Challenges and opportunities for overcoming dog use in agrochemical evaluation and registration.

Progress in developing new tools, assays, and approaches to assess human hazard and health risk provides an opportunity to re-evaluate the necessity of dog studies for the safety evaluation of agrochemicals. A workshop was held where partic­ipants discussed the strengths and limitations of past use of dogs for pesticide evaluations and registrations. Opportunities were identified to support alternative approaches to answer human safety questions without performing the required 90-day dog study. Development of a decision tree for determining when the dog study might not be necessary to inform pesticide safety and risk assessment was proposed. Such a process will require global regulatory authority participation to lead to its acceptance. The identification of unique effects in dogs that are not identified in rodents will need further evaluation and determination of their relevance to humans. The establishment of in vitro and in silico approaches that can provide critical data on relative species sensitivity and human relevance will be an important tool to advance the decision process. Promising novel tools including in vitro comparative metabolism studies, in silico models, and high-throughput assays able to identify metabolites and mechanisms of action leading to development of adverse outcome pathways will need further development. To replace or eliminate the 90-day dog study, a collaborative, multidisciplinary, international effort that transcends organi­zations and regulatory agencies will be needed in order to develop guidance on when the study would not be necessary for human safety and risk assessment.

Integration of toxicodynamic and toxicokinetic new approach methods into a weight-of-evidence analysis for pesticide developmental neurotoxicity assessment: A case-study with DL- and L-glufosinate.

DL-glufosinate ammonium (DL-GLF) is a registered herbicide for which a guideline Developmental Neurotoxicity (DNT) study has been conducted. Offspring effects included altered brain morphometrics, decreased body weight, and increased motor activity. Guideline DNT studies are not available for its enriched isomers L-GLF acid and L-GLF ammonium; conducting one would be time consuming, resource-intensive, and possibly redundant given the existing DL-GLF DNT. To support deciding whether to request a guideline DNT study for the L-GLF isomers, DL-GLF and the L-GLF isomers were screened using in vitro assays for network formation and neurite outgrowth. DL-GLF and L-GLF isomers were without effects in both assays. DL-GLF and L-GLF (1-100 µM) isomers increased mean firing rate of mature networks to 120-140% of baseline. In vitro toxicokinetic assessments were used to derive administered equivalent doses (AEDs) for the in vitro testing concentrations. The AED for L-GLF was ∼3X higher than the NOAEL from the DL-GLF DNT indicating that the available guideline study would be protective of potential DNT due to L-GLF exposure. Based in part on the results of these in vitro studies, EPA is not requiring L-GLF isomer guideline DNT studies, thereby providing a case study for a useful application of DNT screening assays.

Incorporating human exposure information in a weight of evidence approach to inform design of repeated dose animal studies.

Human health risks from chronic exposures to environmental chemicals are typically estimated from potential human exposure estimates and dose-response data obtained from repeated-dose animal toxicity studies. Various criteria are available for selecting the top (highest) dose used in these animal studies. For example, toxicokinetic (TK) and toxicological data provided by shorter-term or dose range finding studies can be evaluated in a weight of evidence approach to provide insight into the dose range that would provide dose-response data that are relevant to human exposures. However, there are concerns that a top dose resulting from the consideration of TK data may be too low compared to other criteria, such as the limit dose or the maximum tolerated dose. In this paper, we address several concerns related to human exposures by discussing 1) the resources and methods available to predict human exposure levels and the associated uncertainty and variability, and 2) the margin between predicted human exposure levels and the dose levels used in repeated-dose animal studies. A series of case studies, ranging from data-rich to data-poor chemicals, are presented to demonstrate that expected human exposures to environmental chemicals are typically orders of magnitude lower than no-observed-adverse-effect levels/lowest-observed-adverse-effect levels (NOAELs/LOAELs) when available (used as conservative surrogates for top doses). The results of these case studies support that a top dose based, in part, on TK data is typically orders of magnitude higher than expected human exposure levels.

Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment.

