Arsenic

Arsenic (metallic As, CAS numer: 7440-38-2; EC number: 231-148-6). Arsenic is a ubiquitous element that ranks 20th in abundance in the earth’s crust.[Mandal & Suzuki 2002]. Arsenic is classified as a metalloid. Elemental arsenic is a steel grey solid material. Arsenic in the environment is combined with other elements such as oxygen, chlorine, and sulfur, and is called as inorganic arsenic. Of the inorganic arsenic compounds, arsenic trioxide, sodium arsenite and arsenic trichloride are the most common trivalent compounds, and arsenic pentoxide, arsenic acid and arsenates (e.g. lead arsenate and calcium arsenate) are the most common pentavalent compounds.(WHO 2000, ASTDR 2007)

Common organic arsenic compounds include arsanilic acid, methylarsonic acid, dimethylarsinic acid (cacodylic acid), and arsenobetaine (WHO, 2000).

Most inorganic and organic arsenic compounds are white or colorless powders that do not evaporate. They have no smell, and most have no special taste. [ASTDR 2007]. Arsenic in its most recoverable form is found in various types of metalliferous deposits.

It is common in iron pyrite, galena, chalcopyrite and less common in sphalerite. The most common arsenic mineral is arsenopyrite [Mandal & Suzuki 2002].

The primary use of arsenic is in alloys of lead. Arsenic is a common n-type dopant in semiconductor electronic devices, and the optoelectronic compound gallium arsenide is the second most commonly used semiconductor after doped silicon. Arsenic and its compounds, especially the trioxide, are used in the production of pesticides, treated wood products, herbicides, and insecticides. Although arsenic can be poisonous in higher doses, it has also been used in some medicines. A form of arsenic is still used to treat an uncommon blood cancer known as acute promyelocytic leukemia.[Grund et al.2008]

Please see the link above to the scoping document on arsenic for this information.

According to the International Agency for Research on Cancer (IARC), arsenic is classified in Group 1 (sufficient evidence of carcinogenicity in humans) In contrast to organic arsenic, iAs is extremely toxic and current risk assessments of dietary exposure to arsenic are entirely based on the inorganic forms. The general population is exposed to iAs via the diet, with food being the major contributor to intake when arsenic concentrations in water are <10 μg/L (the WHO guideline value for drinking water), while drinking water becomes the major source of exposure to iAs when water with arsenic concentrations well above 10 μg/L is used for drinking and cooking (EFSA, 2014; FAO/WHO, 2011). The IARC has established a causal role for oral exposure to iAs on skin, lung, and bladder cancers, and has shown suggestive evidence for liver, kidney, and prostate cancers (IARC, 2012). Apart from cancer – and skin lesions (EFSA, 2014) – a wide range of other adverse health effects such as cardiovascular diseases, developmental toxicity, abnormal glucose metabolism, type II diabetes and neurotoxicity are likely related to chronic ingestion of iAs (FAO/WHO, 2011). Susceptibility to the toxic effects of iAs varies considerably between individuals and populations depending on variations in iAs metabolism related to such factors as age, gender, life stage (e.g. pregnancy, lactation), nutritional status, and genetic polymorphisms in the regulation of enzymes responsible for iAs biotransformation (EFSA, 2014).

Arsenic is found in the environment in the metallic form and in various inorganic and organic complexes. The sources are both natural and anthropogenic.

Soil: Arsenic occurs naturally in soils as a result of the weathering of the parent rock. Anthropogenic activity has resulted in the widespread atmospheric deposition of arsenic the burning of coal and the smelting of non-ferrous metals including copper [EPA 2009a]. The levels of arsenic in the soils of various countries are said to range from 0.1 to 40 mg/kg (mean 6 mg/ kg), 1 to 50 mg/kg (mean 6 mg/kg) and mean 5 mg/kg but varies considerably among geographic regions.

Arsenic is present in soils in higher concentrations than those in rocks [Mandal &Suzuki 2002].Uncontaminated soils usually contain 1–40 mg/kg of arsenic, with lowest concentrations in sandy soils and those derived from granites, whereas larger concentrations are found in alluvial and organic soils. Arsenate reportedly binds strongly to iron and manganese oxides, and therefore remains in the surface soil layer after deposition [ATSDR, 2007]. Arsenic was observed to be still concentrated after 15 years in the top 20–40 cm of orchard soils treated with lead arsenate (Merwin et al. 1994). However, several experimental studies have found that arsenate can be released from iron oxides at alkaline pH as a result of desorption processes [IPCS, 2001; ATSDR, 2007].

