Ramesh V. Bhat

Members Ahti Anttila, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Liisankatu 21 B, 00170 Helsinki, Finland Ramesh V. Bhat, National Institute of Nutrition, Indian Council of Medical Research, Jamai-Osmania PO, Hyderabad-500 007 AP, India James A. Bond, Chemico-Biological Interactions, Toxcon, 5505 Frenchmans Creek, Durham, NC 27713, USA Susan J. Borghoff, CIIT Centers for Health Research, 6 Davis Drive, Box 12137, Research Triangle Park, NC 27709-2127, USA F. Xavier Bosch, Epidemiology Unit and Cancer Registry, Catalan Institute of Oncology, Av. Gran via s/n, Km. 2.7, 08907 L’Hospitalet del Llobregat, Spain Gary P. Carlson, School of Health Sciences, 1338 Civil Engineering Building, Purdue University, West Lafayette, IN 47907-1338, USA Marcel Castegnaro, Les Collanges, 07240 Saint-Jean-Chambre, France George Cruzan, ToxWorks, 1153 Roadstown Road, Bridgeton, NJ 08302-6640, USA Wentzel C.A. Gelderblom, Programme on Mycotoxins and Experimental Carcinogenesis, Medical Research Council (MRC), PO Box 19070, Tygerberg, South Africa 7505 Ulla Hass, Institute of Food Safety and Toxicology, Morkhoj Bygade 19, 2860 Soborg, Denmark Sara H. Henry, 5100 Paint Branch Parkway, College Park, MD 20740-3835, USA Ronald A. Herbert, Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, PO Box 12233, Mail Drop B3-08, Research Triangle Park, NC 27709-2233, USA Marc Jackson, Integrated Laboratory Systems, Inc., PO Box 13501, Research Triangle Park, NC 27709, USA IARC WORKING GROUP ON THE EVALUATION OF CARCINOGENIC RISKS TO HUMANS: SOME TRADITIONAL HERBAL MEDICINES, SOME MYCOTOXINS, NAPHTHALENE AND STYRENE

Consecutive outbreaks of acute aflatoxicosis in Kenya in 2004 and 2005 caused > 150 deaths. In response, the Centers for Disease Control and Prevention and the World Health Organization convened a workgroup of international experts and health officials in Geneva, Switzerland, in July 2005. After discussions concerning what is known about aflatoxins, the workgroup identified gaps in current knowledge about acute and chronic human health effects of aflatoxins, surveillance and food monitoring, analytic methods, and the efficacy of intervention strategies. The workgroup also identified public health strategies that could be integrated with current agricultural approaches to resolve gaps in current knowledge and ultimately reduce morbidity and mortality associated with the consumption of aflatoxin-contaminated food in the developing world. Four issues that warrant immediate attention were identified: a) quantify the human health impacts and the burden of disease due to aflatoxin exposure; b) compile an inventory, evaluate the efficacy, and disseminate results of ongoing intervention strategies; c) develop and augment the disease surveillance, food monitoring, laboratory, and public health response capacity of affected regions; and d) develop a response protocol that can be used in the event of an outbreak of acute aflatoxicosis. This report expands on the workgroup's discussions concerning aflatoxin in developing countries and summarizes the findings.

BACKGROUND: Unseasonal rains beginning in 1995 damaged the maize and sorghum crops harvested in a few villages of the Deccan plateau in India. Human consumption of those grains resulted in a foodborne disease outbreak characterized by abdominal pain, borborygmi and diarrhea. METHODS: A rapid epidemiological survey was conducted in the affected villages and a detailed house to house survey in selected villages. RESULTS: People in 27 out of 50 villages surveyed were affected and disease was seen only in households and subjects consuming the rain damaged moldy sorghum or maize. The disease was self limiting. Diarrhea was reproduced in day old cockerels fed contaminated grains from affected households. All 20 sorghum and 12 maize samples collected from affected households had Fusarium sp. as the dominant mycoflora and contained fumonisin B1 in the range of 0.14-7.8 mg/kg and 0.25-64.7 mg/kg, respectively. In contrast, samples collected from unaffected households had fumonisin B1 in low levels ranging from 0.07-0.36 mg/kg and 0.05-0.24 mg/kg, respectively. CONCLUSION: The higher water activity in the grains left in the field following harvest led to the production of high levels of fumonisin B1 and consumption of such grains by humans resulted in the disease.