Top dose selection for repeated dose animal studies has generally focused on identification of apical endpoints, use of the limit dose, or determination of a maximum tolerated dose (MTD). The intent is to optimize the ability of toxicity tests performed in a small number of animals to detect effects for hazard identification. An alternative approach, the kinetically derived maximum dose (KMD), has been proposed as a mechanism to integrate toxicokinetic (TK) data into the dose selection process. The approach refers to the dose above which the systemic exposures depart from being proportional to external doses. This non-linear external-internal dose relationship arises from saturation or limitation of TK process(es), such as absorption or metabolism. The importance of TK information is widely acknowledged when assessing human health risks arising from exposures to environmental chemicals, as TK determines the amount of chemical at potential sites of toxicological responses. However, there have been differing opinions and interpretations within the scientific and regulatory communities related to the validity and application of the KMD concept. A multi-stakeholder working group, led by the Health and Environmental Sciences Institute (HESI), was formed to provide an opportunity for impacted stakeholders to address commonly raised scientific and technical issues related to this topic and, more specifically, a weight of evidence approach is recommended to inform design and dose selection for repeated dose animal studies. Commonly raised challenges related to the use of TK data for dose selection are discussed, recommendations are provided, and illustrative case examples are provided to address these challenges or refute misconceptions.

Estudio de factores de riesgo para el desarrollo de pie diabético: Campaña 1N / A study of risk factors in the development of diabetic foot: 1N Campaign

Introducción: el examen del pie es fundamental en pacientes con diabetes mellitus (DM). La correcta evaluación del pie en el paciente que concurre a control diabetológico es clave para establecer factores de riesgo para el desarrollo de úlceras, detectar lesiones, tomar medidas preventivas, realizar una derivación temprana y educar en cuidados del pie. Objetivos: en este estudio se examinaron los pies de personas con DM durante la Campaña de Concientización y Prevención del Pie Diabético el 1º de noviembre de 2019 con el fin de evaluar la presencia de síntomas y signos relacionados con neuropatía, enfermedad vascular periférica, y prevalencia de los mismos, y conocer el riesgo. Materiales y métodos: se analizaron 165 pacientes en cuatro centros: Sanatorio Güemes (Servicio de Diabetes y Endocrinología), PREDIGMA (Centro de Medicina Preventiva, Posadas, Misiones), Hospital Central de San Isidro, Nexo Centro Médico (Ciudad de Junín) y Hospital Municipal de General Viamonte (Provincia de Buenos Aires). Resultados: se encontró que el 43,6% presentaba algún síntoma en miembros inferiores y hasta el 57% alteración en las pruebas de tamizaje de neuropatía diabética o enfermedad arterial periférica, con mayor prevalencia a mayor tiempo de evolución de la DM. Los signos más frecuentemente hallados en el examen físico fueron: piel seca (71,5%), distrofia ungueal (60,6%) o alteración de la almohadilla plantar (52,1%). Las comorbilidades más frecuentes fueron: hipertensión (74,5%) y dislipemia (73,3%). La mediana de hemoglobina glicosilada fue de 7,40% (6,70-8,10), mayor en personas con antecedentes de retinopatía (7,8%; p<0,01) y en pacientes que refirieron tener calambres (7,85 a 7,30; p=0,03) o ardor (8,0 vs 7,3; p<0,01). El porcentaje de pacientes con pie de alto riesgo por antecedentes, inspección o tamizaje de neuropatía o enfermedad vascular representó desde el 40% en aquellos con DM de menos de cinco años de evolución hasta el 86% en quienes tenían más de 20 años. Conclusiones: el elevado porcentaje de pacientes con pie de riesgo identificado en este estudio sugiere que, además del correcto examen físico, se requiere la toma de conductas por parte del médico tratante, como la indicación de plantillas o calzado adecuado, así como una fluida derivación al técnico en ortesis, traumatólogo o fisiatra.

