Research Genetic Effects on Toxic and Essential Elements in Humans: Arsenic, Cadmium, Copper, Lead, Mercury, Selenium, and Zinc in Erythrocytes Nicholas G. Martin1 John B. Whitfield,1 Veronica Dy,2 Robert McQuilty,2 Gu Zhu,1 Andrew C. Heath,3 Grant W. Montgomery,1 and 1Genetic Epidemiology Unit, Queensland Institute of Medical Research, Brisbane, Australia; 2Biochemistry Department, Royal Prince Alfred Hospital, Sydney, Australia; 3Midwest Alcoholism Research Center, Washington University, St. Louis, Missouri, USA Background and o Bjectivs : An excess of toxic trace elements or a deficiency of essential ones has been implicated in many common diseases or public health problems, but little is known about causes of variation between people living within similar environments. We estimated effects of per- sonal and socioeconomic characteristics on concentrations of arsenic (As), cadmium (Cd), copper (Cu), mercury (Hg), lead (Pb), selenium (Se), and zinc (Zn) in erythrocytes and tested for genetic effects using data from twin pairs. Methods : We used blood samples from 2,926 adult twins living in Australia (1,925 women and 1,001 men; 30–92 years of age) and determined element concentrations in erythrocytes by induc- tively coupled plasma-mass spectrometry. We assessed associations between element concentrations and personal and socioeconomic characteristics, as well as the sources of genetic and environmental variation and covariation in element concentrations. We evaluated the chromosomal locations of genes affecting these characteristics by linkage analysis in 501 dizygotic twin pairs. r esult : Concentrations of Cu, Se, and Zn, and of As and Hg showed substantial correlations, concentrations of As and Hg due mainly to common genetic effects. Genetic linkage analysis showed significant linkage for Pb [chromosome 3, near SLC4A7 (solute carrier family 4, sodium bicarbonate cotransporter, member 7)] and suggestive linkage for Cd (chromosomes 2, 18, 20, and X), Hg (chromosome 5), Se (chromosomes 4 and 8), and Zn {chromosome 2, near SLC11A1 [solute carrier family 11 (proton-coupled divalent metal ion transporters)]}. c onclusi : Although environmental exposure is a precondition for accumulation of toxic ele- ments, individual characteristics and genetic factors are also important. Identification of the con- tributory genetic polymorphisms will improve our understanding of trace and toxic element uptake and distribution mechanisms. k ey words : arsenic, cadmium, copper, erythrocytes, genetics, lead, mercury, selenium, twins, zinc. Environ Health Perspect 118:776–782 (2010). doi:10.1289/ehp.0901541 [Online 5 January 2010] Many investigators have considered the toxic effects of exposure to metals such as arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg), and there has been substantial expendi- ture on measures to reduce human exposure. Although toxic effects are clearly established for occupationally exposed people and for peo- ple in locations where particularly high levels are present, demonstration of harmful effects population-wide has been more difficult. One possible reason is that at comparatively low levels of exposure, only some people are at risk, and this makes an association more difficult to find (Bellinger 2008). Study of the causes of individual variation could improve the power of epidemiological studies to detect harm to susceptible people. Chronic exposure to As has been associ- ated with diabetes (Coronado-Gonzalez et al. 2007; Navas-Acien et al. 2006), cardiovascular disease (Wang et al. 2007), intellectual impair- ment in children (von Ehrenstein et al. 2007; Wasserman et al. 2007), and lung and bladder cancers (Navarro Silvera and Rohan 2007). Cd primarily affects the kidneys, with tubu- lar proteinuria providing a useful marker of the renal damage. Studies in Cd-polluted areas have reported an excess mortality risk among people showing tubular or glomerular 776 proteinuria, but the causes of this excess mortality are unclear (Satarug et al. 2003). Other claimed adverse effects of Cd include low bone-mineral density and osteoporosis (Alfven et al. 2000, 2004) and lung cancer (Navarro Silvera and Rohan 2007). Hg has been implicated in severe but localized poison- ings (Ekino et al. 2007). Widely publicized concerns about effects of Hg from vaccine pre- servatives have been refuted (Thompson et al. 2007), but effects on intellectual functioning or behavior have been reported or suggested (Axelrad et al. 2007; Davidson et al. 2004). Cardiovascular (Virtanen et al. 2007) and renal (Hodgson et al. 2007) disease have been associated with low-level Hg exposure. For Pb, the main concerns have been about impaired intellectual development in infancy and child- hood (Canfield et al. 2003; Needleman 2004; Pocock et al. 1994; Schwartz 1994), but adult cognitive function may also be affected (Schwartz and Hu 2007; Shih et al. 2007). There is also evidence that higher Pb values are associated with hypertension (Navas-Acien et al. 2007), peripheral vascular disease (Navas- Acien et al. 2004), increased adult mortality (Lustberg and Silbergeld 2002; Schober et al. 2006), and cognitive decline in older people (Weisskopf et al. 2004). Studies on overall and cause-specific mortality suggest a 40–60% increase in adjusted mortality with increas- ing Pb concentration in the U.S. population (Jemal et al. 2002; Lustberg and Silbergeld 2002; Menke et al. 2006; Schober et al. 2006). Exposure is a precondition for accumu- lation of these elements. There is undoubt- edly individual variation in exposure, but this may be only one of several factors influencing toxic element accumulation and body burden. Identification of “host factors” has the potential to clarify the relationships between exposure and harm. These may act through variation in absorption or distribution within the body, brought about by differences in behavior (such as smoking and alcohol consumption), or by genetic differences in metabolic or biotransfor- mation processes. Furthermore, even at a uni- form level of cell or tissue exposure there may be differences in response because of variation in repair mechanisms, antioxidant status, avail- ability of protective elements, or other so far unrecognized factors. Several attempts have been made to test for effects of genetic polymorphisms on toxic element accumulation, particu- larly using blood or bone Pb values. So far there are mixed results, with allelic associa- tions both reported and denied for the ALAD (δ-aminolevulinic acid dehydratase) and VDR [vitamin D (1,25-dihydroxyvitamin D3) receptor] genes. More generally, only a few studies (Bjorkman et al. 2000; Hopper et al. Address correspondence to J.B. Whitfield, Genetic Epidemiology Unit, Queensland Institute of Medical Research, P.O. Royal Brisbane Hospital, Queensland 4029, Australia. Telephone: (61) 7 3362 0229. Fax: (61) 7 3362 0101. E-mail: john.whitfield@qimr.edu.au Supplemental Material is available online (doi:10.1289/ehp.0901541 via http://dx.doi.org/). We thank the twins for their participation. In addi- tion, we thank the staff of the Genetic Epidemiology Unit, Queensland Institute of Medical Research, for project management, subject recruitment and interviews, sample collection, and sample processing. Trace element measurements were made using the facilities of the Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney, Australia. Sample collection and the recruitment and interview- ing of participants was funded by grant AA007535 from the National Institute on Alcohol Abuse and Alcoholism. J.B.W. owns shares in BHP Billiton, a company engaged in mining and minerals processing. The remaining authors declare they have no actual or potential competing financial interests. Received 5 October 2009; accepted 5 January 2010. ovlume 118 | number 6 | June 2010 • Environmental Health Perspectives