Windows of sensitivity to toxic chemicals in the development of the endocrine system: an analysis of ATSDR's toxicological profile database.

This review utilizes the robust database of literature contained in toxicological profiles developed by the Agency for Toxic Substances and Disease Registry. The aim was to use this database to identify developmental toxicity studies reporting alterations in hormone levels in the developing fetus and offspring and identify windows of sensitivity. We identified 74 oral exposure studies in rats that provided relevant information on 30 chemicals from 21 profiles. Most studies located provided information on thyroid hormones, with fewer studies on anterior pituitary, adrenal medulla, ovaries, and testes. No studies pertaining to hormones of the posterior pituitary, pancreas, or adrenal cortex were located. The results demonstrate that development of the endocrine system may be affected by exposure to environmental contaminants at many different points, including gestational and/or lactational exposure. Moreover, this review demonstrates the need for more developmental toxicity studies focused on the endocrine system and specifically alterations in hormone levels.

Chemical interactions and mixtures in public health risk assessment: An analysis of ATSDR's interaction profile database.

The Agency for Toxic Substances and Disease Registry (ATSDR) develops interaction profiles using binary weight of evidence (BINWOE) methodology to determine interaction directions of common environmental mixtures. We collected direction of interactions, BINWOE score determination, and BINWOE score confidence rating from 13 interaction profiles along with toxicodynamic and toxicokinetic influences on interaction direction. By doing so, we quantified the 1) direction of interaction and indeterminate evaluations; 2) characterized confidence in the BINWOE determinations; and 3) quantified toxicokinetic/toxicodynamic, and other influences on projected BINWOE interaction directions. Thirty-nine percent (130/336) of the attempts to make a BINWOE were indeterminate due to no interaction data or inadequate or conflicting evidence. Out of remaining BINWOEs, 25% were additive, 9% were greater-than-additive, and 27% were less-than-additive interactions. Fifty-five percent of BINWOEs were explained by toxicokinetic interactions, 12% and 5% were explained by toxicodynamic and other explanations, respectively. High quality mixture toxicology in vivo studies along with mixture in vitro and in silico studies will lead to greater confidence in interaction directions and influences. Limitations for interpretation of the data were also included.

Per- and polyfluoroalkyl mixtures toxicity assessment "Proof-of-Concept" illustration for the hazard index approach.

The 2018 ATSDR mixture framework recommends three approaches including the hazard index (HI) for environmental mixture toxicity assessment. Per- and polyfluoroalkyls (PFAS) are found in our environment and general populations. Recent experimental mixture toxicity studies of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) and an assessment of 17 PFAS indicate the use of additivity for their joint toxicity assessment. The aim of this investigation was to detail the stepwise procedures and examine the extent and use of the HI approach for PFAS mixture assessment. Using estimated general public lifetime exposures (high, medium, and low), binary mixtures of PFOS and PFOA yielded, respectively, hazard indices (HIs) of 30.67, 8.33, and 3.63 for developmental toxicity; 10.67, 5.04, and 2.34 for immunological toxicity; 3.57, 1.68, and 0.78 for endocrine toxicity; 4.51, 1.73, and 0.79 for hepatic toxicity; and 15.08, 2.29, and 0.88 for reproductive toxicity. A heterogeneous mixture of PFOA, PFAS, dioxin (CDD), and polybrominated compounds (PBDE) for high exposure scenario yielded HIs of 30.99 for developmental, 10.77 for immunological, 3.64 for endocrine, 4.61 for hepatic, and 17.36 for reproductive effects. The HI values are used as a screening tool; the potential concern for exposures rises as HI values increase. For HI values >1, a follow-up including further analysis of specific exposures, use of internal dosimetry, and uncertainty factors is conducted before recommending appropriate actions. The HI approach appears suitable to address present-day PFAS public health concerns for initial assessment of multiple health effects, until further insights are gained into their mechanistic toxicology.The findings and conclusions in this article are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry.

Modeling emissions from CAFO poultry farms in Poland and evaluating potential risk to surrounding populations.

The world-wide use of concentrated animal feeding operations (CAFOs) for livestock production demands the need to evaluate the potential impact to public health. We estimated the exposure of various airborne pollutants for populations residing in close proximity to 10 poultry CAFOs located in Central Poland. Ammonia (NH3), carbon dioxide (CO2), carbon monoxide (CO), hydrogen sulfide (H2S), methane (CH4), nitrogen dioxide (NO2), nitrous oxide (N2O), sulfur dioxide (SO2), and organic dust were the pollutants of interest for this study. Because no monitoring data were available, we used the steady-state Gaussian dispersion model AERMOD to estimate pollutant concentrations for the exposed population in order to calculate the hazard index (HI) for a combined mixture of chemicals. Our results indicate that while the levels of certain pollutants are expected to exceed background levels commonly found in the environment they did not result in calculated hazard indexes which exceeded unity suggesting low potential for adverse health effects for the surrounding community for the mixture of chemicals. The study was conducted through a cooperation between the Agency for Toxic Substances and Disease Registry (ATSDR) in the USA and the Nofer Institute of Occupational Medicine (NIOM) in Poland.

Windows of Sensitivity to Toxic Chemicals in the Development of Cleft Palates.

