Acute toxicity studies are no longer required to support first clinical trials of pharmaceuticals in man. However, it is unclear in the wording of the revised ICH M3 whether acute toxicity studies are required later in drug development (e.g., phase 3) in order to support the management of overdose. The NC3Rs held a workshop in January 2010 with representatives from international poison centres, the pharmaceutical and chemical industries, and regulatory and government bodies to explore further whether acute toxicity studies are used to support the clinical management of overdose of pharmaceuticals and whether this work can be translated to other sectors such as the chemical industry. The consensus formed at the workshop was that acute toxicity studies are not used for managing overdose of pharmaceuticals and are of little value in treating human poisoning from chemicals. In this paper, the authors describe the key considerations in treating human overdose and poisoning, challenge the value of the classification and labelling process of chemicals for this purpose and discuss how acute toxicity studies can be improved to better inform risk assessment.
"Identifying studies that add little in terms of information on the hazardous properties of the substance, and are in effect 'redundant', is a relatively easy way to reduce animal testing and costs to industry, without adversely impacting on the level of protection of human or environmental health. Examples of where this approach has proved fruitful include a review of the need for dermal acute toxicity studies for industrial chemicals and pesticides (Creton et al., 2010) and a review of the need for single dose acute toxicity studies for medicinal compounds (Robinson et al., 2008) and for industrial chemicals (Chapman et al., 2010) all by the UK National Centre for the 3Rs, a review of the need for the second generation in reproductive toxicity studies by the Dutch National Institute for Public Health and the Environment (Janer et al., 2007), and a review of the need for carcinogenicity studies for medicinal products by the German Federal Institute for Drugs and Medical Devices (Friedrich and Olejniczak, 2011) and also by the US drug industry (Sistare et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: A survey conducted on the EU Notification of New Substances (NONS) database suggested that for industrial chemicals with a profile of low toxicity in (sub)acute toxicity tests there is little added value to the conduct of the 90-day repeated dose study. Avoiding unnecessary animal testing is a central aim of the EU REACH chemicals legislation; therefore we sought to verify the profile using additional data. The OECD's eChemPortal was searched for substances that had both a 28-day and a 90-day study and their robust study summaries were then examined from the ECHA CHEM database. Out of 182 substances with high quality 28-day and 90-day study results, only 18 reported no toxicity of any kind in the (sub)acute tests. However, for 16 of these there were also no reported signs of toxicity at or close to the limit dose (1,000 mg/kg bw/d) in the 90-day study. Restricting the 'low (sub)acute toxicity in a high quality dataset' profile to general industrial chemicals of no known biological activity, whilst allowing irritant substances, increases the data set and improves the prediction to 95% (20 substances out of 21 substances). The low toxicity profile appears to be of low prevalence within industrial chemicals (10-15%), nevertheless, avoidance of the conduct of a redundant 90-day study for this proportion of the remaining REACH phase-in substances would avoid the use of nearly 50,000 animals and save industry 50 million Euros, with no impact on the assessment of human health.
"Additionally, acute toxicity studies are no longer used for managing overdose of pharmaceuticals and have been found to be of little value in treating human poisoning from chemicals. This consensus was reached at a workshop held by the NC3Rs which brought together clinicians, toxicologists, regulators and directors of Poison Centres (Chapman et al., 2010; Robinson and Chapman, 2009). In the absence of acute toxicity data, the necessary information can instead be obtained from short term studies (up to 7 days daily dosing) that are already an existing part of the drug development process. "
[Show abstract][Hide abstract] ABSTRACT: Short term toxicity studies are conducted in animals to provide information on major adverse effects typically at the maximum tolerated dose (MTD). Such studies are important from a scientific and ethical perspective as they are used to make decisions on progression of potential candidate drugs, and to set dose levels for subsequent regulatory studies. The MTD is usually determined by parameters such as clinical signs, reductions in body weight and food consumption. However, these assessments are often subjective and there are no published criteria to guide the selection of an appropriate MTD. Even where an objective measurement exists, such as body weight loss (BWL), there is no agreement on what level constitutes an MTD. A global initiative including 15 companies, led by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), has shared data on BWL in toxicity studies to assess the impact on the animal and the study outcome. Information on 151 studies has been used to develop an alert/warning system for BWL in short term toxicity studies. The data analysis supports BWL limits for short term dosing (up to 7 days) of 10% for rat and dog and 6% for non-human primates (NHPs).
[Show abstract][Hide abstract] ABSTRACT: The determination of single high doses of active pharmaceutical ingredients (API) is used mostly to fulfill regulatory demands. Oral LD(50) values in animals for over 300 API were compared to the minimal effective therapeutic doses (METD) in humans in order to find a correlation between animal and human data. The highest correlation between human METD and animal LD(50) was found for the dog (R=0.323), the lowest for the rat (0.287). It was determined that acute oral LD(50) of rats have poor correlation with the METD, and cannot be used as a classification criteria into official acute toxic categories. Only 13% of API has been classified as fatal if swallowed according to the EU CLP regulation, none of the substances with very low therapeutic dose have been identified as EU CLP acute toxicity category 1. Substances with very low therapeutic doses, which could potentially have toxic effects in humans, are not identified with the use of oral LD(50) and current classification system. We propose that the acute toxicity based on rat LD(50) dose is not used as a basis for classification of pharmaceuticals, and that the METD is applied as basis for classification.
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