Environ. Sci. Technol. 2010, 44, 4395–4399
Getting to the bottom of arsenic standards and guidelines ANDREW A. MEHARG* ANDREA RAAB University of Aberdeen
ANDREW MEHARG
Public health policy for arsenic needs to better reflect the ability to detect the risk(s).
and physiological characterization to lower Asi exposure concentrations, finding molecular responses indicating damage (2, 7). Drinking water standards have been set in the U.S. (8) and EU (9), with provisional guidelines also given by the World Health Organisation (WHO) (10). These values converge on 0.01 mg/L, either total As (AsT) for EU, or Asi, for the U.S. and WHO. For food no EU or U.S. standards are set (11). The WHO has a provisional maximum tolerable daily intake (PMTDI) guideline of 0.0021 mg/kg/d (12), to cover risks from both water and food, but no specific food guidelines are given. China has recently set food standards for As, though the rational for the standards set was not outlined (13). This general vacuum in food standards/guidelines means that the WHO PMTDI is used as a fallback to assess risk of Asi from foods (2). The newly published “Scientific Opinion on Arsenic in Food” commissioned by the European Food Safety Authority (EFSA) concluded that the WHO Asi PMTDI “is no longer appropriate”, based on lung and bladder cancer risks posed by Asi (2). Importantly, this review identified that dietary exposure for high level Asi consumers falls within benchmark dose lower confidence limit (BMLD10) and the “possibility of a risk to some consumers cannot be excluded”. For the EU, drinking water was only a small component of dietary exposure; the dominant exposure pathway was from grains, specifically rice (2). The case for food standard setting, in addition to revisiting water standards and the PMTDI, is outlined in this Feature.
Risk Based Setting of Standards/Guidelines
Inorganic arsenic (Asi) is ubiquitous in the environment (1). Asi is a Class 1, nonthreshold carcinogen (2-4), for which risk assessments are based on a linear dose response (2). Thus, in effect, Asi is everywhere and, if current assumptions regarding Asi risk assessment are correct, every exposure constitutes a risk. While there is considerable debate as to whether epidemiological studies conducted on highly exposed populations used to derive dose-response relationships can be extrapolated to low dose scenarios (2-4), we have to assume the linear dose response model until proven otherwise, and indeed this is the case with respect to standard setting by the U.S. Environmental Protection Agency (EPA) (5, 6). Recent scientific studies have extended epidemiological 10.1021/es9034304
2010 American Chemical Society
Published on Web 05/14/2010
The Joint Food and Agriculture Organization (FAO)/WHO Expert Committee on Food Additives (JEFCA) in 1983 considered the, then available, epidemiological information regarding As. JEFCA identified that drinking water containing >1 mg/L Asi resulted in arsenical disease, and that a dose of 0.1 mg/L Asi had presumptive signs of toxicity (12). Daily intakes of Asi were calculated, assuming 1.5 L/d water consumption, with 1.5 mg/d Asi identified as a dose likely to result in arsenical disease, and 0.15 mg/d Asi as a dose that may give rise to disease in some individuals. The PMTDI was derived from this 0.15 mg/d assuming a 75 kg body mass, i.e., 0.002 mg/kg/d. The EFSA scientific review highlights that this PMTDI was set “without clear incorporation of a safety or uncertainty factor” (2). WHO policy on the use of uncertainty factors in risk assessments is clearly defined (10). A factor of 1-10 can be applied for the following parameters: interspecies variation (animals to humans), intraspecies variation (individual variation, including human and animal models), adequacy of the studies on the database, and nature and severity of effect. Uncertainty factors are multiplied together to give an overall uncertainty factor, and then the no observed effect level (NOEL) or the lowest observable adverse effect level (LOAEL) is divided by the overall uncertainty factor to derive standards/guidelines. As Asi is a carcinogen it requires a high uncertainty (10). Humans are variable in their response to Asi (14), enhancing uncertainty. VOL. 44, NO. 12, 2010 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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It could be argued that characterization of effects at low doses is an inadequacy in risk assessment and should lead to higher uncertainties. The “provisional” status of the WHO Asi PMTDI is because of this lack of characterizing low dose exposures (10), yet the appropriate uncertainty factors have not been applied. An alternative approach to using NOELs or LOAELs and applying uncertainty or safety factors is extrapolating dose response curves to characterize risks at thresholds that reflect health targets, such as the goal of not exceeding 1 in 10,000 lifetime excess cancers for a given exposure source, used by both the EPA (5, 6) and considered by the WHO for Asi with respect to implications for guideline setting (15). The WHO has calculated an upper estimated boundary of excess lifetime cancer risk of 1 in 10,000 for Asi as 0.00017 mg/L (15), which is 50 times lower than EU and U.S. standards and WHO current guidelines, though it was noted that this may overestimate risk of skin cancers. The WHO provisional water guideline is directly derived from the PMTDI assuming, with no justification elaborated, a 20% allocation of the PMTDI to water (15). EU documentation on drinking water standards just state the Asi standard with no rationale of why this level was set (9). U.S. standard setting, in contrast, is more clearly defined in a risk assessment context (4, 8). The U.S. water standard, at 0.01 mg/L Asi, has lung and bladder cancer theoretical maximum-likelihood estimates of excess lifetime risk between 12 and 23 per 10,000 people, dependent on cancer type and sex of consumer (4). Therefore, the U.S. drinking water standard was set knowing that the Asi standard exceeded the target risk of 1 in 10,000 according to the interpretation of the most up to date epidemiology then available (5). Using a shallower cancer dose response of 3.6 (mg/kg-d)-1 Asi more recently proposed by the EPA, drinking 1 L of 0.01 mg/L Asi estimates an excess lifetime risk of 5 in 10,000 (5).
