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1.
Regul Toxicol Pharmacol ; 150: 105641, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38723937

RESUMO

In dietary risk assessment of plant protection products, residues of active ingredients and their metabolites need to be evaluated for their genotoxic potential. The European Food Safety Authority recommend a tiered approach focussing assessment and testing on classes of similar chemicals. To characterise similarity, in terms of metabolism, a metabolic similarity profiling scheme has been developed from an analysis of 69 α-chloroacetamide herbicides for which either Ames, chromosomal aberration or micronucleus test results are publicly available. A set of structural space alerts were defined, each linked to a key metabolic transformation present in the α-chloroacetamide metabolic space. The structural space alerts were combined with covalent chemistry profiling to develop categories suitable for chemical prioritisation via read-across. The method is a robust and reproducible approach to such read-across predictions, with the potential to reduce unnecessary testing. The key challenge in the approach was identified as being the need for metabolism data individual groups of plant protection products as the basis for the development of the structural space alerts.


Assuntos
Acetamidas , Herbicidas , Testes de Mutagenicidade , Acetamidas/toxicidade , Acetamidas/química , Medição de Risco , Herbicidas/toxicidade , Herbicidas/química , Resíduos de Praguicidas/toxicidade , Humanos , Mutagênicos/toxicidade , Mutagênicos/química , Animais
2.
Regul Toxicol Pharmacol ; 144: 105484, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37633329

RESUMO

In dietary risk assessment of plant protection products, residues of active ingredients and their metabolites need to be evaluated for their genotoxic potential. The European Food Safety Authority recommend a tiered approach focussing assessment and testing on classes of similar chemicals. To characterise similarity, in terms of metabolism, a metabolic similarity profiling scheme has been developed from an analysis of 46 chemicals of strobilurin fungicides and their metabolites for which either Ames, chromosomal aberration or micronucleus test results are publicly available. This profiling scheme consists of a set of ten sub-structures, each linked to a key metabolic transformation present in the strobilurin metabolic space. This metabolic similarity profiling scheme was combined with covalent chemistry profiling and physico-chemistry properties to develop chemical categories suitable for chemical prioritisation via read-across. The method is a robust and reproducible approach to such read-across predictions, with the potential to reduce unnecessary testing. The key challenge in the approach was identified as being the need for metabolism data and individual groups of plant protection products as the basis for the development of such profiling schemes.

3.
Regul Toxicol Pharmacol ; 129: 105115, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35017022

RESUMO

In dietary risk assessment, residues of pesticidal ingredients or their metabolites need to be evaluated for their genotoxic potential. The European Food Safety Authority recommend a tiered approach focussing assessment and testing on classes of similar chemicals. To characterise similarity and to identify structural alerts associated with genotoxic concern, a set of chemical sub-structures was derived for an example dataset of 74 sulphonyl urea agrochemicals for which either Ames, chromosomal aberration or micronucleus test results are publicly available. This analysis resulted in a set of seven structural alerts that define the chemical space, in terms of the common parent and metabolic scaffolds, associated with the sulphonyl urea chemical class. An analysis of the available profiling schemes for DNA and protein reactivity shows the importance of investigating the predictivity of such schemes within a well-defined area of structural space. Structural space alerts, covalent chemistry profiling and physico-chemistry properties were combined to develop chemical categories suitable for chemical prioritisation. The method is a robust and reproducible approach to such read-across predictions, with the potential to reduce unnecessary testing. The key challenge in the approach was identified as being the need for pesticide-class specific metabolism data as the basis for structural space alert development.


Assuntos
Resíduos de Praguicidas/toxicidade , Compostos de Sulfonilureia/toxicidade , Aberrações Cromossômicas/induzido quimicamente , Testes de Mutagenicidade , Resíduos de Praguicidas/química , Relatório de Pesquisa , Compostos de Sulfonilureia/química
4.
Regul Toxicol Pharmacol ; 106: 55-67, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31028797

RESUMO

We describe a novel experimental method that mimics exposure to dried agrochemical residues on contact surfaces during re-entry into crops. It includes the creation of dry dislodgeable residues and subsequent transfer to human skin for in vitro measurement of dermal absorption within a standard Organisation for Economic Co-operation and Development test guideline (OECD TG) 428 study. A pre-determined volume of spray containing 14C-labelled active substance is transferred onto a polytetrafluorethylene-coated septum and air-dried. The septum is then gently placed onto the pre-wetted skin mounted in a flow-through Franz diffusion chamber. The septum is gently rotated thrice to transfer the dose. Preliminary tests determined transfer efficiency to ensure the appropriate test concentration on the skin. Then, a standard dermal absorption study is performed according to OECD TG 428. Results from 10 compounds indicate that the methodology can be robustly incorporated into a standard TG study. These data show that the dermal absorption from a dry dislodgeable residue is lower than that from the equivalent dose of the aqueous spray, regardless of formulation type or active substance. Studies following the scenario described above can be a suitable tool to better estimate dermal absorption from dry residues in re-entry worker and resident exposure assessment for agrochemicals.


