A Tiered Approach to Systemic Toxicity Testing for Agricultural Chemical Safety Assessment

Aproposal 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\u2019s 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\u2014that 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

Plasma protein binding of furosemide in kidney transplant patients

The present investigation was undertaken in order to determine the in vivo plasma protein binding of furosemide in kidney transplant patients and its possible consequence on furosemide effect. Using an equilibrium dialysis technique, serial plasma samples of furosemide taken after intravenous administration were dialyzed against an equal volume of isotonic Krebs Ringer bicarbonate buffer (pH7.4). Dialysis was performed at 37°C for 5 hr, and furosemide concentrations (total as well as free) were analyzed by HPLC using fluorescence detection. It was observed that kidney transplant patients on concomitant sulfisoxazole treatment (KT+) had a significantly greater value for percent free of furosemide as compared to transplant patients not on sulfisoxazole (KT-) (4.4±0.8 for KT+ vs. 1.7±0.3% for KT- ; p<0.01) as well as to healthy volunteers (4.4±0.8 for KT+ vs. 1.2±0.2% for controls ; p<0.01). In addition, kidney transplant patients not on concomitant sulfisoxazole treatment had a significantly higher value for percent free of furosemide with respect to healthy volunteers (p<0.05). Nonlinear plasma protein binding was also observed for one patient, who had values for percent free of furosemide ranging from 1.3 to 12.9%. However, no significant correlation was found between the fraction of the dose excreted unchanged in the urine and percent free of furosemide .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45028/1/10928_2005_Article_BF01062547.pd

Report from the EPAA workshop: In vitro ADME in safety testing used by EPAA industry sectors

AbstractThere are now numerous in vitro and in silico ADME alternatives to in vivo assays but how do different industries incorporate them into their decision tree approaches for risk assessment, bearing in mind that the chemicals tested are intended for widely varying purposes? The extent of the use of animal tests is mainly driven by regulations or by the lack of a suitable in vitro model. Therefore, what considerations are needed for alternative models and how can they be improved so that they can be used as part of the risk assessment process? To address these issues, the European Partnership for Alternative Approaches to Animal Testing (EPAA) working group on prioritisation, promotion and implementation of the 3Rs research held a workshop in November, 2008 in Duesseldorf, Germany. Participants included different industry sectors such as pharmaceuticals, cosmetics, industrial- and agro-chemicals. This report describes the outcome of the discussions and recommendations (a) to reduce the number of animals used for determining the ADME properties of chemicals and (b) for considerations and actions regarding in vitro and in silico assays. These included: standardisation and promotion of in vitro assays so that they may become accepted by regulators; increased availability of industry in vivo kinetic data for a central database to increase the power of in silico predictions; expansion of the applicability domains of in vitro and in silico tools (which are not necessarily more applicable or even exclusive to one particular sector) and continued collaborations between regulators, academia and industry. A recommended immediate course of action was to establish an expert panel of users, developers and regulators to define the testing scope of models for different chemical classes. It was agreed by all participants that improvement and harmonization of alternative approaches is needed for all sectors and this will most effectively be achieved by stakeholders from different sectors sharing data

Allowing pseudoscience into EU risk assessment processes is eroding public trust in science experts and in science as a whole: The bigger picture.

Allowing pseudoscience into EU risk assessment processes is eroding public trust in science experts and in science as a whole: The bigger picture

A meeting of the Joint FAO/WHO Expert Committee on Food Additives was held at WHO Headquarters, Geneva, from 15 to 24 February 2000

Univ Complutense Madrid, Fac Vet Med, Dept Toxicol & Pharmacol, Madrid, SpainSwedish Univ Agr Sci, Fac Vet Med, Dept Pharmacol & Toxicol, S-75007 Uppsala, SwedenFed Inst Hlth Protect Consumers & Vet Med, Berlin, GermanyFrench Food Safety Agcy, Natl Agcy Vet Med Prod, Fougeres, FranceUniv London Imperial Coll Sci Technol & Med, Div Med, Sect Clin Pharmacol, Sch Med, London, EnglandSokoine Univ Agr, Dept Vet Physiol Biochem Pharmacol & Toxicol, Morogoro, TanzaniaCanadian Food Inspect Agcy, Ctr Vet Drugs Residues, Hlth Anim Lab, Saskatoon, SK, CanadaUS FDA, Off Womens Hlth, Rockville, MD USAUniv Fed Sao Paulo, Sch Vet Med, Appl Pharmacol & Toxicol Lab, Dept Pathol, Sao Paulo, BrazilMinist Agr & Anim Husbandry, Natl Lab Vet Sci, Toxicol & Residues Sect, San Jose, Costa RicaNatl Inst Publ Hlth & Environm, Lab Residue Anal, Bilthoven, NetherlandsUniv Fed Sao Paulo, Sch Vet Med, Appl Pharmacol & Toxicol Lab, Dept Pathol, Sao Paulo, BrazilWeb of Scienc