Contribution of toxicology towards risk assessment of carcinogens

In the last decade many tests have been designed to detect possible carcinogenicity of compounds. Presently, many more or less simple and convenient systems are available to detect mutations, effects on chromosomes, DNA binding and damage and malignant transformation. These systems, which have been extensively refined during the last years, often show reasonably good relevance to carcinogenicity. Although inconsistencies in the patterns of response do indicate that their role as predictive indicators of carcinogenicity remains still uncertain, the use of such short-term tests in carcinogen risk assessment does seem feasible.Factors other than these tests should also be taken into consideration, since other characteristics like chemical structure, biotransformation, toxicokinetics, qualitative and quantitative physiological and/or morphological effects, species, strains, organ specificity, dose-response relation and information on studies in man, if available, are of importance too.In conjunction with the results of adequately performed carcinogenicity tests in mammals, one may attempt to classify carcinogens. Current knowledge does not permit a rigid classification, but may warrant a subclassification into carcinogens acting via a genetic or a non-genetic mechanism. It is emphasized that on theoretical and practical grounds a different extrapolation system should be used for the different types of carcinogens in risk assessment procedures. Evaluations on individual compounds should be made to decide whether such genotoxic or non-genotoxic compounds should be permitted in the human environment.Dedicated to Professor Dr. med. Herbert Remmer on the occasion of his 65th birthday     

Risk assessment of dietary exposures to compounds that are genotoxic and carcinogenic--an overview

The process of risk assessment of dietary exposures to genotoxic carcinogens is summarised. Exposures to six genotoxic carcinogens in food (acrylamide, aflatoxin B(1), benzo(a)pyrene, dimethylnitrosamine, ethyl carbamate, PhIP) have been used to illustrate the process. The margin of exposure (MOE) approach is seen as a useful method to be used in the risk characterisation step of assessing exposures to genotoxic carcinogens. This approach combines information on animal potency and human exposure, and can be used to indicate levels of concern and also the ranking between various exposures to such agents. Both the T25 and the BMDL10 methods may be used as a reference point. Should a specific MOE value be developed as a cut-off between levels of concern and levels of low concern, the value using T25 data is proposed to be 2.5-times higher than using BMDL10 data. Linear low-dose extrapolation using either T25 or BMDL10, may also be applied. However, it should be understood that this approach should not be interpreted as giving a precise estimate of human risk. For exposures to mutagens in food lacking carcinogenicity data, it is proposed to apply the MOE approach to the lowest effective dose (LED) for in vivo genotoxicity.     

Risk assessment of chemical carcinogens and thresholds

The controversial arguments about the existence of “thresholds” for carcinogens are discussed and some conclusions are drawn: (1) The meaning of “threshold” has changed considerably during the last decades. Initially, the discussion focused on the genotoxic properties of chemicals. In dose-response studies the endpoint was tumor incidence. Later, DNA adducts represented the biologically active target dose and whether saturation of metabolic activation could lead to non-linear relationships was tested as a hypothesis. (2) In a next step, the implications of the initiation–promotion model were studied. Carcinogens with tumor-initiating properties showed linear dose-response relationships at low doses without a definable threshold, whereas those with tumor-promoting properties showed non-linear characteristics compatible with the existence of a threshold. However, the results are difficult to transfer to the human situation, and many critical endpoints are subject to other risk factors so that a meaningful value cannot be given. (3) Eventually, it turned out that most carcinogens exhibit genotoxic as well as non-genotoxic properties, and toxicity may be equally important as genotoxicity. (4) In view of the discussion for more than 60 years about the existence of thresholds for carcinogens, it is suggested that the threshold approach not be used to establish acceptable risk limits. (5) Instead of calculating an acceptable risk from cancer risk data, the recommended method is to assess the incremental contribution of exposure to the background of avoidable and unavoidable exposures by using biomonitoring data from human individuals. Such data could help in risk management, in order to reach acceptable limits of exposures on the basis of the “as low as reasonably achievable” or “ALARA” principle.     

