38 research outputs found
Genotoxicity in risk assessment : is it time to use a threshold approach?
No full textSubstances that act via a genotoxic mechanism are considered to follow a low dose linear relationship with the absence of a threshold. The discussion on the existence of a threshold for genotoxic (mutagenic and clastogenic) compounds appears sometimes more an academic exercise than of practical use in public health. However, pragmatically, determination of the PoD, i.e. the dose/concentration from which we derive acceptable exposure levels, should be the goal. This will include appropriate dose response data analysis, with statistically defensible methods and use of mechanistic data, and application of adequate uncertainty factors. The best and full use of the quantitative information can be used to analyse dose–response data, and dismiss the binary classification scheme for use in risk assessment and management. Certainly, in areas such as the relationship between the genotoxic and the carcinogenic effect, the appropriate BenchMark Response (BMR) to be used, the relation between effects in target tissues vs those observed in surrogate tissues, and the uncertainty of our measurements there is a need of more solid data. While the simple binary classification scheme can be of some help for screening and prioritization of substances that need further scrutiny, it is not an adequate tool to be used for risk management decisions. The final step of the assessment for guiding management decisions should be quantitative to the extent possible. Accepting the threshold approach on which to base the risk management decisions has significant beneficial economic and societal impact and implications
RISK 21: an innovative approach for human risk assessment and its application in occupational exposure to plant protection products in viticulture
No full textRISK21 (Risk Assessment in the 21st Century, www.risk21.org) is an initiative developed by the Health and Environmental Sciences Institute (HESI) aimed at proposing a transparent and efficient scientific approach for the assessment of human risk deriving from exposure to chemical compounds. It is a result of six years of work that involved a broad group of experts from academia, industries, government authorities and non-governmental organizations from Europe and North America. The ultimate goal of RISK21 was to create a simple application, flexible, accurate and resources-
based tool for human risk assessment. The added value of RISK21 conceptual risk assessment framework consists on problem formulation which guides the assessor in defining data, tools and procedures for decision taking and finalization of the evaluation. Exposure is assessed soon after problem formulation in order to guide the evaluation making an efficient use of all available information. The allocation of additional resources to retrieve or generate further information, or to define a strategy to take a decision is carried out only if needed. The conceptual framework principles and approach of RISK21 have been extensively described and detailed by Embry et al. (2014) and Pastoor et al. (2014).
The present work shows a case study aimed at emphasizing RISK21 potentiality by its application in regulatory tiered approach risk assessment of agricultural workers exposed to plant protection products (PPP) residues in viticulture
Moderate alcohol consumption during pregnancy increases potency of two different drugs (the antifungal fluconazole and the antiepileptic valproate) in inducing craniofacial defects: prediction by the in vitro rat whole embryo culture
No full textThe prenatal exposure to ethanol (Eth), fluconazole (FLUCO) and sodium valproate (VPA) is related to effects on development, producing characteristic syndromic pictures. Among embryotoxic effects described for the three molecules, the alteration on craniofacial morphogenesis is a common feature in humans and animal models, including rodent embryos developed in vitro. The aim of the present work is to evaluate the developmental effects of low Eth serum concentration (17 mM, corresponding to the legal limit to drive in UK, USA, Canada, and many other countries) in mixture with increasing realistic concentrations of the antifungal drug FLUCO (62.5–500 μM) or with increasing realistic concentrations of the antiepileptic drug VPA (31.25–250 μM). Groups exposed to Eth alone (17–127.5 mM), FLUCO alone (62.5–500 μM) or VPA alone (31.25–750 μM) were also included. The chosen alternative animal model was the post-implantation rat whole embryo