Early signals for emerging food safety risks: From past cases to future identification

Food Control 39 (2014) 75e86

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Food Control journal homepage: www.elsevier.com/locate/foodcont

Review

Early signals for emerging food safety risks: From past cases to future identification F.J. van de Brug*, N.B. Lucas Luijckx, H.J. Cnossen, G.F. Houben TNO, P.O. Box 360, 3700 AJ Zeist, The Netherlands

a r t i c l e i n f o

a b s t r a c t

Article history: Received 12 February 2013 Received in revised form 24 October 2013 Accepted 29 October 2013

During the last decades multiple unexpected and wide spread food safety incidents have occurred. The aim of this study is to learn from the past by studying the early emergence of historic food safety risks and apply these lessons for future early identification of emerging food safety risks. Information on the early signals preceding the emergence of thirteen diverse food safety incidents was collected, categorized and evaluated. It was found that in all cases early signals did precede the actual emergence of the incidents. The time interval between early signal and emergence varied between some months to multiple decades. Almost all early signals identified originated from two textual data sources: science and food safety authorities. It is concluded that in order to detect early signals semantic relationships between three key hazard concepts (food, substance and adverse health effect) must be extracted primarily from these data sources. A conceptual emerging food hazard model to visualize the concepts and relationships is proposed. When new information or a change in information is found for the hazard concepts a new food safety hazard may be emerging. Furthermore, we present the design of the Emerging Risk Identification Support system (ERIS) to support the risk manager with the identification of emerging risks. Some key factors for identifying emerging hazards (or risks) and the requirements of information systems to support this are discussed. With a functional system at hand and using science based information, the risk manager will be able to develop scenarios and, subsequently, the risk manager can initiate measures pro-actively to influence the development of the emerging risks. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Emerging risk Early signal Food safety Hazard model Information system

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Case analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .76 Characteristics of early signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77 Food safety hazard model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 Key factors for emerging risk identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Information system to support the identification of emerging risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

1. Introduction

* Corresponding author. Tel.: þ31 88 866 15 48. E-mail address: [email protected] (F.J. van de Brug). 0956-7135/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.foodcont.2013.10.038

In the past few decades multiple unforeseen food safety incidents occurred. Examples are the BSE crisis that began in 1987 (Baker & Ridley, 1996), the unexpected finding of acrylamide formation in fried potatoes as communicated in an “out of the blue”

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press release in Sweden in 2002 (Lofstedt, 2003) and the adulteration of infant milk with melamine that hit the media headlines following the Beijing Olympic games in 2008 (Xiu & Klein, 2010). Such incidents often, reactively, lead to new legislation or specific control, as it is expected that the contaminations could re-occur. Most food contaminations by specific chemicals or microorganisms will indeed re-occur over time. Examples are the several dioxin contamination incidents, but also many microbiological contaminations, especially the serious verocytotoxin producing Escherichia coli (VTEC) related incidents. Some incidents are related to regional crop growth and storage conditions (e.g. aflatoxins), while other are due to economic fraud (melamine 2008, Sudan red 2004/5). The repeating occurrence, diversity and scale of food safety incidents demonstrate the vulnerability of current industrialized food production chains to hazards, that may threaten human health and animal health. Food safety incidents may also result in considerable economic damage and can even negatively affect a nation’s export. These incidents, generally reported in news and general media, undermine public trust in food production industry and food safety authorities. The repeating occurrence of unexpected food safety incidents and related damage demonstrates the need for the early identification of the hazards involved. The early identification of food safety risks will enable risk managers to develop pro-active measures for prevention and control. The effective development of proactive measures will benefit most when a new risk will be identified as early as possible during its development even at the point where it cannot yet be identified as a risk, but may be only as a hazard. The term emerging risk has been proposed for a risk that results from either a newly identified hazard to which a significant exposure may occur or a known hazard to which an unexpected new or increased exposure may occur (EFSA, 2007). In this definition there is a difference between the term risk and the term hazard. The term risk is defined as a function of the probability of an adverse effect and the severity of that effect, consequential to a hazard(s) in food (Codex Alimentarius, 2001). The term hazard is defined as a biological, chemical or physical agent in food or the condition of food with the potential to cause an adverse health effect (Codex Alimentarius, 2001). Thus, during the early development of an emerging risk it may therefore be more appropriate to use the term hazard than the term risk. The early identification of food safety hazards will enable risk managers to be better prepared for, to reduce and to prevent the negative impact of possible upcoming food contamination incidents on health, trust and economy. Current risk analysis in food businesses as well as international information and monitoring systems, such as HACCP and the European RASFF system, have contributed significantly to safer food over the years. However, these systems have in common that they are primarily based on existing knowledge on known hazards and are not designed to identify new and unexpected hazards (EFSA, 2011; Marvin, Kleter, Frewer et al., 2009). The underlying problem with the identification of new hazards is simply that one does not know what to look for (Cnossen, Wassens, Heeres, & Lucas Luijckx, 2009). Relevant early signals leading to emerging food safety risks may be expected to be found in the total body of data directly and indirectly related to the production of food (Cnossen et al., 2009; Marvin, Kleter, Prandini, Dekkers, & Bolton, 2009). There are, however, some significant challenges to face with regard to the extraction of information on early signals. Firstly, the volume of data is huge and grows quickly by the day. Secondly, the data is stored in many heterogeneous data sources which can only be accessed at sometimes considerable cost. Thirdly, early signals are probably present in very low frequency and may be hard to detect. Fourthly, early signals may be composed of information from

multiple data sources. Finally, the data needs to be revisited regularly to combine new and existing information. Currently, no precise and scalable information extraction systems are in place which are designed to discover the yet undetected from very large and diverse data sources. What is needed is an information support system to find e as a figure of speech e the “needle in the haystack”. The aim of this study is to learn from past historical food safety incidents by analyzing a number of past incidents in retrospect with the aim to identify generic features of the early signals that preceded the first public awareness to the food safety incident. We will discuss the generalized findings from the case analyses. We will propose a generic conceptual model and a generic work flow to end up with describing an information system to support the identification of emerging food safety risks. 2. Case analysis This study was set up as a retrospective multi-case analysis with the aim to describe generic characteristics from a variety of historic cases of food safety incidents. Cases were sought and described to illustrate that early signals can be present for cases that can be typed as a “one-off” or “unexpected”. Also, for these case a chronology of events was available as a starting point. The focus of the case analysis is thus on the early signals and not on the incident or outbreak itself or consecutive impact. The cases were not selected because they occur frequently, such as Salmonella outbreaks and aflatoxin contaminations with a long history of re-occurring incidents, nor because of the impact the incidents have had. A recent review on chemical contamination incidents has already focused on the impact of such cases (Thomson, Poms, & Rose, 2012). As a starting point the overview of 93 hazards described in the text book “The Food Safety Hazard Guidebook” (Lawley, Curtis, & Davis, 2008) was used. We added the more recent hazards melamine and isopropylthioxanthone (ITX) to this list which gave a total of 95 hazards. The long list of hazards contains hazards of different nature such as biological, chemical, fraud related, foodborne, packaging related and environmental. In this study we used cases for which we were able to reconstruct a timeline of published information to mark early events and where a starting point of the chain of events could be identified. In the end, from the initial list of 95 hazards, thirteen hazards could be related to thirteen cases that we analyzed in detail for the case histories. In order to construct timelines with crucial events and with corresponding crucial documents we used the above mentioned text book (Lawley et al., 2008) and we searched in peer-reviewed scientific literature, websites from food safety authorities and Internet searches were performed. We especially looked for descriptions of case chronologies that describe important events and traced back possible relevant references to locate the most early documents that mention particular topics. The gathering and categorizing of information from the case histories was an iterative process between assigning early events to the event categories as described below and defining the criteria for the actual assignment task. Since we were not able to find a suitable structured method in literature to describe emerging food safety incidents we developed a new structured way to describe the development of early signals to a public food safety incident. The events from the documented case histories were mapped to the data table containing four discrete event categories. The table was designed using a left-toright order of events with the assumption that this order would most often match with the historical sequential order of the events. In total, four categories of events were used:  First indirect or possible link of hazard to the food product;  First direct link of hazard to the food product;

