Applying a modified systematic review and integrated assessment framework (SYRINA) - a case study on triphenyl phosphate.

This work presents a case study in applying a systematic review framework (SYRINA) to the identification of chemicals as endocrine disruptors. The suitability and performance of the framework is tested with regard to the widely accepted World Health Organization definition of an endocrine disruptor (ED). The endocrine disrupting potential of triphenyl phosphate (TPP), a well-studied flame retardant reported to exhibit various endocrine related effects was assessed.

A systematic evidence map for the evaluation of noncancer health effects and exposures to polychlorinated biphenyl mixtures.

Assessing health outcomes associated with exposure to polychlorinated biphenyls (PCBs) is important given their persistent and ubiquitous nature. PCBs are classified as a Group 1 carcinogen, but the full range of potential noncancer health effects from exposure to PCBs has not been systematically summarized and evaluated. We used systematic review methods to identify and screen the literature using combined manual review and machine learning approaches.

Systematic evidence map (SEM) template: Report format and methods used for the US EPA Integrated Risk Information System (IRIS) program, Provisional Peer Reviewed Toxicity Value (PPRTV) program, and other "fit for purpose" literature-based human health analyses.

Background: Systematic evidence maps (SEMs) are gaining visibility in environmental health for their utility to serve as problem formulation tools and assist in decision-making, especially for priority setting. SEMs are now routinely prepared as part of the assessment development process for the US Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) and Provisional Peer Reviewed Toxicity Value (PPRTV) assessments. SEMs can also be prepared to explore the available literature for an individual chemical or groups of chemicals of emerging interest.

Use of systematic evidence maps within the US environmental protection agency (EPA) integrated risk information system (IRIS) program: Advancements to date and looking ahead.

Systematic evidence maps (SEMs) are increasingly used to inform decision-making and risk management priority-setting and to serve as problem formulation tools to refine the focus of questions that get addressed in full systematic reviews. Within the U.S.

Health Effects of Naphthalene Exposure: A Systematic Evidence Map and Analysis of Potential Considerations for Dose-Response Evaluation.

Background: Naphthalene is a polycyclic aromatic hydrocarbon that has been associated with health effects, including cancer. As the state of the science on naphthalene toxicity continues to evolve, updated toxicity reference value(s) may be required to support human health risk assessment.

Objectives: We present a systematic evidence map of studies that could be used to derive toxicity reference value(s) for naphthalene.

Applying evidence-based methods to the development and use of adverse outcome pathways.

The workshop “Application of evidence-based methods to construct mechanistic frameworks for the development and use of non-animal toxicity tests” was organized by the Evidence-based Toxicology Collaboration and hosted by the Grading of Recommendations Assessment, Development and Evaluation Working Group on June 12, 2019. The purpose of the workshop was to bring together international regulatory bodies, risk assessors, academic scientists, and industry to explore how systematic review methods and the adverse outcome pathway framework could be combined to develop and use mechanistic test methods for predicting the toxicity of chemical substances in an evidence-based manner. The meeting covered the history of biological frameworks, the way adverse outcome pathways are currently developed, the basic principles of systematic methodology, including systematic reviews and evidence maps, and assessment of cer­tainty in models, and adverse outcome pathways in particular.

Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies.

Background: Diethyl phthalate (DEP) is widely used in many commercially available products including plastics and personal care products. DEP has generally not been found to share the antiandrogenic mode of action that is common among other types of phthalates, but there is emerging evidence that DEP may be associated with other types of health effects.

Objective: To inform chemical risk assessment, we performed a systematic review to identify and characterize outcomes within six broad hazard categories (male reproductive, female reproductive, developmental, liver, kidney, and cancer) following exposure of nonhuman mammalian animals to DEP or its primary metabolite, monoethyl phthalate (MEP).

A Physiologically Based Pharmacokinetic Model for Naphthalene With Inhalation and Skin Routes of Exposure.

Naphthalene, a volatile organic compound present in moth repellants and petroleum-based fuels, has been shown to induce toxicity in mice and rats during chronic inhalation exposures. Although simpler default methods exist for extrapolating toxicity points of departure from animals to humans, using a physiologically based pharmacokinetic (PBPK) model to perform such extrapolations is generally preferred. Confidence in PBPK models increases when they have been validated using both animal and human in vivo pharmacokinetic (PK) data.

A novel study evaluation strategy in the systematic review of animal toxicology studies for human health assessments of environmental chemicals.

A key aspect of the systematic review process is study evaluation to understand the strengths and weaknesses of individual studies included in the review. The present manuscript describes the process currently being used by the Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) Program to evaluate animal toxicity studies, illustrated by application to the recent systematic reviews of two phthalates: diisobutyl phthalate (DIBP) and diethyl phthalate (DEP). The IRIS Program uses a domain-based approach that was developed after careful consideration of tools used by others to evaluate experimental animal studies in toxicology and pre-clinical research.

