Improving risk assessment approaches for chemicals with both endogenous and exogenous exposures.

To conduct risk assessments of exogenous chemicals for which there are also endogenous exposures, knowledge of the chemistry and biology of both types of exposures needs to be integrated into problem formulation and carried through to risk characterization. This issue is framed in a risk assessment context, highlighting the importance of quantifying increments of dose from all sources of the same or similar chemicals interacting with biological targets; understanding the influence of endogenous chemical concentrations on disease risk; and assessing total dose to targets in evaluating risk from incremental environmental exposures. Examples of recent assessments illustrate the importance of addressing this issue. Evaluations of data on blood or organ concentrations of ammonia, methanol, formaldehyde, acetaldehyde, and three gaseous signaling molecules (hydrogen sulfide, carbon monoxide, and nitric oxide) provide examples where current data are already informing perspectives on relative exposures at the portal of entry and systemically. To facilitate quality risk assessments of exogenous chemicals with endogenous exposures, a series of specific questions are presented that need to be addressed in systematic review to enhance problem formulation, improve the development of holistic conceptual models, and to facilitate the identification of priority data needs for improving risk assessments.

Development of a refined database of mammalian relative potency estimates for dioxin-like compounds.

The toxic equivalency factor (TEF) approach has been widely accepted as the most feasible method available at present for evaluating potential health risks associated with exposure to mixtures of dioxin-like compounds (DLCs). The current mammalian TEFs for the DLCs were established by the World Health Organization (WHO) following the meeting of an international expert panel in June of 1997. The TEFs recommended by WHO were determined based on a consensus of scientific judgment and were presented as point estimates. However, the relative potency estimates (REPs) underlying the TEFs were derived from a heterogeneous data set and often span several orders of magnitude. In this article, we present a refined database of mammalian REPs that we believe will facilitate better characterization of the variability and uncertainty inherent in the data. The initial step involved reviewing the REP database used by the WHO panel during its review in 1997. A set of criteria was developed to identify REPs that were determined to be the most representative measure of a biological response and of adequate quality for use in quantitative analyses. REPs were determined to be inappropriate for use in quantitative analyses if any of the established exclusion criteria were met. Comparison of data records to the established exclusion criteria resulted in the identification of a substantial number of REPs believed to be inappropriate for use in quantitative analyses. Next, studies published after 1997 were added to the database. The availability of such a refined database will improve risk assessment for this class of compounds by including additional information from new studies and facilitating the use of quantitative approaches in the further development of TEFs.

The 2005 World Health Organization reevaluation of human and Mammalian toxic equivalency factors for dioxins and dioxin-like compounds.

In June 2005, a World Health Organization (WHO)-International Programme on Chemical Safety expert meeting was held in Geneva during which the toxic equivalency factors (TEFs) for dioxin-like compounds, including some polychlorinated biphenyls (PCBs), were reevaluated. For this reevaluation process, the refined TEF database recently published by Haws et al. (2006, Toxicol. Sci. 89, 4-30) was used as a starting point. Decisions about a TEF value were made based on a combination of unweighted relative effect potency (REP) distributions from this database, expert judgment, and point estimates. Previous TEFs were assigned in increments of 0.01, 0.05, 0.1, etc., but for this reevaluation, it was decided to use half order of magnitude increments on a logarithmic scale of 0.03, 0.1, 0.3, etc. Changes were decided by the expert panel for 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.3), 1,2,3,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.03), octachlorodibenzo-p-dioxin and octachlorodibenzofuran (TEFs = 0.0003), 3,4,4',5-tetrachlorbiphenyl (PCB 81) (TEF = 0.0003), 3,3',4,4',5,5'-hexachlorobiphenyl (PCB 169) (TEF = 0.03), and a single TEF value (0.00003) for all relevant mono-ortho-substituted PCBs. Additivity, an important prerequisite of the TEF concept was again confirmed by results from recent in vivo mixture studies. Some experimental evidence shows that non-dioxin-like aryl hydrocarbon receptor agonists/antagonists are able to impact the overall toxic potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, and this needs to be investigated further. Certain individual and groups of compounds were identified for possible future inclusion in the TEF concept, including 3,4,4'-TCB (PCB 37), polybrominated dibenzo-p-dioxins and dibenzofurans, mixed polyhalogenated dibenzo-p-dioxins and dibenzofurans, polyhalogenated naphthalenes, and polybrominated biphenyls. Concern was expressed about direct application of the TEF/total toxic equivalency (TEQ) approach to abiotic matrices, such as soil, sediment, etc., for direct application in human risk assessment. This is problematic as the present TEF scheme and TEQ methodology are primarily intended for estimating exposure and risks via oral ingestion (e.g., by dietary intake). A number of future approaches to determine alternative or additional TEFs were also identified. These included the use of a probabilistic methodology to determine TEFs that better describe the associated levels of uncertainty and "systemic" TEFs for blood and adipose tissue and TEQ for body burden.