Experience of a premarketing alert

A very effective and well-tolerated beta-blocking agent was withdrawn from preregistration clinical development because a pattern of endocrine-related tumours was observed in high-dose, long-term studies in rodents. The use of doses of up to 90 times the maximum dose in man was the result of regulatory agency insistence at that time that the maximum dose tolerated by the rodents must be used. In addition, the relevance of the differences between genotoxic and non-genotoxic carcinogenicity to man was not fully understood or accepted. More appropriate criteria are now used to select dose levels in long-term rodent studies, and the relevance of the differences in carcinogenicity is accepted.     

Approaches to the safety assessment of engineered nanomaterials (ENM) in food

A systematic, tiered approach to assess the safety of engineered nanomaterials (ENMs) in foods is presented. The ENM is first compared to its non-nano form counterpart to determine if ENM-specific assessment is required. Of highest concern from a toxicological perspective are ENMs which have potential for systemic translocation, are insoluble or only partially soluble over time or are particulate and bio-persistent. Where ENM-specific assessment is triggered, Tier 1 screening considers the potential for translocation across biological barriers, cytotoxicity, generation of reactive oxygen species, inflammatory response, genotoxicity and general toxicity. In silico and in vitro studies, together with a sub-acute repeat-dose rodent study, could be considered for this phase. Tier 2 hazard characterisation is based on a sentinel 90-day rodent study with an extended range of endpoints, additional parameters being investigated case-by-case. Physicochemical characterisation should be performed in a range of food and biological matrices. A default assumption of 100% bioavailability of the ENM provides a ‘worst case’ exposure scenario, which could be refined as additional data become available. The safety testing strategy is considered applicable to variations in ENM size within the nanoscale and to new generations of ENM.     

Threshold and non-threshold chemical carcinogens: A survey of the present regulatory landscape

For the proper regulation of a carcinogenic material it is necessary to fully understand its mode of action, and in particular whether it demonstrates a threshold of effect. This paper explores our present understanding of carcinogenicity and the mechanisms underlying the carcinogenic response. The concepts of genotoxic and non-genotoxic and threshold and non-threshold carcinogens are fully described. We provide summary tables of the types of cancer considered to be associated with exposure to a number of carcinogens and the available evidence relating to whether carcinogenicity occurs through a threshold or non-threshold mechanism. In light of these observations we consider how different regulatory bodies approach the question of chemical carcinogenesis, looking in particular at the definitions and methodologies used to derive Occupational Exposure Levels (OELs) for carcinogens. We conclude that unless proper differentiation is made between threshold and non-threshold carcinogens, inappropriate risk management measures may be put in place - and lead also to difficulties in translating carcinogenicity research findings into appropriate health policies. We recommend that clear differentiation between threshold and non-threshold carcinogens should be made by all expert groups and regulatory bodies dealing with carcinogen classification and risk assessment.     

Risk assessment of botanicals and botanical preparations intended for use in food and food supplements: emerging issues

At present there is a growing interest for use of botanicals and botanical ingredients in medicines, for teas or in foods and in food supplements. In addition, a number of plant-derived food items form an integral part of regular human diets. Currently, there is an increasing awareness among safety experts and regulators of risks associated with the use of botanicals and botanical ingredients in food including food supplements. It is becoming clear that "natural" does not equal "safe" and that, in modern society, adverse health effects can occur as a result of (mis)use. With the growing awareness of these issues efforts to ensure safety of botanicals and botanical ingredients are also increasing. Several guidance documents on safety assessment of botanicals and botanical preparations to be used as ingredients in food and food supplements have been published, although, at present, relevant legislative frameworks and guidances for risk assessment are not established yet. Furthermore, when defining possible guidance documents for risk assessment of botanicals, several issues emerge that need to be developed beyond the present state-of-the-art. The present paper describes some of the issues to be considered and developed to a further extent to improve risk assessment of botanicals and botanical preparations, illustrated by examples based on some allylalkoxybenzenes. It is concluded that, for an improved and more accurate future risk assessment of botanicals, it is necessary to further develop and validate: (i) the use of the margin of exposure (MOE) concept for compounds that are both genotoxic and carcinogenic; (ii) new ways to quantify and incorporate matrix effects into risk assessment strategies; (iii) the use of analytical chemistry approaches, enabling complete chemical characterisation of complex mixtures. Defining new approaches in risk assessment would be in line with the inspiring attitude of the late Professor Robert Kroes, who, for example by supporting the threshold of toxicological concern (TTC) concept, was a pioneer for development and implementation of new paradigms in the field of risk assessment and food safety.     