Use of the Adverse Outcome Pathway (AOP) framework to evaluate species concordance and human relevance of Dibutyl phthalate (DBP)-induced male reproductive toxicity.

Dibutyl phthalate (DBP) is a phthalate ester used as a plasticizer, and solvent. Studies using rats consistently report that DBP exposure disrupts normal development of the male reproductive system in part via inhibition of androgen synthesis. However, studies using xenograft models report that in human fetal testis DBP exposure is unlikely to impair testosterone synthesis.

Proposed Key Characteristics of Male Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Evidence in Human Health Hazard Assessments.

Background: Assessing chemicals for their potential to cause male reproductive toxicity involves the evaluation of evidence obtained from experimental, epidemiological, and mechanistic studies. Although mechanistic evidence plays an important role in hazard identification and evidence integration, the process of identifying, screening and analyzing mechanistic studies and outcomes is a challenging exercise due to the diversity of research models and methods and the variety of known and proposed pathways for chemical-induced toxicity. Ten key characteristics of carcinogens provide a valuable tool for organizing and assessing chemical-specific data by potential mechanisms for cancer-causing agents.

Hazards of diisobutyl phthalate (DIBP) exposure: A systematic review of animal toxicology studies.

Background: Biomonitoring studies indicate a trend towards increased human exposure to diisobutyl phthalate (DIBP), a replacement for dibutyl phthalate (DBP). Recent reviews have found DIBP to be a male reproductive toxicant, but have not evaluated other hazards of DIBP exposure.

Objective: To inform chemical risk assessment, we performed a systematic review to identify and characterize outcomes within six broad hazard categories (male reproductive, female reproductive, developmental, liver, kidney, and cancer) following exposure of nonhuman mammalian animals to DIBP or the primary metabolite, monoisobutyl phthalate (MIBP).

An object-oriented Bayesian network approach for establishing swine manure-borne natural estrogenic compounds budget.

A facility-wide estrogen budget model was developed to assess the excretion of natural estrogens by swine in a commercial swine farrowing concentrated animal feeding operations (CAFO) in North Carolina, using an object-oriented Bayesian network (OOBN) approach. The OOBN model is the combination of twelve objects of Bayesian network models, which characterize the estrogen budget flows based on the sow reproductive cycle (i.e.

A decision analysis framework for estimating the potential hazards for drinking water resources of chemicals used in hydraulic fracturing fluids.

Despite growing concerns over the potential for hydraulic fracturing to impact drinking water resources, there are limited data available to identify chemicals used in hydraulic fracturing fluids that may pose public health concerns. In an effort to explore these potential hazards, a multi-criteria decision analysis (MCDA) framework was employed to analyze and rank selected subsets of these chemicals by integrating data on toxicity, frequency of use, and physicochemical properties that describe transport in water. Data used in this analysis were obtained from publicly available databases compiled by the United States Environmental Protection Agency (EPA) as part of a larger study on the potential impacts of hydraulic fracturing on drinking water.

Sharing the Roles: An Assessment of Japanese Medaka Estrogen Receptors in Vitellogenin Induction.

Teleost fish express at least three estrogen receptor (ER) subtypes. To date, however, the individual role of these ER subtypes in regulating expression of estrogen responsive genes remains ambiguous. Here, we investigate putative roles of three ER subtypes in Japanese medaka (Oryzias latipes), using vitellogenin (VTG) I and II as model genes.

Estimating the Potential Toxicity of Chemicals Associated with Hydraulic Fracturing Operations Using Quantitative Structure-Activity Relationship Modeling.

The United States Environmental Protection Agency (EPA) identified 1173 chemicals associated with hydraulic fracturing fluids, flowback, or produced water, of which 1026 (87%) lack chronic oral toxicity values for human health assessments. To facilitate the ranking and prioritization of chemicals that lack toxicity values, it may be useful to employ toxicity estimates from quantitative structure-activity relationship (QSAR) models. Here we describe an approach for applying the results of a QSAR model from the TOPKAT program suite, which provides estimates of the rat chronic oral lowest-observed-adverse-effect level (LOAEL).

Using In Vitro High-Throughput Screening Data for Predicting Benzo[k]Fluoranthene Human Health Hazards.

Today there are more than 80,000 chemicals in commerce and the environment. The potential human health risks are unknown for the vast majority of these chemicals as they lack human health risk assessments, toxicity reference values, and risk screening values. We aim to use computational toxicology and quantitative high-throughput screening (qHTS) technologies to fill these data gaps, and begin to prioritize these chemicals for additional assessment.

Overview of Chronic Oral Toxicity Values for Chemicals Present in Hydraulic Fracturing Fluids, Flowback, and Produced Waters.

Concerns have been raised about potential public health effects that may arise if hydraulic fracturing-related chemicals were to impact drinking water resources. This study presents an overview of the chronic oral toxicity values-specifically, chronic oral reference values (RfVs) for noncancer effects, and oral slope factors (OSFs) for cancer-that are available for a list of 1173 chemicals that the United States (U.S.