The Role of Standards/Guidelines This discrepancy between calculated risk and set Asi guideline/standard for both the WHO and the U.S. raises the question: what these are for? With the best of current knowledge they were not set as what constitutes “safe”, with both the U.S. and WHO defining a “safe” exposure dose as having lower than 1 in 10,000 excess lifetime risk (5, 15, 16). The function of standards/guidelines is pragmatic. Standards are achievable targets for water providers to comply with. Guidelines are goals that one would strive to widely achieve. Guidelines should be used where compliance, currently, is not enforced. To comply with the 2006 U.S. water standard of 0.01 mg/L Asi (the superseded standard being 0.05 mg/L Asi) the EPA made a $3.6 billion fund available (17). A limit as low as 0.003 mg/L was considered (17), but setting a lower standard would have incurred more cost. Such cost-benefit considerations are routine across a range of public healthcare scenarios (18). The contrast to U.S. investment in water treatment technologies to remove As from public drinking water supplies is Bangladesh, where 35% of drinking water supplies exceed 0.05 mg/L and 51% exceed 0.01 mg/L (1). Given the scale of As drinking water contamination, and the limited water treatment infrastructure, the WHO provisional guideline is not, as yet, achievable and a national standard of 0.05 mg/L is in place (1), though not enforced. A number of other floodplain and delta Holocene aquifer systems of SE Asia, besides the Ganges and Brahmaputra that give rise to the problems in Bangladesh and in neighboring West Bengal, India, are known also to have elevated arsenic in groundwaters. Examples include the Indus, Irrawaddy, Mekong, and Red River systems (19). Arsenic elevated drinking waters are 4396
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problematic elsewhere in the world outside SE Asia, including large regions of the Americas (such as the Pamplonan Plain, Argentina and the Alto Plano, Chile) and Inner Mongolia, China (19). Effort should be focused on reducing groundwater As for both the high exposure groups and to decreasing drinking water As exposure of the wider population. The ultimate target for Asi in drinking water must be a standard/ guideline based on risk targets, such as excess lifetime cancer risks not exceeding 1 in 10,000.