An estimated 500 million of the poorest people in sub-Saharan Africa, Latin America, and Asia are exposed to mycotoxins at levels that substantially increase mortality and morbidity (Pitt et al., 2012). The problem is not newly recognized. Shortly after the discovery of aflatoxins, the impact on child health was brought into immediate focus. After the reporting of several deaths in children in Africa due to consumption of aflatoxin- contaminated meal, a decision was made in 1966 by the FAO/WHO/ UNICEF Protein Advisory Group to set a limit of 30 ppb aflatoxin in protein supplements made from groundnuts (Anonymous, 1966). In contrast to the situation today, in 1966 throughout most of Africa the proportion of calories from maize was modest, with a greater proportion coming from sorghum, millet, and cassava. Executive summary The International Agency for Research on Cancer (IARC) of the World Health Organization convened a Working Group Meeting in Lyon from 30 June to 3 July 2014. This IARC Working Group Report provides a systematic, independent review of the scientific evidence base on the adverse health effects from aflatoxin and fumonisin exposure through consumption of contaminated maize and groundnuts. An evaluation is provided of interventions, available on an individual and a community level, to reduce human exposure and disease. Therefore, this Report provides an authoritative basis for action at an international level, enabling decision-makers to invest with confidence in effective strategies to save lives. It also provides guidance on additional critical studies needed to yield further evidence of the merit of specific intervention approaches. The Working Group addressed current scientific knowledge in four key areas: the extent of exposures to aflatoxin and fumonisin; the effects on prenatal, infant, and child health; relevant mechanistic information; and effective intervention strategies in low-income settings. In the past, the focus has largely been on the impact of aflatoxin on cancer risk. Considering several recent studies, mainly in Africa, this Report also considers the potentially far greater burden of growth faltering after weaning (child stunting). Stunting in children results from chronic undernutrition, leading to adverse effects on survival, health, and development, entailing a large Executive summary. Mycotoxin control in low- and middle-income countries ix global population burden; in 2012, an estimated 162 million children younger than 5 years worldwide were stunted. Poor-quality diets and high rates of infection, both in pregnancy and in the first years of life, result in poor child growth, but the relative contributions to stunting are unknown. At the same time, provision of all of the established nutrition-specific interventions in the most affected regions would reduce the prevalence of stunting by only about 20% (Bhutta et al., 2013), illustrating the large knowledge gap in how to prevent stunting, including the potential impact of exposure to mycotoxins. This Report concludes that surveillance data on exposure to aflatoxins are generally lacking outside the developed countries. However, available data from measurements of contaminated crops and through the use of exposure biomarkers in exposed populations demonstrate that mycotoxin exposures can be high throughout Africa, as well as in Latin America and parts of Asia. More recently, among maize-consuming populations in these regions, the high concurrent exposure to aflatoxins and fumonisins has been documented. Notwithstanding the challenges, future mycotoxin monitoring programmes should be prioritized. Assessment of possible implementation within existing surveillance systems should be considered. In the short term, data from individual studies of sufficient quality should be added to the Global Environment Monitoring System (GEMS)/Food Contamination Database. Finally, a rapid screening approach aimed at the field/subsistence-farming level that is inexpensive and user-friendly and has a wide dynamic range should be developed. This could support a rapid alert system that informs responses and appropriate actions for food safety. Aflatoxins are a cause of human liver cancer and, in high doses, have caused deaths from aflatoxicosis. More recently, significant negative effects of aflatoxin on child growth have been reported, as well as immune modulation. These observations are consistent with impaired fetal development and immune system and gut function in animal models. Taken together, the few well-documented population-based studies and the mechanistic data in relevant animal models suggest that mycotoxin exposure contributes to stunting, independent of and with other risk factors. Further longitudinal studies of mycotoxin exposure and child stunting, including studies of the underlying mechanisms, merit investment. The Working Group assessed the question of effective interventions in low-income countries using studies where there was reliable direct or indirect evidence of improvement of health, including reduced mycotoxin biomarker levels. Using widely accepted criteria for evaluating evidence about public health interventions, some 15 interventions were placed into one of four categories: (1) sufficient evidence for implementation, (2) needs more field evaluation, (3) needs formative research, and (4) no evidence or ineffective. Recommendations on how to approach the necessary further investigation and potential scale-up were also considered. Four of the interventions were judged to be ready for implementation. The intervention for which the strongest evidence of improvement of health exists, but which is also the most difficult to achieve, was to increase dietary diversity. Other strategies deemed ready for implementation were sorting of the crop; a package of post-harvest measures, including improved storage; and, in Latin America for maize, optimized nixtamalization. Several interventions were considered that might be used in emergency situations of extremely high contamination (e.g. chemoprotectants, agents that can be put into the diet to ameliorate the effects of aflatoxin once ingested). As currently envisaged, the recommendations would be relevant for investment of public, nongovernmental organization, and private funds at the scale of the subsistence farmer, the smallholder, and through to a more advanced value chain.

BACKGROUND: Oral submucous fibrosis associated with chewing of betel nut products has an estimated prevalence of 0.2-1.2% in India. The increasing use of pan masala/gutkha, a mix of tobacco and a less moist form of betelquid lacking the betel leaf, seems associated with an earlier age of onset of oral submucous fibrosis. METHOD: A prospective study examined the in vivo effects of pan masala/gutkha and betelquid chewing on buccal mucosal cytology in 50 patients with oral submucous fibrosis and 40 controls. RESULTS: The percentage of nucleolated intermediate cells or proliferative fraction of buccal mucosa cells was significantly higher in all habitual chewers than controls. Pan masala/gutkha chewers presented with oral submucous fibrosis after 2.7 +/- 0.6 y of use whereas the betelquid users presented with oral submucous fibrosis reported 8.6 +/- 2.3 y of use (p < 0.05). CONCLUSIONS: Habitual chewing of pan masala/gutkha is associated with earlier presentation of oral submucous fibrosis than betelquid use. Factors which may be responsible for these differences are the tobacco content, the absence of the betel leaf and its carotenes and the much higher dry weight of pan masala/gutkha.