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 Consecutive events;  First public announcement on the link or hazard to the food product. For each categorized event the year of the event and the data source type were noted. For this study the approach to distinguish between direct and indirect early signals as proposed by Marvin, Kleter, Frewer et al. (2009) was adopted and therefore two types of early signals were defined. Indirect early signals are defined as the earliest documented notions of a possible indirect link of a hazard to the food product as mentioned in the first public announcement of the risk. Direct early signals are defined as the first written evidence of a direct link of the hazard to the food product. Interesting events between the first direct link to food and the first public announcement of the hazard were captured in the category labeled consecutive events. As end point of the sequence of events the first public announcement of the hazard was taken as a category. Here “public” means publication in media like press releases (including recall or warning announcements) and news published on websites and in newspapers, information easily accessible by the general public. Further in this paper lessons will be drawn from both the particular characteristics of the case histories as well as from the structured case analysis. These lessons will give input to risk management and to the design of an information system to support the identification of emerging risks. The cases described in Table 1 form a heterogenic collection, which can be subdivided, into a number of subgroups depending on the criterion chosen. Below we will illustrate possible groupings by the nature of the hazard, source of the hazard and way of discovery of the hazard. The number of chemical contamination issues immediately strikes attention, eleven out of thirteen cases. Due to the selection criteria this is a logical consequence, since rarely new microorganisms appear. A recent (striking) occasion was Cronobacter sakazakii (Gurtler, Kornacki, & Beuchat, 2005). Another very specific case concerns BSE (Bovine Spongiform Encephalopathy). Here a specific prion protein is the causative disease agent. The BSE case is in fact part of a long history around a group of similar neurodegenerative diseases (Baker & Ridley, 1996; Collee & Bradley, 1997). The most early written history goes back to the first descriptions of scrapie in sheep (1750) and kuru in man (1950s). For this study we went back to 1959 when the observed etiological and neuropathological similarities between these diseases suggested the experimental transmission of kuru using brain tissue (Hadlow, 1959). This observation can be considered as an (important) early signal. In addition, the cases can be grouped based on the source (origin) of the hazard. Sources may include fraud (melamine, sudan red), environment (PFOS/PFOA, dioxins), processing (acrylamide, benzene, 3-MCPD) and packaging materials (ITX, semicarbazide). Fraud or food adulteration, which has gained a lot attention in recent years is first of all a criminal act mostly for economic gain. Although there can be early signals predicting this, these signals are of a different type and order than we might search for. Two major recent cases where possible human health threats are involved are the melamine case and the Sudan red case. In the melamine case there was a preceding issue (1 year) in pet food that could have been an indication that there was more to look for (Brown et al., 2007). Also in the Sudan red case there were preceding signals that foods were being adulterated for higher profits (Dixit et al., 1995). Chemicals in the environment can either be man-made, like PFOS/PFOA, or from natural origin. Dioxins are well known, since the early 80s, environmental contaminants of the food chain. Since then they are regularly monitored in priority food and feed

77

commodities. In the specific dioxin case we selected (Hoogenboom & Zeilmaker, 2010) the analysis of unusual amounts of dioxins in raw milk led to an unsuspected source (potato peels as feed) and eventually to the use of a known source of dioxins (kaolin clay) in a newly designed process (potato sorting) in a part of the food chain remote to the source of contamination. This particular characteristic of an interrelationship between two different food chains made us to select this case although as a mere dioxin case it was a re-occurring one and not a first. An example of a process contaminant is benzene in fruit juices, as it is formed from the preservative benzoate and vitamin C under low pH conditions (Gardner & Lawrence, 1993). This mechanism was unraveled following the initial case of benzene in Perrier water. In processing foodstuffs, in particular heating, all kinds of chemicals may form often not yet known to a full extent. The high cost of targeted chemical analysis of the unknown chemicals and subsequent toxicological assessment hampers the full safety assessment. It has recently been proposed that the application of the concept of threshold of toxicological concern for complex matrices will reduce the cost for chemical analysis and make risk assessment easier and more appropriate (Rennen, Koster, Krul, & Houben, 2011). Finally, groups can be made according to the way of discovery. A striking example is the acrylamide case as the discovery was triggered by the unexpected finding in a control group during an occupational health study following an environmental pollution related to the construction of a railway tunnel. Like acrylamide more than half of the chemical issues were found by coincidence or analysis for other purposes, e.g. the specific dioxin case in this paper, benzene in soft drinks, Sudan red, perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in fish and drinking water, semicarbazide and ITX in infant foods (both through packaging). Melamine was discovered as causative agent after the unexplained disease in infants and children had been reported. Two cases developed into an issue due to new insights in health and toxicology developing over a period of time (bisphenol A and 3monochloropropane-1,2-diol (3-MCPD)). 3. Characteristics of early signals The current retrospective multi-case analysis resulted in a structured table overview by using generic event categories to describe the early signals, consecutive events and the first publication to a general public. The frequent discussions between the authors who categorized the case events led to agreed criteria (see Table 2) to classify the case events as this contributed to a consistent quality of the categorization task. The event Table 1 was used as the base to draw generic conclusions. In all cases the chronology of historical events could be matched with the left-to-right order of the categories in Table 1. The first public announcement in the historical cases appeared to be publications, in news or public media, with frequent involvement of governmental bodies on an alert, an outbreak, a product recall, a ban or a phase-out of a chemical. The general media have a clear established role in reporting incidents for the first time to a wide public. It was noted that in general, following the first public announcement the number of publications both in news media and in science may grow quickly. Consecutive events and circumstances (timing, other (bigger) news, perceived risk or interest) influence time intervals and actual publicity. For all cases it was possible to identify and to classify early signals from the constructed timelines that preceded the first public announcement in news and media. This finding confirms the previous assumption that early information is present prior to the actual public awareness of food safety incidents (Marvin, Kleter, Frewer et al., 2009). The confirmation that early signals for

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Table 1 The data table showing the result of the categorization of the historical sequence of events to the four discrete categories. The cases were sorted in alphabetical order. First indirect or possible link of the hazard to the food product

First direct link of the hazard to the food product

Consecutive events

First public announcement on the link of the hazard to the food product

3-MCPD in soy sauce

Not found

Late 80ties the first non-Czech publications appeared. Following the SCF opinion in 1994 saying that 3-MCPD must be regarded as "a genotoxic carcinogen" more studies on 3-MCPD were published on levels in food (SCF, 1994).

Acrylamide in fried food

In 1997, Bergmark published the unexpected finding of acrylamide in non-exposed controls (Bergmark, 1997). Also in 1997, following a Swedish occupational incident with acrylamide grouting, control persons without known exposure had acrylamide in their blood (Albin et al., 1998). In February 1990, an environmental testing lab using Perrier water as a test standard found benzene in the water. The FDA enforced that Perrier mineral water was found to be contaminated with benzene (FDA, 1990a). Perrier later said it was due to not having replaced a filter in the equipment during maintenance. Not found

3-MCPD was since late 60ties known for its toxic effect on male fertility. In 1978 it was shown that 3-MCPD could be formed in hydrolyzed vegetable proteins produced by acid hydrolysis from edible oil extracts (Velisek et al., 1978). Publications on this topic were dominated through the early 80ties by Czech researchers. In 2000, Tareke et al. found acrylamide in rats fed fried feed. Tareke suggested that cooking of food is a major source of background acrylamide levels in humans (Tareke, Rydberg, & Karlsson, 2000).

In 2000 (Macarthur et al., 2000) levels on 3MCPD in retail products were published. The SCF opinion (SCF, 1994) was updated in 2001 and set a regulatory limit. In 2001 the United Kingdom Food Standards Agency found in oyster sauces and soy sauces that some samples contained 3-MCPD at levels higher than those deemed safe by the European Union. In 2002, April, the Swedish food safety authority announced that food product may contain acrylamide (Lofstedt, 2003).

