Relevance of the 1-year dog study in assessing human health risks for registration of pesticides. An update to include pesticides registered in Japan.

Over 400 active pesticides are registered in Japan (FAMIC 2013). The results of dog toxicity studies (usually, the 1-year study) were used by the Japanese regulatory authorities to establish the acceptable daily intake (ADI) for 45 pesticide active ingredients (about 9%). A retrospective review of ADIs established in Japan with dog studies as pivotal data for their derivation was performed: the ADIs were reassessed under the assumption that the 1-year dog study would not be available and an alternate ADI was derived based on the remaining toxicology database. In 35 of the 45 cases (77.8%) the ADI resulting from the absence of the 1-year dog study was no greater than twice the Japanese ADI, a difference considered not to be of biological significance. In 6 cases (13%) the resulting ADI was 2-5 times higher, which is considered of questionable biological relevance. On further evaluation of the database, three of these six cases were assessed as to clarify that there is no clear difference and for the other three additional studies to clarify that uncertain findings would have been required. In 3 of the 45 cases (7%) there may be a real difference within the ADI ratio of 2-5. Only in 1 case (2.2%) ADI was five times higher than that has been set. Accordingly, the absence of a 1-year dog study does not appear to influence the ADI derivation in a relevant manner in more than 98% of cases. For the four compounds with a real difference in ADI, consumer exposure would still be well below the alternative ADI. Therefore, a strong case can be made that the standard mandatory requirement to conduct a 1-year dog study, in addition to the 3-month study, is not justified and of no additional value in protecting human health. In addition, a substantial reduction in test animals could be achieved.

A 1-year toxicity study in dogs is no longer a scientifically justifiable core data requirement for the safety assessment of pesticides.

A review of publications on pesticides assessing the need for 1-year toxicity studies in dogs was performed. Four key peer-reviewed papers with different approaches investigated the value of a 1-year dog study in addition to a 3-month study. Despite different databases and approaches, each concluded with the recommendation to limit the testing of pesticides in dogs to a duration of 3 months. The combined weight of evidence presented in this review reinforces these independent conclusions. Therefore, the routine inclusion of a 1-year dog study as a mandated regulatory requirement for the safety assessment of pesticides is no longer justifiable and a globally harmonized approach should be taken to match the latest legislation of the European Union and the US EPA.

Overall impact of the regulatory requirements for genotoxic impurities on the drug development process.

In the last decade a considerable effort has been made both by the regulators and the pharmaceutical industry to assess genotoxic impurities (GTI) in pharmaceutical products. Though the control of impurities in drug substances and products is a well established and consolidated procedure, its extension to GTI has given rise to a number of problems, both in terms of setting the limits and detecting these impurities in pharmaceutical products. Several papers have dealt with this issue, discussing available regulations, providing strategies to evaluate the genotoxic potential of chemical substances, and trying to address the analytical challenge of detecting GTI at trace levels. In this review we would like to discuss the available regulations, the toxicological background for establishing limits, as well as the analytical approaches used for GTI assessment. The final aim is that of providing a complete overview of the topic with updated available information, to address the overall GTI issue during the development of new drug substances.

Critical evaluation of the use of dogs in biomedical research and testing in Europe.

Dogs are sometimes referred to as "man's best friend" and with the increase in urbanization and lifestyle changes, dogs are seen by their owners as family members. Society expresses specific concerns about the experimental use of dogs, as they are sometimes perceived to have a special status for humans. This may appear somewhat conflicting with the idea that the intrinsic value of all animals is the same, and that also several other animal species are used in biomedical research and toxicology. This aspect and many others are discussed in an introductory chapter dealing with ethical considerations on the use of dogs as laboratory animals. The report gives an overview on the use of dogs in biomedical research, safety assessment and the drug developmental process and reflects the discussion on the use of dogs as second (non-rodent)species in toxicity testing. Approximately 20,000 dogs are used in scientific procedures in Europe every year, and their distinct genetic, physiological and behavioral characteristics may support their use as models for e.g. behavioral analysis and genetic research. Advances in the 3Rs (Replacement, Reduction and Refinement of experiments using dogs) are described, potential opportunities are discussed and recommendations for further progress in this area are made.