Toxic metal species and food regulations—making a healthy choice

Abstract

As a safeguard for human health, guidelines and regulations stipulating maximum permissible concentrations (MPCs) of metals in foods have been set to limit our dietary exposure to toxic metals. It is now well accepted, however, that the chemical form of the metal must be considered when assessing the possible human health consequences of exposure, and this in turn has led to discussion on the incorporation of speciation data in the setting of MPCs for metals in foods. Some practical aspects and implications of framing food legislation in terms of metal species are presented.

Regulations regarding food composition and nutritional status have been compiled over many years and are meant primarily to provide guidelines for assessing and maintaining food quality and safety for consumers. Food composition can be a strong marketing tool, and producers rightly display the natural attributes of their particular products, be they general constituents such as nutrients, vitamins, or fibre, or more specific constituents such as omega-3 fatty acids or “organic selenium”. But foods may also contain chemicals detrimental to human health, such as organochlorine pesticides or toxic metals, and the levels of such chemicals must be carefully monitored and controlled. The case of organochlorine pesticides is relatively straightforward: their sole source is anthropogenic and hence once toxic effects and risk factors have been established, maximum permissible concentrations (MPC)¹ can be set for the various organochlorine pesticides found in foods. The situation for toxic metals is more complex because metals are natural constituents of foods, often at rather high concentrations, and their presence does not necessarily indicate anthropogenic contamination.

The presence of different species of a metal in foods adds a further layer of complexity. It is well known, and oft-quoted, among those in the metal speciation research area, that data on metal concentrations provide only a part picture of a metal's environmental and biological significance, and ultimately its toxic effects on man. Consequently, so it goes, we need to know the types and concentrations of metal species to assess these effects and, since a large part of man's exposure to metals is through food, speciation data are needed to set realistic MPCs for metals in foods. But do we really need to do this? And if we do, which metals and metal species should we focus on? The following article explores these questions by looking at four toxic metals—namely, cadmium, lead, mercury, and arsenic which have recently been the subject of a dietary exposure assessment in some European Union member states²—and examines possible grounds for extending the data set by incorporating metal speciation analysis.

Toxic metals in food: natural constituents and anthropogenic contaminants

The fact that toxic metals are natural constituents of foods provides a considerable dilemma for health authorities. On the one hand, they wish to protect human health from food containing too much toxic metal, while on the other hand, they may not wish to ban a food just because it naturally contains elevated metal concentrations. The outcome is usually a compromise in which naturally-occurring metals appear to be treated leniently: the MPC is often set at a level that is just above that of the typical metal concentration in most common foods.

This approach is clearly seen by the regulations and amendments (the latest was January 2005) adopted by the European Commission over the last 6 years,³ and a report assessing the dietary exposure to arsenic, cadmium, lead, and mercury.² An abridged version of those data sets is shown here as Table 1. The current situation is that MPCs, on a wet mass basis, have been set for a variety of foods for cadmium (ranging from 0.05 µg g⁻¹ for various meats to 1.0 µg g⁻¹ for bivalve molluscs), and lead (0.1 µg g⁻¹ for some vegetables, up to 1.5 µg g⁻¹ for bivalve molluscs). For mercury, however, MPCs apply only to seafoods. Thus, “fisheries products”, including molluscs, crustaceans and most finfish species, were given an MPC of 0.5 µg g⁻¹, and certain finfish species (generally the larger piscivorous species) were granted an MPC of 1.0 µg g⁻¹. Regulations for arsenic in foods were not set.

Table 1 Typical concentrations^a and Maximum Permissible Concentrations (MPCs),^b set by the Commission of European Communities, for lead, cadmium, mercury, and arsenic for selected foods. Values are in mg kg⁻¹ wet mass; see notes 2 and 3 for source details