Approaches for describing and communicating overall uncertainty in toxicity characterizations: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) as a case study.

Single point estimates of human health hazard/toxicity values such as a reference dose (RfD) are generally used in chemical hazard and risk assessment programs for assessing potential risks associated with site- or use-specific exposures. The resulting point estimates are often used by risk managers for regulatory decision-making, including standard setting, determination of emission controls, and mitigation of exposures to chemical substances. Risk managers, as well as stakeholders (interested and affected parties), often have limited information regarding assumptions and uncertainty factors in numerical estimates of both hazards and risks. Further, the use of different approaches for addressing uncertainty, which vary in transparency, can lead to a lack of confidence in the scientific underpinning of regulatory decision-making. The overarching goal of this paper, which was developed from an invited participant workshop, is to offer five approaches for presenting toxicity values in a transparent manner in order to improve the understanding, consideration, and informed use of uncertainty by risk assessors, risk managers, and stakeholders. The five approaches for improving the presentation and communication of uncertainty are described using U.S. Environmental Protection Agency's (EPA's) Integrated Risk Information System (IRIS) as a case study. These approaches will ensure transparency in the documentation, development, and use of toxicity values at EPA, the Agency for Toxic Substances and Disease Registry (ATSDR), and other similar assessment programs in the public and private sector. Further empirical testing will help to inform the approaches that will work best for specific audiences and situations.

Research strategies for safety evaluation of nanomaterials, part II: toxicological and safety evaluation of nanomaterials, current challenges and data needs.

This article summarizes a roundtable discussion held at the 2005 Society of Toxicology Annual Meeting in New Orleans, LA. The purpose of the roundtable was to review the current challenges and data needs for conducting toxicological and safety evaluations for nanomaterials, with the goals of presenting the current state-of-the science on the safety of nanomaterials and bringing together scientists representing government, academia, and industry to identify priorities for developing data to facilitate risk assessments for these materials. In this summary, the unique physicochemical properties associated with nanomaterials are reviewed in the context of the difficulties associated with measuring and characterizing them. In addition, the development of appropriate hazard data, the collection of accurate human and environmental exposure information, and the development of a better fundamental understanding of the modes of action for nanomaterials are discussed as factors that will impact the development of comprehensive toxicological and safety evaluations.

Prevalencia de sífilis y características del comportamiento de los jóvenes indígenas del Paraguay, 2016 / Prevalence of syphilis and characteristics of the behavior of indigenous young people of Paraguay, 2016

