A toxicological risk assessment procedure: A proposal for a surveillance index for hazardous chemicals

Through an approach called the Surveillance Index (SI), the U.S. Food and Drug Administration (FDA) is systematically evaluating the potential health risk of pesticides that may be present as residues in foods. The SI is being used as a primary tool in the establishment of monitoring priorities. Each pesticide is classified and assigned to one of 5 levels of potential risk. The SI documents that are prepared for individual pesticides summarize the information used to assess potential dietary exposure and health risk, provide the rationale for the assigned classification, and identify needs and actions necessary to accomplish appropriate monitoring of the food supply. Reasons are described for the development of the SI, the content of the SI Documents, and the use of the SI in planning and redirecting FDA pesticide monitoring activities.

Original proposal objectives: Our main original goal was to develop ultra-fast methods and instrumentation for the analysis of hazardous chemicals in the food supply. We proposed to extend the QuEChERS approach to veterinary drugs and other contaminants, and conduct fast and ultra-fast analyses using novel 5MB-MS instrumentation, ideally with real samples. Background to the topic: The international trade of agricultural food products is a $1.2 trill ion annual market and growing. Food safety is essential to human health, and chemical residue limits are legislated nationally and internationally. Analytical testing for residues is needed to conduct risk assessments and regulatory enforcement actions to ensure food safety and environmental health, among other important needs. Current monitoring methods are better than ever, but they are still too time-consuming, laborious, and expensive to meet the broad food testing needs of consumers, government, and industry. As a result, costs are high and only a tiny fraction of the food is tested for a limited number of contaminants. We need affordable, ultra-fast methods that attain high quality results for a wide range of chemicals. Major conclusions, solutions and achievements: This is the third BARD grant shared between Prof. Amirav and Dr. Lehotay since 2000, and continual analytical improvements have been made in terms of speed, sample throughput, chemical scope, ease-of-use, and quality of results with respect to qualitative (screening and identification) and quantitative factors. The QuEChERS sample preparation approach, which was developed in conjunction with the BARD grant in 2002, has grown to currently become the most common pesticide residue method in the world. BARD funding has been instrumental to help Dr. Lehotay make refinements and expand QuEChERS concepts to additional applications, which has led to the commercialization of QuEChERS products by more than 20 companies worldwide. During the past 3 years, QuEChERS has been applied to multiclass, multiresidue analysis of veterinary drug residues in food animals, and it has been validated and implemented by USDA-FSIS. QuEChERS was also modified and validated for faster, easier, and better analysis of traditional and emerging environmental contaminants in food. Meanwhile, Prof. Amirav has commercialized the GC-MS with 5MB technology and other independent inventions, including the ChromatoProbe with Agilent, Bruker, and FUR Systems. A new method was developed for obtaining truly universal pesticide analysis, based on the use of GC-MS with 5MB. This method and instrument enables faster analysis with lower LaDs for extended range of pesticides and hazardous compounds. A new approach and device of Open Probe Fast GC-MS with 5MB was also developed that enable real time screening of limited number of target pesticides. Implications, both scientific and agricultural: We succeeded in achieving significant improvements in the analysis of hazardous chemicals in the food supply, from easy sample preparation approaches, through sample analysis by advanced new types of GC-MS and LCMS techniques, all the way to improved data analysis by lowering LaD and providing greater confidence in chemical identification. As a result, the combination of the QuEChERS approach, new and superior instrumentation, and the novel monitoring methods that were developed will enable vastly reduced time and cost of analysis, increased analytical scope. and a higher monitoring rate. This provides better enforcement, an added impetus for farmers to use good agricultural practices, improved food safety and security, increased trade. and greater consumer confidence in the food supply.