Introduction: foot examination is essential in patients with diabetes mellitus (DM). The correct evaluation of the foot in the patient who attends diabetes control is key to establish risk factors for the development of ulcers, detect injuries, take preventive measures, make an early referral and educate in foot care. Objectives: in this study, the feet of people with DM were examined during the Diabetic Foot Awareness and Prevention Campaign on November 1, 2019 in order to assess the presence of symptoms and signs related to neuropathy, peripheral vascular disease, prevalence of the same and know the risk. Materials and methods: 165 patients were analyzed in four centers: Sanatorio Güemes (Diabetes and Endocrinology Service), PREDIGMA (Preventive Medicine Center, Posadas, Misiones), Central Hospital of San Isidro, Nexo Medical Center (Junín City) and Hospital Municipal of General Viamonte (Province of Buenos Aires). Results: it was found that 43.6% had some symptoms in the lower limbs and up to 57% had an alteration in the screening tests for diabetic neuropathy or peripheral arterial disease, with a higher prevalence the longer the evolution of DM. The most frequent signs found in the physical examination were: dry skin (71.5%), nail dystrophy (60.6%) or alteration of the foot pad (52.1%). The lost frequent comorbidities were: hypertension (74.5%) and dyslipidemia (73.3%). The median glycated hemoglobin was 7.40% (6.70-8.10), higher in people with a history of retinopathy (7.8%; p <0.01) and in patients who reported having cramps (7, 85 to 7.30; p = 0.03) or burning (8.0 vs 7.3; p <0.01). The percentage of patients with high-risk foot due to antecedents, inspection or screening for neuropathy or vascular disease represented from 40% in those with DM of less than five years of evolution to 86% in those who were older than 20 years. Conclusions: this high percentage of patients with foot at risk identified in this study suggests that, in addition to the correct physical examination, the attending physician requires the taking of behaviors, such as the indication of appropriate footwear or insoles, as well as a fluid referral to the orthotic technician, orthopedic surgeon, or physiatrist.

Efecto de los factores relacionados al cuidado de la diabetes mellitus tipo 2 y motivos de no adhesión en Argentina / Effect of factors related to the care of type 2 diabetes mellitus and reasons for non-adherence in Argentina

Introducción: analizar la injerencia de la adherencia al tratamiento en la evaluación clínica optimiza el uso de pruebas y evita intensificar tratamientos que pueden aumentar riesgos en los pacientes. Conocer sobre las variables influyentes implica el conocimiento y el control de factores relativos al cuidado de la diabetes mellitus tipo 2 (DM2). Objetivos: analizar el efecto de la adherencia al tratamiento en adultos con DM2 en Argentina. Materiales y métodos: estudio transversal. Se incluyeron 1.520 pacientes adultos con DM2 con tres o más meses de antigüedad de enfermedad residentes en Argentina. Se aplicó un cuestionario validado autorreferido. Se evaluó el grado de adherencia reportada, las recomendaciones dadas por el equipo de salud, las formas de adhesión y los motivos de incumplimiento por medio del Summary of Diabetes Self-Care Activities (SDSCA). Resultados: representando diferentes regiones geográficas, la media de adherencia general para todas las características fue 4,32 (61,71%); los peores puntajes para la adherencia correspondieron a la actividad física, el monitoreo glucémico y la dieta en orden ascendente. Se observaron carencias en las recomendaciones por parte del equipo de salud al momento de indicar medidas higiénico dietéticas. Conclusiones: los resultados nacionales observados guardan similitud en la dieta, la actividad física y la disminución en el consumo de tabaco con respecto a los datos prevalentes proveniente de la Cuarta Encuesta Nacional de Factores de Riesgo

Introduction: analyzing the interference of adherence to treatment in clinical evaluation optimizes the use of tests and avoids intensifying treatments that may increase risks in patients. Knowing about the influential variables implies the knowledge and control of factors related to the care of diabetes mellitus type 2 (T2D). Objectives: to analyze the effect of adherence to treatment in adults with T2D in Argentina. Materials and methods: transversal study. We included 1.520 adult patients with T2D with 3 or more months of illness in Argentina. A validated self-reported questionnaire was applied. The degree of adherence reported, the recommendations given by the health team, the forms of adherence and the reasons for non-compliance through the Summary of Diabetes Self-Care Activities (SDSCA) were evaluated. Results: representing different geographical regions, the mean of general adherence for all the characteristics was 4.32 (61.71%); the worst scores for adherence corresponded to physical activity, glycemic monitoring and diet in ascending order. There were shortcomings in the recommendations by the health team when indicating hygienic dietary measures. Conclusions: the observed national results are similar in diet, physical activity and the decrease in tobacco consumption with respect to prevailing data from the Fourth National Survey of Risk Factors.

