The FDA New Animal Drug Approval Process
Rebecca A. Krimins in Learning from Disease in Pets, 2020
For drugs used in food-producing animals, the HFS technical section is comprised of three parts: toxicology; residue chemistry, which includes the analytical method for detecting residues; and microbial food safety. Toxicology generally evaluates a series of studies such as testing for systemic toxicity, developmental and reproductive toxicity, genotoxicity, and when applicable, carcinogenicity, effects on human intestinal flora, neurotoxicity, and immunotoxicity. Information from these studies is used to establish the acceptable daily intake (ADI), which most often will be set on the basis of the drug’s toxicological, microbiological, or pharmacological properties. This value, usually expressed in micrograms or milligrams of the total drug residues per kilogram of body weight per day, represents the daily intake of drug residue in animal tissue that may be consumed during the entire life of a human without adverse effects or harm to the health of the consumer. This ADI, together with food consumption values for edible tissues, is then used to determine safe concentrations. The safe concentration is the amount of total residue of a new animal drug that can be consumed from each edible tissue every day for up to the lifetime of a human without exposing the human to residues in excess of the ADI. Safe concentrations, expressed as parts per million (ppm) or parts per billion (ppb), are used for tolerance determinations.
Errors in Toxicology
David Woolley, Adam Woolley in Practical Toxicology, 2017
In a similar vein, aspartame, a rigorously tested and widely used artificial sweetener, has been the subject of much public gnashing of teeth and brouhaha. In a comprehensive EFSA review of aspartame in 2013, it was found to be “not of safety concern” at EFSA’s current acceptable daily intake of 40 mg/kg-bw per day. It is considered as “safe” for use as a sweetener by a number of national food standard and health agencies (EFSA 2013). If some of the websites devoted to its dangers are to be believed, this is not the case, and it is in fact directly responsible for vast number of medical conditions. These websites, however, pale in comparison to the extent that one American citizen went to prove its danger. Motivated by a need to show the adverse effects of aspartame, she conducted her own (non-GLP-compliant, one assumes) carcinogenicity bioassay in her garden. The validity of the positive outcome may have been somewhat tainted by her nonstandard techniques including (but not limited to) buying rats from a pet store (not a homogenous population with historical control values), selecting the control groups based on her favorite rats, dosing the animals with packets of NutraSweet (which contained substances other than aspartame), and a total lack of any pathology other than a visible external analysis of “tumor” (which were all assumed to be “cancerous”).
Managing chemical hazards *
Jamie Bartram, Rachel Baum, Peter A. Coclanis, David M. Gute, David Kay, Stéphanie McFadyen, Katherine Pond, William Robertson, Michael J. Rouse in Routledge Handbook of Water and Health, 2015
Researchers in the United Kingdom’s Department of Environment, Food and Rural Affairs have developed an approach for prioritizing pesticides and their transformation products in drinking water supplies that addresses some of the limitations of a qualitative approach by considering chemical and soil properties relevant to environmental mobility and quantitative toxicity information. This prioritization approach could be extended to other anthropogenic contaminants and applied even in settings with no water quality monitoring data, although data on the extent of use (or extent of natural sources) of each chemical are needed.9 The approach involves calculating a dimensionless exposure index (E)—the product of the relative amount of chemical in use, the fraction likely to end up in water (determined from the chemical’s physical properties) and the fraction lost through degradation (determined from degradation studies). The exposure index is divided by the chemical’s acceptable daily intake (or another relevant health risk metric) to provide an overall risk index.
Relevance of animal studies in the toxicological assessment of oil and wax hydrocarbons. Solving the puzzle for a new outlook in risk assessment
Published in Critical Reviews in Toxicology, 2021
Juan-Carlos Carrillo, Dirk Danneels, Jan Woldhuis
The long history and use of petroleum-derived oils and waxes in the industry has generated a significant amount of data followed by a no less rigorous number of regulatory evaluations to ensure safe use. Although alkanes are relatively simple and non-reactive chemicals, their safety assessment as complex hydrocarbon products (i.e. oils and waxes) has not been without stumbling blocks and controversies, especially the discussion about the relevance of the F-344 rat for the assessment of mineral waxes and oils since the 90’s. This has led to the situation where acceptable daily intake – ADI – values have been set or revoked based on a complicated and puzzling data base of chemical compositions, toxicological endpoints, internal and external dose differences, rat strain differences and opinions on the relevance of these for human risk assessment. An extensive literature review on long-term toxicity of mineral waxes and oils has been recently published which provides a novel visualization of the data points and a general insight into two key points namely, hepatic granuloma and alkane accumulation (Pirow et al. 2019).
Prenatal exposure to artificial food colorings alters NMDA receptor subunit concentrations in rat hippocampus
Published in Nutritional Neuroscience, 2021
Duygu Kumbul Doguc, Firdevs Deniz, İlter İlhan, Esin Ergonul, Fatih Gultekin
Food colorings are added to food to restore the natural colors lost in processing and also to impart, preserve, or enhance the color of food to produce esthetically and psychologically attractive products [1,2]. Food colorings are classified as artificial (synthetic) and natural, depending on their source [2]. The synthetic colors widely used in the food industry, referred to as artificial food coloring additives (AFCAs), have been implicated in the development of neurobehavioral disorders in children [3,4]. The adverse effects of AFCAs on children’s behavior was first proposed in 1975 by Feingold, who theorized that hypersensitivity to food additives, especially AFCAs, may be the underlying cause of the hyperactivity observed in some children [5,6]. McCann et al. published a study in 2007 which brought about renewed interest in the hypothesis of AFCAs’ adverse effect on neurobehavior [7]. Other studies have supported a link between long-term or repeated ingestion of AFCAs and childhood behavioral hyperactivity [8–10]. However, none of these studies have led to a consensus on a particular AFCA or any other food additives, which are periodically re-evaluated by a scientific committee of the European Food Safety Authority (EFSA) to determine their safety and acceptable daily intake (ADI) values.
Subacute oral toxicity investigation of selenium nanoparticles and selenite in rats
Published in Drug and Chemical Toxicology, 2019
Niels Hadrup, Katrin Loeschner, Karen Mandrup, Gitte Ravn-Haren, Henrik L. Frandsen, Erik H. Larsen, Henrik R. Lam, Alicja Mortensen
Selenite was included to compare the nanoparticle formulation with that of selenite, a commonly used Se species in food supplements. Selenite decreased body weight gain only in animals that received the mid-dose of this Se preparation. At this dose, the relative liver weight was also increased as observed also for SeNP. An increase in urinary pH at the mid-dose was a finding not seen for rats dosed with SeNP. Altogether these data suggest a NOAEL of 0.05 mg Se/kg bw for selenite. We note that this dose is 1.5-fold the human tolerable upper intake level of Se when converted by difference in body surface area; and 10-fold the recommended human high level when considered per body weight. And thus, based on our data, the tolerable upper intake levels could be considered to be too high, as assessment factors of at least 100 would be needed to calculate an acceptable daily intake based on a NOAEL in mg/kg bw.
Related Knowledge Centers
- Dietary Reference Intake
- Drinking Water
- Threshold Limit Value
- Food Additive
- No-Observed-Adverse-Effect Level
- Tolerable Daily Intake
- Reference Dose