Developing methods that can analyze multiple categories of organic chemical residues such as pesticides, veterinary drugs, mycotoxins, human drugs, and environmental contaminants in food with a single analytical procedure is a growing trend. These methods for mixed organic chemical residues and contaminants focus on the chemical properties of these analytes rather than how they are used and adulterate the food supply. This paper highlights recently published methods for mixed residue and contaminant methods in food including advances in technology (instrumental hardware, data processing programs, and sample cleanup) that allow for a larger number of compounds to be monitored simultaneously. The factors that determine the scope, or number and type of analytes in a given method, including needs for specific food commodities, complexity of the analytical procedure, and the intended purpose (qualitative vs quantitative analysis) will be examined. Although there are clear advantages to expanding the number of unwanted chemicals being monitored in the global food supply, challenges to developing and implementing mixed organic residue and contaminant methods will also be discussed. Going forward, it will be important to implement these methods to more thoroughly protect the food supply for a wide variety of targeted and non-targeted chemical residues and contaminants while also having the regulatory framework in place to effectively manage the results of these comprehensive analyses. Graphical abstract.

Bearing in mind that cosmetic products are applied throughout the lifetime and that they can contain potentially harmful and toxic substances, valid EU regulation in this area has set strict requirements regarding their safety. Manufacturers are required to provide a cosmetic product safety report containing a toxicological assessment made by experts. Toxicological assessment is based on existing in vivo toxicological data, and in particular in silico and in vitro, since EU regulations in the field of cosmetic products prohibit new animal studies. Although sporadic cases of serious poisoning after the application of cosmetic products have been recorded, adverse effects after normal and reasonably foreseeable use of cosmetic products are usually mild (allergic reactions and skin irritation) and completely reversible. EU regulations require mandatory reporting of serious adverse effects (functional incapacity, hospitalization, disability, etc.) in order to detect ingredients of cosmetic products that potentially endanger human health and prevent similar effects from recurred. The paper describes the procedure of toxicological risk assessment for cosmetic ingredients because the assessment of the safety of the cosmetic product is based on the assessment of the safety of its ingredients.

Climate-related hazards can lead to agricultural losses and affect local and wider food supply via food trade. This study estimates the potential for adverse effects of climate hazards on food supply across Indian States and Union Territories (hereafter ‘states’) by quantifying climate hazard risks. Risks were estimated using the most recent data available on hazard presence, vulnerability, and volume of per capita food supply that is exposed to hazards. Historical (2000–2020) climatological and geological data sourced from meteorological stations and satellite imagery were used to estimate the state-level presence of eight climate-related hazards (droughts, forest fires, floods, extreme rainfall, landslides, cyclones, extreme temperatures, sea level rise). For each state and hazard type, we distinguished between risk to food supply produced in the state and the risk to food supply imported from other states. The source of food supply was estimated from a supply and demand balance model for 30 major food items that uses government data from 2011–12. We found that climate hazard risks to food supply vary across states and by hazard type. The largest climate hazard risks to state food supply are in Bihar, Madhya Pradesh, and Assam, where the majority of risk is to locally produced supply. Food supply in each state is at risk to all eight climate hazards via food imports from other Indian states. For 14 states, the climate hazard risk is greater for imported food supply than for locally produced supply. Just five states contribute to more than half of the climate hazard risk in interstate food trade. The findings indicate that climate-related hazards in Indian states could have potentially adverse effects on national food supply, affecting both local production and interstate trade. For policy-makers, these climate hazard risks identify potential priorities for enhancing food system resilience to mitigate impacts on local and national food security.

