Angelika Tritscher

The Melamine Incident: Implications for International Food and Feed Safety

Background A major food safety incident in China was made public in September 2008. Kidney and urinary tract effects, including kidney stones, affected about 300,000 Chinese infants and young children, with six reported deaths. Melamine had been deliberately added at milk-collecting stations to diluted raw milk ostensibly to boost its protein content. Subsequently, melamine has been detected in many milk and milk-containing products, as well as other food and feed products, which were also exported to many countries worldwide. Objectives The melamine event represents one of the largest deliberate food contamination incidents. We provide a description and analysis of this event to determine the global implications on food and feed safety. Discussions A series of factors, including the intentional character of the milk contamination, the young age of the population affected, the large number of potentially contaminated products, the global distribution of these products, and the delay in reporting led this event to take on unexpected proportions. This incident illustrated the complexity of international trade of food products and food ingredients that required immediate actions at international level. Conclusion Managing food-safety events should be done internationally and early on as soon as multinational consequences are expected. Collaboration between food-safety authorities worldwide is needed to efficiently exchange information and to enable tracking and recalling of affected products to ensure food safety and to protect public health.

Polybrominated Dibenzo-p-Dioxins, Dibenzofurans, and Biphenyls: Inclusion in the Toxicity Equivalency Factor Concept for Dioxin-Like Compounds

In 2011, a joint World Health Organization (WHO) and United Nations Environment Programme (UNEP) expert consultation took place, during which the possible inclusion of brominated analogues of the dioxin-like compounds in the WHO Toxicity Equivalency Factor (TEF) scheme was evaluated. The expert panel concluded that polybrominated dibenzo-p-dioxins (PBDDs), dibenzofurans (PBDFs), and some dioxin-like biphenyls (dl-PBBs) may contribute significantly in daily human background exposure to the total dioxin toxic equivalencies (TEQs). These compounds are also commonly found in the aquatic environment. Available data for fish toxicity were evaluated for possible inclusion in the WHO-UNEP TEF scheme (van den Berg et al., 1998). Because of the limited database, it was decided not to derive specific WHO-UNEP TEFs for fish, but for ecotoxicological risk assessment, the use of specific relative effect potencies (REPs) from fish embryo assays is recommended. Based on the limited mammalian REP database for these brominated compounds, it was concluded that sufficient differentiation from the present TEF values of the chlorinated analogues (van den Berg et al., 2006) was not possible. However, the REPs for PBDDs, PBDFs, and non-ortho dl-PBBs in mammals closely follow those of the chlorinated analogues, at least within one order of magnitude. Therefore, the use of similar interim TEF values for brominated and chlorinated congeners for human risk assessment is recommended, pending more detailed information in the future.

Tumor necrosis factor involvement in 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated endotoxin hypersensitivity in C57BL/6J mice congenic at the Ah locus

An experimental model of endotoxin-induced release of tumor necrosis factor-alpha (TNF) into the serum of C57BL/6J mice congenic at the Ah locus was used to investigate the effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on TNF production. TCDD exposure of Ah-responsive mice (Ahbb) resulted in a dose-dependent increase in the concentration of TNF in the serum of endotoxin-exposed mice, with a significant increase observed at a dose of 10 micrograms/kg TCDD. At a dose of 500 micrograms/kg TCDD, Ahbb mice demonstrated a 46-fold increase in serum TNF levels compared to control. In contrast, congenic Ah-receptor deficient mice (Ahdd) did not show a significant increase in serum TNF levels until exposed to 150 micrograms/kg TCDD, and the maximum response was an 8-fold increase over control. These data suggest that increased TNF production may be responsible for endotoxin hypersensitivity in TCDD-treated mice and that the Ah locus mediates this response.

Increased oxidative DNA damage in livers of 2,3,7,8-tetrachlorodibenzo-p-dioxin treated intact but not ovariectomized rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a more potent hepatocarcinogen in female than in male or ovariectomized rats. A possible mechanism for this increased sensitivity is through enhanced metabolic activation of estrogens by TCDD-induced enzymes leading to oxidative damage in the cell. As a marker for oxidative DNA damage, 8-oxo-deoxyguanosine (8-oxo-dG) was quantitated in livers of intact and ovariectomized Sprague-Dawley rats chronically treated with TCDD (125 ng/kg per day) with and without diethylnitrosamine as initiator. Elevated levels of 8-oxo-dG were detected in a significantly greater number of the intact compared to ovariectomized TCDD-treated rats. Expression of CYP1B1 mRNA, a newly identified cytochrome P450 with proposed estrogen hydroxylase activity, was highly induced by TCDD. The results are consistent with the hypothesis that increased metabolism of endogenous estrogens to catechols by TCDD-induced enzymes may lead to increased oxidative DNA damage and hence contribute to TCDD-mediated hepatocarcinogenicity in female rats.