Product	Lead		Cadmium		Mercury		Arsenic
	Typical levels	MPC	Typical levels	MPC	Typical levels	MPC	Typical levels	MPC
a Typical concentrations (levels) have been subjectively assessed by the author from the large body of data compiled in the SCOOP report.^2 They are meant as a guide only, and represent values likely to be found from these uncontaminated foods collected across Europe. b MPC ≡ ML (maximum level, the term used in the European Commission regulations). c Farm animals include cattle, pigs, sheep, and poultry: different MPCs apply for game meat and horsemeat. d Liver and kidney MPCs are stated separately for some elements in the EC regulations, but are combined here. e Fisheries products is a term used in the mercury and arsenic data sets, but not for the lead or cadmium data sets.
Vegetables	0.005–0.23	0.1 or 0.3	0.01–0.2	0.05, 0.1, or 0.2	0.001–0.05	MPCs have not been set for Hg for these foods	0.01–0.02	MPCs have not been set for arsenic for any food
Fruits	0.01–0.05	0.2	0.01–0.05	0.05	0.0006–0.002		0.006–0.01
Cereals	0.01–0.27	0.2	0.02–0.06	0.1	0.002–0.02		0.01–0.05
Meats (various farm animals^c)	0.01–0.1	0.1	0.002–0.02	0.05	0.002–0.006		0.01–0.02
Offal (including liver and kidney;^d various farm animals)	0.01–0.16	0.5	0.01–0.2	0.5 or 1.0	0.005–0.04		0.01–0.02
Crustaceans (muscle)	0.02–0.1	0.5	0.02–0.2	0.5	0.02–0.2	0.5	1–20
Bivalve molluscs	0.1–1.0	1.5	0.1–1.0	1.0	0.02–0.2	0.5	1–20
Fisheries products^e (including molluscs, crustaceans, and most fish species)	—	—	—	—	0.02–0.2	0.5	1–20
Fish muscle (particular species)	0.01–0.1	0.2 or 0.4	0.01–0.1	0.05, 0.1, or 0.3	0.1–0.4	1.0	1–20

Considering the many years of data collection and assessment underpinning these recent EU regulations, one might anticipate that regulations based on metal species will be a long time coming. But if this goal is worthwhile, a very clear path must be followed incorporating varied aspects such as analytical, toxicological, food preparation, and the practicality of enforcement, if necessary. All these factors will contribute to the decision whether to press ahead with regulations covering a particular metal species or group of species, and consideration of currently available data might be helpful in limiting the field of possible candidates. In this regard the four metals recently assessed for MPCs for total element data will now be considered in turn as possible candidates for food regulations based on metal species.

Cadmium and lead

Knowledge of the organic chemistry of cadmium is limited, and toxicity data available for cadmium are based mainly on inorganic species. Where cadmium occurs naturally at high concentrations, for example in shellfish such as bivalves and crustaceans, a large part of the cadmium may be bound to metallothioneins through cysteine residues,⁴ and this might be seen as an argument for a further relaxation of the MPC for shellfish based on speciation data. Cd-metallothioneins, however, are not particularly stable, and readily degrade on senescence of the animal, presumably to inorganic cadmium species. In addition, protons compete with cadmium for the S-cysteine binding sites, and in the acidic conditions of the human stomach (pH 2–3), ingested Cd-metallothionein (from fresh oyster for example), is likely to immediately release inorganic cadmium. Cadmium absorption by humans is influenced by nutritional factors (e.g. iron levels), but it is generally low (<10%), and there appears to be no major difference in the absorption and retention of cadmium ingested as Cd-metallothionein compared with dissolved inorganic cadmium ion.⁵ The toxicological chemistry of lead is similarly dominated by inorganic forms, notwithstanding previous wide use of organolead compounds as fuel additives, resulting in the past in slight contamination of some food products.⁶ Thus, current MPCs based on total cadmium or lead data, and toxicity data based on inorganic species, adequately address the issue of the presence of these two metals in foods, and there appears to be no compelling case for the inclusion of cadmium or lead speciation data in food regulations.

Mercury

The mercury poisoning events in Minamata Bay⁷ in the 1960s were very significant for the field of speciation analysis and its relevance to issues of human health. Research carried out at that time, and subsequently, demonstrated that inorganic mercury of anthropogenic or natural origin underwent biomethylation in aquatic systems yielding methylmercury, a lipid-soluble species considered to be more toxic than inorganic mercury. Moreover, the lipophilicity of methylmercury facilitates its bioaccumulation up aquatic food chains resulting in high concentrations in predatory fish, even when the fish are taken from clean waters. These processes of methylation are not dominant in terrestrial systems, and hence foods of terrestrial origin generally contain low levels of total mercury, and most of this is present as inorganic species. Although there may be traces of other mercury forms in foods, the major species by far are inorganic mercury (Hg²⁺) and methylmercury (MeHg⁺), and so for simplicity further discussion is restricted to these two.