Water: Arsenic is found at low concentration in natural water. The maximum permissible concentration of arsenic in drinking water is 50 mcg/l and recommended value is 10 mcg/l by EPA and WHO [IPCS 2001]. The seawater ordinarily contains 0.001–0.008 mg/l of arsenic. The concentration of arsenic in unpolluted fresh waters typically ranges from 1–10 g/l1, rising to 100–5000 g/l in areas of sulfide mineralisation and mining [Mandal &Suzuki 2002].

Only a very minor fraction of the total arsenic in the oceans remains in solution in seawater, as the majority is sorbed on to suspended particulate materials. The high levels of arsenic are in waters from areas of thermal activity in New Zealand up to 8.5 mg/l. Geothermal water in Japan contains 1.8–6.4 mg/l and neighboring streams about 0.002 mg/l. Although normally groundwater does not contain methylated form of arsenic but lake and pond waters contain arsenite, arsenate as well as methylated forms, i.e. MMA and DMA [Mandal &Suzuki 2002]..

Air: In air, arsenic exists predominantly absorber on particulate matters, and is usually present as a mixture of arsenite and arsenate, with the organic species being of negligible importance except in areas of arsenic pesticide application or biotic activity [Mandal & Suzuki 2002]. The human exposure of arsenic through air is generally very low and normally arsenic concentrations in air ranges from 0.4 to 30 ng/m³. According to USEPA the estimated average national exposure in the U.S. is at 6 ng As/m³. Absorption of inhaled arsenic ranges between 30 and 85%, depending on the relative portions of vapour and particulate matters. USEPA estimates that the general public will be exposed to a range of approximately 40–90 ng per day by inhalation. The amount of arsenic inhaled per day is about 50 ng or less (assuming that about 20 m³ of air is inhaled per day) in unpolluted areas. The daily respiratory intake of arsenic is approximately 120 ng of which 30 ng would be absorber.Typical arsenic levels for the European region are currently quoted as being between 0.2 and 1.5 ng/m³ in rural areas, 0.5 and 3 ng/m³ in urban areas and no more than 50 ng/m³ in industrial areas. [European Commission 2000]

Animals and human beings: As in plant tissue, arsenic is cumulative in animal tissue, allowing for a wide variation in concentration due to the variance in arsenic ingested in different areas. Among marine animals, arsenic is found to be accumulative to levels of from 0.005 to 0.3 mg/kg in coelenterates, some molluscs and crustaceans. Some shellfish may contain over 100 mcg/g of arsenic. The average arsenic content in freshwater fish is of 0.54 mcg/g on the basis of total wet weight, but some values reach as high as 77.0mcg/g in the liver oil of freshwater bass. In mammals it is found that the arsenic accumulates in certain areas of the ectodermic tissue, primarily the hair and nails [Mandal & Suzuki 2002].

Human exposure: Humans are exposed to many different forms of inorganic and organic arsenic species (arsenicals) in food, water and other environmental media. Each of the forms of arsenic has different physicochemical properties and bioavailability and therefore the study of the kinetics and metabolism of arsenicals is a complex matter.

General population: For the general population, the principal route of exposure to arsenic is likely to be the oral route, primarily via food, and drinking water. Intake from air, is usually much less. Dermal exposure can occur, but is not considered a primary route of exposure. The epidemiologic evidence for an cross the placenta is insufficient, although there exists limited evidence for arsenic concentrations found in cord blood and maternal blood of maternal-infant pairs exposed to high arsenic-containing drinking water.[ASTDR 2007.]

Occupational exposure population: Occupational exposure to arsenic may be significant in several industries, mainly nonferrous smelting, arsenic production, wood preservation, glass manufacturing. Occupational exposure would be via inhalation and dermal contact.