Development and evolution of risk assessment for food allergens

The need to assess the risk from food allergens derives directly from the need to manage effectively this food safety hazard. Work spanning the last two decades dispelled the initial thinking that food allergens were so unique that the risk they posed was not amenable to established risk assessment approaches and methodologies. Food allergens possess some unique characteristics, which make a simple safety assessment approach based on the establishment of absolute population thresholds inadequate. Dose distribution modelling of MEDs permitted the quantification of the risk of reaction at the population level and has been readily integrated with consumption and contamination data through probabilistic risk assessment approaches to generate quantitative risk predictions. This paper discusses the strengths and limitations of this approach and identifies important data gaps, which affect the outcomes of these predictions. These include consumption patterns among allergic individuals, analytical techniques and their application, severity-dose relationships, and the impact of extraneous factors which alter an individual’s physiology, such as infection or exercise. Nevertheless, application of these models has provided valuable insights, leading to further refinements and generating testable hypotheses. Their application to estimate the risk posed by the concurrent consumption of two potentially contaminated foods illustrates their power.     

Risk assessment in clinical pharmacy

Medication error forms a major proportion of the errors in the medical system. Despite many studies of adverse drug events, there are no systematic ways of ensuring safety, or of assessing how safe a pharmaceutical system is. Risk assessment is required in hazardous industries such as nuclear power or oil and gas. Risk assessments involve identifying the defences and assessing their effectiveness and are relatively uncommon in clinical pharmacy , as opposed to reactive approaches involving incident analyses. Risk factors, that degrade barriers, can be identified and their effect measured. A risk assessment structure for pharmacy processes is proposed that can also be used to support incident investigation and analysis processes and provide a standard for audit.     

Application of bacterial reverse mutation assay for detection of non-genotoxic carcinogens

Non-genotoxic carcinogens may play a significant role in development of cancer. Currently short-term assays for mutagenicity classify genotoxic carcinogens and lack the abilities to detect epigenetic carcinogens. The need to develop an endpoint always remains to recognize potentially carcinogenic agents employing rapid and practical bioassays. For this, the present study utilized TA98 and TA1537 tester strains of Salmonella typhimurium to evaluate four non-genotoxic carcinogenic agents (Coumarin, β-Myrcene, Bis(2-ethylhexyl) phthalate and trans-anethole). These chemicals were tested individually and in combination with promutagens 2-aminoanthracene (2AA) and benzo(a)pyrene (BP) in presence of metabolic activation system (S9) by plate incorporation method. Exposure to all four test chemicals revealed marked increase of revertant colonies in promutagen combined groups as compared to promutagens alone. However significantly greater fold responses were observed with 2AA combination groups (Coumarin +2AA, β-Myrcene +2AA, Bis(2-ethylhexyl) phthalate +2AA and trans-anethole +2AA) with TA98 strain as compared with TA1537, which seems to have enhanced the mutagenic response of 2AA in metabolically activated conditions. It is concluded that out of both tester strains TA98 strain of Salmonella typhimurium has the potential to detect non-genotoxic carcinogens when combined with potent promutgens either by inhibiting or modulating activities of liver microsomal enzymes biochemically which may indirectly contribute to neoplastic alterations. Further this simple, short-term alternative assay may provide rapid information during extrapolative toxicology for differentiating genotoxic and non-genotoxic carcinogens.     

The impact of food regulation on the food supply chain

Food regulation in the main is aimed at protecting the consumer's health, increasing economic viability, harmonizing well-being and engendering fair trade on foods within and between nations. Consumers nowadays are faced with food or food ingredients that may derive from distant countries or continents, and with a less transparent food supply. Safety concerns must cover the range of different food chains relevant to a certain food product or product group, including all relevant producers, manufacturing sites and food service establishments within a country as well as those importing into the country. Hazard analysis at critical control points (HACCP), good manufacturing practice (GMP) and good hygiene practice (GHP) are major components of the safety management systems in the food supply chain. Principally, "a hazard" is a biological, chemical or physical agent in, or condition of, food that has the potential to cause an adverse health effect. The likelihood of occurrence and severity of the same is important for the assessment of the risk presented by the hazard to the food supply chain. The Government's regulatory mechanisms in accordance with the WTO agreements (HACCPs, sanitary and phytosanitary measures, etc.) oversee the analyses of public health problems and their association to the food supply. Under the WTO SPS Agreements and the codes of practices issued by the Codex Alimentarius Commission, there now exists a benchmark for international harmonization that guarantee the trade of safe food. Inevitably, food safety is still mainly the responsibility of the consumer.     