During production, storage, and administration, drug products (and their intermediates) are in contact with many different types of materials, which include manufacturing components, container closure systems, and administration materials; therefore, there is a potential for their interactions and the introduction of leachables. The presence of leachables may impact key quality attributes of drug products in many ways. These include potential alterations in drug product stability, resulting in a reduced shelf-life, compromised drug product efficacy due to degradation or inactivation of active pharmaceutical ingredients, and impaired drug product physical acceptability due to precipitation, discolouration and/or change in odour or flavour. Moreover, some leachables may be inherently toxic (mutagenic, carcinogenic, immunogenic, etc.) posing direct risks to patient safety. Comprehensive toxicological evaluation of extractables and leachables is therefore essential. Documented cases demonstrate that presence of leachables can lead to serious and clinically significant adverse effects, underscoring the importance of their identification, quantification, and toxicological assessment during pharmaceutical development. This paper provides an overview of the toxicological limits used in the analyses of extractables and leachables and illustrates how they are translated into analytical limits. It also outlines the workflow for toxicological risk assessment of extractables and/or leachables, including evaluations of mutagenicity and other relevant toxicological endpoints. Special attention is given to the interpretation of the draft ICH Q3E guideline, which represents a pivotal development in harmonizing global expectations for extractables and leachables safety assessments. Understanding and correctly applying ICH Q3E is crucial, as it will shape regulatory strategies, analytical approaches, and risk management practices across the pharmaceutical industry. The paper concludes by highlighting emerging challenges that demand sustained advancements in both scientific methodologies and regulatory frameworks.

10 - Nanobiotechnological strategies for toxigenic fungi and mycotoxin control

Background: Hepatotoxicity is a major reason for medication withdrawal from the markets. Unfortunately, serious adverse hepatic effects can occur after marketing with limited indicators during clinical development. Therefore, finding possible predictors for hepatotoxicity might guide the monitoring program of various stakeholders such as drug regulatory authorities. Objective: To explore the potential of drugs, pre-approval regulatory factors as predictors for the occurrence of hepatotoxicity-related post-marketing regulatory actions. Pre-approval factors were specified as: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. Methods: Using publicly accessible FDA data, we examined clinical review documents for drugs approved in the USA during the period from 2011 to 2016 to evaluate their hepatic safety profile, identifying the 3 specified indicators for analysis. Predictors (Covariates): We assessed whether these medications meet: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. Outcome (Dependent Variable): Post-marketing regulatory action related to hepatotoxicity including products withdrawal and updates to either warning, precaution or adverse effects sections. Statistical Analysis: Drugs that were approved between 2011 and 2016 were included in the analysis with follow-up time from the date of approval until end of December 2019 or the date of first post-marketing regulatory action related to hepatotoxicity, whichever occurred first. The hazard ratio (HR) was estimated using Cox-regression analysis. Results: A total of 192 medications were included in the study. We classified 48 drugs with grade ≥3 hepatotoxicity, 43 with accelerated approval status, and 74 with labeled information about hepatotoxicity prior to marketing. The adjusted HRs for post-marketing regulatory action for products with grade ≥3 hepatotoxicity was 0.61 (95% confidence interval [CI], 0.17–2.23), 0.92 (95% CI, 0.29–2.93) for drug approved via accelerated approval program, and 0.91 (95% CI, 0.33–2.56) for drugs with labeled hepatotoxicity information at approval time. Conclusion: Hy’s Law with hepatotoxicity grade ≥3, accelerated approval, and label information on hepatotoxicity were not identified as predictors for post-marketing additional regulatory actions concerning liver adverse effects. However, the evidence is inconclusive due to small sample size and potential channeling bias.

We manipulated hatching pattern and brood size in 102 European Starling (Sturnus vulgaris) broods to test the "brood reduction" hypothesis for the adaptive significance of asynchronous hatching. According to this hypothesis, asynchronous hatching in food-limited broods reduces mortality or improves the condition of nestlings in comparison with synchronous hatching.

The ultimate result of scientific research regarding a food contaminant is a determination of the need to regulate the level of that contaminant in the food supply, and if the need exists, to determine a scientifically appropriate level at which to regulate. Suitable regulatory actions are necessarily based on sound science. Sound science in this case consists of properly designed safety assessments using appropriate models based on reliable and adequate toxicity studies and inputting sufficiently accurate data with regard to rates of contaminant occurrence and level of contamination when it occurs. Adequate toxicity studies in turn depend upon appropriate study design and relevant biological endpoints. Accurate data depends upon appropriate sampling plans and suitable analytical technology to determine the presence or absence of a contaminant and the level present in the food supply when the contaminant is found. Processing will often reduce the exposure level to mycotoxins in the food supply and this effect must be taken into account when considering regulatory action.

