Contaminants in food supplements and associated health risks

Summary Through the increasing use and availability of food supplements on the market, safety Aconcerns relating to the safety of these food supplements are growing as well. The aim of the present PhD thesis was to investigate the presence and actual levels of contaminants of concern in selected food supplements on the Dutch market and to estimate the associated health risks. First, in chapter 1, an overview is provided on the food supplements selected for the studies, which are clay products for oral use, herbal food supplements used to enhance sexual potency and herbal food supplements used for weight loss. Furthermore, an overview is given on the Dutch en European legal provisions for food supplements. In the first study described in chapter 2 of this theses data are presented on the occurrence of metals such as lead, mercury and cadmium and the metalloid arsenic in clay products which are used via the oral route by pregnant and lactating women. For lead, the use of 34 of the 36 traditional clays and two of the 27 health clays would result in intake levels exceeding the selected health based guidance values, by up to 20-fold. In the case of inorganic arsenic, the use of 15 of the 35 traditional clays and 11 of the 27 health clays would result in intake levels exceeding the health based guidance values by up to 19-fold. The second study, described in chapter 3 of the thesis, reports data on the presence of dioxins in 33 clay products, which were collected on the Dutch market and in some African countries. Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) were detected in clay products from the Dutch market, in concentrations ranging from 66 to 103 pg TEQ g-1, whereas PCDD/F concentrations in the suspected clay products from African countries varied from 24 to 75 pg TEQ g-1. Furthermore, in this study congener patterns in African clay products were compared with those of pooled human milk samples collected by WHO in eight African countries, to investigate a possible relation between PCDD/Fs in human milk with contaminated clay used for consumption. From the similarity between the patterns in clays and the human milk samples from the Democratic Republic of The Congo and Côte d’Ivoire, it can be concluded that there is probably a relationship with the consumption of contaminated clay. The aim of the third study, described in chapter 4 of this thesis, was to determine whether herbal food supplements on the Dutch market contain active pharmacological ingredients (APIs) known to inhibit phosphodiesterase type 5 (PDE-5), such as sildenafil and other known analogous PDE-5 inhibitors. Therefore, herbal food supplements intended to enhance sexual potency (n=71), and two soft drinks, were analysed. In 23 herbal supplements, nine different PDE-5 inhibitors were identified, in a few cases (n=3) more than one. The presence of these APIs was however not stated on the label. Subsequently, it was estimated whether intake of the supplements with the detected PDE-5 inhibitors could result in pharmacological effects. It was concluded that 18 of the 23 herbal food supplements with PDE-5 inhibitors, when used as recommended, would have pharmacological effects due to the added APIs. In the fourth study, described chapter 5 of in this thesis, another group of herbal food supplements, claiming to reduce weight, was investigated for the presence of APIs that can be used for the treatment of overweight and obesity. To this end, 30 herbal food supplements for weight loss on the Dutch market were collected and analysed for the presence of APIs with weight loss properties. In 24 samples the APIs sibutramine, desmethylsibutramine (DMS), didesmethylsibutramine (DDMS), rimonabant, sildenafil, and/or the laxative phenolphthalein were identified 41 times. The potential pharmacological effects of the detected APIs were estimated, and use of 20 of the 24 herbal food supplements, may result in potential pharmacological effects. Furthermore, a risk assessment of phenolphthalein regarding its carcinogenic effects, resulted in Margin of Exposure (MOE) values of 96-30,000. MOE values lower than the minimum required 10,000 (96-220) were calculated for the daily intake levels of four out of the ten supplements in which phenolphthalein was found. However, taking into account that weight loss preparations may be used for only a few weeks or months rather than during lifetime, MOE values may be two to three orders of magnitude higher. This study shows that the use of food supplements with sibutramine, DMS, DDMS, and/or phenolphthalein could result in both pharmacological but also other health effects. From the studies described in this thesis it can be concluded (chapter 6) that, in addition to concerns over naturally occurring endogenous toxins present in herbal supplements, the presence of exogenous contaminants in herbal supplements can pose a health concern. Furthermore, the results of the present thesis also lead to the conclusion that in order to refine the risk assessment on the presence of contaminants such as metals, metalloids, dioxins and APIs in (herbal) food supplements more precise data are required on bioaccessibility of contaminants of concern from the food matrix. Also information on groups at increased risk may need to be increased. Additionally, the presence of APIs in herbal supplements, which may originate from drop outs in the drug development process, is of concern. In order to screen for unknown APIs the use of effect-based bioassays should be considered more often, as they have been shown to be successful in detecting unexpected and as yet unknown active ingredients. From the results obtained for the food supplements included in our studies it can be concluded that consumers should be aware that food supplements may not be without risks. The overall conclusion from the work described in this thesis is that for food supplements ‘natural’ does not equal ‘safe’

Levels of lead, arsenic, mercury and cadmium in clays for oral use on the Dutch market and estimation of associated risks

