General Principles to Justify Plant Biostimulant Claims.

The forthcoming European Union (EU) Fertilizing Products Regulation proposes a claim-based definition of plant biostimulants, stipulating that "plant biostimulant" means a product stimulating plant nutrition processes independently of the product's nutrient content, with the aim of improving one or more of the following characteristics of the plant: nutrient use efficiency, tolerance to abiotic stress, crop quality traits or availability of confined nutrients in the soil and rhizosphere. The future regulation also specifies that a plant biostimulant "shall have the effects that are claimed on the label for the plants specified thereon." This creates an onus for manufacturers to demonstrate to regulators and customers that product claims are justified. Consequently, the justification of the agronomic claim of a given plant biostimulant will be an important element to allow it to be placed on the EU market once this new European regulation is applied. In this article, members of the European Biostimulant Industry Council (EBIC) propose some general guiding principles to follow when justifying plant biostimulant claims, that are outlined in this article. These principles are expected to be incorporated into harmonized European standards that are being developed by the European Committee for Standardization (CEN) to support the implementation of the regulation.

PEGylated proteins: evaluation of their safety in the absence of definitive metabolism studies.

During the development of any PEGylated protein or peptide, toxicology in relevant species will be conducted prior to human exposure. Normally, comprehensive metabolism data accompany the toxicity studies for a small molecule. We have examined whether such studies would be relevant in the safety assessment of PEGylated material. Literature data indicate that the polyethylene glycol (PEG) associated with a biological molecule should provide no extra concern because the exposure-toxicity relationship of PEG in animals and humans has been thoroughly investigated and metabolism/excretion of PEG is well understood. Based on the comparisons of PEG exposure from PEGylated biological products and the exposure of PEG associated with toxicity in humans, the therapeutic index is large (approximately 600-fold or greater). Therefore, assuming that toxicological evaluation of a biological molecule of interest is complete and satisfactory therapeutic windows are achieved, the data contained in this review indicate that the PEG associated with a protein or other biological molecule does not represent an additional unquantified risk to humans.

A tiered approach to systemic toxicity testing for agricultural chemical safety assessment.

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. The ACSA Systemic Toxicity Task Force proposes an approach to systemic toxicity testing as one part of the overall assessment of a compound's potential to cause adverse effects on health. The approach is designed to provide more relevant data for deriving reference doses for shorter time periods of human exposure, and includes fewer studies for deriving longer term reference doses-that is, neither a 12-month dog study nor a mouse carcinogenicity study is recommended. All available data, including toxicokinetics and metabolism data and life stages information, are taken into account. The proposed tiered testing approach has the potential to provide new risk assessment information for shorter human exposure durations while reducing the number of animals used and without compromising the sensitivity of the determination of longer term reference doses.

Cardiac safety strategies. 25-26 October 2005, the Radisson SAS Hotel, Nice, France.

This meeting was organised by IIR Life Sciences. It was chaired by Brian Guth, (head of General Pharmacology at Boehringer Ingelheim Pharma) and brought together scientists and clinicians from the pharmaceutical industry, university and regulatory agencies. The meeting presented emerging trends in cardiac safety, including its regulatory context pertaining to ICH S7A, S7B and E14. ICH S7A and S7B highlight the importance of the hERG test and telemetric studies in non-rodents. ICH E14 describes the clinical 'thorough QT study' that is required by the FDA for any new drug. Marked physiological variability in QT interval over time can be observed, partly as a result of fluctuation in autonomic tone. Beat-to-beat QT variability and T-wave morphology should be considered as a part of an integrated estimate of proarrhythmic risk. A case study illustrated the predictivity of preclinical data for proarrhythmic risk in humans, showing the importance of evaluating QT effects in patients to establish a safety margin.