Risk assessment of micronutrients

Risk assessment of micronutrients has to take into account two different intake-response relationships; the risk of deficiency, which decreases with increase in intake, and the risk of toxicity, which increases with increase in intake. The available databases on micronutrients tend to focus on benefits at low intakes, and there are usually few reliable data on hazard identification and characterisation at high intakes. Application of the usual default uncertainty factors for species differences, human variability and database inadequacy could result in "recommended" upper intake levels that would cause deficiency. There have been a number of comprehensive reviews that have used low, and largely arbitrary, uncertainty factors to establish tolerable upper intake levels for vitamins and minerals. A recent FAO/WHO Workshop developed a structured approach to the application of a single composite uncertainty factor. Risk-benefit approaches have been developed recently that balance the risk of toxicity against the risk of deficiency, and offer the potential for more scientifically based methods.     

FDA'S food ingredient approval process: Safety assurance based on scientific assessment

Fifty years ago, the Food and Drug Administration (FDA) began implementing new provisions of the Federal Food, Drug, and Cosmetic Act aimed at assuring the safety of new food additives before they enter the marketplace. Today, the agency's procedures for premarket evaluation of food additive safety have evolved into a scientifically rigorous, sound and dependable system whose objective and independent evaluations by FDA scientists assure that new food additives are safe for their intended uses before they arrive on the consumer's plate. Although controversy often surrounds food additives in the popular media and culture, and science-based challenges to FDA's decisions do arise, the agency's original safety judgments successfully withstand these challenges time and again. This article reviews the basic components of the FDA's decision-making process for evaluating the safety of new food additives, and identifies characteristics of this process that are central to assuring that FDA's decisions are marked by scientific rigor and high integrity, and can continue to be relied on by consumers.     

食品安全与风险评估选修课的教学探索

食品安全是全球关注的一个日益重要的公共卫生问题,风险评估是世界卫生组织所倡导的一种保证食品安全的措施.文章从教学目的、教学内容、教学方法与手段、考核形式等方面介绍了《食品安全与风险评估》选修课的实践和探索.     

The Threshold of Toxicological Concern (TTC) in risk assessment

The Threshold of Toxicological Concern (TTC) is a level of human intake or exposure that is considered to be of negligible risk, despite the absence of chemical-specific toxicity data. The TTC approach is a form of risk characterisation in which uncertainties arising from the use of data on other compounds are balanced against the low level of exposure. The approach was initially developed by the FDA for packaging migrants, and used a single threshold value of 1.5mug/day (called the threshold of regulation). Subsequent analyses of chronic toxicity data resulted in the development of TTC values for three structural classes with different potentials for toxicity (1,800, 540 and 90mug/day). These TTC values have been incorporated into the procedure that is used internationally for the evaluation of flavouring substances. Further developments included additional TTC values for certain structural alerts for genotoxicity (0.15mug/day), and for the presence of an organophosphate group (18mug/day). All of these TTC values were incorporated into an extended decision tree for chemicals, such as contaminants, which might be present in human foods. The TTC approach has been shown to have potential applications to risk assessments of cosmetic ingredients, household products and impurities in therapeutic drugs.     