culture (WEC). E9.5 embryos were exposed in vitro to the test molecules during the whole test period (48 h, corresponding to the developmental stages characteristics of any vertebrate, for human embryos post-fertilization days 23–31). Data were statistically analyzed and processed for modelling applying the benchmark dose (BMD) and relative potency factor (RPF) approaches. Concentration-related effects on facial outcomes were observed in all experimental groups, with a significant enhancement in the groups co-exposed with Eth in comparison to the single exposures. Data obtained by the present work suggest an additional alert for the assumption of even low levels of alcohol in pregnant women during FLUCO or VPA therapy
Relative potency ranking of azoles altering craniofacial morphogenesis in rats : an in vitro data modelling approach
No full textFacial malformations represent one of the most frequent abnormality in humans. The adverse outcome pathway involved in facial defects seems to be related to retinoic acid (RA) pathway imbalance. Environmental agents inducing craniofacial malformations in experimental models include pesticides (especially azole fungicides). By using the in vitro alternative method postimplantation rat whole embryo culture (WEC), we evaluated the intrinsic embryotoxic activity of some azole antifungals (cyproconazole, CYPRO; triadimefon, FON; flusilazole, FLUSI; and prochloraz, PCZ), in comparison to RA. All the tested molecules induced in a dose-related manner specific defects of the craniofacial structures (fused branchial arches), similar to those induced by RA. Collected data were modelled using PROAST 65.5 software to characterise the relative potency factors (RPFs) versus RA. In comparison to RA, all the evaluated azoles were less potent, showing among them a similar potency. Our data suggest a possible azole-related RA signalling perturbation to be further investigated. Moreover, the present results indicate the approach used in this work to be an interesting tool applicable to the hazard evaluation of novel compounds or the assessment of combined exposure to azoles or other dismorphogens
Advantages and disadvantages of the use of Xenopus laevis embryos and Zebra fish as alternative methods to assess teratogens
No full textTraditional teratological protocols in mammals are mandatory for pharmaceutical and chemical product registration, but require hundreds of animals and are complex and money/time-consuming. Among alternative methods, low vertebrate (the teleost zebrafish and the amphibian Xenopus) whole embryo
developmental toxicological tests appear evolutionary closer to humans than invertebrates and produce more useful data for human health extrapolation. At least during early stages, in fact, all vertebrate embryos share, from both morphological and molecular point of view, developmental pathways. By
consequence similar toxicological responses of embryos to toxicant are expected. Advantages and disadvantages of these two alternative whole organism tests are briefly reviewed
Predisposizione e valutazione critica di scenari di esposizione in ambito REACh: sostanze ad attività disendocrina (Ftalati).
No full textThe new REACH legislation formally introduces the control and development of exposure scenarios for substances deemed capable of altering the hormonal system. Example of compounds that alter the endocrine system (endocrine disruptors) and subject of this thesis are the phthalates.
Phthalates are organic chemicals derived by esterification of phthalic anhydride. They are used to make soft and flexible a variety of products, including toys. These articles are used by children, most likely subpopulation.
The main objective of the project is to conduct a risk assessment for these substances. The first phase of the evaluation was to determine the toxic properties of these substances (by literature search), after that, taking into account the most likely population, we have been developed hypothetical scenarios of exposure (using the software ConsExpo) for 3 classes: Babies (4.5 months), newborn (7.5 months), children (13.5 months).
Finally, to perform the risk characterization, was made in connection the dangers of these substances with the exposure and was rated the likelihood or occurrence of adverse effects on children.
The results obtained from the risk assessment (using as a method the Margin of Safety), lead to the conclusion that there is a negligible risk in the use of toys containing phthalates even if concentration was above legal limits (DEHP: 43.3%, and DINP: 49.9%).