Pregnant women in Africa, Asia and Suriname, and some immigrants in Western societies, traditionally consume clay products known by a variety of names such as mabele, calabash chalk, sikor and pimba. Furthermore, clay is used for health purposes in Western societies. Because certain clays can contain high levels of metals and metalloids, the aim of this study was to determine lead, arsenic, mercury and cadmium in clay products for oral use available on the Dutch market. Traditional clays originating from Africa (n = 10) and Suriname (n = 26), and health clays (n = 27) were sampled from 2004 up to and including 2012. Total metal and metalloid contents were measured by ICP-MS and showed maximum levels of lead, arsenic, mercury and cadmium of 99.7, 45.1, 2.2 and 0.75 mg kg(-1), respectively. In the absence of maximum limits for these type of clays, the potential exposure was estimated from the determined concentration, the estimated daily use level of the clays, and the estimated bioaccessibility of the different metals and arsenic. The intake estimates were compared with existing health-based guidance values. For lead, the use of 34 of the 36 traditional clays and two of the 27 health clays would result in intake levels exceeding the toxicological limit by up to 20-fold. Use of 15 of the 35 traditional clays and 11 of the 27 health clays would result in intake levels exceeding the toxicological limit for inorganic arsenic by up to 19-fold. Although limited bioaccessibility from the clay may limit the exposure and exceedance of the health-based guidance values, it was concluded that lead and arsenic intakes from some clay products could be of concern also because of their use by pregnant women and the potential developmental toxicity. As a result the use of these products, especially by pregnant women, should be discourage

Active pharmaceutical ingredients detected in herbal food supplements for weight loss samples on the Dutch market

Herbal food supplements claiming to reduce weight may contain active pharmacological ingredients (APIs) that can be used for the treatment of overweight and obesity. The aim of this study was to determine whether herbal food supplements for weight loss on the Dutch market contain APIs with weight loss properties. Herbal food supplements intended for weight loss (n = 50) were sampled from August 2004 to May 2013. An HPLC-DAD-MS/MS method was used to screen for the presence of the APIs in herbal supplements. In 24 samples the APIs sibutramine, desmethylsibutramine (DMS), didesmethylsibutramine (DDMS), rimonabant, sildenafil and/or the laxative phenolphthalein were identified 41 times. The presence of these APIs was, however, not stated on the label. The potential pharmacological effects of the detected APIs were estimated using data from reported effective doses of approved drugs. Use of 20 of the 24 herbal food supplements may result in potential pharmacological effects. Furthermore, risk assessment of phenolphthalein, a suspected carcinogen and found to be present in 10 supplements, based on the margin of exposure (MOE) approach, resulted in MOE values of 96–30 000. MOE values lower than 10 000 (96–220) were calculated for the daily intake levels of four out of these 10 supplements in which phenolphthalein was found. However, taking into account that weight loss preparations may be used for only a few weeks or months rather than during a lifetime, MOE values may be two to three orders of magnitude higher. The current study shows that the use of food supplements with sibutramine, DMS, DDMS and/or phenolphthalein could result in pharmacological effects

Sildenafil and analogous phosphodiesterase type 5 (PDE-5) inhibitors in herbal food supplements sampled on the Dutch market

Herbal food supplements, claiming to enhance sexual potency, may contain deliberately added active pharmacological ingredients (APIs) that can be used for the treatment of erectile dysfunction (ED). The aim of this study was to determine whether herbal food supplements on the Dutch market indeed contain APIs that inhibit phosphodiesterase type 5 (PDE-5) inhibitors, such as sildenafil and analogous PDE-5 inhibitors. Herbal food supplements intended to enhance sexual potency (n=71), and two soft drinks, were sampled from 2003 up to and including 2012. In 23 herbal supplements, nine different PDE-5 inhibitors were identified; in a few cases (n=3), more than one inhibitor was indentified. The presence of these APIs was however not stated on the label. The concentrations of PDE-5 inhibitors per dose unit were analysed. Furthermore, the potential pharmacologically active properties of the detected PDE-5 inhibitors were estimated by using data from the scientific and patent literature regarding (1) in vitro PDE-5 activity, (2) reported effective doses of registered drugs with PDE-5 inhibitor activity and (3) similarity to other structural analogues. It was concluded that 18 of the 23 herbal food supplements, when used as recommended, would have significant pharmacological effects due to added APIs. Adequate use of existing regulation and control measures seems necessary to protect consumers against the adverse effects of these products

Dioxins (polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-furans) in traditional clay products used during pregnancy

Geophagy, the practice of consuming clay or soil, is encountered among pregnant women in Africa, Eastern Asia and Latin America, but also in Western societies. However, certain types of clay are known to contain high concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). The aim of this study was to determine the PCDD/F contents of orally consumed clays purchased from Dutch and African markets. Congener patterns were compared with those of pooled human milk samples collected in eight African countries, to investigate a possible relationship with clay consumption. From the Dutch market thirteen clay products were examined, seven of African and six of Suriname origin. From seven African countries, twenty clay products were collected. All 33 clay products were screened with a cell-based bioassay and those showing a high response were analyzed by GC/HRMS. High PCDD/F concentrations were measured in three clay products from the Dutch market, ranging from 66 to 103 pg TEQ g(-1), whereas clay products from African countries were from 24 to 75 pg TEQ g(-1). Patterns and relatively high concentrations of PCDD/Fs in human milk samples from the Democratic Republic of the Congo and Côte d'Ivoire suggest a relationship with the consumption of contaminated clay. Frequent use of PCDD/F contaminated clay products during pregnancy may result in increased exposure of the mother and subsequently the developing fetus and new-born child. The use of these contaminated clays during pregnancy should be carefully considered or even discouraged