In view of the toxicity of mercury, and its widespread occurrence at varying concentrations in foods, it is not surprising that it has been the metal to attract most public attention over the last 40 years regarding food legislation and the setting of MPCs. The pragmatic outcome is clear to see in the values that have been set (Table 1); foods naturally high in mercury such as fish muscle tissue from particular (piscivorous) species have been accorded an MPC of 1 mg kg⁻¹, whereas no MPC has been set for terrestrial foods which generally have low concentrations of mercury (<0.02 mg kg⁻¹). These regulations would “miss” those terrestrial foods that may have been contaminated from anthropogenic sources to harmful levels, and thus the legislation might be considered inadequate. The situation, however, is not amenable to the inclusion of speciation data to rationalise the food legislation because when total mercury concentrations are low, the mercury is present predominantly as toxic inorganic mercury, and when it is high, e.g. in fish, it is mostly present (>90%) as the more toxic methylated species.

Thus, by maintaining an MPC based on total mercury concentrations, rather than on MeHg⁺ values, health authorities are in no danger of missing “unsafe food”. Indeed this approach may be seen as conforming to the precautionary principle, whereby the total metal concentration should be assumed to be the most toxic form, so that any measured value less than the worst case MPC means that the food is safe. Furthermore, such an interpretation does not appear to be unfair to food producers. Thus, speciation analyses for methylmercury, which are analytically more difficult to perform than are total mercury analyses, would provide no useful additional information in terms of setting food legislation.

There is one further issue, similar to the case for cadmium described above, to be considered. Although we refer to MeHg⁺ as the species of interest, in the actual fish tissue the mercury is present as a methylated species bound presumably to insoluble proteins through S-cysteine bonds. The Hg speciation methods use strong acid (or base) to cleave the Hg–S bond and the released MeHg⁺ is then determined. It has been suggested that full toxicological assessment of mercury in fish can only be done when the complete structure of the mercury species is known, and not just the structure of the analyte generated during sample preparation. We have conducted preliminary tests, however, that suggest that in the acidic conditions of the stomach, methylmercury is readily released from fish tissue, and hence knowledge of the complete structure of mercury in fish tissue is unlikely to have toxicological relevance. This point needs to be supported by further experimentation.

Arsenic

Arsenic has a rich organic chemistry, and this is reflected in the diversity of the organoarsenicals reported⁸ in biological samples, many of which occur in common foods. Although there are apparent similarities between arsenic and mercury in terms of the relative concentrations and distributions of the inorganic and organic forms, there are also marked differences, and it is interesting to follow and compare the increasingly divergent speciation pathways for these two elements.

Inorganic arsenic is a well known toxic substance; it constitutes the majority of the arsenic in most terrestrial foods, but the concentrations are generally low (usually <0.05 mg kg⁻¹). Organoarsenic occurs in seafoods, sometimes at alarmingly high concentrations (>50 mg kg⁻¹ wet mass), and seafood is by far the major contributor of arsenic to the European diet.² The observation that seafoods contained high concentrations of arsenic in an unknown organic form was first made in the 1920s, but little additional work was done until the “mercury scare” emanating from the Minimata Bay disaster in the 1960s. The discovery that the natural organic form of mercury in fish was more toxic than inorganic mercury immediately raised questions about the safety of the organic form of arsenic naturally present in seafoods, and fuelled research into identifying and testing these arsenicals. Up to that point, arsenic and mercury showed strong similarities, but further research led to the identification of arsenobetaine (Me₃As⁺CH₂COO⁻) as the major arsenic compound in most common seafoods (particularly in fish and crustaceans), and subsequent toxicological work⁹ established the completely harmless nature of this arsenical.

Thus, a major difference in seafood mercury and seafood arsenic is apparent—although the inorganic forms of both mercury and arsenic are toxic, methylation of mercury produces the more toxic MeHg⁺ species whereas methylation of arsenic produces, as an end product, the innocuous arsenobetaine, and both these species occur at elevated concentrations in seafoods. The situation for arsenic, however, is more complex still, because in addition to arsenobetaine, many other arsenicals are formed in marine systems and occur in seafoods, and the toxicity of these species is largely unknown. The clear case for arsenic speciation analysis, and why no such case can be put for mercury, is presented schematically in Fig. 1. Although mercury speciation data would provide no additional useful information for the setting of MPCs, arsenic speciation data certainly would. Such data, when combined with appropriate toxicity testing, would provide scientifically-grounded safeguards for human health without unduly penalising suppliers of seafood products.

Fig. 1 A simplified schematic representation of the mercury and arsenic species present in terrestrial foods and seafoods. In terrestrial foods, both mercury and arsenic occur at low concentrations as toxic inorganic species. In fish muscle (fillets), mercury occurs at high concentration as the highly toxic methylmercury species, whereas arsenic, although it also occurs at high concentrations, is present mainly as the harmless arsenobetaine. Other seafoods present intermediate cases for arsenic.