Risk assessment of chlorpyrifos on rice and cabbage in China

Chlorpyrifos is a widely used organophosphorus insecticide in agricultural pest control. To understand the residue behavior of chlorpyrifos and to evaluate the dietary risk of chlorpyrifos residue in food in China, a number of residue studies were conducted on rice and cabbage. The supervised trial median residues (STMRs) for rice and cabbage were less than 0.010 and 0.227 mg kg⁻¹, respectively. Only 7.4% and 13.3% of acceptable daily intake (ADI) (0–0.01 mg kg⁻¹ bw) of chlorpyrifos is occupied by dietary daily intake to the Chinese adult and children, respectively, due to the consumption of rice and cabbage. These results on risk assessment were consistent with that of JMPR. Incorporation of market survey residue data gave a 5-fold reduction in the estimated exposures to chlorpyrifos. Concerning the acute exposure, the national estimated short-term intake (NESTI) represents 0.077% and 10.6% for rice and cabbage, respectively, of the acute reference dose (ARfD) (0–0.1 mg kg⁻¹ bw). The application of chlorpyrifos at the recommended dose on rice and cabbage is unlikely to pose any public health issues if it is applied according to the good agricultural practices (GAPs) established by each country.     

我国居民中药材中铅暴露的风险评估

目地:评估我国居民中药材铅暴露量及其潜在的健康风险,评价我国当前执行的中药材中铅限量标准的适宜性。方法2008-2016年在全国采集各类中药材2056份,检测铅含量水平。采用多阶段分层随机抽样方法,在黑龙江、辽宁、江西、贵州和甘肃5省份采用入户面对面问卷方式调查5739名18岁及以上成年人中药材消费情况。结合中药材中铅含量水平和中药材消费量数据,采用确定性评估方法,对我国居民中药材中铅暴露风险进行评估。并对我国当前执行的中药材中铅限量标准的适宜性进行评价。结果检测的2056份中药材样本,铅平均含量为1.04mg/kg,超标率3.79%,其中动物类药材铅平均含量2.96mg/kg,高于植物类药材平均含量0.97mg/kg。暴露评估结果显示,常规服用中药材人群铅暴露的健康风险较低;但对于作为药膳食用中药材的人群和长期以较高剂量服用/食用中药材者,铅暴露导致的健康风险相对较高。结论在当前中药材铅残留量水平下,我国大部分居民因中药材导致铅暴露的健康风险较低,但对于终生长期服用或作为药膳大量食用中药材者,铅暴露导致的健康风险需要关注。     

Risk assessment of ‘endocrine substances’: Guidance on identifying endocrine disruptors

The European regulation on plant protection products (1107/2009) and other related legislation only support the marketing and use of chemical products on the basis that they do not induce endocrine disruption in humans or wildlife species. This legislation would appear to make the assumption that endocrine active chemicals should be managed differently from other chemicals presumably due to an assumed lack of a threshold for adverse effects. In the absence of agreed scientific criteria and guidance on how to identify and evaluate endocrine activity and disruption within these pieces of legislation, a European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) task force was formed to provide scientific criteria that may be used within the context of these three legislative documents. The first ECETOC technical report and associated workshop, held in 2009, presented a science-based concept on how to identify endocrine activity and disrupting properties of chemicals for both human health and the environment. Specific scientific criteria for the determination of endocrine activity and disrupting properties that integrate information from both regulatory toxicity studies and mechanistic/screening studies were proposed. These criteria combined the nature of the adverse effects detected in studies which give concern for endocrine toxicity with an understanding of the mode of action of toxicity so that adverse effects can be explained scientifically. A key element in the data evaluation is the consideration of all available information in a weight-of-evidence approach.     

EMS in Viracept—Initial (‘traditional’) assessment of risk to patients based on linear dose response relations

Prior to having performed in depth toxicological, genotoxicological and DMPK studies on ethyl methanesulfonate (EMS) providing solid evidence for a thresholded dose response relationship, we had prepared and shared with regulatory authorities a preliminary risk estimate based on standard linear dose–effect projections. We estimated that maximal lifetime cancer risk was in the order of 10⁻³ (for lifetime ingestion of the maximally contaminated tablets) or 10⁻⁴ for the exposure lasting for 3 months. This estimate was based on a lifetime cancer study with methyl methanesulfonate (MMS; as insufficient data were available for EMS) in rodents and default linear back extrapolation. Analogous estimates were made specifically for breast cancer based on short term tumorigenicity studies with EMS in rats, for the induction of heritable mutations based on specific locus and dominant lethal tests in mice and for the induction of birth defects based on teratogenicity studies in mice. We concluded that even under worst case assumptions of linear dose relations the chance of experiencing these adverse effects would be very small, comprising at most a minute additional burden among the background incidence of the patients.