Calidad de vida y prestaciones en salud de pacientes con diabetes mellitus tipo 2 según región geográfica en Argentina / Quality of life and health benefits in patients with type 2 diabetes according to geography region in Argentina

Introducción: la adherencia al tratamiento de la diabetes mellitus tipo 2 (DM2) en el adulto es un tema complejo y multifactorial que aúna aspectos propios de la enfermedad como no propios, los cuales impactan en la calidad de vida. En Argentina se presentan grandes dificultades al costear la totalidad del tratamiento de la enfermedad. El impacto del ingreso sobre el gasto en salud en DM2 es mayor para los niveles más bajos de ingresos. Objetivos: analizar en adultos con DM2 en Argentina diferencias en variables de calidad de vida y objetivos metabólicos según regiones geográficas y prestación en salud; conocer el gasto de bolsillo en salud y los costos en salud vinculados a DM2; establecer la asociación entre el gasto de bolsillo con variables socioeconómicas y el cumplimiento de los objetivos metabólicos. Materiales y métodos: sobre ocho regiones geográficas de la República Argentina se incluyeron 1.520 pacientes adultos con DM2 y se los clasificó según prestación en salud (sin prestación, con prestación o jubilados). Se aplicó cuestionario validado autorreferido. Resultados: se encontraron diferencias significativas por región geográfica para jubilación prematura por DM2, pérdida de percepción de calidad de vida y cumplimiento de los objetivos metabólicos. Se encontró significancia estadística del gasto de bolsillo con la presencia de subsidio familiar, la jubilación prematura por DM2 y el cumplimiento de los objetivos metabólicos. Conclusiones: se observó disparidad entre las variables de calidad de vida, el gasto en salud y la percepción de subsidios

Introduction: adherence to treatment of diabetes mellitus type 2 (DT2) in the adult is a complex and multifactorial issue that combines aspects of the disease as not own, which impact on the quality of life. In Argentina there are great difficulties in paying for the entire treatment of the disease. The impact of income on health spending in DT2 is greater for lower income levels. Objectives: to analyze differences in quality of life and metabolic objectives according to geographic regions and health benefits in adults with DT2 in Argentina; know the out of pocket expenses in health and health costs linked to DT2; establish an association between out of pocket spending with socioeconomic variables and compliance with metabolic objectives. Materials and methods: over eight geographic regions of the Argentine Republic, 1.520 adult patients with DT2 were classified according to health benefit (without benefit, with benefits or retirees). Validated self-reported questionnaire was applied. Results: significant differences were found by geographic region for premature retirement due to DT2, the loss of perception of quality of life and the fulfillment of metabolic objectives. Statistical significance of out-of-pocket spending was found with the presence of family allowance, early retirement by DT2 and compliance with metabolic objectives. Conclusions: disparity between the variables of quality of life, health expenditure and perception of subsidies was observed

Adherencia al tratamiento en pacientes con diabetes mellitus tipo 2 en Argentina durante 2015 / Adherence to treatment in patients with type 2 diabetes melltius in Argentina during 2015

Introducción: la interrupción en la adherencia a los tratamientos prescriptos genera obstáculos importantes los cuales impactan negativamente en los indicadores de salud. Objetivos: evaluar la adherencia al tratamiento en pacientes adultos con diabetes mellitus tipo 2 (DM2) en Argentina, y establecer la asociación con el tipo de prestación de atención en salud y la ubicación geográfica. Materiales y métodos: se incluyeron 1.520 individuos pertenecientes a ocho regiones diferentes de la República Argentina durante 2015. Se realizó un estudio transversal. Se aplicó un cuestionario validado autorreferido de opciones múltiples con respuestas policotómicas de puntuación simple. Se empleó una escala cuantitativa y un análisis multivariado de componentes principales. Resultados: la edad media fue de 60,2 años y la antigüedad de DM2 referida correspondió a 10,1 años. La media de HbA1c fue de 7,85%. La media de adherencia general para todas las características fue 4,32 (61,71%). Los resultados de adherencia encontrados se asemejan a otros países en desarrollo a excepción del cuidado de los pies. El factor cuidado de los pies en nuestro país reporta escalas de mayor adherencia. Se detectaron resultados tal vez redundantes como la mayor adherencia al monitoreo en las terapias de uso con insulina, y menores para dieta, ejercicio y solo uso de antidiabéticos orales (ADO), así como también la mayor adherencia en medicación en las terapias con insulina e insulina más ADO. Conclusiones: son alarmantes las bajas escalas referidas al grupo con solo dieta y ejercicio