A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens

Quantitative methods for estimation of cancer risk have been developed for daily, lifetime human exposures. There are a variety of studies or methodologies available to address less-than-lifetime exposures. However, a common framework for evaluating risk from less-than-lifetime exposures (including short-term and/or intermittent exposures) does not exist, which could result in inconsistencies in risk assessment practice. To address this risk assessment need, a committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute conducted a multisector workshop in late 2009 to discuss available literature, different methodologies, and a proposed framework. The proposed framework provides a decision tree and guidance for cancer risk assessments for less-than-lifetime exposures based on current knowledge of mode of action and dose-response. Available data from rodent studies and epidemiological studies involving less-than-lifetime exposures are considered, in addition to statistical approaches described in the literature for evaluating the impact of changing the dose rate and exposure duration for exposure to carcinogens. The decision tree also provides for scenarios in which an assumption of potential carcinogenicity is appropriate (e.g., based on structural alerts or genotoxicity data), but bioassay or other data are lacking from which a chemical-specific cancer potency can be determined. This paper presents an overview of the rationale for the workshop, reviews historical background, describes the proposed framework for assessing less-than-lifetime exposures to potential human carcinogens, and suggests next steps.

WHO/UNEP global surveys of PCDDs, PCDFs, PCBs and DDTs in human milk and benefit–risk evaluation of breastfeeding

Since 1987, the World Health Organization (WHO) carried out global surveys on polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) in human milk. This study presents a review of the three most recent surveys from 2000 to 2010, including DDT. The objective was to identify global quantitative differences and provide baseline information for 52 countries or provide time-trends for countries with previous data. Individual human milk samples were collected following a WHO-designed procedure and combined to form a national pooled sample. Here, we report global levels for PCDDs, PCDFs, PCBs and the sum of o,p′-DDT, p,p′-DDT, o,p′-DDE, p,p′-DDE, o,p′-DDD and p,p′-DDD (ΣDDTs). A concise risk–benefit evaluation related to human milk contamination with these persistent organic pollutants (POPs) was also done. Large global and regional differences were observed. Levels of PCDDs and PCDFs were highest in India and some European and African countries. PCB levels were highest in East and West Europe. The highest levels of ΣDDTs were found in less industrialized countries. A temporal downward trend for PCDDs, PCDFs and PCBs is indicated. A risk–benefit assessment indicates that human milk levels of PCDDs, PCDFs and PCBs are still significantly above those considered toxicologically safe, while ΣDDTs are below or around those considered safe. With respect to potential adverse health effects, a more dominant role of in utero exposure versus lactational exposure is indicated. If potential adverse effects are balanced against positive health aspects for (breastfed) infants, the advantages of breastfeeding far outweigh the possible disadvantages. Our observations provide a strong argument to plea for further global source-directed measures to reduce human exposure further to dioxin-like compounds.

Induction of Lung Lesions in Female Rats Following Chronic Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

2,3,7,8,-Tetrachlorodibenzo- p-dioxin (TCDD) has been classified as a known human carcinogen, and epidemiologic studies identify the lung as one of the target organs. Few experimental studies have attempted to characterize pulmonary effects of TCDD exposure. In this study, we characterize the induction of lesions in the lung by chronic oral TCDD exposure in diethylnitrosamine (DEN)-initiated or noninitiated female Sprague-Dawley rats. Two or 18 weeks after initiation, rats were treated with TCDD continuously for 14, 30, or 60 weeks by biweekly oral gavage (1,750 ng TCDD/kg) at a dose equivalent to 125 ng/kg body weight per day (controls received corn oil). To assess the time dependence and reversibility of potential changes, some groups included withdrawal periods of 16 or 30 weeks after 30 weeks of TCDD treatment. TCDD treatment alone for 60 weeks caused significant increases in alveolar-bronchiolar (AB) metaplasia. TCDD treatment of DEN-initiated animals for 60 weeks resulted in a significant increase in bronchiolar epithelial hyperplasia. These increases were not observed in animals treated with TCDD for 30 weeks followed by corn oil for 30 weeks, indicating that the development of these lesions required continuous exposure to TCDD. AB hyperplasia increased in an age-dependent manner after DEN initiation but was unaffected by TCDD treatment. Expression of the aromatic hydrocarbon receptor (AHR) and induction of CYP1A1 was observed only in bronchiolar Clara and ciliated cells, indicating that the mechanism of induction of AB metaplasia may be mediated by the AHR. TCDD elimination half-life was monophasic in the lung, and serum and was estimated to be 39.7 days and 44.6 days, respectively, independent of age, tissue TCDD concentration, or body weight. This is the first report to identify the AB region as a target for TCDD-induced metaplastic and proliferative changes after chronic oral exposure.

Carcinogenicity of TCDD in laboratory animals: implications for risk assessment.

Today, there is more scientific information relevant to the use of animal cancer data for the estimation of human risks than ever before. However, much of the data concerning tumor incidence in experimental animals that was available in 1988 demonstrated that TCDD is a carcinogen at multiple sites in both sexes of rats and mice. Some of the cancers occurred following particularly low doses. Since 1988, TCDD has been shown to be a carcinogen in hamsters, and some of the tumor incidence data in rat liver has been reevaluated during the last three years.