Benzene in soft drinks

Bisphenol A in canned foods

BSE in cow meat

C. sakazakii in infant formula

Dioxin via clay in cow’s milk

In the 1982 (Bolton, McKinley, & Prusiner, 1982; Prusiner et al., 1982) the causative infectious agent in the group of Transmissible Spongiform Encephalopathies (TSEs) diseases was established to be a single protein (named “prion protein” or PrP) in brain tissue. In 1929 the "yellow-pigmented coliform" was firstly reported to cause septicemia in an infant (Pangalos, 1929). The name Enterobacter sakazakii was first proposed late 1970’s, 1980 (Farmer et al., 1977; Farmer, Asbury, Hickman, Brenner, & The Enterobacteriaceae Study Group, 1980). Infections caused by E. sakazakii and death are rarely reported. Various routes of exposure, including food, of E. sakazakii were discussed. Not found

In 2001 Tornqvist reported the presence of moderate levels of acrylamide in fried hamburgers in the Swedish journal Vår Föda (Törnqvist, 2001).

In December 1990, in an FDA Memorandum of Meetings the formation of benzene from ingredients in soft drinks is suggested (FDA, 1990b).

Gardner and Lawrence (1993) describe the chemical formation of benzene in soft drinks. In 1998 and 1999 there are product recalls due to benzene contaminations.

In November 2005, the FDA received private laboratory results reporting low levels of benzene in a small number of soft drinks (FDA, 2012). In 2006 FDA performed additional analyses.

Since 1938 BPA is known as an artificial estrogen (Dodds & Lawson, 1938). In 1993 it was accidently found that BPA leaching from autoclaved laboratory flasks had estrogen activity (Krishnan, Stathis, Permuth, Tokes, & Feldman, 1993). Later, Brotons et al. showed that estrogenic activity in food cans was due to bisphenol-A leached from the lacquer coating (Brotons, Olea-Serrano, Villalobos, Pedraza, & Olea, 1995). In 1989, the Southwood Working Party (UK) posed the hypothesis that if BSE were to be transmitted to humans then it would resemble CJD. The SWP advised to do CJD surveillance (Bridgeman, Ferguson-Smith, & Phillips of Worth Matravers, 2000). In a 1980 publication E. sakazakii was first isolated from a can of previously unopened non-fat dried milk (Farmer et., 1980). In 1988 a publication described that E. sakazakii was cultured from multiple milk-substitute infant formulas samples from multiple countries (Muytjens, Roelofs, & Jaspar, 1988).

In 1993, EPA published a reference dose of 0.05 mg/day (EPA, 1993). In 1996, FDA assessed that BPA is safe at estimated exposures of 0.11 mg/day for adults and 0.07 mg/day for infants (FDA, 1996). In 1997 it was first described that exposure to low levels of BPA, within or below the range of human exposure, increases prostate size in male mouse (Nagel et al., 1997; vom Saal et al., 1997). This is the first of many studies on low-dose BPA toxicity.

In 2001, the NTP subpanel is not persuaded that the low dose effect of BPA is a reproducible finding (NTP, 2001). In 2002, the SCF published a tolerable daily intake level of 0.01 mg/day (SCF, 2002) with considering the effects on very young animals. In2003e2006, the NIH assessed that BPA is safe in low doses. The EWG pressure group critics the assessment (EWG, 2011). From 2008 there is a shift to BPA-free products as announced by retailers and some countries. On 20 March 1996, UK government announced the circumstantial evidence between BSE and the human equivalent disease, CJD (BBC, 1998).

In July 1997, FDA reported that the feed additive ball clay was found to contain dioxin. This discovery was made following a dioxin contamination of various animal products (FDA,

In 1999, FDA mentions dioxin contamination in other mined clay products other than ball clay (FDA, 1999). In June 1999, triggered by the recent Belgium dioxin case, the Austrian

Belgium, February 5, 2002: a 5 days old infant died from meningitis caused by Enterobacter sakazakii (IBFAN, 2002). On May 5, 2002 the Belgium Federal Agency for Food Safety asked producer Nestle to recall the specific dry infant formula product. March 29, 2002: In the USA a recall of a special infant formula was initiated after death of a premature infant in April 2001 from meningitis caused by formula contaminated with Enterobacter sakazakii (FDA, 2002). At the end of 2004, the EU based RASSF reported that dioxin had been found in milk from Dutch farms (RASFF, 2004).

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Cases

1997). The scientific publication in 1998 by Rappe et al. refers to this case (Rappe, Bergek, Fiedler, & Cooper, 1998). Not found

Furan and its derivatives have long been known to occur in many foodstuffs (Maga, 1979) with the highest levels found in coffee. Furan in coffee was already described in 1938 (Johnston & Frey, 1938).

ITX in infant formula

In a patent filed in 2002, the potential of ITX migration from packaging to food was addressed in a United States Patent Application. In the patent application the Sun Chemical Corporation says “.unreacted thioxanthone derivatives of this type have a tendency to migrate from printing inks into, for example, packaged foodstuffs” (Herlihy & Lawrence, 2002). In late 2003 and 2004 dogs in Asia got ill with renal failure, linked to commercial pet foods. The precise cause of the effect was not determined (Jeong, & Do, 2006).

Not found

Melamine in infant milk powder

PFOS/PFOA in drinking water

Semicarbazide in food

Sudan I in chilli products

Late 1960’s, non-occupational exposure to organic fluorine was described (Guy, Taves, & Brey, 1965). In 1993, mortality related to occupational exposure to PFOS was described (Gilliland & Mandel, 1993). In 1999, it was reported that PFOS was found in groundwater on fire fighting sites (Moody & Field, 1999). In 1999, the company 3M summarizes the health effects of PFOS. In 2001 it was first published in science that fluorochemicals such as PFOS were accumulating in wildlife throughout the world (Giesy & Kannan, 2001). In 1995, the European Commission (EU, 1995) prohibits the use of nitrofurazone as therapeutic drug in food-producing animals. In order to measure compliancy, the persistent tissue-bound nitrofurazone metabolite semicarbazide is used as the marker residue for monitoring the nitrofurazone administration. There is some evidence for toxic effects of semicarbazide. During the 80ties, Sudan I became more known as a genotoxic carcinogen (IARC, 1975). Till the EC directive 94/36 (EU, 1994) Sudan Red I was not forbidden as a food colorant and hence could still be used untill at least 1994 (depending on implementation in national legislation). From the point of its EU ban in

In early 2007 there was an outbreak of feedrelated renal failure in cats and dogs in North America (FDA, 2007) The toxic compound was proposed to be melamine and cyanuric acid in wheat, rice and corn components. In September 2007, the United States banned the import of wheat gluten from China because it was found that it was tainted with melamine. In 2007, the causative agent in the earlier 2004 case was identified as melamine and cyanuric acid (Brown et al., 2007). In may 2006 high levels of PFOS/PFOA were unexpectedly found in surface and drinking water in Germany (Skutlarek, Exner, & Färber, 2006a). This was presented as a poster in May 2006 and later published in a scientific journal (Skutlarek, Exner, & Färber, 2006b).

Not found

In 1995, a scientific paper was published describing the positive finding of Sudan I in Indian chilli power (Dixit, Pandey, Das, & Khanna, 1995). On May 9, 2003, France informed the European Commission that testing had detected the illegal dye Sudan I in hot chilli products originating from India. EU emergency

Using improved detection tools, the FDA reported in May 2004 that furan was found in a broad range of thermally processed foods. Among them were baby foods and infant formulas and many foods in sold in jars and cans (FDA, 2004). End of November 2005, market recalls of infant formula are announced (The Guardian, 2005). December 2005, a notification from the Italian authorities to EU Rapid Alert System for Food and Feed (RASFF, 2005) has shown the occurrence of the ink photoinitiator 2-isopropyl thioxanthone (ITX) in liquid milk for babies packaged in printed carton. On September 11, 2008, the Chinese authorities announced a recall of infant milk powder that was contaminated by melamine. Consumption of melamine caused infants to develop renal failure and some infants had died (Xiu & Klein, 2010).