There are several potential biomarkers for arsenic exposures. Preferred biomarkers are determination of As and its chemical forms in urine. Non-invasive, ease collection and because the majority of absorbed arsenic and its metabolites is eliminated via urine puts this type of markings in a privileged position. Moreover, the analytical techniques allows arsenic speciation in urine, but not hair and nails (due to mineralisation). The short half-life of inorganic and organic arsenic species in blood and invasive collection limits the utility of arsenic biomarkers in blood, similar to determination As in hair and nails. Advantages for this these biomarkers in hair and nails are is assessment of integrated exposures, but these markers include arsenic derived from all way organic arsenic (non-toxic) and inorganic species. (Hughes 2006; Navas-Acien and Guallar, 2008). When exposure to a compound results in multiple biomarkers and the mode of action is not known with certainty, it is recommended to sum as many of the metabolites in a Biomonitoring Equivalent (BE) calculation as long as the metabolites are specific to exposures of concern (Aylward et al., 2009). Sum of iAs, MMA, DMA correlate well with drinking water concentration (Calderon et al., 1999; Hall et al., 2006) or estimated daily dose calculated using drinking water concentrations (Navas-Acien et al., 2009; Agusa et al., 2009). The concentrations of total arsenic and iAs, MMA, and DMA are all fairly constant over time with small intra-individual variabilities (Navas-Acien et al., 2009; Kile et al., 2009). First morning voids of total arsenic are indicative of and correlated with subsequent voids throughout the day (Calderon et al., 1999 ). For these reasons, speciated arsenic in urine (iAs III, iAs V , MMA, and DMA) are the preferred biomarker(s) for exposures to inorganic arsenic ( Lauwerys and Hoet, 2001) but as described Buchet et al., 1994 certain types of seafood can contain small quantities of DMA than the urine sample should abstain from eating seafood for 3–4 days prior to urine collection (Lauwerys and Hoet, 2001 ). In such cases where diet cannot be controlled, Lauwerys and Hoet (2001) have recommended using iAs concentration in urine as opposed to the sum of iAs, MMA, and DMA in urine as the biomarker of choice. Since MMA is not affected by seafood consumption, both iAs and MMA should be reliable biomarkers of inorganic arsenic exposures. Then, the recommendations are for using sums of all three (iAs, MMA, and DMA) as a biomarkers for As .when no exposures to seafood have occurred.

The determination of arsenic in biological specimens requires sensitive analytical methods, performed under good quality control conditions. Various methods exist that differ in sample preparation technique and/or the detections system. Determination of total As concentration can be done by ICP MS, inorganic arsenic as well as MMA and DMA can be done by AAS technique with hydrogen generation.

Speciation of arsenic requires coupled analytical techniques (ICP-MS-HPLC) and procedures and expensive reagents and equipment, which are not routinely available in analytical laboratories. Speciation analysis is necessary to differentiate between inorganic and organic arsenic exposure.

The symptoms and signs caused by long-term elevated exposure to inorganic arsenic differ between individuals, population groups and geographical areas. Thus, there is no universal definition of the disease caused by arsenic. This complicates the assessment of the burden on health of arsenic.

There is a need to harmonise exposure biomarkers and to validate biomarkers of susceptibility, selection of exposure biomarkers, and include the role of genetic polymorphisms in contributing to population variability in pharmacokinetics and sensitivity to the adverse effects of exposure to arsenic.[Ladeira C, Viegas S. 2016; Chen et al. 2005; Janasik et al. 2018]

It is important to harmonise the approaches used to investigate different study populations. The selection of best suited matrices and biomarkers of exposure is crucial. Markers of susceptibility need to be validated. These are important for understanding the human health effects of low-level As exposure as a basis for future research efforts, risk assessment, and exposure remediation policies worldwide. As speciation in urine, would provide characterisation of species-specific exposure at levels relevant for European population. In recent years interest in gene-environment interaction has grown substantially, because of the progress in laboratory techniques, improved understanding of genetics and realisation of complex mechanisms between genetics and environment. Identification and validation of novel biomarkers of susceptibility is therefore an important part in investigation of exposure-health relationships.

Following on the Advisory Board’s advice to strengthen the science-policy interface, HBM4EU developed a strategic and systematic approach to outreach and align science and policy. A legislative mapping exercise was done by RPA Consultants, providing relevant public policy processes that may benefit from the knowledge generated under HBM4EU. The documents are available for consultation here, with the tables presented here.

Food safety

Maximum levels for arsenic in certain foods have been established by Commission Regulation (EC) No 2015/1006 (future section 3.5 of the Annex to Regulation (EC) No 2006/1881, applicable from 1 January 2016 onwards).

The EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) assessed the risks to human health related to the presence of arsenic in food. More than 100,000 occurrence data on arsenic in food were considered with approximately 98 % reported as total arsenic. Making a number of assumptions for the contribution of inorganic arsenic to total arsenic, the inorganic arsenic exposure from food and water across 19 European countries, using lower bound and upper bound concentrations, has been estimated to range from 0.13 to 0.56 µg/kg bodyweight (b.w.) per day for average consumers, and from 0.37 to 1.22 µg/kg b.w. per day for 95th percentile consumers. Dietary exposure to inorganic arsenic for children under three years of age is in general estimated to be from 2 to 3‐fold higher that of adults. The CONTAM Panel concluded that the provisional tolerable weekly intake (PTWI) of 15 µg/kg b.w. established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) is no longer appropriate as data had shown that inorganic arsenic causes cancer of the lung and urinary bladder in addition to skin, and that a range of adverse effects had been reported at exposures lower than those reviewed by the JECFA. The CONTAM Panel modelled the dose‐response data from key epidemiological studies and selected a benchmark response of 1 % extra risk of cancers of the lung, skin and bladder, as well as skin lesions (BMDL₀₁ = 0.3-8 μg/kg bw/day).

The estimated dietary exposures to inorganic arsenic for average and high level consumers in Europe are within the range of the BMDL01 values identified, and therefore there is little or no margin of exposure and the possibility of a risk to some consumers cannot be excluded.

Chemicals

Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006, concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals, Official Journal No. L 396/1 of 30.12.2006 (hereinafter “REACH”) aims at ensuring a high level of protection for human health and environment, while promoting the efficient functioning of the EU internal market and stimulating innovation and competitiveness in the chemical industry.

Having a common interest in fulfilling the requirements under REACH, the members of the As Consortium have therefore created the As Consortium back in 2009, in order to share human and financial resources involved in complying with REACH.

According to the harmonised classification and labelling (CLP) approved by the European Union, this substance is toxic if swallowed, is toxic if inhaled, is very toxic to aquatic life and is very toxic to aquatic life with long lasting effects. Moreover, some uses of this substance are restricted under Annex XVII of REACH.

Occupational health and safety

Proposal for a DIRECTIVE OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL amending Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work. This proposal aims to improve workers’ health protection by reducing occupational exposure to five carcinogenic chemical  agents, to provide more clarity for workers, employers and enforcers, and to contribute to a level playing field for economic operators.

The following policy-related questions relate to commitments under this frame.

1. What is the current exposure of the EU population to arsenic?
2. What biomonitoring and exposure (environmental and occupational) data on arsenic, relevant to the European population, are currently available?
3. What is the geographic spread of the current exposure and how does it relate to different exposure sources (environmental; dietary sources)?
4. Which population groups are most at risk?
5. What factors (genetic polymorphisms) make people more susceptible or not to the risk of health effects due to arsenic exposure? How are the best and more sensitive biomarkers for identification of reliable arsenic exposure and to link to potential adverse health-effect?
6. What are possible health effects resulting from chronic low exposure to arsenic from food consumption?
7. What are the best analytical methods should allow for differentiating species in urine?
8. How can harmonised, validated and comparable information be collected to support and evaluate current policies?
9. How can transfer of knowledge & technology be facilitated to support current policies?
10. How can HBM4EU results support European policy decisions?

Please find answers to the Policy-related questions here

In the interest of transparency and accountability, HBM4EU invites interested stakeholders to submit comments on the scoping document.

All submitted comments will be made available for download on this webpage and will be taken into consideration by the HBM4EU consortium, where possible.

Please click here to submit your comments.

Please click here to access the Substance Report.

