Life Course Considerations in Environmental Health: Developmental Neurotoxicity of Domoic Acid at Doses Below Acute Effect Levels in Adult Humans.

Background: Current US federal action levels for domoic acid (DA) in seafood are based on acute toxicity observed in exposed adult humans. Life course considerations have not been incorporated. The potential for developmental neurotoxicity (DNT) at permissible DA levels has previously been noted, but not methodically assessed.

Consensus on the key characteristics of metabolism disruptors.

Metabolism-disrupting agents (MDAs) are chemical, infectious or physical agents that increase the risk of metabolic disorders. Examples include pharmaceuticals, such as antidepressants, and environmental agents, such as bisphenol A. Various types of studies can provide evidence to identify MDAs, yet a systematic method is needed to integrate these data to help to identify such hazards.

Application of probabilistic methods to address variability and uncertainty in estimating risks for non-cancer health effects.

Human health risk assessment currently uses the reference dose or reference concentration (RfD, RfC) approach to describe the level of exposure to chemical hazards without appreciable risk for non-cancer health effects in people. However, this "bright line" approach assumes that there is minimal risk below the RfD/RfC with some undefined level of increased risk at exposures above the RfD/RfC and has limited utility for decision-making. Rather than this dichotomous approach, non-cancer risk assessment can benefit from incorporating probabilistic methods to estimate the amount of risk across a wide range of exposures and define a risk-specific dose.

Modeling the transplacental transfer of small molecules using machine learning: a case study on per- and polyfluorinated substances (PFAS).

Background: Despite their large numbers and widespread use, very little is known about the extent to which per- and polyfluoroalkyl substances (PFAS) can cross the placenta and expose the developing fetus.

Objective: The aim of our study is to develop a computational approach that can be used to evaluate the of extend to which small molecules, and in particular PFAS, can cross to cross the placenta and partition to cord blood.

Methods: We collected experimental values of the concentration ratio between cord and maternal blood (R) for 260 chemical compounds and calculated their physicochemical descriptors using the cheminformatics package Mordred.

Consensus on the Key Characteristics of Immunotoxic Agents as a Basis for Hazard Identification.

Background: Key characteristics (KCs), properties of agents or exposures that confer potential hazard, have been developed for carcinogens and other toxicant classes. KCs have been used in the systematic assessment of hazards and to identify assay and data gaps that limit screening and risk assessment. Many of the mechanisms through which pharmaceuticals and occupational or environmental agents modulate immune function are well recognized.

Animal evidence considered in determination of cannabis smoke and Δ -tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint); Part I. Somatic development.

Objectives: On December 11, 2019, California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) met to consider the addition of cannabis smoke and Δ -THC to the Proposition 65 list as causing reproductive toxicity (developmental endpoint). As the lead state agency for implementing Proposition 65, the Office of Environmental Health Hazard Assessment (OEHHA) reviewed and summarized the relevant scientific literature in the form of a hazard identification document (HID). Here we provide reviews based on the HID: shortened, revised, and reformatted for a larger audience.

Animal evidence considered in determination of cannabis smoke and Δ -tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action.

This review summarizes the most common potential pathways of neurodevelopmental toxicity due to perinatal exposure to Δ -tetrahydrocannabinol (Δ -THC) that lead to behavioral and other adverse outcomes (AOs). This is Part III in a set of reviews highlighting the animal-derived data considered by California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) in 2019. The Hazard Identification Document (HID) provided to the DARTIC included a summary of human, whole animal, and mechanistic data on the neurodevelopmental toxicity of cannabis smoke and Δ -THC.

Animal evidence considered in determination of cannabis smoke and Δ -tetrahydrocannabinol (Δ -THC) as causing reproductive toxicity (developmental endpoint); Part II. Neurodevelopmental effects.

This review focuses on neurodevelopmental effects observed in animal studies of cannabis smoke and Δ -THC. Effects in offspring after preconceptional, prenatal, or perinatal exposure to cannabis smoke or Δ -THC were considered. Locomotor and exploratory behavior effects were noted in rats.

Key Characteristics of Cardiovascular Toxicants.

Background: The concept of chemical agents having properties that confer potential hazard called key characteristics (KCs) was first developed to identify carcinogenic hazards. Identification of KCs of cardiovascular (CV) toxicants could facilitate the systematic assessment of CV hazards and understanding of assay and data gaps associated with current approaches.

Objectives: We sought to develop a consensus-based synthesis of scientific evidence on the KCs of chemical and nonchemical agents known to cause CV toxicity along with methods to measure them.

Using the Key Characteristics of Carcinogens to Develop Research on Chemical Mixtures and Cancer.

Background: People are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit.

The Key Characteristics of Carcinogens: Relationship to the Hallmarks of Cancer, Relevant Biomarkers, and Assays to Measure Them.

The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification.

Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification.

Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing the risk of adverse health outcomes, including cancer, reproductive impairment, cognitive deficits and obesity. A complex literature of mechanistic studies provides evidence on the hazards of EDC exposure, yet there is no widely accepted systematic method to integrate these data to help identify EDC hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we have developed ten KCs of EDCs based on our knowledge of hormone actions and EDC effects.

Proposed Key Characteristics of Female Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Data in Hazard Assessment.