In June 2006, in a press conference the authorities announced the finding of PFOS/ PFOA in river waters (WDR, 2012). In 2006 the EU restricts the use of perfluorooctane sulfonates (EU, 2006).

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Furans in coffee

Ministry of Agriculture initiated a program to control feedstuffs for its dioxin content. The ministry reported on kaolinitic clay as a new source of dioxin contamination (Malisch, 2000). Following an NTP study in 1993, 1995 IARC classified furan as carcinogenic to animals. No reference to food as route of exposure was found in these assessments (IARC, 1995).

In early 2003, industry reported to EFSA that semicarbazide was found in purely-vegetable based food products during routine monitoring. In July 2003 EFSA issues a preliminary advice on the possible occurrence of SEM in certain packaged foods (EFSA, 2003, pp. 1e36). In 2004, scientific evidence was provided that semicarbazide is formed from the blowing agent used in seal formulations (Stadler et al., 2004). On February 18, 2005, the EFSA announced the discovery of Sudan in many products in England, largest recall ever in England follows (FSA, 2007). Also on February 18, the FSA issues their first public warning and publishes a list of around 360 products at risk. Sudan 1 was contained in a chilli powder which was used to 79

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decision June 2003 (EU, 2003). July 2003: the UK Food Standards Agency issues its first warnings (FSA, 2007). 1994, Sudan I became a known hazard not expected to occur in food in view of international legislation.

Abbreviations: BSE: Bovine spongiform encephalopathy; TSEs: Transmissible spongiform encephalopathies; CJD: Creutzfeldt Jakob disease; PFOS: Perfluorooctanesulfonic acid; PFOA: Perfluorooctanoic acid; 3-MCPD: 3monochloropropane-1,2-diol; ITX: Isopropylthioxanthone; BPA: Bisphenol A.

Cases

Table 1 (continued )

First indirect or possible link of the hazard to the food product

First direct link of the hazard to the food product

Consecutive events

produce Worcester sauce. The sauce was then added to a variety of foodstuffs, including soups, sauces and ready meals.

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First public announcement on the link of the hazard to the food product

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Table 2 Criteria for assigning the historic case events to the predefined event categories. The specific events to which the criteria apply can be found in Table 1. Event

Criteria

First indirect or possible link of hazard to the food product

Other product/non-food matrix linked to the substance; causative disease agent not identified Product linked to substance or health effect linked to product, but not published to the general public Events occurring between first direct link and the public announcement Publication available to general public; event can be labeled as “incident”

First direct link of hazard to the food product Consecutive events First public announcement on the link of hazard to the food product

emerging risks do exist is crucial as it is the primary rationale to start the development of emerging risk identification systems. In Table 3, in the left column, the early signals from the historical case analysis are described in generic terms without specifying the chemical or biological hazard and the food product. The envisaged information system should support the identification of information on these early signals irrespective of the specific hazard, the link to food and the specific negative health effect. This will be discussed further in this paper. Although the variety of early signals listed in Table 1 is diverse, the key common denominators are the following three concepts: substance (chemical or micro-organism), food or exposure through food and negative health effect. When a new link appears between different bits of information, e.g. a substance with an adverse health effect and then that substance linked to the food chain, then an emerging hazard or risk can possibly be recognized. So, in addition to the three key concepts there is the aspect of novelty that addresses a change in information, knowledge and/or insight. This whole idea led us to design a conceptual model that underlies the early identification of emerging food safety risks. 4. Food safety hazard model As shown in Fig. 1 the conceptual hazard model is visualized as a triangular representation of the crucial links to find. The framework of the model consists of the three key risk concepts: substance, food Table 3 Early signals identified from the case histories and described in generic terms. Early signals

Cases

A toxic substance detected in humans without known route of exposure Although perceived as a first time occurrence, the contamination has occurred before but was forgotten Case reports of humans or animals that get ill without known causative agent Local use of hazardous chemicals that are not allowed elsewhere A first time link of hazardous chemicals that accumulate in the environment to food contamination Packaging materials that may release chemicals to food, especially for vulnerable groups A first characterization of a hazardous organism and possible link to food Low concentration effect studies on food chemicals that may trigger consumer pressure groups Studies on new food contaminations that are performed by specific research groups Unlinked toxicological information on a chemical and the occurrence of the chemical in food

Acrylamide Dioxin, benzene

Melamine, BSE Sudan I PFOS/PFOA

ITX, semicarbazide Cronobacter sakazakii Bisphenol A

3-MCPD Furan

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Fig. 1. The food safety hazard model as the conceptual foundation for the early identification of emerging risks.

and negative health effect, which are positioned as the three nodes in the tri-angular model. In this model the concept of food stands for products, processes, raw materials, ingredients, additives, processing aids and contact materials used in food production and it includes feed. The concept of substance stands for all agents including biological, chemical and physical agents that have the ability to cause negative health effects. The concept of negative health effect stands for all adverse health effects including signs, symptoms, diseases and pathology findings not limited to man, but including domestic, laboratory and wild animals. The three concepts can be thought of as being related and when a relationship is confirmed this triggers the first onset of an emerging hazard. When two relations are confirmed the building of a scenario constructing the third one closes the triangle and opens up the possibilities for pro-active risk management. When for any of the three possible relationships between the risk concepts new information becomes available it can be said that a new food safety risk may be emerging. It is here noted that, in literature, new aspects on the three types of relationships are described by using a variety of ways to express the novelty of the finding. This means that first of all any information system to support the identification of emerging risks should also address the aspect of novelty and, secondly, that this should be done with taking into account the numerous ways novelty may be expressed and how this relates to what is already the state of knowledge at a certain time at an organization. As the envisaged information system supports the identification of new hazards, it is the subsequent risk manager’s task to confirm the novelty and the certainty of the three relationships. It is then possible for the risk manager to develop new research questions or scenarios which can be followed by pro-active measures, including monitoring of the issue or substance. 5. Key factors for emerging risk identification Emerging food safety risks can either result from previously known hazardous substances or they can result from previously unknown hazardous substances (Marvin, Kleter, Frewer et al., 2009). The latter type of cases has no history of earlier related cases. Cases that were previously known as hazards may be forgotten over time and when they re-emerge they firstly appear as new. A typical example is the case of dioxin contaminated kaolin clay which led to an incident in 2004 in the Netherlands. What

