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).

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.

In utero exposure to simvastatin reduces postnatal survival and permanently alters reproductive tract development in the Crl:CD(SD) male rat.

We showed previously that in utero exposure to the cholesterol-lowering drug simvastatin (SMV) during sex differentiation lowers fetal lipids and testicular testosterone production (T Prod) in Hsd:SD rats. Here, the effects of SMV on fetal lipids and T Prod in Crl:CD(SD) rats were correlated with postnatal alterations in F1 males. The current study was conducted in two parts: 1) a prenatal assessment to confirm and further characterize the dose response relationship among previously reported alterations of SMV on fetal T Prod and the fetal lipid profile and 2) a postnatal assessment to determine the effects of SMV exposure during the periods of major organogenesis and/or sexual differentiation on F1 offspring growth and development.

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).

A comparison of three liquid chromatography (LC) retention time prediction models.

High-resolution mass spectrometry (HRMS) data has revolutionized the identification of environmental contaminants through non-targeted analysis (NTA). However, chemical identification remains challenging due to the vast number of unknown molecular features typically observed in environmental samples. Advanced data processing techniques are required to improve chemical identification workflows.

Simvastatin and dipentyl phthalate lower ex vivo testicular testosterone production and exhibit additive effects on testicular testosterone and gene expression via distinct mechanistic pathways in the fetal rat.

Sex differentiation of the male reproductive tract in mammals is driven, in part, by fetal androgen production. In utero, some phthalate esters (PEs) alter fetal Leydig cell differentiation, reducing the expression of several genes associated with steroid synthesis/transport, and consequently, lowering fetal androgen and Insl3 hormone levels. Simvastatin (SMV) is a cholesterol-lowering drug that directly inhibits HMG-CoA reductase.