El objetivo fue determinar la prevalencia de sífilis y características de comportamiento de los jóvenes indígenas del Paraguay en el 2016. Se realizó un estudio observacional, descriptivo de corte transversal con muestro probabilístico estratificado bietapico, que incluyó a jóvenes indígenas de 15 a 18 años de cinco familias lingüísticas de Paraguay. Se utilizó un cuestionario estructurado y para el tamizaje de sífilis se utilizó una test rápido treponémico y para confirmar los resultados reactivos se realizó VDRL, considerando como resultado positivo si el test rápido era positivo + VDRL positivo a una dilución de 1:4 o mayor y si la VDRL era menor a 1:4 con TPHA positivo. Los resultados se expresan como medidas de tendencia central, dispersión y proporciones. Ingresaron al estudio 546 jóvenes de 15 a 18 años, el 67,03% era del sexo femenino. Se identificaron 36 casos de sífilis, que representa una prevalencia de 6,6% (IC95%: 4,7-9,0). Mayor prevalencia de sífilis se observó en los jóvenes que consumieron alcohol en la última relación sexual 20,6% (14/68) (p<0,001), sexo transaccional 40% (2/5) (p=0,010) y no utilización de condón 20,6% (14/68) (p<0,001). Se encontró una alta prevalencia de sífilis en la población juvenil indígena, relacionada al consumo de alcohol en la última relación, práctica de sexo transaccional y no utilización de preservativos. Se recomienda la implementación de estrategias específicas con abordaje intercultural apropiadas para una población joven, orientadas a disminuir las prácticas de riesgo y promocionar la utilización de preservativos(AU)

Identification and characterization of adverse effects in 21st century toxicology.

The practice of toxicology is changing rapidly, as demonstrated by the response to the 2007 NRC report on "Toxicity Testing in the 21(st) Century." New assays are being developed to replace animal testing; yet the use of data from these assays in decision making is not clear. A Health and Environmental Sciences Institute committee held a May 2011 workshop to discuss approaches to identifying adverse effects in the context of the NRC report. Scientists from industry, government, academia, and NGOs discussed two case studies and explored how information from new, high data content assays developed for screening can be used to differentiate adverse effects from adaptive responses. The terms "adverse effect" and "adaptive response" were defined, as well as two new terms, the relevant pathways of toxicological concern (RPTCs) and relevant responses for regulation (RRRs). RPTCs are biochemical pathways associated with adverse events and need to be elucidated before they are used in regulatory decision making. RRRs are endpoints that are the basis for risk assessment and may or may not be at the level of pathways. Workshop participants discussed the criteria for determining whether, at the RPTC level, an effect is potentially adverse or potentially indicative of adaptability, and how the use of prototypical, data-rich compounds could lead to a greater understanding of RPTCs and their use as RRRs. Also discussed was the use of RPTCs in a weight-of-evidence approach to risk assessment. Inclusion of data at this level could decrease uncertainty in risk assessments but will require the use of detailed dosimetry and consideration of exposure context and the time and dose continuum to yield scientifically based decisions. The results of this project point to the need for an extensive effort to characterize RPTCs and their use in risk assessment to make the vision of the 2007 NRC report a reality.

IPCS framework for analyzing the relevance of a cancer mode of action for humans.

The use of structured frameworks can be invaluable in promoting harmonization in the assessment of chemical risk. IPCS has therefore updated and extended its mode of action (MOA) framework for cancer to address the issue of human relevance of a carcinogenic response observed in an experimental study. The first stage is to determine whether it is possible to establish an MOA. This comprises a series of key events along the causal pathway to cancer, identified using a weight-of-evidence approach based on the Bradford Hill criteria. The key events are then compared first qualitatively and then quantitatively between the experimental animals and humans. Finally, a clear statement of confidence, analysis, and implications is produced. The IPCS human relevance framework for cancer provides an analytical tool to enable the transparent evaluation of the data, identification of key data gaps, and structured presentation of information that would be of value in the further risk assessment of the compound, even if relevancy cannot be excluded. This might include data on the shape of the dose-response curve, identification of any thresholds and recognition of potentially susceptible subgroups, for example, the basis of genetic or life-stage differences.

Ecological risk assessment issues identified during the U.S. Environmental Protection Agency's examination of risk assessment practices.

Recently, the U.S. Environmental Protection Agency examined its current risk-assessment principles and practices. As part of the examination, aspects of ecological risk-assessment practices were reviewed. Several issues related to ecological risk assessment were identified, including the use of organism-level versus population-level attributes to characterize risk, the possible opportunities associated with the increased use of probabilistic approaches for ecological risk assessment, and the notion of conservatism in estimating risks. The agency examination provides an understanding of current practices and is intended to begin a dialogue in which the risk assessment community can engage in addressing the identified issues to improve and enhance ecological risk assessment.