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happened in 2004 was that the change of a production process did perhaps not undergo an in depth risk analysis and consequences of the change were obviously not fully investigated. It can thus be argued that in 2004 or before one could have known about earlier and much related cases, such as the 1997 USA case and later cases in Europe. It must here be noted that the first incident in 1997 could probably not have been predicted or foreseen with emerging risk identification systems, the subsequent cases with the same or comparable clay sources of dioxin could have. The second type of emerging risks comes from unexpected and previously unknown hazardous chemicals or pathogenic microorganisms occurring in foods. A typical example is the acrylamide case which when announced publicly in 2002 came as a surprise to many in industry and at governmental bodies. Although there was information available to be interpreted toward the event. However, at that time no information systems were there to support the discovery and learning ability of organizations on unexpectedly upcoming new food safety risks. From the analysis of cases different dynamics of how emerging risk develop can be recognized. Some cases, like melamine, come up suddenly in the public domain within a very short time window. In other cases there is scientific evidence that accumulates during the course of years and the issue at some point reaches a phase that risk management measures need to be taken. The level of attention the new scientific evidence is given may also vary. Examples are the 3-MCPD and bisphenol A (BPA) cases. With 3-MCPD there seems to be a 20 year lag phase between proven occurrence in food, known toxicology and measures, although the most early sources of analysis in foods might have been (dis)missed (Czech publications, while still behind the iron curtain) by experts. In the BPA case it were pressure groups that actually triggered the authorities to take measures. The estrogenic effect of BPA has been known since 1938, but repeatedly authorities and researchers have assessed BPA to be safe at low doses and for infants. It is actually quite recent (1980s) that hormonal effects are considered to be very critical as obviously the reproductive system and development of the unborn and children might be affected and also the development of certain cancers might be promoted. This is clearly a case where precautionary action could have been taken based on scenarios with new scientific information as supporting evidence, particularly since there was known exposure of vulnerable groups. The case of furans has not ended yet, these substances are since long known as contaminants of many (thermally processed) foodstuffs, it was shown in coffee as early as 1938 and recently found in baby and infant foods. The substance was classified as carcinogenic to animals (IARC, 1995). Till now, there are no particular measures in legislation to regulate furan levels in food. The major value of the identification of early signals for emerging food safety risks lies in the use of the time window preceding a possible food safety incident as it provides the opportunity to influence the development of the risk or to take other measures. As visualized in Fig. 2 it is clear that for most of the historical cases reviewed in this study there is indeed time between the first early signal and the first public announcement and moreover, that the time interval length varied considerably from some months to multiple decades. This variation in time intervals stresses the need to keep track of all information, old and new, and to combine it in one system (finding the relations), as older information may still carry relevance for current food and food production. Early signals may be accompanied with uncertain and incomplete scientific evidence and this in turn may hamper proper interpretation of the early signal whether the signal may develop into a risk. Moreover, it may be very difficult to develop scenarios on the further spread of the hazard. The triangular model (Fig. 1)

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Fig. 2. Time intervals (in number of years) between the early signals and the first public announcement. There are two possible episodes depicted: i) time interval starting with the first indirect link or possible link of a hazard (in dark gray) and ii) time interval starting with the first direct link (in light gray) to the first public announcement. The first public announcements are all positioned at zero on the x-axis.

can help the risk manager in developing research questions and scenario’s. The missing or uncertain link can be the trigger to develop a research question or a scenario that then needs to be confirmed. Actual food safety crises or issues start when a food source (contamination or not) is connected to a negative human health effect. However, the time between overt clinical signs and the actual exposure can be many years. As the problem here mostly is to prove the causal relationship and then the action to be taken should be based on the precautionary principle. A principle well under fire, because its application suffers from lack of argumentation and evidence, with implications of arbitrariness. This kind of thinking was applied in the BSE case. Following the assessment in the early 80ties of the causative prion agent for the TSE group of animal diseases, it was possible to speculate that if a TSE disease was transmissible to humans then the disease would resemble the human Creutzfeldt-Jakob disease (CJD) (Bridgeman et al., 2000). In 1989, after the recognition of BSE as a new TSE disease in cows, the recall of the hypothesis posed in the 80ties led to the CJD surveillance in man in the UK. We acknowledge that research proving these causal relationships can and will take many years and that scientists will therefore always enrobe early results with uncertainties. It is however in hindsight that we suggest to be more vigilant on early knowledge and to be more proactive in measures, based on relevant scenarios. Information systems can help to underpin scenario’s by providing information, although sometimes incomplete, at predicted steps or leaps in the scenario. One does not need all parts of the jig saw to get the picture. 6. Information system to support the identification of emerging risks This section describes the key requirements of an information system to support the identification of emerging food safety hazards or risks, the Emerging Risk Identification Support system (ERIS). In addition, a use case will be described to illustrate how the ERIS system works. The triangular conceptual food safety model as proposed earlier in this paper (Fig. 1) describes the key concepts and the types of relationships that are most relevant. It is important to emphasize here that the information system should not be restricted to, for

example, specific substanceefood combinations that can be thought of in advance, otherwise new and unexpected combinations will unlikely be identified from the data sources when published for the first time. For example, in the year 2000 the combination of the key words “acrylamide” and “fried feed” were not likely to be used in a literature search for emerging risks without prior knowledge on the forthcoming publication by Tareke et al. (2000) that preceded the press release in 2002. As this example illustrates, targeted searching using specific keyword combinations will thus be insufficient to identify early signals for unexpected emerging risks. What is required is an open approach that identifies meaningful relationships in textual documents between potentially unknown substances, products and adverse health effects. We have developed a food safety ontology and populated it with relevant terminology for the concepts and relationships as shown in Fig. 1. Such a food safety ontology is used to feed the text mining rules that are applied to the linguistic structure of sentences in the documents to identify meaningful relationships. Whereas the application of text mining for the scientific food safety domain is still new, in the biomedical research domain the application of text mining for the identification of relationships between genes, diseases and drugs from scientific literature is extensively supported (Abulaish & Dey, 2006; Ananiadou, Pyysalo, Tsujii, & Kell, 2010; Feldman, Regev, Hurvitz, & Finkelstein-Landau, 2003; Hristovski, Rindflesch, & Peterlin, 2013; Rinaldi, Schneider, & Clematide, 2012). The current analysis of historic food safety incidents shows that almost all early signals that preceded the first public announcement originated from two textual data source types. The first most important source type is the collection of peer reviewed scientific full text papers and, in addition, the bibliographic data with abstracts. The second important source type is volume of the documents and websites produced by food safety authorities. Additional data sources may include company research reports, patents and global news. The body of peer reviewed scientific and science based (“grey literature”) data is not only diverse, but the total volume is already huge and grows at a steady pace. The basic set up of our ERIS system is depicted in Fig. 3, where it is shown how the food safety ontology and the data sources feed the text mining system to give a table of results. An example output is printed in the figure. The ERIS system is based on text

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Fig. 3. Design of the information system, showing some example results, to support the early identification of emerging food safety risks.

mining technology as provided by SAS Enterprises (Cary, US). Text mining technology is the core of the ERIS system. Combining relevant key words with known and unknown bits of information is crucial. In this paper we will demonstrate the system by describing a use case. The current use case is to find linguistic relationships in scientific abstracts between names of products of plant origin and names of hazardous chemicals. The hazardous chemicals can either be chemicals that are endogenous to plants or chemicals that have an external source for example by contamination. The major variables in the text mining rules were the presence of verbs or prepositions between the two concepts, the number of words between the concepts and the presence of the concepts within one sentence. In addition, a text mining rule was designed that uses specific word patterns to identify chemical names that were not yet covered by the ontology. All relevant terminology was stored in the in-house built ontology and was used to feed the text mining rules. A number of cases that were selected from the text mining results are presented in Table 4 to illustrate what can be said as a first shallow evaluation of the information that was found. Each case is shortly headed with the combination of key words by which a snippet text in a scientific abstract was found. Some of these examples may be known on the basis of the specific combination of key words, however there may be new information that points to other relevant aspects On the basis of such a short annotation a decision for a more in depth investigation can be made. It is clear that the ERIS text mining system is able to retrieve relevant information from huge amounts of data. In order to reduce the numbers

of hits to comprehensive and manageable lists, human (expert) interaction is needed as well as regular feedback to improve the text mining rules. The level of expert analysis must be managed by using clear and transparent criteria to be used as guidance for the evaluation. In a forthcoming publication the authors will elaborate more on how to evaluate the information that may point to emerging risks. 7. Conclusions To identify early signals for emerging food safety risks we need to know what to look for. In this paper we confirmed that early signals for past food safety incidents do exist and that there is a time window that provides the opportunity to influence the development of the risk or to take other measures. We described the past early signals in generic terms and also described the key characteristics of early signals at a higher level of detail using a triangular conceptual model for new food safety hazards. This conceptual model was used as the base for developing search strategies to find early signals. When new information or a change in information is found for the hazard concepts a new food safety hazard may be emerging. It is emphasized here that search strategies must be designed “open” and must not be restricted to a priori known specific hazards related to specific food products as then unexpected relationships would be missed. It is essential to look beyond the current state of food safety knowledge as for example is laid down in text books and reviews.