Introduction: the interruption in the adherence to the prescribed treatments generates important obstacles which negatively impact on health indicators. Objectives: to evaluate adherence to treatment in adult patients with diabetes mellitus type 2 (DT2) in Argentina; associate with the type of health care provision and location. Materials and methods: we included 1.520 individuals belonging to eight different geographical regions of the Argentine Republic during 2015. A cross-sectional study was conducted. A self-reported validated questionnaire of multiple options with simple scoring polycotomic responses was applied. A quantitative scale and a multivariate analysis of main components were applied. Results: the average age was 60.2 years and the seniority of the referred DT2 corresponded to 10.1 years. The average HbA1c was 7.85%. The average general adherence for all characteristics was 4.32 (61.71%). The adherence results found are similar to other developing countries except for the care of the feet. The care factor of the feet in our country report scales of greater adherence. Redundant results are observed, such as greater adherence to monitoring in insulin therapy and less for diet and exercise and only oral antidiabetic drugs (ADO), as well as greater medication adherence in insulin and insulin therapies more ADO. Conclusions: the low scales referred to the group with only diet and exercise are alarming

Profiling the reproductive toxicity of chemicals from multigeneration studies in the toxicity reference database.

Multigeneration reproduction studies are used to characterize parental and offspring systemic toxicity, as well as reproductive toxicity of pesticides, industrial chemicals and pharmaceuticals. Results from 329 multigeneration studies on 316 chemicals have been digitized into standardized and structured toxicity data within the Toxicity Reference Database (ToxRefDB). An initial assessment of data quality and consistency was performed prior to profiling these environmental chemicals based on reproductive toxicity and associated toxicity endpoints. The pattern of toxicity across 75 effects for all 316 chemicals provided sets of chemicals with similar in vivo toxicity for future predictive modeling. Comparative analysis across the 329 studies identified chemicals with sensitive reproductive effects, based on comparisons to chronic and subchronic toxicity studies, as did the cross-generational comparisons within the multigeneration study. The general pattern of toxicity across all chemicals and the more focused comparative analyses identified 19 parental, offspring and reproductive effects with a high enough incidence to serve as targets for predictive modeling that will eventually serve as a chemical prioritization tool spanning reproductive toxicities. These toxicity endpoints included specific reproductive performance indices, male and female reproductive organ pathologies, offspring viability, growth and maturation, and parental systemic toxicities. Capturing this reproductive toxicity data in ToxRefDB supports ongoing retrospective analyses, test guideline revisions, and computational toxicology research.

Stress and resilience in the oral histories of rural older women.

Oral history research has seldom focused on the reflections of rural older women. The purpose of this qualitative study was to identify: (a) stresses associated with major historical events that affected the lives of rural older women, and (b) strategies they used to deal with those stresses. Oral histories were gathered from a cross-section of 25 older women living in a small rural Midwestern community and analyzed using the method of constant comparison (Glaser & Straus, 1967). Content analysis revealed that economic hardship, disruption of family life, and fears and uncertainties were stressors associated with the Great Depression and world wars of the 20th century. Resilience was demonstrated by frugality, reliance on social supports, and acceptance. Implications for intervention with rural older women are discussed.

Introduction to the ILSI Research Foundation/Risk Science Institute reports from the expert working group on neurodevelopmental endpoints.

In 2004 the International Life Sciences Institute (ILSI) Risk Science Institute established an expert working group to assess the lessons learned from the implementation of standardized tests for developmental neurotoxicity in experimental animals. This introduction summarizes the working group process and the four reports from the expert working group addressing: the use of positive controls, understanding variability, appropriate statistical techniques, and interpretation. The reports address the 1991 US Environmental Protection Agency standardized protocol for evaluation of developmental neurotoxicity (DNT) and the 2007 Organisation for Economic Co-operation and Development (OECD) Test Guidelines for DNT. The EPA protocol is comprised of tests for evidence of deficits in neurobehavioral function, including auditory startle habituation, motor activity, associative learning and memory, and neuropathologic examination, including simple morphometric analysis.

Intravitreal triamcinolone for the treatment of diabetic macular edema.

