote Y, Shamim Z, Kielsen K, Weihe P, Grandjean P, Ryder LP, et al. Children's white blood cell counts in relation to developmental exposures to methylmercury and persistente organic pollutants. Reprod Toxicol 2017; 68:207-14.^,6969. Shenker BJ, Rooney C, Vitale L, Shapiro IM. Immunotoxic effects of mercuric compounds on human lymphocytes and monocytes. I. Suppression of T-cell activation. Immunopharmacol Immunotoxicol 1992; 14:539-53.^,7070. Shenker BJ, Guo TL, Shapiro IM. Mercury-induced apoptosis in human lymphoid cells: evidence that the apoptotic pathway is mercurial species dependent. Environ Res 2000; 84:89-99.. The latter effect on lymphocytes was observed in six out of seven studies, which might corroborate this theory.

Some hematological effects are considered quite severe according to preestablished criteria and can lead to a number of critical clinical conditions. They were seen at this review as a consequence of mercury’s direct effect on blood cell and their corresponding clinical pictures, mainly as severe bleeding, but also as renal insufficiency, multiple organ dysfunction syndrome and sepsis. Despite the reports of other potential severe hematological effects, such as polycythemia, thrombocytosis and lymphocytosis, there were no cases of thrombosis or hematological cancer.

Mercury is a toxic substance that can lead to death. Its lethal dose is defined at 150 to 300mg/70kg ⁶6. Hong YS, Kim YM, Lee KE. Methylmercury exposure and health effects. J Prev Med Public Health 2012; 45:353-63.. There were 29 reports of it mainly on non-occupational exposure, especially due to use of medicine in a chronic way. In the past it was prescribed as laxative, diuretic and antiseptic. Nowadays, mercury is still present in some traditional therapies and religious practices (e.g. Santería, Espiritismo or Ayurvedic medicine) ⁷¹71. Masur LC. A Review of use of mercury in historic and current ritualistic and spiritual practice. Altern Med Rev 2011; 16:314-20.^,7272. Wu ML, Deng JF, Lin KP, Tsai WJ. Lead, mercury na arsenic poisoning due to topical use of traditional chinese medicines. Am J Med 2013; 126:451-54. as well as in vaccine preservative. All the five occupational deaths were related to higher level of mercury exposure at acute setting.

There are some explanations for some mercury hematological effects, such as: pancytopenia due to direct toxic effect on bone marrow ¹¹11. Priya N, Nagaprabhu VN, Kurian G, Seethalakshmi N, Rao GG, Unni VN. Aplastic anemia and membranous nephropathy induced by intravenous mercury. Indian J Nephrol 2012; 22:451-4.^,6767. Winship KA. Toxicity of mercury and its inorganic salts. Adverse Drug React Acute Poisoning Rev 1985; 4:129-60.; anemia due to apoptosis ¹⁴14. Zolla L, Lupidib GL, Bellellic A, Amiconicet G. Effect of mercuric ions on human erythrocytes. Relationships between hypotonic swelling and cell aggregation. Biochim Biophys Acta 1997; 1328:273-80.^,1515. Suwalsky M, Ungerer B, Villena F, Cuevas F, Sotomayor CP. HgCl2 disrupts the structure of the human erythrocyte membrane and model phospholipid bilayers. J Inorg Biochem 2000; 81:267-73., loss of blood from direct effect on gastrointestinal mucosa ⁷³73. Doolan PD, Hess WC, Kyle LH. Acute renal insufficiency dure to biclhoride of mercury - observations on gastrointestinal hemorrhage and Bal. N Engl J Med 1953; 249:273-6. and hemolysis ¹⁴14. Zolla L, Lupidib GL, Bellellic A, Amiconicet G. Effect of mercuric ions on human erythrocytes. Relationships between hypotonic swelling and cell aggregation. Biochim Biophys Acta 1997; 1328:273-80.^,1515. Suwalsky M, Ungerer B, Villena F, Cuevas F, Sotomayor CP. HgCl2 disrupts the structure of the human erythrocyte membrane and model phospholipid bilayers. J Inorg Biochem 2000; 81:267-73.^,3636. De Palma G, Mariotti O, Lonati D, Goldoni M, Catalani S, Mutti A, et al. Toxicokinetics and toxicodynamics of elemental mercury following self-administration. Clin Toxicol (Phila) 2008; 46:869-76.; polycythemia from increased level of erythropoietin ⁴⁵45. Zabinski Z, Dabrowski Z, Moszczynski P, Rutowski J. The activity of erythrocyte enzymes and basic indices of peripheral blood erythrocytes from workers chronically exposed to mercury vapours. Toxicol Ind Health 2000; 16:58-64.^,7474. Campbell G, Leitch D, Lewington AJP, Dargan PI, Baker RJ. Minimal change nephrotic syndrome due to ocupational mercury vapor inhalation. Clin Nephrol 2009; 3:216-9.; leukopenia, neutropenia, lymphopenia and basopenia due to passed inflammatory reaction ⁴⁶46. Frisk P, Danersund A, Hudecek R, Lindh U. Changed clinical chemistry pattern in blood after removal of dental amalgam and other metal alloys supported by antioxidant therapy. Biol Trace Elem Res 2007; 120:163-70. and apoptosis ⁶⁹69. Shenker BJ, Rooney C, Vitale L, Shapiro IM. Immunotoxic effects of mercuric compounds on human lymphocytes and monocytes. I. Suppression of T-cell activation. Immunopharmacol Immunotoxicol 1992; 14:539-53.^,7070. Shenker BJ, Guo TL, Shapiro IM. Mercury-induced apoptosis in human lymphoid cells: evidence that the apoptotic pathway is mercurial species dependent. Environ Res 2000; 84:89-99.; leukocytosis and neutrophilia due to lung inflammatory reaction (pneumonitis) ⁷⁵75. Kanamaru M, Suzuki H, Katoh M, Nishikawa T, Ohyama Y, Noda H. Effects of agricultural chemicals on rural inhabitants in Miye prefecture: a report on the findings of health examinations. Journal of the Japanese Association of Rural Medicine 1984; 33:159-66.^,7676. Maramba NPC, Reyes JP, Francisco-Rivera AT, Panganiban LCR, Dioquino C, Dando N, et al. Environmental and human exposure assessment monitoring of communities near an abandoned mercury mine in the Philippines: a toxic legacy. J Environ Manage 2006; 81:135-45.; eosinophilia related to hypersensitivity ⁷⁷77. Tschanz C, Prins C. Drug rash with eosinophilia and systemic symptoms caused by topical application of mercury. Dermatology 2000; 201:381-2.^,7878. Tunnessen WW, McMahon KJ, Baser M. Acrodynia: exposure to mercury from fluorescente light bulbs. Pediatrics 1987; 79:786-9. and idiosyncrasy ⁷⁹79. Al-Sinani S, Al-Rawas A, Dhawan A. Mercury as a cause of fulminant hepatic failure in a child: case report and literature review. Clin Res Hepatol Gastroenterol 2011; 35:580-2.; lymphocytosis due to increased calcium content in cytoplasm ²³23. Moszczynski P, Slowinski S, Rutkowski J, Bem S, Jakus-Stoga D. Lymphocytes, T and NK cells, in men occupationally exposed to mercury vapours. Int J Occup Med Environ Health 1995; 8:49-56., and; thrombocytopenia immunologically mediated ³⁹39. Fuortes LJ, Weismann DN, Graeff ML, Bale JF, Tannous R, Peters C. Immune thrombocytopenia and elemental mercury poisoning. Clin Toxicol (Phila) 1995; 33:449-55.^,8080. Gys YF, Fadeev AP. Clinical aspects of occupational intoxications by organic mercury toxic chemicals among agricultural workers in the Chelyabinsk region. Scientific Transactions of Leningrad Postgraduate Medical Institute 1971; 8:127-33..