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Table 4 Examples of evaluated hits from the text mining results. Key words Snippet

Reference title Annotation

Key words Snippet

Reference title Annotation

Key words Snippet

Reference title Annotation

Key words Snippet Reference title

Annotation

Key words Snippet Reference title Annotation

Key words Snippet Reference title

Annotation

Acacia and catechins It is a proprietary blend of 2 flavonoids, baicalin and catechins, which are derived from the botanicals Scutellaria baicalensis and Acacia catechu, respectively. Acute liver injury due to flavocoxid (Limbrel), a medical food for osteoarthritis: a case series (Chalasani et al., 2012) This piece of information may be relevant, because Acacia is the source plant for Arabic gum that is used as an additive in food. The acute health effects stem from certain substances in Acacia and when these substances can also be found in a food additive gum there may be health risk. This is the kind of reasoning that, if more knowledge is not available, should be the trigger for further literature research. Berries and 1,8-cineole This led us to carry out further studies to quantify the levels of 1,8-cineole found in grape berries, leaves, and stems at set distances from Eucalyptus trees over multiple vintages. Vineyard and fermentation studies to elucidate the origin of 1,8cineole in Australian red wine (Capone, Jeffery, & Sefton, 2012) The chemical 1,8 cineole, a major constituent of Eucalyptus oil, has known toxicity at higher levels. This reference suggests exposure through wine consumption. If more knowledge is not available, further literature research is required. Vegetable oils and 3-MCPD Results of a recent German research project are presented examining possibilities for reducing risk of formation of 3monochloro-1,2-propanediol (3-MCPD) esters and related compounds, such as glycidyl esters, during manufacture of vegetable oils. Mitigation of 3-MCPD esters in refined vegetable oils (Matthäus et al., 2012) Although 3-MCPD is a known issue, here the suggestion is made for a new process for reduction of 3-MCPD. The here found information does not point to a hazard, but directs to the opposite direction of mitigation. Omega-3 fatty acid and 4-oxo-2-hexenal 4-oxo-2-hexenal, a mutagen formed by omega-3 fat peroxidation, causes DNA adduct formation in mouse organs. 4-oxo-2-hexenal, a mutagen formed by omega-3 fat peroxidation, causes DNA adduct formation in mouse organs (Kasai et al., 2005). Here the title contains all three corner concepts of the triangle: a substance (4-oxo-2-hexenal), a health effect (mutagenic) and a food or exposure (omega-3 fatty acids). Here further research is warranted to find more support for the mutagenicity of the chemical as well as its potential exposure. Coffee and furan Analysis and risk assessment of furan in coffee products targeted to adolescents. Analysis and risk assessment of furan in coffee products targeted to adolescents (Waizenegger et al., 2012). Although furan is a known issue in coffee, the specific target group here suggested is interesting as there may be a higher risk than previously assumed. Barley and aflatoxins Co-occurrence of aflatoxins, ochratoxin A and zearalenone in barley from a northern region of Spain. Co-occurrence of aflatoxins, ochratoxin A and zearalenone in barley from a northern region of Spain (Ibáñez-Veaa, GonzálezPeñasa, Lizarragaa, & López de Cerainb, 2012). Although this information concerns a known issue, the multiple contamination and the possible combined exposure may be a new aspect of the issue. Further literature research is needed here.

Knowing what to look for precedes the challenge of how to find the early signals for future emerging risks. Past early signals were hidden in very large volumes of scientific and science-based data. Given the challenge of processing such large volumes of data a sensitive and dedicated information system is needed for which we sketched the design. The system’s smart engine is ontologysupported text mining using natural language processing that is capable of high precision extraction of relevant relationships from documents.

Whatever the quality of the system’s output, expert involvement will always be needed. Food safety experts need to interpret and evaluate the system’s output using clear and transparent criteria to filter out the true positive hits that indicate emerging food safety risks. These true positive hits can give input to proactive risk assessment and scenario development. Emerging risk identification support systems will contribute to maintaining current food safety levels and to being better prepared for new risks. By using emerging risk identification support systems, risk managers in food industry and at governmental bodies are equipped with a tool that supports them in the validation of current risk analyses at the one hand and at the other hand the ability to use science-based information as a base to handle issues and incidents. Emerging risk identification support systems can provide input for horizon scanning and foresight programs which are currently being discussed at food safety authorities and at food industries. Finally, as food production has become more global and more dynamic than ever before and the fast growing volume of data from science hampers oversight and insight. The use of dedicated information systems that support the identification of early signals for emerging food safety risks is inevitable. While timely identification of early signals will undoubtedly continue to be a challenge as the information landscape will keep changing, the challenge is and remains effective interpretation of results and taking proactive measures with a sense of precaution and dealing with uncertainty. Conflicts of interest All authors declare that there are no conflicts of interest. Acknowledgments This work was commissioned by the Food Safety Program Management of TNO. The authors wish to thank Dr. M.J.B. Mengelers from the National Institute for Public Health and the Environment (RIVM) in the Netherlands for his valuable comments to the manuscript. References Abulaisha, M., & Deyb, L. (2007). Biological relation extraction and query answering from MEDLINE abstracts using ontology-based text mining. Data & Knowledge Engineering, 61(2), 228e262. Albin, M., Törnqvist, M., Tinnerberg, H., Kautiainen, A., Eriksson, A., & Magnusson, A. L. (1998). Resultat av hälsoundersökning av boende på hallandsåsen e möjlig exponering för utsläpp av rhoca-gil, besvär och hemoglobinaddukter av akrylamid. In Tunnel commission, kring hallandsåsen. delrapport av tunnelkommissionen, statens offentliga utredningar (governmental official report). Stockholm: Government of Sweden, Office for Administrative Affairs. Ananiadou, S., Pyysalo, S., Tsujii, J., & Kell, D. B. (2010). Event extraction for systems biology by text mining the literature. Trends Biotechnology, 28(7), 381e390. http://dx.doi.org/10.1016/j.tibtech.2010.04.005. Baker, H. F., & Ridley, R. M. (1996). What went wrong in BSE? from prion disease to public disaster. Brain Research Bulletin, 40(4), 237e244. BBC. (1998). BSE timeline. Retrieved 11.01.13, from http://news.bbc.co.uk/2/hi/uk_ news/218676.stm. Bergmark, E. (1997). Hemoglobin adducts of acrylamide and acetonitrile in laboratory workers, smokers and nonsmokers. Chemical Research in Toxicology, 10, 78e84. Bolton, D. C., McKinley, M. P., & Prusiner, S. B. (1982). Identification of a protein that purifies with the scrapie prion. Science, 218(4579), 1309e1311. Bridgeman, J., Ferguson-Smith, M., & Phillips of Worth Matravers. (2000). Volume 4: The southwood working party, 1988-89. In The BSE inquiry: Report, evidence and supporting papers of the inquiry into the emergence and identification of bovine spongiform encephalopathy (BSE) and variant creutzfeldt-jakob disease (vCJD) and the action taken up to 20 march 1996. London: Stationery Office. http:// webarchive.nationalarchives.gov.uk/20060715141954/bseinquiry.gov.uk/. Brotons, J. A., Olea-Serrano, M. F., Villalobos, M., Pedraza, V., & Olea, N. (1995). Xenoestrogens released from lacquer coatings in food cans. Environmental Health Perspectives, 103(6), 608e612.