Diabetic macular edema is one of the leading causes of visual loss in first world countries and the first cause in diabetic retinopathy. The Early Treatment Diabetic Retinopathy Study showed a significant benefit in using focal laser photocoagulation for the treatment of macular edema, more specifically defined as clinically significant macular edema. Nevertheless, progressive visual loss is found in the 26% of patients with diabetic macular edema treated with photocoagulation. The failure of laser treatment and the destructive nature of the therapy has forced researchers to pursue new alternatives including vitrectomy with or without internal limiting membrane peels, the use of proteinkinase C inhibitors, intravitreal injections of antibodies that inhibit the vascular endothelial growth factor, somatostatin analog, or the intravitreal injection with corticosteroids. Triamcinolone acetonide is glucocoticosteroid with antiangiogenic and antiedematous properties. Publications evaluating the safety and efficacy of intravitreal injection of triamcinolone in the treatment of diabetic macular edema show varying outcomes with respect to the increases of visual acuity and decreases in foveal thickness. Despite this, intravitreal triamcinolone is a treatment that has evolved quickly and is considered increasingly useful.

Diversidad y abundancia de moluscos en las praderas de Thalassia testudinum de la Bahía de Mochima, Parque Nacional Mochima, Venezuela / Diversity and abundance of molluscs in Thalassia testudinum prairie of the Bay of Mochinma, Mochima National Park, Venezuela

The diversity and abundance of benthic malacological communities associated to Thalassia testudinum beds was studied at four localities of Mochima Bay, Sucre state, Venezuela. At each locality, samples were taken monthly on perpendicular transect at different depths (0-4 m), from January 1991 to December 1991, using a quadrate (0.25 m2) for collecting mollusks and sediments. A total of 2,988 organisms of infauna and epifauna belonging to 81 species of the classes Gastropoda (41) and Bivalvia (40) were collected. More abundant species were Anadara notabilis, Codakia orbicularis, Cerithium litteratum, Cerithium eburneum, Batillaria minima, Modiolus squamosus, Modulus modulus, Chione cancellata, Turritella variegata, Arca zebra, y Laevicardium laevigatum. There were significant differences in number of organisms between depth and month at La Gabarra which presented the highest value of total (4.51 bits/ind) and monthly diversity (2.71-3.90 bits/ind). Biomass and abundance were low in the Mochima Bay while Varadero station presented the highest value. The bivalve A. notabilis and gastropod M. modulus were species common to the four stations.

[Diversity and abundance of molluscs in Thalassia testudinum prairie of the Bay of Mochinma, Mochima National Park, Venezuela]. / Diversidad y abundancia de moluscos en las praderas de Thalassia testudinum de la Bahía de Mochima, Parque Nacional Mochima, Venezuela.

The diversity and abundance of benthic malacological communities associated to Thalassia testudinum beds was studied at four localities of Mochima Bay, Sucre state, Venezuela. At each locality, samples were taken monthly on perpendicular transect at different depths (0-4 m), from January 1991 to December 1991, using a quadrate (0.25 m2) for collecting mollusks and sediments. A total of 2,988 organisms of infauna and epifauna belonging to 81 species of the classes Gastropoda (41) and Bivalvia (40) were collected. More abundant species were Anadara notabilis, Codakia orbicularis, Cerithium litteratum, Cerithium eburneum, Batillaria minima, Modiolus squamosus, Modulus modulus, Chione cancellata, Turritella variegata, Arca zebra, y Laevicardium laevigatum. There were significant differences in number of organisms between depth and month at La Gabarra which presented the highest value of total (4.51 bits/ind) and monthly diversity (2.71-3.90 bits/ind). Biomass and abundance were low in the Mochima Bay while Varadero station presented the highest value. The bivalve A. notabilis and gastropod M. modulus were species common to the four stations.

Adenosarcoma mulleriano heterólogo en la adolescencia: presentación de un caso clínico y revisión de la literatura / Mullerian, heterologous, adenosarcoma in adolescence: one case presentation and literature review

Se presenta el caso clínico de una paciente de 16 años de edad, con diagnóstico histopatológico de sarcoma mulleriano mixto heterólogo, entidad poco frecuente en la adolescencia. Asimismo se realiza una revisión de sarcomas del útero, su epidemiología, clasificación, perfil clínico, pronóstico y tratamiento