In this chapter, the use of the term residue relates primarily to the trace amounts of materials found in foods of various origins resulting from the application of chemicals during production. In order to focus on the type of sampling and the underlying statistical basis, the approach used for estimating the incidence of residues in animal products is presented in this chapter. The primary focus of the enforcement analytical work was related to antibiotic/antimicrobial assays and accounted for >99% of the samples. In sheep the incidence is 2.2%, approximately 2.5 times that reported in 2004, while in goats the 2005 frequency is 43% of that of 2004. A common acrylamide-forming reaction occurs when naturally occurring sugars react with asparagine at elevated temperatures. The most important point to be made is that acrylamide is considered a potential carcinogen and that the levels found in foods can be reduced during food preparation. The administration of the pesticide regulatory system is quite complex. Pesticide residues were not detected in 62.7% of domestic and 71.8% of imported samples. Of those samples, 2.4% of domestic and 6.1% of imported samples had violative levels. The problems with the U.S. food supplies are not the overall-occurring chemical residues but more likely the wide variety of bacteriological residues occurring from processing and distribution systems.

Striking while the iron is hot for action against chemical residues in food, a coalition of organizations has filed a lawsuit and a petition charging the Environmental Protection Agency with failure to safeguard the nation's food supply by permitting residues of carcinogenic pesticides that concentrate in processed foods. The plaintiffs are California's attorney general; three California children and their parents, who are exposed to pesticide residues in processed foods; the AFL-CIO; and environmental and consumer activist groups—the Natural Resources Defense Council and the Ralph Naderaffiliated Public Citizen. The issues they raise were also debated last week at a House subcommittee hearing, and earlier last month at House and Senate hearings. Both houses are now considering bills calling for steps the coalition backs. The suit and petition come amidst a firestorm already ignited by NRDC against use of the growth regulator Alar (daminozide) on apples (C&EN, May 22, page 4). Senate action is imminen...

Considerable time, regulation and consumer concern is associated with the question of chemical residues in food. Potential residues in food span a broad range from natural contaminants (mycotoxins) through environmental contaminants (dioxins, PCBs), agrochemicals (nitrates, pesticides), veterinary drugs (anthelmintics, antibiotics), prohibited substances (hormonal growth promoters), chemicals arising in processing (nitrosamines), packaging components (plasticisers) to contaminants arising in domestic food preparation (heavy metals). The occurrence or avoidance of these chemicals as residues in food is to a greater or lesser extent under the control of the food producer, processor and consumer in the activities of growing/producing, treating, storing, processing, packaging and cooking. The fundamental question is to what extent do or can residues in food constitute a food safety hazard for the consumer. Many of these substances are regulated as to their use and as to their acceptable levels in food while others, by their nature, arise as more random occurrences and, as such, are less prone to regulation. Of particular concern to the producer, processor and retailer of food is what steps may be taken to ensure that the food supply is safe. Best practice in plant and animal husbandry by the producer, in sourcing of material and in control of food manufacturing by the processor, and in sourcing of food products by the retailer combine to assure the safety of food to the consumer. This paper describes the various classes of chemicals which can arise as residues in food, particularly agrochemicals and veterinary drugs, the usage patterns which decrease/increase the likelihood of the occurrence of residues at unacceptable levels, how and in what form(s) residues can occur in foods, and the contribution of food processing to a reduction or otherwise of residue levels in food consumed. Consideration will be given, also, to quantifying the risk posed by chemical residues in food and to a study of the results from a Residue Database and from residue monitoring/surveillance as an indicator of risk to the consumer.