F.J. van de Brug et al. / Food Control 39 (2014) 75e86 Brown, C. A., Jeong, K. S., Poppenga, R. H., Puschner, B., Miller, D. M., Ellis, A. E., et al. (2007). Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007. Journal of Veterinary Diagnostic Investigation, 19(5), 525e531. Capone, D. L., Jeffery, D. W., & Sefton, M. A. (2012). Vineyard and fermentation studies to elucidate the origin of 1,8-cineole in Australian red wine. Journal of Agricultural and Food Chemistry, 60(9), 2281e2287. http://dx.doi.org/10.1021/jf204499h. Chalasani, N., V, R., Navarro, V., Fontana, R., Bonkovsky, H., Barnhart, H., et al. (2012). Acute liver injury due to flavocoxid (limbrel), a medical food for osteoarthritis: a case series. Annals of Internal Medicine, 156(12), 857e860. Cnossen, H., Wassens, M., Heeres, H., & Lucas Luijckx, N. (2009). Vulnerabilities in the food chain. A stakeholders’ guide. Codex Alimentarius. (2001). In Codex Alimentarius Commission (Ed.), Codex alimentarius commission e Procedural manual (12th ed.). FAO and WHO. Collee, J. G., & Bradley, R. (1997). BSE: a decade on-part I. The Lancet, 349(9052), 636e641. Dixit, S., Pandey, R. C., Das, M., & Khanna, S. K. (1995). Food quality surveillance on colours in eatables sold in rural markets of Uttar Pradesh. Journal of Food Science and Technology, 32(5), 373e376. Dodds, E. C., & Lawson, W. (1938). Molecular structure in relation to oestrogenic activity. compounds without a phenanthrene nucleus. Proceedings of the Royal Society of London. Series B, Biological Sciences, 125(839), 222e232. EFSA. (2003). EFSA expert group looks at semicarbazide: Too early for any conclusions (Vol. 219). Press Release. EFSA. (2007). Definition and description of "emergings risks" within the EFSA’s mandate. Retrieved 08.01.13, from http://www.efsa.europa.eu/en/emrisk/ aboutemrisk.htm. EFSA. (2011). Development of web monitoring systems for the detection of emerging risks. The EFSA Journal, 7(10). EPA, Bisphenol A. (CASRN 80-05-7), 1993, Retrieved 12.11.13, from http://www.epa. gov/iris/subst/0356.htm. EU. (1994). European parliament and council directive 94/36/EC of 30 june 1994 on colours for use in foodstuffs. Official Journal of the European Communities, L 237(13). EU. (1995). Commission regulation (EC) no 1442/95. Official Journal of the European Communities, L 143(26). EU. (2003). Commission decision of 20 June 2003 on emergency measures regarding hot chilli and hot chilli products 2003/460/EC. Official Journal of the European Union, L 154(114). EU. (2006). Directive 2006/122/EC of the European parliament and of the council of 12 December 2006. Official Journal of the European Union, L 372(32). EWG. (2011). Timeline: BPA from invention to phase-out. Retrieved 17.01.13, from http://www.ewg.org/reports/bpatimeline. Farmer, J. J., III, Hickman, W., & Brenner, D. J. (1977). Abstract annual meeting of the American Society of Microbiology. C 154, 61. The Enterobacteriaceae Study Group. (1980). Enterobacter sakazakii, new species of enterobacteriaceae isolated from clinical specimens. International Journal of Systematic and Evolutionary Microbiology, 30(3), 569e584. FDA. (1990a). FDA enforcement report for February 28, 1990. Retrieved 08.01.13, from http://web.archive.org/web/20070929145842/www.fda.gov/bbs/topics/ ENFORCE/ENF00080.html. FDA. (1990b). Benzene residues in soft drinks. Retrieved 08.01.13, from http://sci. tech-archive.net/Archive/sci.med.diseases.cancer/2006-01/msg00069.html. FDA. (1996). Cumulative exposure estimates for bisphenol A (BPA), individually for adults and infants, from its use in epoxy-based can coatings and polycarbonate (PC) articles. verbal request of 10-23-95. Chemistry Review Branch. HFS-247. FDA. (1997). FDA stops distribution of some eggs and catfish because of dioxincontaminated animal feed. Hhs News. T-97-29. FDA. (1999). Guidance for industry: dioxin in anti-caking agents used in animal feed and feed ingredients. Federal Register, 64(199), 55948. FDA, Health professionals letter on Enterobacter sakazakii infections associated with use of powdered (dry) infant formulas in Neonatal Intensive Care Units, 2002, Retrieved 12.11.13, from http://www.fda.gov/Food/ RecallsOutbreaksEmergencies/SafetyAlertsAdvisories/ucm111299.html. FDA. (2004). Exploratory data on furan in food. data through april 28, 2004. Retrieved 25.01.13, from http://www.fda.gov/Food/FoodSafety/FoodContaminantsAdulte ration/ChemicalContaminants/Furan/ucm078469.htm. FDA. (2007). Recall of pet foods manufactured by menu foods, inc. Retrieved 08.01.13, from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ ucm108871.htm. FDA. (2012). Data on benzene in soft drinks and other beverages, data through may 16, 2007. Retrieved 08.01.13, from http://www.fda.gov/Food/FoodSafety/FoodContaminants Adulteration/ChemicalContaminants/Benzene/ucm055815.htm. Feldman, R., Regev, Y., Hurvitz, E., & Finkelstein-Landau, M. (2003). Mining the biomedical literature using semantic analysis and natural language processing techniques. Biosilico, 1(2), 69e80. FSA. (2007). Report of the sudan I review panel. Retrieved 08.01.13, from http://www. food.gov.uk/multimedia/pdfs/sudanreview.pdf. Gardner, L. K., & Lawrence, G. D. (1993). Benzene production from decarboxylation of benzoic acid in the presence of ascorbic acid and a transition-metal catalyst. Journal of Agricultural and Food Chemistry, 41(5). Giesy, J. P., & Kannan, K. (2001). Global distribution of perfluorooctane sulfonate in wildlife. Environmental Science & Technology, 37(7), 1339e1342. Gilliland, F. D., & Mandel, J. S. (1993). Mortality among employees of a perfluorooctanoic acid production plant. Journal of Occupational and Environmental Medicine, 35(9), 950e954.