Accumulation of polychlorinated dibenzo-p-dioxins and dibenzofurans in liver of control laboratory rats

Polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and biphenyls belong to a class of compounds, the polyhalogenated aromatic hydrocarbons (PHAHs), which are ubiquitous environmental contaminants. Due to the existence of a common mechanism of action, i.e., binding to the Ah receptor, the activity of members of this class of compounds is generally expressed relative to the prototypical 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as toxic equivalency factors (TEFs). In the present studies we examined the presence of liver of untreated PCDFs in standard laboratory feed and in the liver of untreated rats at three different ages (60, 140, and 200 days) in terms of concentration and in toxic equivalents (TEQs, TEF x concentration). Feed was shown to contain trace amounts of PCDDs and PCDFs and control rat liver was shown to contain several PCDD and PCDF congeners in terms of concentration of congener and concentration of TEQs contributed by that congener. The total concentration of TEQs increased with increasing age in rat liver, going from 20 ppt TEQ at 60 days to 78 ppt TEQ at 200 days of age. This accumulation in dioxin-like activity was due primarily to PCDFs. In particular the congener 2,3,4,7,8-pentachlorodibenzofuran accrued in untreated rat liver accounting for approximately 80% of the total TEQ at 200 days of age. These studies affirm the pervasive presence of PHAHs and suggest prudence in evaluating chronic rat studies in which interference from background levels of PCDDs and PCDFs may be a factor.

Ensuring food safety and nutrition security to protect consumer health: 50 years of the Codex Alimentarius Commission

The globalization of trade, which has contributed to food availability and diversification throughout the world, has also increased the chances that the food produced in one place will affect the health and diet of people living in another. As a result, global food safety and nutrition measures applicable across borders, institutions and disciplines, including the establishment of evidence-based international standards on food safety and nutrition, are more important than ever before. Since its inception in 1963, the Codex Alimentarius Commission has developed hundreds of such standards and provided guidance for improving food safety and nutrition in each of its member states and globally. The Commission, whose 186 members represent 99% of the world’s population, is the principal body of the Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Food Standards Programme.1 In addition to international food safety and nutrition standards, it develops guidelines and codes of practice, also intended to protect consumers’ health as well as to ensure fair practices in the food trade. Its standards and related texts cover an impressively wide range of subjects of international relevance having to do with biotechnology, pesticides, pathogens, additives and contaminants, food labelling, reference values for nutrients (particularly those related to the risk of noncommunicable diseases) and many other areas. In 1995, the World Trade Organization Agreement on the Application of Sanitary and Phytosanitary Measures called on members of the World Trade Organization to harmonize their national regulations to Codex standards,2 which have since become international benchmarks for food safety. Over the decades the Commission has benefited from the scientific and technical advice provided by WHO. In collaboration with FAO, WHO has convened international meetings of experts to address emerging or emergency issues and provide independent risk assessments, and the recommendations from these meetings feed directly into the Commission’s standard-setting process. Four expert groups meet regularly: the Joint FAO/WHO Expert Committee on Food Additives has carried out risk assessments related to food additives, contaminants, natural toxins and veterinary drug residues in food since 1956; the Joint FAO/WHO Meeting on Pesticide Residues has assessed since 1963 the potential health effects of pesticide residues and recommends safe maximum residue levels for specific food commodities; the Joint FAO/WHO Expert Meeting on Microbiological Risk Assessment has focused since 2000 on risk assessments for selected pathogen–commodity combinations, and the recently-established Joint FAO/WHO Expert Meetings on Nutrition provide scientific advice on nutritional matters. Although Codex standards are sometimes viewed as “trade standards”, their primary purpose is to protect consumers’ health by ensuring the safety and nutritional quality of food products traded worldwide. The importance of this work is evidenced by the large burden of food- and diet-related disorders and illness. Foodborne and waterborne diarrhoeal diseases kill an estimated 2.2 million people annually, most of them children3 and food containing harmful levels of chemicals can cause serious health problems, including cancer. Excessive intake of calories can lead to obesity and to conditions such as diabetes mellitus, coronary heart disease, cancer, hypertension and stroke.4,5 On the other hand, lack of sufficient food and vitamin and mineral deficiencies also cause enormous numbers of deaths and disability. Stunting, a mark of chronic undernutrition, affects 165 million children younger than 5 years and an estimated 35% of all deaths among children in this age group are associated with undernutrition.6 Foodborne diseases and malnutrition undermine not only human health and productivity, but also countries’ potential for sustainable development. As the Commission celebrates 50 years of successful work, it may be a good time to reflect on its trajectory and how it can serve the public interest even better. Over the years the Commission has become more inclusive. Thanks to the work of the FAO/WHO Project and Trust Fund for Enhanced Participation in Codex, launched in 2003, more countries in development and with economies in transition are actively participating in the Commission. The openness, transparency and precision of its reporting and prioritization procedures have been improved. Nonetheless, today’s rapid changes in trade, travel and commerce call for an international standard-setting system that is able to respond more quickly to new situations. One way to achieve this might be through better use of modern information technology. Stronger support of national Codex contact points is needed as well, but equally necessary are heightened political will and an acknowledgement of the importance of food safety and nutrition in public health. Because trade, nutrition and food safety are so closely connected, closer collaboration between different sectors and strengthened interactions between the Codex and other global players will be essential.