The actual dimension of mercury’s hematologic effects is unknown for many reasons that come from the lack of studies that could evaluate this topic as a primary goal, which was discussed by two studies ³⁹39. Fuortes LJ, Weismann DN, Graeff ML, Bale JF, Tannous R, Peters C. Immune thrombocytopenia and elemental mercury poisoning. Clin Toxicol (Phila) 1995; 33:449-55.^,8181. Schwartz JG, Snider TE, Montiel MM. Toxicity of a family from vaccumed mercury. Am J Emerg Med 1992; 10:258-61. to the lack of knowledge of mercury role on this subject. In the latter, two situations were observed: the physician did not request mercury biomarker when evaluating an hematological effect or he did not request blood cell count when evaluating a case of mercury intoxication, merely because of the lack of knowledge. In this review, only 14 studies had hematological effect as main outcome of mercury exposure and 381 out of 1,158 studies were excluded due to the fact of not requesting blood cell count.

A meta-analysis was not pursued because the only hematological effect that had a sufficient number of comparable groups and a statistical measure (correlation coefficient r) was lymphocytes alteration (lymphocytosis or lymphopenia). There were differences in reporting this measure: one study did not report the r value and four, its statistical significance.

We have tried to mitigate the publication bias by a comprehensive, sensitive, unrestricted search for language, with a long period of time (more than 70 years) and search in the gray literature (e.g. congress, master and thesis). We were able to retrieve a significant amount of normal blood cell count results between exposed people as a consequence of a more sensitive search that included blood cell count as a key term. As a meta-analysis was not done, both the visual evaluation of the funnel plot and the statistical tests of hypothesis were not performed.

The quality assessment of these studies was considered weak according to EPHPP, a quality assessment tool (global ratings: 3) for 75 studies out of 80. This poor quality of most studies, mainly due to the study design, absence of possible confounders’ evaluation and presence of bias risk, limited the power of the epidemiological studies included. However, these data were able to identify, in absolute terms, 20% of hematological effects on the presence of mercury exposure, in particular for anemia, lymphopenia, neutrophilia and basophilia, as statistical tools with significant p-value were used. Without any doubt, this should stimulate further researches with special attention to studies of methodological elaboration. All steps of this process must be thoroughly thought, including random selection, comparison between exposure and non-exposure groups, control for confounders according to bone marrow cell affected (e.g. micronutrients, enteroparasitosis, malaria, others infections, glutathione S transferase deletion polymorphisms) and data collection methods that should be reliable and valid. For obvious ethical reasons, no clinical trials will be conducted to study this potential association. However, there are some others observational studies that can be done aiming, for example the frequency of this outcome (cross-sectional with comparing groups; case-control; multicentric cohort studies), the risk assessment of this exposure, as well to ascertain the clinical significance of this relationship.

Conclusion

This review was able to retrieve a significant number of studies for an issue with sparse information, although only few of them have evaluated hematological effect as the primary outcome. Despite the fact that the majority of exposed individuals had normal blood cell count and mercury hematological effects do not seem very usual, few studies reported association from refined observational study designs including robust statistical analysis, especially for anemia, lymphopenia, neutrophilia and basophilia. In this way, the effects of mercury on health should receive worldwide attention because of its toxicity and wide source of human exposure. Researchers, as well as health practitioners, should be aware of the potential hematological effect as sometimes it can be severe and even lethal.

Acknowledgments

We thank Roberto J. G. Unger (Public Health Institute, Federal University of Rio de Janeiro) and Prof. Eliane Pedra Dias (School of Medicine, Fluminense Federal University) for their assistance in the article review.

References

Publication Dates

History