Low Level As Detection Determining the lowest concentration that can be confidently determined for a particular analysis is crucial to the enforcement of standards, and to the setting of guidelines. If a standard is set at a concentration that is lower than what can be robustly detected, then there is no way of monitoring or enforcing the standard. A number of statistical approaches have been derived to determine the lowest level of a concentration that can be reported with defined confidence. The EPA developed the lowest concentration minimum reporting level (LCMRL) (20), while the limit of quantification (LOQ) is widely used by analytical chemists. The LOQ, for example, is defined as the analyte concentration in the blank plus 10 times the standard deviation of repeat measurement of the blank used to calculate that mean. Inductively coupled plasma-mass spectroscometry (ICP-MS) for arsenic has the lowest LOQs, and is the least subject to interferences of instrumental techniques suitable for low-level detection, given that Se and ArCl (40Ar35Cl+ has the same nominal m/z as 75As+) can be detected by measuring masses associated with Se, and/or that ArCl interferences can be removed by reaction cell technology (21, 22). Cost and infrastructural considerations have hindered ICP-MS deployment in developing countries, yet this has proven no barrier to extensive ICP-MS characterization of the As problem in SE Asia, and elsewhere, by shipping the samples internationally for characterization (1). However, expanding the capacity for high-quality, low-level As determination in so-affected regions of the world should be a priority. One of the arguments for setting WHO Asi guidelines at 0.01 mg/L was the limitation in availability of technologies for low level As detection (15). “Low” cost technologies for detecting Asi in waters are based on the formation of arsine (AsH3) from Asi reduction (10). While the WHO classifies hydride generation-atomic absorption spectroscopy (HG-AAS) as suitable (10), it does not include the less expensive and more portable HG-atomic fluorescence technology (AFS) which has performance an order of magnitude lower in sensitivity than HG-AAS, approaching that of the gold standard ICP-MS (21). However, caution is required when using any HG technologies, both in batch and continuous flow mode, for determination in waters, as sulphides, which are common in reduced groundwaters such as the As releasing aquifers of SE Asia (1), inhibit arsine generation (23). Also, it cannot be assumed that methylated As species are not present in waters, and these species suffer from kinetic interferences for hydride generation, being slower to form corresponding arsines than Asi (24). With the wider deployment of ICP-MS, standards/ guidelines can be set based on low LOQ/LCMRL achievable by ICP-MS. Figure 1 plots LOQ for As in 44 analytical batches, along with a natural water certified reference material (CRM) NIST 1640 included in each batch, for a quadrapole ICP-MS (Agilent Technologies 7500). LOQ varied between 0.00002 and 0.0006 mg/L As, with the average of the 44 batches being 0.00022, and a standard deviation of 0.00014 mg/L As. This LOQ for As by ICP-MS is ∼50-fold lower than EU and U.S. drinking water standards and the WHO guideline. Analytical
FIGURE 1. LOQ and natural water CRM NIST 1640 for 44 batches of analysis run over a 5 y period by reaction cell quadrapole ICP-MS. NIST 1640 is certified as being 0.02667 mg/L, and the average value for these 44 batches of analysis was 0.0256 mg/L, with a standard deviation of 0.00169 mg/L.
considerations should not hinder the lowering of standards/ guidelines to at least 0.001 mg/L As, if scientific evaluation warrants.
Practical Considerations for Setting Food Standards/ Guidelines A problem in setting food standards/guidelines is quantification of As speciation, as it is Asi that drives risk assessment, not AsT (i.e., organometallic and inorganic). The latter normally equates to Asi in waters, and AsT measurements are used as less expensive surrogates of Asi detection because Asi speciation incurs more cost and requires more sophisticated analytical technologies (21). For foods, the relationship between Asi and AsT is more variable (11). Also, it is more difficult to extract and speciate Asi from foodstuffs because of complex and highly variable matrices (11). Seafoods, in particular, have a high AsT and a low Asi content, with the bulk of As being as organic As (AsO) species (2, 11). These AsO species are thought to have low toxicity, but this is under continuing scrutiny as metabolism may produce toxic intermediates and end products (25, 26). Rice, on the other hand, generally has much lower AsT than seafood but a higher Asi content (2, 11). The EFSA sponsored review of As in EU diets found that, at median consumption rates, rice dominated Asi contribution to the “grain and cereal” products class. This class was responsible for over 50% of dietary Asi exposure, whereas tap water was less than 1.5% (Figure 2). Drinking water is generally more elevated in As in the U.S. compared to EU, but rice grain has been identified as a major dietary Asi exposure route for the U.S. (5, 27). While a wide range of Asi contents of other foods of terrestrial origin have been explored, none approach rice as a widespread contributor to dietary Asi exposure (2). Pragmatically, it could be argued that, focusing food regulations regarding arsenic on rice would have the most impact on reducing dietary Asi from foodstuffs. Unlike many dietary items, methodologies for determining Asi content of rice have been well characterized (28). Furthermore, numerous studies are now published on As speciation in rice grain enabling inorganic As contents to be extrapolated from AsT measurements, with Asi and dimethylarsinic acid (DMA) dominating speciation (29). If guidelines/standards are set for As in rice, rice AsT could be used as a surrogate of Asi,
similar to current EU mercury (Hg) regulations in seafoods (11), and any monitoring based on totals will err on the side of caution. Analysis of AsT is more rapid and less expensive than Asi, and appropriate CRMs already exist for AsT in rice products, such as NIST 1568a rice flour (28). The lack of appropriate speciated CRMs is noted by the EFSA review of As in food as a hurdle to standard/guideline setting (2). Researchers working on As in rice have navigated around this problem by adopting rice flour CRM 1568a as a quality control check for speciation analysis (28). The impetus is to produce CRMs for food products, such as tuna fish BCRCRM-627 (30), for As speciation. A further complicating factor in food standard setting is the issue of gut bioavailability of Asi from foodstuffs, as this could be expected to vary by food type given the heterogeneity of biological matrices. However, studies on rice suggest gut bioavailability of Asi is high (31). Until accurately determined, assuming 100% gut availability would enact the precautionary principle that should be deployed when considering carcinogens (10).