Although the results are encouraging, in the future will need to conduct further analysis and risk assessment for phthalates, taking into account the cumulative effect of the different phthalates and the effect of phthalates and other substances with the same mechanism of action or the same target organs
Cumulative risk assessment methodology applied to non-dietary exposures: developmental alterations in professional agricultural settings
No full textAbstract The safety assessment of combined exposure to xenobiotics has been an emerging topic for several years. Methodologies and approaches for cumulative risk assessment (CRA) are being developed primarily for the dietary risk assessment of pesticides, thus focusing only on consumer exposure. However, as highlighted in recent years, non-dietary exposures, such as those encountered by professionals in agricultural settings, may pose a significant risk due to their higher levels compared to dietary exposure. Despite this, existing methodologies for cumulative risk assessment (CRA) have not adequately addressed this critical aspect. In the EU, even if several legislations highlight the need to address the non-dietary CRA, no legal requirements are in place yet, therefore, there are no harmonized methodologies and approaches currently available. In a first step to fill this gap, this study is aimed at exploring CRA methodology applied to non-dietary exposure to pesticide in agricultural settings, specifically targeting operators, re-entry workers, and bystanders. The primary objective of the study was to verify the feasibility of an electronic register of plant protection treatments as data source for identifying and characterizing in field mixtures and consequently estimating cumulative non-dietary systemic exposure in real life. The relevant active substances selected for this investigation were those listed in foetal craniofacial alterations cumulative assessment groups (CAGs), established by the European Food Safety Authority (EFSA) for dietary CRA. Exposures to pesticides were estimated using European Union agreed mathematical models. The preliminary findings of this investigation effectively revealed the value of the register of treatments in assessing real-life plant protection products (PPP) usage in professional agricultural settings. In conclusion, the study provides encouraging insights into using the pesticide dietary CRA approach for non-dietary risk assessment in agricultural settings, underlining the necessity for further research and investigation of its feasibility for the evaluation of other acute effects but also for long-term effects related CAGs
Insecticides
No full textInsecticides include a variety of compounds that act against different target species targeting different receptors, enzymes or functions. Hence, there are many chemical groups that also present different species specificity and toxicity for humans. They are used in agriculture, in public health to fight against vectors of disease or nuisance insects, and in veterinary medicine. Some, for example, avermectins, are also used in human medicine. In general, they act on different molecular targets within the nervous system with variable species specificity. For instance, carbamates inhibit acetylcholinesterase (AChE) without significant differences in potency between insects and mammals, while there is a significantly higher sensitivity to neonicotinoids of insects' nicotinic receptors as compared to mammalian ones. Also, significant differences in metabolism are responsible of the low toxicity of pyrethroids to mammalians as compared to insects. Application of insecticides is usually upwards; hence, human exposure during their application may be higher than that following the application of herbicides. Factors that impact on the level of exposure include the amount of active ingredient per hectare, water volume (dilution), the protective equipment used. Dermal exposure is considered to be the most relevant, inhalation accounting for about 10% of total exposure. The Insecticide Resistance Action Committee (IRAC) lists mode of actions and related compounds (www.irac-online.org). It will not be possible to deal with all compounds in this chapter. Therefore, groups with significant current uses will be dealt with. In addition, organophosphates are considered in a separate chapter
Herbicides
No full textHerbicides are used in agriculture to eliminate weeds that would otherwise damage the crop of interest or to provide practical advantages in facilitating the harvesting of crops (e.g., glyphosate on cereals). They are also used in areas of public interest (e.g., railways, public and private gardens, or lawns). Their phytotoxic action occurs either on the site of contact or following absorption by the plant and systemic translocation to other organs. Postemergence herbicides are applied on developed undesired weeds, while preemergence herbicides are typically applied on the ground soon after seeding of the desired culture to prevent weed's development. Herbicides have different selectivity for plants. The amount of global herbicide use has been increasing over the years, from approximately of 600,000 tonnes in 1990 to more than 1,200,000 tonnes yearly since 2011. When herbicides are applied downward, human exposure during their application may be less than that following the application of insecticides or fungicides. Exposure can quantitatively change if the application is performed by handheld or by vehicle, with the latter generally reporting a lower exposure. In addition, since herbicides exert their pesticidal mode of action on metabolic processes that are generally unique to plants, they are, in principle, of low toxicity in mammals with the notable exception of paraquat. Some herbicides were reported to have irritating properties. Formulated products may contain adjuvants (stabilizers, penetrants, surfactants, dispersants) that could have, alone or in combination, more severe toxicity or irritating properties than the active herbicide alone
