A comparative assessment of the CLP calculation method and in vivo testing for the classification of plant protection products.

In Europe, animal testing for the purpose of regulatory plant protection product (PPP) assessment should be undertaken only as a last resort. Nevertheless, there is a need to improve the acceptance of alternative methods, which has been slow due to a lack of data regarding the predictivity of in vivo effects. The CLP calculation method is an alternative method based on the concentration addition of all adverse substances in a mixture. It is often applied as a conservative approach for the estimation of toxicodynamic interactions. However, PPPs consist of pesticides and co-formulants, which in combination can also exhibit altered toxicokinetic properties. Our analysis revealed that oral and inhalation toxicity was underestimated for approximately 45% of the in vivo classified products by the CLP calculation method as compared to in vivo testing. With regard to skin and eye irritation, the CLP calculation method underestimated the irritating potential in 22% and 6% of PPPs, respectively. Based on specific concentration limits, skin sensitisation was underestimated in 34% of PPPs. Similar false negative rates have been reported for PPP in vitro testing. Hence, we suggest the development of an integrated assessment strategy, weighing all available information and considering relevant parameters influencing predictivity and uncertainty.

Lacking applicability of in vitro eye irritation methods to identify seriously eye irritating agrochemical formulations: Results of bovine cornea opacity and permeability assay, isolated chicken eye test and the EpiOcular™ ET-50 method to classify according to UN GHS.

In vitro methods have gained regulatory acceptance for the prediction of serious eye damage (UN GHS Cat 1). However, the majority of in vitro methods do not state whether they are applicable to agrochemical formulations. This manuscript presents a study of up to 27 agrochemical formulations tested in three in vitro assays (three versions of the bovine corneal opacity and permeability test (BCOP, OECD TG 437) assay, the isolated chicken eye test (ICE, OECD TG 438) and the EpiOcular™ ET-50 assay). The results were compared with already-available in vivo data. In the BCOP only one of the four, one of five in the ICE and six of eleven tested formulations in the EpiOcular™ ET-50 Neat Protocol resulted in the correct UN GHS Cat 1 prediction. Overpredictions occurred in all assays. These data indicate a lack of applicability of the three in vitro methods to reliably predict UN GHS Cat 1 of agrochemical formulations. In order to ensure animal-free identification of seriously eye damaging agrochemical formulations testing protocols and/or prediction models need to be modified or classification rules should be tailored to in vitro testing rather than using in vivo Draize data as a standard.

Natural products, their derivatives, mimics and synthetic equivalents: role in agrochemical discovery.

Natural products (NPs) have a long history as a source of, and inspiration for, novel agrochemicals. Many of the existing herbicides, fungicides, and insecticides have their origins in a wide range of NPs from a variety of sources. Owing to the changing needs of agriculture, shifts in pest spectrum, development of resistance, and evolving regulatory requirements, the need for new agrochemical tools remains as critical as ever. As such, NPs continue to be an important source of models and templates for the development of new agrochemicals, demonstrated by the fact that NP models exist for many of the pest control agents that were discovered by other means. Interestingly, there appear to be distinct differences in the success of different NP sources for different pesticide uses. Although a few microbial NPs have been important starting points in recent discoveries of some insecticidal agrochemicals, historically plant sources have contributed the most to the discovery of new insecticides. In contrast, fungi have been the most important NP sources for new fungicides. Like insecticides, plant-sourced NPs have made the largest contribution to herbicide discovery. Available data on 2014 global sales and numbers of compounds in each class of pesticides indicate that the overall impact of NPs to the discovery of herbicides has been relatively modest compared to the impact observed for fungicides and insecticides. However, as new sourcing and approaches to NP discovery evolve, the impact of NPs in all agrochemical arenas will continue to expand. © 2016 Society of Chemical Industry.

GHS additivity formula: A true replacement method for acute systemic toxicity testing of agrochemical formulations.

Acute systemic (oral, dermal, inhalation) toxicity testing of agrochemical formulations (end-use products) is mainly needed for Classification and Labelling (C&L) and definition of personal protection equipment (PPE). A retrospective analysis of 225 formulations with available in vivo data showed that: A) LD50/LC50 values were above limit doses in <20.2% via oral route but only in <1% and <2.4% of cases via dermal and inhalation route, respectively; B) for each formulation the acute oral toxicity is always equal or greater than the Acute Toxicity Estimate (ATE) via the other two routes; C) the GHS (Global Harmonised System) computational method based on ATE, currently of limited acceptance, has very high accuracy and specificity for prediction of agrochemical mixture toxicity according to the internationally established classification thresholds. By integrating this evidence, an exposure- and data-based waiving strategy is proposed to determine classification and adequate PPE and to ensure only triggered animal testing is used. Safety characterisation above 2000 mg/kg body weight or 1.0 mg/L air should not be recommended, based on the agrochemical exposure scenarios. The global implementation of these tools would allow a remarkable reduction (up to 95%) in in vivo testing, often inducing lethality and/or severe toxicity, for agrochemical formulations.

