Concentration- and time-dependent toxicity of commonly encountered pesticides and pesticide mixtures to honeybees (Apis mellifera L.).

Honeybees are exposed to a wide range of pesticides for long periods via contaminated water, pollen and nectar. Some of those pesticides might constitute health hazards in a time- and dose-dependent manner. Time-dependent toxicity profiles for many applied pesticides are lacking, despite the fact that such profiles are crucial for toxicological evaluations. Therefore, we sought to determine the time-dependent toxicities of pesticides/pesticide metabolites frequently found in Israeli beehives, namely, amitraz metabolites, N'-(2,4-dimethylphenyl)-N-methylformamidine (DMPF) and N-(2,4-dimethylphenyl)-formamide (DMF), coumaphos, imidacloprid, thiacloprid, acetamiprid and dimethoate (toxic reference). By applying accepted methodological approaches such as the modified Haber's rule (product of concentration and exposure duration leads to a constant effect) and comparisons between cumulative doses at different time points, we determined the time-dependent toxicities of these pesticides. We also studied the mixture toxicities of frequently occurring pesticide combinations and estimated their potential contributions to the overall toxicities of neonicotinoids. Thiacloprid was the only pesticide that complied with Haber's rule. DMPF, dimethoate and imidacloprid exhibited time-diminished -toxicities. In contrast, DMF and acetamiprid exhibited time-reinforced toxicities. Neither the binary mixtures nor the tertiary mixtures of DMF, DMPF and coumaphos at 10 times their environmentally relevant concentrations potentiated the neonicotinoids' toxicities. DMPF and imidacloprid were found to present the greatest hazard to honeybees, based on their 50% lethal cumulative dose and 50% lethal time. Amitraz's instability, its low detection frequency and high toxicity profile of its metabolite, DMPF, lead us to the conclusion that DMPF constitutes the actual toxic entity responsible for amitraz's toxic effect.

Pharmacokinetic and pharmacodynamic evaluation of 5-methoxy-2-aminoindane (MEAI): A new binge-mitigating agent.

5-Methoxy-2-aminoindane (MEAI) is a novel psychoactive aminoindane derivative, exerting euphoric, alcohol-like tipsy experience and reduced desire to consume alcoholic beverages. Our previous toxicological evaluation of MEAI in rats, clearly indicated MEAI's potential to be further evaluated as a promising binge mitigating agent due to its favorable safety profile. In the light of these observations, we have determined MEAI's pharmacokinetic (PK) profile in rats and evaluated in-vitro its pharmacodynamics (PD) profile. Following oral and intravenous administration of MEAI, two metabolites were identified, namely, N-acetyl-MEAI and 5-hydroxy-N-acetyl-AI, arising from N-acetylation and oxidative demethylation. The PK-parameters of MEAI and N-acetyl-MEAI were derived from single i.v. bolus (10 mg/kg) and single oral doses (10 and 90 mg/kg) of MEAI to rats. MEAI displayed extensive total clearance (2.8 L/h/kg) and a very short plasma and brain half-life (0.5-0.7 h). At 10 mg/kg, MEAI displayed low oral bioavailability (25%) and a plasma to brain ratio in the range of 3-5.5, with brain MEAI peak levels attained rapidly. Non-linear pharmacokinetic behavior was observed in the 90 mg/kg oral group, in which the bioavailability increased by 500%. The non-linear behavior was also evident by the significant increase in plasma half-life of MEAI and its metabolite, N-acetyl-MEAI. N-acetyl-MEAI levels in plasma and brain were about ten times lower than the parent compound, indicative of its minor contribution to MEAI's pharmacological effect. MEAI displayed weak to moderate ligand binding inhibition at the 5-HT2B receptor, while the remaining neurochemical targets were unaffected. Further studies, in non-rodent species are required, in-order to assess MEAI's PK and PD profile adequately.

Toxicological evaluation of 5-methoxy-2-aminoindane (MEAI): Binge mitigating agent in development.

5-Methoxy-2-aminoindane (MEAI) is a psychoactive compound of the aminoindane class, which in recent years has been recreationally used by many people, who reported of a mild euphoric, alcohol-like tipsy experience and reduced desire to consume alcoholic beverages. In the light of these observations it was decided to progress MEAI through a preliminary drug development route and evaluate the acute and subacute toxicity of MEAI administrated orally to Sprague Dawley rats, as well as to determine potential in-vitro cytotoxic and mutagenic effects using state-of-the-art protocols. Furthermore, the interaction of MEAI at the highest non-toxic concentration (100mg/L) with ethanol at cytotoxic levels of 6% and 7.5% was explored, in order to identify possible additive or synergistic effects. MEAI showed a good safety profile in rats at 10 and 30mg/kg body weight, corresponding to the human doses of 1.6mg/kg and 4.8mg/kg body weight, respectively. Cytotoxic effect was demonstrated using concentrations of 500 and 1000mg/L with calculated IC50 value of 368.2mg/L for rat brain striatum primary neurons and 403.1mg/L for human primary healthy hepatocytes. The combination of 6% or 7.5% ethanol with 100mg/L MEAI revealed no statistically significant increase of cytotoxic effect. Further studies, especially long term chronic and addictive behavior studies, are required in-order to assess MEAI safety profile.

The new Israeli feed safety law: challenges in relation to animal and public health.

The Israeli feed safety legislation, which came to prominence in the early 1970s, has undergone a major change from simple feed safety and quality regulations to a more holistic concept of control of feed safety and quality throughout the whole feed production chain, from farm to the end user table. In February 2014, a new law was approved by the Israeli parliament, namely the Control of Animal Feed Law, which is expected to enter into effect in 2017. The law is intended to regulate the production and marketing of animal feed, guaranteeing the safety and quality of animal products throughout the production chain. The responsibility on the implementation of the new feed law was moved from the Plant Protection Inspection Service to the Veterinary Services and Animal Health. In preparation for the law's implementation, we have characterized the various sources and production lines of feed for farm and domestic animals in Israel and assessed the current feed safety challenges in terms of potential hazards or undesirable substances. Moreover, the basic requirements for feed safety laboratories, which are mandatory for analyzing and testing for potential contaminants, are summarized for each of the contaminants discussed. © 2016 Society of Chemical Industry.