Background: Identification of female reproductive toxicants is currently based largely on integrated epidemiological and toxicology data and, to a lesser degree, on mechanistic data. A uniform approach to systematically search, organize, integrate, and evaluate mechanistic evidence of female reproductive toxicity from various data types is lacking.

Objective: We sought to apply a key characteristics approach similar to that pioneered for carcinogen hazard identification to female reproductive toxicant hazard identification.

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.

An Integrated Approach Using Publicly Available Resources for Identifying and Characterizing Chemicals of Potential Toxicity Concern: Proof-of-Concept With Chemicals That Affect Cancer Pathways.

We developed an integrated, modular approach to predicting chemical toxicity relying on in vitro assay data, linkage of molecular targets to disease categories, and software for ranking chemical activity and examining structural features (chemotypes). We evaluate our approach in a proof-of-concept exercise to identify and prioritize chemicals of potential carcinogenicity concern. We identified 137 cancer pathway-related assays from a subset of U.

Assessing health risks from multiple environmental stressors: Moving from G×E to I×E.

Research on disease causation often attempts to isolate the effects of individual factors, including individual genes or environmental factors. This reductionist approach has generated many discoveries, but misses important interactive and cumulative effects that may help explain the broad range of variability in disease occurrence observed across studies and individuals. A disease rarely results from a single factor, and instead results from a broader combination of factors, characterized here as intrinsic (I) and extrinsic (E) factors.

Cumulative effects of prenatal-exposure to exogenous chemicals and psychosocial stress on fetal growth: Systematic-review of the human and animal evidence.

Background: Adverse effects of prenatal stress or environmental chemical exposures on fetal growth are well described, yet their combined effect remains unclear.

Objectives: To conduct a systematic review on the combined impact and interaction of prenatal exposure to stress and chemicals on developmental outcomes.

Methods: We used the first three steps of the Navigation Guide systematic review.

Identifying Chemical Groups for Biomonitoring.

Regulatory agencies face daunting challenges identifying emerging chemical hazards because of the large number of chemicals in commerce and limited data on exposure and toxicology. Evaluating one chemical at a time is inefficient and can lead to replacement with uncharacterized chemicals or chemicals with structural features already linked to toxicity. The Office of Environmental Health Hazard Assessment (OEHHA) has developed a process for constructing and assessing chemical groups for potential biomonitoring in California.

The Next Generation of Risk Assessment Multi-Year Study-Highlights of Findings, Applications to Risk Assessment, and Future Directions.

Background: The Next Generation (NexGen) of Risk Assessment effort is a multi-year collaboration among several organizations evaluating new, potentially more efficient molecular, computational, and systems biology approaches to risk assessment. This article summarizes our findings, suggests applications to risk assessment, and identifies strategic research directions.

Objective: Our specific objectives were to test whether advanced biological data and methods could better inform our understanding of public health risks posed by environmental exposures.

Application of the Navigation Guide systematic review methodology to the evidence for developmental and reproductive toxicity of triclosan.

Background: There are reports of developmental and reproductive health effects associated with the widely used biocide triclosan.

Objective: Apply the Navigation Guide systematic review methodology to answer the question: Does exposure to triclosan have adverse effects on human development or reproduction?

Methods: We applied the first 3 steps of the Navigation Guide methodology: 1) Specify a study question, 2) Select the evidence, and 3) Rate quality and strength of the evidence. We developed a protocol, conducted a comprehensive search of the literature, and identified relevant studies using pre-specified criteria.

Using ToxCast to Explore Chemical Activities and Hazard Traits: A Case Study With Ortho-Phthalates.

US EPA's Toxicity Forecaster (ToxCastTM) is a tool with potential use in evaluating safer consumer products, conducting chemical alternatives analyses, prioritizing chemicals for exposure monitoring, and ultimately performing screening-level risk assessments. As a case study exploring a potential use of ToxCast, we evaluated ToxCast results for ortho-phthalates focused on the well-established toxicological endpoints of some members of this class. We compared molecular perturbations measured in ToxCast assays with the known apical toxicity endpoints of o-phthalates reported in the open literature to broadly reflect on the predictive capability of the high-throughput screening (HTS) assays.

Cumulative Environmental Impacts: Science and Policy to Protect Communities.

Many communities are located near multiple sources of pollution, including current and former industrial sites, major roadways, and agricultural operations. Populations in such locations are predominantly low-income, with a large percentage of minorities and non-English speakers. These communities face challenges that can affect the health of their residents, including limited access to health care, a shortage of grocery stores, poor housing quality, and a lack of parks and open spaces.

Screening for Chemical Contributions to Breast Cancer Risk: A Case Study for Chemical Safety Evaluation.

Background: Current approaches to chemical screening, prioritization, and assessment are being reenvisioned, driven by innovations in chemical safety testing, new chemical regulations, and demand for information on human and environmental impacts of chemicals. To conceptualize these changes through the lens of a prevalent disease, the Breast Cancer and Chemicals Policy project convened an interdisciplinary expert panel to investigate methods for identifying chemicals that may increase breast cancer risk.

Methods: Based on a review of current evidence, the panel identified key biological processes whose perturbation may alter breast cancer risk.