Agricultural Applications for Antimicrobials. A Danger to Human Health: An Official Position Statement of the Society of Infectious Diseases Pharmacists.

The use of antibiotics in agriculture, particularly in food-producing animals, is pervasive and represents the overwhelming majority of antibiotic use worldwide. The link between antibiotic use in animals and antibiotic resistance in humans is unequivocal. Transmission can occur by ingesting undercooked meats harboring resistant bacteria, by direct contact of animals by animal handlers, and by various other means. Antibiotics used in aquaculture and antifungals used in horticulture are also an evolving threat to human health. Regulations aimed at decreasing the amount of antibiotics used in food production to limit the development of antibiotic resistance have recently been implemented. However, further action is needed to minimize antibiotic use in agriculture. This article describes the extent of this current problem and serves as the official position of the Society of Infectious Diseases Pharmacists on this urgent threat to human health.

Multiparametric characterisation of neuronal network activity for in vitro agrochemical neurotoxicity assessment.

The last few decades have seen the marketing of hundreds of new pesticide products with a forecasted expansion of the global agrochemical industry. As several pesticides directly target nervous tissue as their mechanism of toxicity, alternative methods to routine in vivo animal testing, such as the Multi Electrode Array (MEAs)-based approach, have been proposed as an in vitro tool to perform sensitive, quick and low cost neuro-toxicological screening. Here, we examined the effects of a training set of eleven active substances known to have neuronal or non-neuronal targets, contained in the most commonly used agrochemicals, on the spontaneous electrical activity of cortical neuronal networks grown on MEAs. A multiparametric characterisation of neuronal network firing and bursting was performed with the aim of investigating how this can contribute to the efficient evaluation of in vitro chemical-induced neurotoxicity. The analysis of MFR, MBR, MBD, MISI_B and % Spikes_B parameters identified four different groups of chemicals: one wherein only inhibition is observed (chlorpyrifos, deltamethrin, orysastrobin, dimoxystrobin); a second one in which all parameters, except the MISI_B, are inhibited (carbaryl, quinmerac); a third in which increases at low chemical concentration are followed by decreases at high concentration, with exception of MISI_B that only decreased (fipronil); a fourth in which no effects are observed (paraquat, glyphosate, imidacloprid, mepiquat). The overall results demonstrated that the multiparametric description of the neuronal networks activity makes MEA-based screening platform an accurate and consistent tool for the evaluation of the toxic potential of chemicals. In particular, among the bursting parameters the MISI_B was the best that correlates with potency and may help to better define chemical toxicity when MFR is affected only at relatively high concentration.

Guía de uso responsable agroquímicos / Guide for responsible agrochemical use

La Guía de Uso Responsable de Agroquímicos es un conjunto de directrices básicas para la comercialización, transporte, manejo, utilización, aplicación y disposición final de envases y residuos de agroquímicos, en función de la responsabilidad de los distintos actores que intervienen en el proceso, las necesidades de capacitación, el uso de los elementos de protección personal, los controles de salud y los planes para emergencias. A los fines de esta Guía, el término agroquímicos se refiere a las sustancias o mezclas de sustancias destinadas a controlar o evitar la acción de plagas agrícolas, regular el crecimiento de las plantas, defoliar, desecar o proteger del deterioro, el producto o subproducto cosechado (ver Glosario). La Guía tiene como objetivos prevenir daños a la salud y el ambiente, facilitar el cumplimiento de la legislación vigente en la materia, orientar y capacitar a los distintos actores del ámbito productivo, educativo, tecnológico, político, sanitario y de atención de emergencias sobre el uso correcto de los agroquímicos

Application of the dangerous Preparation Directive: consequences on plant protection products in the internal market.

Legislative Decree March 2003, n. 65 brought about implementation of Directive 1999/45/ EC of the European Parliament and of the Council dated 31 May 1999 and Directive 2001/60/EC of the Commission dated 7 August 2001 concerning laws, regulations and administrative provisions of the Member States relating to the classification, packaging and labelling of dangerous preparations come into force. Directive 1999/45/EC brought about a series of modifications representing the new regulatory framework for dangerous preparations. The above-mentioned Decree supplies the criteria for the evaluation of hazardous preparations, regardless of their intended use, and completes previously undertaken steps, in strict connection with the analogous Directives of the EU, for the problematic complexity of the classification, packaging and labelling of dangerous substances and preparations. The applicative importance of Directive 99/45/EC derives directly from these innovations. Among these, for the first time, the category of "dangerous for the environment" has been extended also to preparations. Moreover, also for the first time, the scope of the Directive is extended to plant protection products and biocides. This paper provides an overview on the results of the hazard classification procedure carried out at national level for plant protection products in light of the new rules and the outcomes in terms of variations of the labels through comparison between previous and new classification. Furthermore the most significant issue which come up during the classification process and the criteria applied for their solution are also reported.