1. Abhyankar L. N. , Jones M.R., Guallar E., and Navas-Acien A.,2012 Arsenic exposure and Hypertension: A systematic Review, EHP 120(4), 494-500
2. ACGIH (2014) TLV® and BEIs® based on the documentation of the threshold limit values for chemical substances and physical agents & biological exposure indices. ACGIH®, Cincinnati, OH
3. Agency for Toxic Substances Disease Registry. 2007. Toxicological profile for arsenic (Update). U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry. http://www.atsdr.cdc.gov/toxprofiles/tp2-p.pdf. January 23, 2015.
4. Agusa, T., Kunito, T., Minh, T.B., Kim Trang, P.T., Iwata, H., Viet, P.H., Tanabe, S., 2009. Relationship of urinary arsenic metabolites to intake estimates in residents of the Red River Delta, Vietnam. Environ. Pollut. 157, 396–403.
5. Annual Report of the European Food Safety Authority (EFSA) 2014 Dietary exposure to inorganic arsenic in the European population doi: 10.2903/j.efsa.2014.3597EFSA Journal 2014;12(3):3597
6. Apostoli P, Bartoli D, Alessio L, Buchet JP (1999) Biological monitoring of occupational exposure to inorganic arsenic. Occup Environ Med 56:825–832. doi:10.1136/oem.56.12.825
7. Arsenic, Environmental Health Criteria 224, Arsenic and Arsenic Compounds; World Health Organisation, Geneva, 2004
8. Aylward, L.L., Hays, S.M., Gagné, M., Krishnan, K., 2009. Derivation of Biomonitoring Equivalents for di(2-ethylhexyl)phthalate (CAS No. 117-81-7). Regul. Toxicol. Pharmacol. 55, 249–258.
9. Buchet, J.P., Pauwels, J., Lauwerys, R., 1994. Assessment of exposure to inorganic arsenic following ingestion of marine organisms by volunteers. Environ. Res. 66, 44–51
10. Calderon, R.L., Hudgens, E., Le, X.C., Schreinemachers, D., Thomas, D.J., 1999. Excretion of arsenic in urine as a function of exposure to arsenic in drinking water. Environ. Health Perspect. 107, 663–667
11. CDC (2005). Third National Report on Human Exposure to Environmental Chemicals. Atlanta, GA: Centers for Disease Control and Prevention.
12. Chen CJ, Hsu LI, Wang CH, Shih WL, Hsu YH, Tseng MP, Lin YC, Chou WL, Chen CY, Lee CY, Wang LH, Cheng YC, Chen CL, Chen SY, Wang YH, Hsueh YM, Chiou HY, Wu MM.2005 Biomarkers of exposure, effects and succeptibility of arsenic- induced health hazards in Taiwan. Toxicol Appl Pharmacol.;206(2):198-206.
13. Chen CL, Chiou HY, Hsu LI, Hsueh YM, Wu MM, Chen CJ. Ingested arsenic, characteristics of well water consumption and risk of different histological types of lung cancer in northeastern Taiwan. Environ Res. 2010; 110:455–462.
14. Cohen SM, Arnold LL, Beck BD, Lewis AS, Eldan M. Evaluation of the carcinogenicity of inorganic arsenic. Crit. Rev. Toxicol. 2013; 43:711–752.
15. Cohen SM, Arnold LL, Eldan M, Lewis AS, Beck BD. Methylated arsenicals: the implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Crit. Rev. Toxicol 2006;36(2): 99–133.
16. Commission Regulation (EC) No 2015/1006 (future section 3.5 of the Annex to Regulation (EC) No 2006/1881, applicable from 1 January 2016 onwards
17. Cubadda F, Ciardullo S, D’Amato M, Raggi A, Aureli F, Carcea M. Arsenic contamination of the environment-food chain: a survey on wheat as a test plant to investigate phytoavailable arsenic in Italian agricultural soils and as a source of inorganic arsenic in the diet. J. Agric. Food Chem. 2010; 58:10176–10183.
18. Cubadda F, D’Amato M, Aureli F, Raggi A, Mantovani A. Dietary exposure of the Italian population to inorganic arsenic: the 2012-2014 Total Diet Study. Food Chem. Toxicol. 2016; 98:148–158.
19. Cubadda F, D’Amato M, Mancini FR, Aureli F, Raggi A, Busani L, Mantovani A. Assessing human exposure to inorganic arsenic in high-arsenic areas of Latium: a biomonitoring study integrated with indicators of dietary intake. Ann. Ig. 2015; 27:39–5