The next step

It may seem unusual to be advocating speciation data in food legislation for an element, such as arsenic, that has not yet been given an MPC based on total concentrations. But the lack of an arsenic MPC is at least partly attributable to the complex situation with arsenic in regard to the multiplicity of species and gaps in our knowledge of its toxicity and metabolism. The approach taken to fill these scientific gaps should be multi-disciplinary involving researchers from the areas of human health, food science, toxicology, and analytical chemistry. A relevant issue, which has so far received minimal attention, is the metabolic pathways available to arsenic following its ingestion with food. For example, arsenic-containing lipids (of currently unknown structures) present in fish oils were shown¹⁰ to be bioavailable to man, and were efficiently biotransformed to several water-soluble arsenic metabolites. Thus, more than just knowledge of the form of arsenic in food is necessary—metabolic pathways and products must also be investigated. Such studies are difficult to perform with humans, and future work should focus on the development of in vitro methods for studying biotransformations such as the use of simulated gastrointestinal systems and cell cultures.

The pivotal role in these studies will be that of the arsenic speciation analyst whose work will delineate the occurrence and extent of the various arsenic species in foods, contribute to understanding their biotransformation and toxicology, and finally develop robust quantitative methods for the determination of the designated important arsenicals. Although the analytical techniques, based largely on HPLC/mass spectrometry, are now available to attempt such work, the analytical challenges are considerable, particularly if one needs to account for transient but possibly toxicologically relevant metabolites. Presentation of the data in a form understandable and useful to consumers and legislators would also be a difficult but necessary task. This broad-based approach would be a large undertaking, but if done correctly it would provide much needed data in this important area of food regulations and protection of human health. If the work is not attempted, there will be ever the doubt concerning arsenic in foods, and recurrent adverse reporting of those foods “discovered” by the ill-informed to be high in arsenic. Such an outcome would be continually and unfairly damaging for fisheries products and of no tangible benefit to the consumer.

References and notes

1. The terms used to describe this concept vary between countries and between contaminant type. For convenience the term Maximum Permissible Concentration (MPC), which is suitably descriptive, will be used throughout this article. The European Commission currently uses the (rather vague) term Maximum Level (ML) when dealing with metals in foods.
2. European Commission (2004), Report of experts participating in Task 3.2.11 “Assessment of the dietary exposure to arsenic, cadmium, lead, and mercury of the population of the EU Member States”, European Commission, Directorate-General Health and Consumer Protection, Reports on tasks for scientific co-operation (SCOOP), March 2004.
3. Commission Regulation (EC) No 466/2001 (adopted 8 March 2001), Commission Regulation (EC) No 221/2002 (adopted 6 February 2002), and Commission Regulation (EC) No 78/2005 (adopted 19 January 2005).
4. W. J. Langston, M. J. Bebianno and G. R. Burt, Metal handling strategies in molluscs, in Metal Metabolism in Aquatic Environments, ed. W. J. Langston and M. J. Bebianno, Chapman & Hall, London, 1998, pp. 219–283.
5. H. M. Chan, Metal accumulation and detoxification in humans, in Metal Metabolism in Aquatic Environments, ed. W. J. Langston and M. J. Bebianno, Chapman & Hall, London, 1998, pp. 415–438.
6. R. Lobinski, C. Witte, F. C. Adams, P. L. Teissedre, J. C. Cabanis and C. F. Boutron, Organolead in wine, Nature, 1994, 370, 24.
7. Y. Takazawa, Epidemiology of mercury poisoning, in The Biogeochemistry of Mercury in the Environment, ed. J. O. Nriagu, Elsevier/North-Holland Biomedical Press, Amsterdam, Oxford, New York, 1979, pp. 325–365.
8. K. A. Francesconi and D. Kuehnelt, Determination of arsenic species: A critical review of methods and applications, 2000–2003, Analyst, 2004, 129, 373–395.
9. T. Kaise, S. Watanabe and K. Itoh, The acute toxicity of arsenobetaine, Chemosphere, 1985, 14, 1327–1332.
10. E. Schmeisser, A. Rumpler, M. Kollroser, G. Rechberger, W. Goessler and K. A. Francesconi, Arsenic fatty acids are human urinary metabolites of arsenolipids present in cod liver, Angew. Chem., 2006, 45, 150–154.

---