The role of toxicology to characterize biomarkers for agrochemicals with potential endocrine activities.

The paper discusses current knowledge and possible research priorities on biomarkers of exposure, effect and susceptibility for potential endocrine activities of agrochemicals (dicarboximides, ethylene bisdithiocarbammates, triazoles, etc.). Possible widespread, multiple-pathway exposure to agrochemicals highlights the need to assess internal exposure of animals or humans, which is the most relevant exposure measure for hazard and risk estimation; however, exposure data should be integrated by early indicators predictive of possible health effects, particularly for vulnerable groups such as mother-child pairs. Research need include: non-invasive biomarkers for children biomonitoring; novel biomarkers of total exposure to measure whole endocrine disrupter-related burden; characterization of biomarkers of susceptibility, including the role of markers of nutritional status; anchoring early molecular markers to established toxicological endpoints to support their predictivity; integrating "omics"-based approaches in a system-toxicology framework. As biomonitoring becomes increasingly important in the environment-and-health scenario, toxicologists can substantially contribute both to the characterization of new biomarkers and to the predictivity assessment and improvement of the existing ones.

[Pesticides use by flower companies associated with the Colombian Association of Flower Exporters]. / Descripción del uso y manejo de plaguicidas en las empresas de flores afiliadas a Asocolflores.

INTRODUCTION: In Colombia, pesticide exposure has became a public health problem, as the use of these substances continues to increase. OBJECTIVE: The current study accumulated information concerning pesticides used by flower companies in Bogotá and Rionegro (Antioquia) that were associated with Asociación Colombiana de Exportadores de Flores (Asocolflores) in Colombia. MATERIALS AND METHODS: Eighty-four companies were stratified by geographic location and size. Company and worker information was collected, and for each company, the process of pesticide application and maintenance of the cultivated flowers was carefully observed. Univariate and bivariate, and correlation analyses were applied for data analysis. RESULTS: Sex of workers was 39.4% male and 60.6% female. Pesticides were grouped into 4 toxicity classes: 14.3% were class I, 14.4% class II, 52.0% class III, and 19.2% class IV. Dithiocarbamates was the group of pesticides more commonly used (11.7%). The equipment most frequently used for pesticide application was the "bomba móvil" (92.8%), and the "lanza" (92.9%). Cholinesterase activity measured by the Michel-Aldrige method was the biological marker for exposure to pesticides used in 85.9% of the companies. Recommendations for improvements in their use and for measures to further reduce exposure of workers are made.

Impacto da legislação no registro de agrotóxicos de maior toxicidade no Brasil / Impact of legislation on registration of acutely toxic pesticides in Brazil

OBJETIVO: Avaliar o impacto da aplicação da "Lei dos Agrotóxicos" (Lei nº 7.802/89) no perfil da classificação toxicológica dos agrotóxicos registrados no Brasil no período de 1990 a 2000. MÉTODOS: Analisaram-se dados dos produtos comerciais que se encontravam registrados nos anos de 1990 e 2000, segundo a classe toxicológica, época do registro do ingrediente ativo (anterior ou posterior à Lei) e classe de uso (inseticidas, fungicidas, herbicidas e outros). Utilizou-se o teste de qui-quadrado de tendência em dados ordenáveis para verificar diferença estatística entre as distribuições segundo as classes toxicológicas. RESULTADOS: Dos 863 produtos comerciais que estavam registrados em 2000, 46,6 por cento já se encontravam registrados antes da "Lei dos Agrotóxicos". Dos 461 produtos registrados após essa Lei, 59,2 por cento eram derivados de ingredientes ativos que já estavam registrados anteriormente à mesma e 41,4 por cento estavam nas classes toxicológicas I e II, de maior periculosidade. Não foi constatada diferença significativa entre a distribuição, segundo a classe toxicológica, dos produtos derivados dos ingredientes ativos "antigos", que estavam registrados antes da Lei e a dos "novos", que foram registrados após a Lei (p<0,0859). CONCLUSÕES: Passados dez anos da promulgação da "Lei dos Agrotóxicos", não foi identificada melhoria expressiva no perfil da classificação toxicológica do conjunto dos agrotóxicos registrados. Deve-se isso sobretudo à permanência de registros anteriores à Lei, ao registro de produtos derivados de ingredientes ativos "antigos" e à continuidade de elevadas proporções de registros nas classes de maior periculosidade. Recomenda-se restabelecer a reavaliação periódica obrigatória de todos os produtos registrados.