20. D’’Ippoliti D, Santelli E, De Sario M, Scortichini M, Davoli M, Michelozzi P. Arsenic in drinking water and mortality for cancer and chronic diseases in central Italy, 1990-2010. PloS One. 2015; 10:e0138182.
21. Deutsche Forschungsgemeinschaft (DFG), Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, ““List of MAK and BAT Values 2017. Report 53,”” WILEY-VCH Verlag GmbH & Co. KgaA, Weinheim, 2017.
22. ENVIRONMENT AGENCY, 2009a. Using Soil Guideline Values. Science Report SC050021/SGV introduction. Bristol: Environment Agency. (http://www.environment-agency.gov.uk/clea).
23. Environmental Protection Agency . Health assessment document for inorganic arsenic. Research Triangle Park: Environmental Protection Agency; 1983. P. 351.
24. European Chemicals Authority (ECHA), ““Information on Chemicals -– Harmonized Classification -– Annex VI of Regulation (EC) 1272/2008 (CLP),”” [Online]. Available: https://echa.europa.eu/el/information-on-chemicals/cl-inventory-database/-/discli/details/15915. [Accessed 15 10 2018].
25. EUROPEAN COMMISSION, 2000, European Commission Working Group on Arsenic, Cadmium and Nickel Compounds. Ambient air pollution by As, Cd and Ni compounds. Position Paper, October 2000. Available at: http://europa.eu.int/comm/environment/air/pdf/pp_as_cd_ni.pdf
26. Feldmann J, Krupp EM. Critical review or scientific opinion paper: arsenosugars -– a class of benign arsenic species or justification for developing partly speciated arsenic fractionation in foodstuffs? Anal. Bioanal. Chem. 2011; 399:1735–1741.
27. Food and Agriculture Organization of the United Nations World Health Organization (JECFA) JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES 2011
28. Frery N, Vandentorren S, Etchevers A, Fillol C (2012). Highlights of recent studies and future plans for the French human biomonitoring (HBM) programme. Int J Hyg Environ Health, 215(2):127–32.
29. García-Esquinas E, Pollán M, Umans JG, Francesconi KA, Goessler W, Guallar E, Howard B, Farley J, Best LG, Navas-Acien A. Arsenic exposure and cancer mortality in a US-based prospective cohort: the strong heart study. Cancer Epidem. Biomar. 2013; 22:1944–1953.
30. Grund, Sabina C.; Hanusch, Kunibert; Wolf, Hans Uwe, (2008) “Arsenic and Arsenic Compounds”, Ullmann’s Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a03_113.pub2
31. Hakala E, Pyy L (1995) Assessment of exposure to inorganic arsenic by determining the arsenic species excreted in urine. Toxicol Lett 77:249–258. doi:10.1016/0378-4274(95)03304-1
32. HallHall, M., Chen, Y., Ahsan, H., Slavkovich, V., van Geen, A., Parvez, F., Graziano, J., 2006. Blood arsenic as a biomarker of arsenic exposure: results from a prospective study. Toxicology 225, 225–233.
33. Helene CH, Chon J, Fowler A (2007) Arsenic. In: Nordberg GF, Fowler BA, Nordberg M, Friberg LT (eds) Handbook on the toxicology of metals, 3rd edn. Elsevier, Amsterdam, pp 367–406
34. Hopenhayn-Rich C, Biggs ML, Smith AH. Lung and kidney cancer mortality associated with arsenic in drinking water in Cordoba, Argentina. Int. J. Epidemiol. 1998; 27:561–569.
35. IARC (1987) Monographs on the evaluation of carcinogenic risk to humans. Overall valuations of carcinogenicity: an updating of IARC. Lyon, Supplement 7: 100
36. IARC. 2012. Arsenic, metals, fibres, and dusts. International Agency for Research on Cancer. IARC Monogr Eval Carcinog Risks Hum 100(Pt C):11-465.
37. IARC. 2014. Agents classified by the IARC monographs. Volumes 1–111. Lyon, France: International Agency for Research on Cancer. http://monographs.iarc.fr/ENG/Classification/ClassificationsCASOrder.pdf. September 9, 2014.
38. Janasik B., Reszka E., Stanislawska M., Jablonska E., Kuras R.,Wieczorek E., Malachowska B., Fendler W., Wasowicz W. 2018, Effects of arsenic exposure on NRF2-KEAP1 Pathway and Epigenetic Modification. Biol Trace Elem Res 185(1), 11-19