Assuntos
Agroquímicos/metabolismo , Organização para a Cooperação e Desenvolvimento Econômico , Resíduos de Praguicidas/metabolismo , Absorção Cutânea , Pele/metabolismo , Agroquímicos/química , Agroquímicos/farmacocinética , Difusão , Humanos , Resíduos de Praguicidas/química , Resíduos de Praguicidas/farmacocinética , Pele/química
5.
Regul Toxicol Pharmacol ; 72(1): 58-70, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25765508

RESUMO

Dermal absorption is a key parameter in non-dietary human safety assessments for agrochemicals. Conservative default values and other criteria in the EFSA guidance have substantially increased generation of product-specific in vitro data and in some cases, in vivo data. Therefore, data from 190 GLP- and OECD guideline-compliant human in vitro dermal absorption studies were published, suggesting EFSA defaults and criteria should be revised (Aggarwal et al., 2014). This follow-up article presents data from an additional 171 studies and also the combined dataset. Collectively, the data provide consistent and compelling evidence for revision of EFSA's guidance. This assessment covers 152 agrochemicals, 19 formulation types and representative ranges of spray concentrations. The analysis used EFSA's worst-case dermal absorption definition (i.e., an entire skin residue, except for surface layers of stratum corneum, is absorbed). It confirmed previously proposed default values of 6% for liquid and 2% for solid concentrates, irrespective of active substance loading, and 30% for all spray dilutions, irrespective of formulation type. For concentrates, absorption from solvent-based formulations provided reliable read-across for other formulation types, as did water-based products for solid concentrates. The combined dataset confirmed that absorption does not increase linearly beyond a 5-fold increase in dilution. Finally, despite using EFSA's worst-case definition for absorption, a rationale for routinely excluding the entire stratum corneum residue, and ideally the entire epidermal residue in in vitro studies, is presented.


Assuntos
Praguicidas/química , Praguicidas/metabolismo , Absorção Cutânea/fisiologia , Pele/metabolismo , Humanos , Medição de Risco , Solventes/química , Solventes/metabolismo , Água/química , Água/metabolismo
6.
Carcinogenesis ; 32(11): 1675-83, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21856997

RESUMO

Epidemiological data indicate that intake of estrogens and isoflavones may be beneficial for the prevention of colorectal cancer (CRC). Based on this data, the aim of the study was to investigate estrogen receptor (ER) subtype-specific effects on intestinal homeostasis. Ovariectomized (OVX) female Wistar rats were either treated with 17ß-estradiol (4 µg/kg body wt/day) (E2), an ERα-specific agonist (ALPHA) (10 µg/kg body wt/day), an ERß-specific agonist (BETA) (100 µg/kg body wt/day) or genistein (GEN) (10 mg/kg body wt/day) for three weeks. Vehicle-treated OVX and SHAM animals and those cotreated with BETA and the pure antiestrogen Fulvestrant (ICI 182780) (100 µg/kg body wt/day and 3 mg/kg body wt/day) served as controls. GEN and BETA treatment but not E2 and ALPHA administration reduced proliferation in ileal and colonic mucosa cells. The rate of apoptosis in the small intestine and colon was increased by treatment with BETA and GEN, but not by E2. BETA induced antiproliferative and proapoptotic activity also in SHAM animals. The effects were antagonized by the pure antiestrogen Fulvestrant. Polymerase chain reaction gene array analysis revealed that BETA resulted in the downregulation of the oncogene transformation-related protein 63 (p63). Our data indicate that activation of the ERß by specific ERß agonists and GEN induces antiproliferative and proapoptotic effects in the intestinal tract. This observation can be taken as an indication that intake of GEN and specific ERß agonists may protect the ileal and colonic epithelium from tumor development via modulation of tissue homeostasis.


Assuntos
Anticarcinógenos/farmacologia , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/agonistas , Receptor beta de Estrogênio/agonistas , Genisteína/farmacologia , Intestino Grosso/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Western Blotting , Sinergismo Farmacológico , Estradiol/análogos & derivados , Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios/farmacologia , Feminino , Fulvestranto , Perfilação da Expressão Gênica , Técnicas Imunoenzimáticas , Intestino Grosso/metabolismo , Intestino Delgado/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
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