85

Gurtler, J. B., Kornacki, J. L., & Beuchat, L. R. (2005). Enterobacter sakazakii: a coliform of increased concern to infant health. International Journal of Food Microbiology, 104(1), 1e34. Guy, W. S., Taves, D. R., & Brey, W. S. (1965). Organic fluorocompounds in human plasma: prevalence and characterization. In Biochemistry involving carbonfluorine bonds, ACS symposium series (Vol. 28; pp. 117e134). Hadlow, W. J. (1959). Scrapie and kuru. The Lancet, 274(7097), 289e290. Originally Published as Volume 2, Issue 7097 http://dx.doi.org/10.1016/S0140-6736(59) 92081-1. Herlihy, & Lawrence, S. (2002). In Sun Chemical Corporation (Ed.), Patent: 20050014860. multi-functional thioxanthone photoinitiators (522/53 ed.). United States: C07D335/16; C08F2/46; C08F2/50; C09D11/10; (IPC1-7): C08F2/46; C08J3/28. Hoogenboom, R., & Zeilmaker, M. (2010). Kaolinic clay derived PCDD/Fs in the feed chain from a sorting process for potatoes. Chemosphere, 78(2), 99e105. Hristovski, D., Rindflesch, T., & Peterlin, B. (2013). Using literature-based discovery to identify novel therapeutic approaches. Cardiovascular & Hematological Agents in Medicinal Chemistry, 11(1), 14e24. IARC. (1975). Some aromatic azo compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 8, 225. IARC. (1995). Dry cleaning, some chlorinated solvents and other industrial chemicals. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 63, 393. Ibáñez-Veaa, M., González-Peñasa, E., Lizarragaa, E., & López de Cerainb, A. (2012). Co-occurrence of aflatoxins, ochratoxin A and zearalenone in barley from a northern region of spain. Food Chemistry, 132(1), 35e42. http://dx.doi.org/ 10.1016/j.foodchem.2011.10.023. IBFAN. (2002). How safe are infant formulas? The death of a one-week old formula-fed baby in Belgium. Retrieved 15.01.13, from http://www.ibfan.org/news-2002safe_formulas.html. Jeong, W., & Do, S. (2006). Canine renal failure syndrome in three dogs. Journal of Veterinary Science, 7(3), 299e301. Johnston, W. R., & Frey, C. N. (1938). The volatile constituents of roasted coffee. Journal of the American Chemical Society, 60, 1638. Kasai, H., Maekawa, M., Kawai, K., Hachisuka, K., Takahashi, Y., Nakamura, H., et al. (2005). 4-oxo-2-hexenal, a mutagen formed by omega-3 fat peroxidation, causes DNA adduct formation in mouse organs. Industrial Health, 43(4), 699e701. Krishnan, A. V., Stathis, P., Permuth, S. F., Tokes, L., & Feldman, D. (1993). BisphenolA: an estrogenic substance is released from polycarbonate flasks during autoclaving. Endocrinology, 132(6), 2279e2286. Lawley, R., Curtis, L., & Davis, J. (2008). The food safety hazard guidebook. Cambridge (UK): The Royal Society of Chemistry. Lofstedt, R. E. (2003). Science communication and the swedish acrylamide “alarm”. Journal of Health Communication, 8(5), 407e432. Macarthur, R., Crews, C., Davies, A., Brereton, P., Hough, P., & Harvey, D. (2000). 3monochloropropane-1,2-diol (3-MCPD) in soy sauces and similar products available from retail outlets in the UK. Food Additives and Contaminants, 17(11), 903e916. Maga, J. A. (1979). Furans in foods. Critical Reviews in Food Science and Nutrition, 4, 355e399. Malisch, R. (2000). PCDD/F in kaolinitic clays and its relevance for feeding stuff, food and cosmetics. Organohalogen Compounds, 47, 326e329. Marvin, H. J. P., Kleter, G. A., Frewer, L. J., Cope, S., Wentholt, M. T. A., & Rowe, G. (2009). A working procedure for identifying emerging food safety issues at an early stage: implications for european and international risk management practices. Food Control, 20(4), 345e356. Marvin, H. J. P., Kleter, G. A., Prandini, A., Dekkers, S., & Bolton, D. J. (2009). Early identification systems for emerging foodborne hazards. Food and Chemical Toxicology, 47(5), 915e926. Matthäus, B., Freundenstein, A., Vosmann, K., Pudel, F., Rudolph, T., Franke, K., et al. (2012). Mitigation of 3-MCPD esters in refined vegetable oils. Sweet Baking, 1, 12e14. Moody, C. A., & Field, J. A. (1999). Determination of perfluorocarboxylates in groundwater impacted by fire-fighting activity. Environmental Science & Technology, 33(16), 2800e2806. Muytjens, H. L., Roelofs, W. H., & Jaspar, G. H. J. (1988). Quality of powdered substitutes for breast milk with regard to members of the family Enterobacteriaceae. Journal of Clinical Microbiology, 26, 743e746. Nagel, S. C., vom Saal, F. S., Thayer, K. A., Dhar, M. G., Boechler, M., & Welshons, W. V. (1997). Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environmental Health Perspectives, 105(1), 70e76. NTP. (2001). National Toxicology Program’s report of the endocrine disruptors low-dose peer review. Retrieved 12.11.13, from http://ntp.niehs.nih.gov/ntp/htdocs/liason/ LowDosePeerFinalRpt.pdf. Pangalos, G. (1929). Sur un bacille chromogene isole par hemoculture. Comptes Rendus Des Seances De La Societe De Biologie, 100, 1097. Prusiner, S. B. (1982). Novel proteinaceous infectious particles cause scrapie. Science, 216(4542), 136e144. Rappe, C., Bergek, S., Fiedler, H., & Cooper, K. R. (1998). PCDD and PCDF contamination in catfish feed from Arkansas, USA. Chemosphere, 36(13), 2705e2720. RASFF. (2004). Notification detail e 2004.555. Dioxins (910 ng/kg e ppt) in kaolinitic clay. Retrieved 15.01.13, from https://webgate.ec.europa.eu/rasff-window/ portal/index.cfm?event¼notificationDetail&NOTIF_REFERENCE¼2004.555.

86

F.J. van de Brug et al. / Food Control 39 (2014) 75e86

RASFF. (2005). Notification detail e 2005. DEO. Migration of isopropyl thioxanthone (26.9 mg/kg e ppb) from packaging of milk for babies from France. Retrieved 17.01.13, from https://webgate.ec.europa.eu/rasff-window/portal/index.cfm? event¼notificationDetail&NOTIF_REFERENCE¼2005.DEO. Rennen, M. A. J., Koster, S., Krul, C. A. M., & Houben, G. F. (2011). Application of the threshold of toxicological concern (TTC) concept to the safety assessment of chemically complex food matrices. Food and Chemical Toxicology, 49(4), 933e940. Rinaldi, F., Schneider, G., & Clematide, S. (2012). Relation mining experiments in the pharmacogenomics domain. Journal of Biomedical Informatics, 45(5), 851e861. http://dx.doi.org/10.1016/j.jbi.2012.04.014. vom Saal, F. S., Timms, B. G., Montano, M. M., Palanza, P., Thayer, K. A., Nagel, S. C., et al. (1997). Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proceedings of the National Academy of Sciences of the United States of America, 94(5), 2056e 2061. SCF. (1994). Opinion on 3-monochloro-propane, 1,2-diol (3-MCPD). Retrieved 08.01.13, from http://ec.europa.eu/food/fs/sc/scf/out91_en.pdf. SCF. (2002). Opinion of the Scientific Committee on Food on Bisphenol A. Retrieved 12.11.13, from http://ec.europa.eu/food/fs/sc/scf/out128_en.pdf. Skutlarek, D., Exner, M., & Färber, H. (2006a). Perfluorinated surfactants in surface and drinking waters. Environmental Science and Pollution Research, 13(5), 299e307. Skutlarek, D., Exner, M., & Färber, H. (2006b). Bestimmung von perfluorierten tensiden (PFC) in der aquatischen umwelt und trinkwasser mittels HPLC-MS/ MS. poster at the may 22 th-24 th, 2006. In 72th annual meeting of the waterchemical society (Division of the German Chemical Society) in Celle (D).

Stadler, R. H., Mottier, P., Guy, P., Gremaud, E., Varga, N., Lalljie, S., et al. (2004). Semicarbazide is a minor thermal decomposition product of azodicarbonamide used in the gaskets of certain food jars. The Analyst, 129(3), 276e281. Tareke, E., Rydberg, P., & Karlsson, P. (2000). Acrylamide: a cooking carcinogen? Chemical Research in Toxicology, 6(13), 517e522. The Guardian. (2005). Baby milk fears spread across europe. Retrieved 17.01.13, from http://www.guardian.co.uk/world/2005/nov/23/foodanddrink. Thomson, B., Poms, R., & Rose, M. (2012). Incidents and impacts of unwanted chemicals in food and feeds. Quality Assurance and Safety of Crops & Foods, 4(2), 77e92. http://dx.doi.org/10.1111/j.1757-837X.2012.00129.x. Törnqvist, M. (2001). Akrylamid e inte bara i hallandsåen utan även i stekta hamburgare [Acrylamide, not only in hallandsås but also in fried hamburgers]. Vår Föda, 2, 28e29. Velísek, J., Davídek, J., Hajslová, J., Kubelka, V., Janícek, G., & Mánková, B. (1978). Chlorohydrins in protein hydrolysates. Zeitschrift Für Lebensmittel-Untersuchung Und -Forschung, 167(4), 241e244. Waizenegger, J., Winkler, G., Kuballa, T., Ruge, W., Kersting, M., Alexy, U., et al. (2012). Analysis and risk assessment of furan in coffee products targeted to adolescents. Food Additives and Contaminants. Part A, Chemistry, Analysis, Control, Exposure & Risk Assessment, 29(1), 19e28. http://dx.doi.org/10.1080/ 19440049.2011.617012. WDR. (2012). Chronik der PFT-verseuchung: Wie der skandal langsam durchsickerte. Retrieved 15.01.13, from http://www1.wdr.de/themen/panorama/pftskandal100. html. Xiu, C., & Klein, K. K. (2010). Melamine in milk products in china: examining the factors that led to deliberate use of the contaminant. Food Policy, 35(5), 463e470.