Lowering Asi Intake Water and food offer differing challenges with respect to reducing Asi intake. Compared to foodstuffs, water is a simple matrix that can be passed over, or mixed with, with a solid phase adsorbent to remove As (32). Solid phase adsorbents, many based on widely available and low-cost matrices such as FeOOH or charcoal, can be incorporated into simple technologies (32). The challenge for lowering As concentrations in water using such adsorbent-based technologies, given that the infrastructure is present to deploy a given technology and to educate regarding use/maintenance, is monitoring to determine which individual supplies need treatment, as well as the efficacy of that treatment over time. Without regular monitoring to determine if an adsorbent-based treatment is working from just after it is installed, or if it suffers a failure during sustained use, the efficacy of mitigation cannot be guaranteed. As household or community water supplies normally are delivered through a point source, such as wells, alternative water supplies, such as rainwater harvesting or safe surface water supplies, if available, could be used to deliver low As water. VOL. 44, NO. 12, 2010 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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FIGURE 2. Percentage contribution of different food sources to median dietary Asi intake in the EU from EFSA commissioned report (2). Food, by its nature, is extremely heterogeneous in its constitution, even before processing/cooking, and foodstuffs are not readily treatable to remove As as the As is sequestered in a complex biological matrix. If technologies were to be developed to process food for low As, this would have to be done on a food type by food type basis, for a specific end product. Cooking rice in high volumes of As-free water, for example, can remove a component of the Asi content, but leaves much remaining (28). Food is also heterogeneous in its sourcing, with the exception of subsistence farming. Many food items are subject to vast and complex global supply and demand chains, with foodstuffs elevated in As from one region exported to others: the global trade in rice is an example of this (29). Heterogeneity may also be observed at local scales, such as in variation at the between, or within, field level; again rice provides an example of this (33). One subsistence farmer may be producing food for his family from a field that leads to enhanced elevation of As in food-stuffs, while the neighboring farmer may be producing food of a lower As content. Water can be readily piped, given infrastructure and resources, over considerable distances if necessary, to mitigate affected communities. If a farm produces elevated As in food, abandoning the farm is usually not an option, and agronomic and/or food processing technology solutions must be sought. The EFSA scientific review of Asi “recommended that dietary exposure to inorganic As should be reduced” (2). In a EU context, and for many regions of the world that do not suffer from elevated As in drinking water, the simplest way to achieve this is to reduce dietary exposure of Asi from rice, given its exposure dominance (Figure 2). Rice as a primary dietary Asi exposure source is even more the case for SE Asia (29). This is not to say that where other foodstuffs are elevated in As that they should not be regulated, or agronomic efforts made to reduce As content. Reducing Asi intake from rice, or from any other food source identified as problematic, can be done by either decreasing Asi content and/or by limiting consumption. For rice, this latter option is only feasible were suitable alternative carbohydrate staples are widely and cheaply available, and 4398
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would not be suitable for SE Asia, for example. Reducing As content of rice for countries dependent mainly, or exclusively, on import of this commodity could be achieved by sourcing rice of lower As content, bearing in mind the economic implications that such changes in trade patterns may precipitate. Globally, sourcing low As rice is feasible; for example, Himalayan basmati and Egyptian short grain rice are both low in AsT and Asi (28). Agronomic practice can also be managed to reduce food Asi content, and has been considered in most detail for rice (34). As consumption is compounded in rice-consuming regions that suffer from elevated Asi in water supplies, because cooking rice with Asi elevated water leads to enhanced Asi in the cooked compared to raw rice (34). Water-derived-As and rice can be further interlinked with respect to human Asi exposures where this water is used for the agricultural irrigation of dry season rice, a practice widely conducted in As groundwater affected regions of Bangladesh and West Bengal, India, leading to enhanced rice grain Asi (33, 35). Contaminated irrigation and cooking water is also problematic for other food items in high As groundwater regions, further exacerbating As exposure (36). There are specific products where low Asi foods should be prioritized. The EFSA commissioned report concluded that particular subpopulations may be at risk from dietary exposure to Asi, such as children