39. Janasik, B., Reszka, E., Stanislawska, M., Wieczorek, E., Fendler, W., & Wasowicz, W. (2014). Biological monitoring and the influence of genetic polymorphism of As3MT and GSTs on distribution of urinary arsenic species in occupational exposure workers. International Archives of Occupational and Environmental Health, 88, 807–818.
40. Järup L, Pershagen G, Wall S (1989) Cumulative arsenic exposure and lung cancer in smelter workers: a dose-response study. Am J Ind Med 15:31–41. Doi:10.1002/ajim.4700150105
41. Kile, M.L., Hoffman, E., Hsueh, Y.M., Afroz, S., Quamruzzaman, Q., Rahman, M., Mahiuddin, G., Ryan, L., Christiani, D.C., 2009. Variability in biomarkers of arsenic exposure and metabolism in adults over time. Environ. Health Perspect. 117, 455–460
42. Kolossa-Gehring M, Becker K, Conrad A, Schroter-Kermani C, Schulz C, SeiwertM (2012). Environmental surveys, specimen bank and health related environmental monitoring in Germany. Int J Hyg Environ Health, 215(2):120–6.
43. Kurokawa M, Ogata K, Idemori M, Tsumori S, Miyaguni H, Inoue S, Hotta N. Investigation of skin manifestations of arsenicism due to intake of arsenic-contaminated groundwater in residents of Samta, Jessore, Bangladesh. Arch. Dermatol. 2001; 137:102–103.
44. Ladeira c., Viegas S. 2016 Human Biomonitoring – An overview on biomarkers and their application in Occupational and Environmental Health; Biomonitoring 3:15-24 ;De Gruyter
45. Lauwerys R, Hoet P (2001) Industrial chemical exposure –guidelines for biological monitoring, 3rd edn. Lewis Publishers, CRC Press, Boca Raton, FL, pp 36–49
46. Leonardi G, Vahter M, Clemens F, Goessler W, Gurzau E, Hemminki K, Hough R, Koppova K, Kumar R, Rudnai P, Surdu S, Fletcher T. Inorganic arsenic and basal cell carcinoma in areas of Hungary, Romania, and Slovakia: a case-control study. Environ. Health Persp. 2012; 120:721–726.
47. Mandal B.K., Suzuki K.T. (2002) Arsenic round the world: a review, Talanta 58, pp 201-235
48. Merwin, I.A., W.C. Stiles, and H.M. van Es. 1994. Orchard groundcover management impacts on soil physical properties. J. Amer. Soc. Hort. Sci. 119:216–222.
49. Michael F. Hughes Biomarkers of Exposure: A Case Study with Inorganic Arsenic Environ Health Perspect. 2006 Nov; 114(11): 1790–1796.
50. Moon KA, Guallar E, Umans JG, Devereux RB, Best LG, Francesconi KA, Goessler W, Pollak J, Silbergeld EK, Howard BV, Navas-Acien A. Association between exposure to low to moderate arsenic levels and incident cardiovascular disease. A prospective cohort study. Ann. Intern. Med. 2013; 159:649–59.
51. Nachman K.E. Ginsberge G.L., Miller M.D., Murray C.J., Nigra A.E., and Pendergrast C.B., 2017 Mitigating dietary arsenic exposure: Current status in the United States and recommendations for an improved path forward; Sci Total Environ. 2017 581-582: 221–236.
52. Navas-Acien A., Silbergeld E.K. Streeter R.A., Clark J.M. Burke T. A. And Guallar E., 2006 Arsenic Exposure and Type 2 Diabetes: A Systematic Review of the Experimental and Epidemiologic Evidence, EPH 114(5), 641-648
53. Navas-Acien A1, Silbergeld EK, Pastor-Barriuso R, Guallar E. Arsenic exposure and prevalence of type 2 diabetes in US adults. JAMA. 2008 Aug 20;300(7):814-22
54. Navas-Acien, A., Umans, J.G., Howard, B.V., Goessler, W., Francesconi, K.A., Crainiceanu, C.M., Silbergeld, E.K., Guallar, E., 2009. Urine arsenic concentrations and species excretion patterns in American Indian communities over a 10-year period: the Strong Heart Study. Environ. Health PerspectEPH. 117, 1428–1433.
55. NRC (National Research Council) (2001) Arsenic in drinking water: update. National Academy Academies Press, Washington DC
56. NRC (National Research Council) (2014) Critical Aspects of EPA’s IRIS Assessment of Inorganic Arsenic: Interim Report. National Academies Press