Approximately 150 scientists attended the Human Health Safety of Animal Feeds workshop at the Centers for Disease Control and Prevention (CDC) on January 23, 2004, to discuss issues pertaining to Salmonella-contaminated animal feed and their impact on public health. The workshop followed an article published in Clinical Infectious Diseases, which provided three recommendations to reduce human foodborne disease caused by Salmonella-contaminated animal feed (1). The first recommendation stressed the need for microbial contamination surveillance to determine how feed contaminants, particularly Salmonella, pass through the food chain. The second recommendation was to establish hazard analysis and critical control point programs to minimize Salmonella contamination by identifying and controlling sources of feed contamination. The third recommendation was to implement the Salmonella-negative standard in the feed industry. The purpose of the workshop was to elicit discussion on these and other recommendations concerning the human health safety of animal feed. A variety of organizations were represented at the workshop, including international government agencies, the United States Department of Agriculture (USDA), the United States Food and Drug Administration (FDA), and consumer groups. Speakers offered perspectives on bacterial contamination of animal feed, including examples of human illnesses traced to Salmonella-contaminated feed, and data showing how contaminated animal feed contributes to human foodborne illness. The opening plenary session focused on international experiences in controlling Salmonella in animal feed. Officials from the National Veterinary Institute of Sweden and the Norwegian Agriculture Inspection Service gave an overview of the control measures implemented in Sweden and Norway to ensure Salmonella-negative animal feed. Norway and Sweden have extensive surveillance programs for Salmonella control in animal feed. The measures implemented in Norway and Sweden are important contributing factors to the virtual absence of Salmonella in the food supply in their countries. Several U.S. government agencies, including CDC; USDA; and the National Institutes of Health, National Institute of Allergy and Infectious Diseases, presented research findings at the workshop. Presentations included results from animal feed commodity studies that look at the factors contributing to microbial pathogens, mycotoxins, and chemical residues in animal feed. Researchers from FDA and Washington State University also provided data indicating that contaminated animal feed continues to be a source of Salmonella in food animals. Further studies are necessary to document the precise contribution of contaminated animal feed to human illness. Nevertheless, some presentations suggest that practical interventions are available to reduce the prevalence of Salmonella-contaminated animal feed. Collaboration among all groups was stressed as a useful measure in controlling contaminated animal feed in the future. A compact disk, including all of the presentations, agenda, and list of participants from the workshop, is available online at http://www.cdc.gov/narms/mce/animalfeeds.htm.

Trans fats are desired by the edible oil industry as they impart firmness, plasticity, and oxidative stability to oil. However, clinical trials have demonstrated the adverse effects of trans fats in food on human health and nutrition. Regulatory actions have been taken up by government and non-government bodies worldwide to eliminate the presence of trans fats in the food supply. The World Health Organization (WHO) has launched a "REPLACE" action plan to eliminate trans-fat from the global food industry by 2023. A few enabling technologies are developed to mitigate trans fats namely, trait-enhanced oils, modification in the hydrogenation process, interesterification, fractionation, blending, and oleogelation. Some of them have the drawback of replacing trans-fat with saturated fats. Interesterification and oleogelation are in-trend techniques with excellent potential in replacing trans fats without compromising the desired functionality and nutritional quality attributes. This review presents an overview of trans fatty acid for example, its dietary intake in food products, possible adverse health impact, regulations, and approaches to reduce the usage of trans fats for food application. PRACTICAL APPLICATION: The requirement for the replacement of trans fatty acids (TFAs) in food supply globally has challenged the food industry to find a novel substitute for trans fats without compromising the desired functionality and nutritional property. This review presents detailed background on trans fats, their health impacts and current trends of reformulation of oils and fats to mitigate their presence in food supply chains. Information compiled in this paper will help food scientists and technologists, chemists, food processors, and retailers as there is an urgent need to find novel technologies and substitutes to replace trans fats in processed foods.