[The agrochemical arsenal versus the enemies of plants. General considerations]. / L'arsenal phytosanitaire face aux ennemis des plantes. Considérations générales.

Plants are attacked, not only by various microorganisms, but also by other enemies, such as molluscs, nematods, mites, and insects. They have evolved complex and efficient mechanisms to defend themselves against pathogens (hypersensitive response, systemic acquired resistance) and herbivores (release of volatile compounds that attract predators of the herbivores, accumulation of proteinase inhibitors). Yet, the confrontation of the plants with their invaders can also turn to the advantage of the latter. In the past, the attacks of crops regularly brought about dramatic economic losses. From the World War II onwards, the development of organic chemistry associated with a growing awareness of the problems of agriculture has resulted in the production of a constantly growing number of plant protection products. They are currently divided into about ten classes, the herbicides, fungicides, and insecticides-acaricides making up more than 90% of the world market. Most of the agrochemical products put on the market over these last three decades are used in relatively low doses and have a more favourable toxicological and ecotoxicological profile than those of the former pesticides, many of which are now withdrawn from the market. Several more or less recent families are derivatives of metabolites from various organisms. Thus, the improvement achieved in the protection of crops is outstanding. However, one on the main side-effect is an environmental imbalance that has entailed a dependency on agrochemicals. Quite judiciously, alternative strategies (elicitors, genetic engineering, etc.) have been initiated or developed over the last decade.

Controlled release urea as a nitrogen source for spring wheat in Western Canada: yield, grain N content, and N use efficiency.

Controlled release nitrogen (N) fertilizers have been commonly used in horticultural applications such as turf grasses and container-grown woody perennials. Agrium, a major N manufacturer in North and South America, is developing a low-cost controlled release urea (CRU) product for use in field crops such as grain corn, canola, wheat, and other small grain cereals. From 1998 to 2000, 11 field trials were conducted across western Canada to determine if seed-placed CRU could maintain crop yields and increase grain N and N use efficiency when compared to the practice of side-banding of urea N fertilizer. CRU was designed to release timely and adequate, but not excessive, amounts of N to the crop. Crop uptake of N from seed-placed CRU was sufficient to provide yields similar to those of side-banded urea N. Grain N concentrations of the CRU treatments were higher, on average, than those from side-banded urea, resulting in 4.2% higher N use efficiency across the entire N application range from 25 to 100 kg ha(-1). Higher levels of removal of N in grain from CRU compared to side-banded urea can result in less residual N remaining in the soil, and limit the possibility of N losses due to denitrification and leaching.

[Agricultural antiparasitics evaluated for their potential cancerogenic, mutagenic and toxic reproductive effects]. / Antiparassitari agricoli valutati per potenziali effetti cancerogeni, mutageni E tossico-riproduttivi.

This paper reviews the evaluations of the potential carcinogenic, mutagenic and toxic-reproductive effects of the active ingredients and solvents contained in the pesticide products used in Italy. The information on the products (name and CAS number of the active ingredients and of the solvents, number of the products in which they are present, and the range of concentration percentages of a.i.) were obtained from the Pesticide Registry, a database operating at the Italian National Institute of Health since 1985. The evaluations of the toxic effects of these products are those which have been formulated by the Italian National Advisory Toxicological Committee, the European Union, the International Agency for Research on Cancer, and the Environmental Protection Agency of the United States. The aim of this study was to present an ample organic review of the main information issued by national and international centers on pesticides, chemicals of wide occupational use and diffusion in the environment. The presence is highlighted of some substances with carcinogenic potential (for example, 1,3-dichloropropene, alachlor, formaldehyde) for which it is therefore, necessary to carry out a careful risk assessment regarding exposure to many substances for which further study is indicated, and for others which have not, so far, produced toxic effects (bentazon, cypermetrin). Benzene "a proven human carcinogen" was present in three products. In addition, the presence was observed out of mixtures of active ingredients and solvents for which clear evidence of carcinogenic and/or reproductive toxicity exists. This information can be useful to assess the carcinogenic risk associated to pesticides in the occupationally exposed population, as also established in official regulations.

Pesticide-related dermatoses in agricultural workers.

We need to improve education of farm workers and their families to the potential hazards of exposure to the chemicals and other agents that they are in contact with on a daily basis. Simple measures such as showers in the fields and a change of clothes after work might lower the cutaneous reactions to these chemicals significantly. To that end, physicians can better educate themselves to highlight this area more intensely to residents in training, to offer lectures on the subject at dermatology conferences, and to foster better communication between our public health agencies and the pesticide industry itself. Companies are often cooperative when made aware of the benefits of irritant- and allergic-potential testing. Pesticide registration should require from the companies patch-testing before the product comes to market to determine the threshold irritant concentration and irritant potential of the vehicle.