57. Pino A, Amato A, Alimonti A, Mattei D, Bocca B (2012). Human biomonitoring for metalsin Italian urban adolescents: data from Latium Region. Int J Hygiene Environ Health, 215(2):185–90.
58. 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 (Text with EEA relevance)
59. Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006, concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals, Official Journal No. L 396/1 of 30.12.2006 (hereinafter “REACH”)
60. Saravanabhavan G., K. Werry K., M. Walker M., D. Haines D., M. Malowany M.and C. Khoury C., ““Human biomonitoring reference values for metals and trace elements in blood and urine derived from the Canadian Health Measures Survey 2007–2013,”” International Journal of Hygiene and Environmental Health, vol. 220, no. 2 , Part A, pp. 189-200, 2017.
61. Schoeters G, Den Hond E, Colles A, Loots I, Morrens B, Bruckers L et al. (2012a). The Flemish Environment and Health Study (FLEHS) – Second Survey (2007–2011): Establishing Reference Values for Biomarkers of Exposure in the Flemish Population. In: Knudsen E, Merlo DF, editors. Biomarkers and human biomonitoring. Volume 1. London: Royal Society of Chemistry, 135–165 (Issues in Toxicology, No.1).
62. Schulz C, Conrad A, Becker K, Kolossa-Gehring M, Seiwert M, Seifert B (2007b). Twentyyears of the German Environmental Survey (GerES): Human biomonitoring – temporaland spatial (West Germany/East Germany) differences in population exposure. Int J Hygiene Environ Health, 210(3–4): 271–97.
63. Schulz C., M. Wilhelm , U. Heudorf and M. Kolossa-Gehring, “Update of the reference and HBM values derived by the German Human Biomonitoring Commission,” International Journal of Hygiene and Environmental Health, vol. 215, no. 1, pp. 26-35, 2011.
64. Smith AH, Goycolea M, Haque R, Biggs ML. Marked increase in bladder and lung cancer mortality in a region of Northern Chile due to arsenic in drinking water. Am. J. Epidemiol. 1998; 147:660–669.
65. Snoj Tratnik J, Mazej D, Horvat M (2012). Human biomonitoirng studies in Slovenia –toxic metals, arsenic and essential elements. In: Human Biomonitoring (HBM) – LinkingEnvironment to Health and Supporting Policy. Proceedings of the Conference, Larnaca, Cyprus, 22–25 October 2012. Nicosia: Ministry of Health, 88.
66. Thomas DJ., Li J., Waters SB., Xing W., Adair BM., Drobna Z., Devesa V. and Styblo M. Arsenic (+3 Oxidation State) Methyltransferase and the Methylation of Arsenicals. Exp Biol Med January 2007;232(1):3-13
67. Tremblay M., R. Langlois R., S. Bryan S., D. Esliger D., J. Patterson J. Canadian health measures survey pre-test: design, methods, results Health Rep., 18 (Suppl) (2007), pp. 21-30
68. Tseng C-H (2009) A review on environmental factors regulating arsenic methylation in humans. Toxicol Appl Pharmacol 235:338–350.
69. US FDA (U.S. Food and Drug Administration). Arsenic in Rice and Rice Products Risk Assessment Report. 2016. Available at http://www.fda.gov/Food/FoodScienceResearch/RiskSafetyAssessment/default.htm
70. Vahter M (1999) Methylation of inorganic arsenic in different mammalian species and population groups. Sci Prog Lond 82:69–88
71. Vahter M (2002) Mechanisms of arsenic biotransformation. Toxicology 181–182:211–217.
72. WHO. 2000. Air quality guidelines for Europe. WHO Regional Publications, European Series, No. 91. Geneva, Switzerland: World Health Organization. http://www.euro.who.int/__data/assets/pdf_file/0005/74732/E71922.pdf. January 26, 2015.
73. World Health Organization (WHO), “Human Biomonitoring – Facts and Figures,” 2015.
74. Zheng LY, Umans JG, Tellez-Plaza M, Yeh F, Francesconi KA, Goessler W, Silbergeld EK, Guallar E, Howard BV, Weaver VM, Navas-Acien A. Urine arsenic and prevalent albuminuria: evidence from a population-based study. Am. J. Kidney Dis. 2013; 61:385–394.