Cleft lip and cleft palate are among the most common birth defects worldwide. There is a genetic component to the development of these malformations, as well as evidence that environmental exposures and prescription drug use may exacerbate or even produce these manifestations. Thus, it is important to understand the underlying mechanisms and when these exposures affect development of the growing fetus. The purpose of this investigation was to critically review the available literature related to orofacial cleft formation following chemical exposure and identify specific time frames for windows of sensitivity. Further, an aim was to evaluate the potential for predicting effects in humans based on animal studies. Evidence indicates that chemical causes of cleft palate development are due to dose and timing of exposure, susceptibility of the species (i.e., the genetic makeup), and mechanism of action. Several studies demonstrated that dose is a crucial factor; however, some investigators argued that even more important than dose was timing of exposure. Data show that the window of sensitivity to environmental teratogens in the development of cleft palates is quite narrow and follows closely the window of palatogenesis in the fetus of any given species.

Public health decisions: actions and consequences.

The goal of public health is to promote the best possible health for the whole population. Public health issues are numerous and can be unbelievably complex in form, scope, and possible consequence. Most public health decisions involve assessing several different options, weighing the respective benefits and risks of those options, and making difficult decisions that hopefully provide the greatest benefit to the affected populations. Many risk management decisions involve a variety of societal factors which modify risk assessment choices. The purpose of this paper is to point out difficulties in making decisions that impact public health. The intent of such decisions is to improve public health, but as illustrated in the paper, there can be unintended adverse consequences. Such unplanned issues require continued attention and efforts for responsible officials in the protection of environmental public health. This article presents examples of such events, when in the past, it was necessary to assess and regulate a number of potentially hazardous chemicals commonly used as insecticides, gasoline additives, and wood preservatives.

Joint toxicity of alkoxyethanol mixtures: contribution of in silico applications.

Exposure to chemicals occurs often as mixtures. Presented in this paper is information on alkoxyethanols and the impact they might have on human health in combination with some commonly found aliphatic and aromatic compounds. Our studies to evaluate the joint toxicity of these chemicals among themselves and in combination with other chemicals reveal a variety of possible outcomes depending on the exposure scenario. The interactions are predominantly based on metabolic pathways and are common among several solvents and organic compounds. Quantitative structure activity relationship (QSAR) analysis can be used with high confidence to identify chemicals that will interact to influence overall joint toxicity. Potential human exposure to a combination of alkoxyethanol, toluene and substituted benzenes may increase reproductive and developmental disease conditions. Inheritable gene alterations result in changes in the enzyme function in different subpopulations causing variations in quantity and/or quality of particular isoenzymes. These changes are responsible for differential metabolism of chemicals in species, genders, and life stages and are often the basis of a population's susceptibility. Unique genotypes introduced as a function of migration can alter the genetic makeup of any given population. Hence special consideration should be given to susceptible populations while conducting chemical health risk assessments.

Chemical risk assessment and uncertainty associated with extrapolation across exposure duration.

The Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on priority substances in which available epidemiologic and toxicologic data are reviewed, summarized, and interpreted. When adequate data are available, ATSDR derives health guidance values called minimal risk levels (MRLs) for acute, intermediate, and chronic durations of exposure for oral and inhalation routes of exposure. The MRLs are generally derived by use of the no-observed-adverse-effect level (NOAEL) or the lowest-observed-adverse-effect level/uncertainty factor (LOAEL/UF) approach. The UF usually employed are for LOAEL-to-NOAEL extrapolation, animal to -human extrapolation, and inter-human variability. These health guidance values are intended to serve as screening tools for health assessors and other responders to identify contaminants of concern and potential health effects in the community at hazardous waste sites and during unplanned releases. When guidance values are not available for a specific exposure scenario because of a lack of chronic data, extrapolation across exposure durations may be made. For example, chronic guidance values may be derived from subchronic data by applying an additional uncertainty factor of 10 for extrapolation to chronic exposure duration. In this paper, we analyzed the ratio of chemical-specific LOAELs from acute to intermediate and from intermediate to chronic durations for oral and inhalation exposure routes. In addition, we investigated the impact of chemical structure and chemical structure activity relationship on validation of predictions across exposure durations.

Chemical mixtures: evaluation of risk for child-specific exposures in a multi-stressor environment.

Evaluating the health impact from exposure to chemical mixtures is multifaceted. One component is exposure. Exposure, and consequently risk assessment for mixtures and chemicals in general, are often viewed in terms of a given exposure to a given population at a given location over a given time period. However, environmental exposures are present throughout human lifetime. As a result, an evaluation of risk must include the distinctive characteristics related to chemical exposures which will impact risk depending upon the particular life stage where exposure occurs. Risks to offspring may be associated with unique exposures in utero, during infancy, childhood, or adolescent periods. For example, exposure of infants to anthropogenic chemicals via breast milk may be of concern. The Agency for Toxic Substances and Disease Registry's (ATSDR's) approach to evaluating risks associated with exposure to mixtures of chemicals is presented. In addition to the breast milk issues, indoor exposure to combined air pollutants, drinking water contaminants, and soil and dust contaminants are discussed. The difference between a mixture's risk evaluation for children and adults is in the distinct exposure scenarios resulting from variations in behavior, physiology, and/or pharmacokinetics between adults and children rather than in the method for the specific mixtures evaluation per se.

Risk assessment of chemicals and pharmaceuticals in the pediatric population: a workshop report.

ATSDR and RIVM organized an Expert Panel Workshop on the Differences Between Children and Adults and Their Relevance to Risk Assessment. The workshop was held in June 2003, in Brussels, Belgium. The purpose of the workshop was to identify data gaps in current scientific knowledge related to children's health and to recognize areas of mutual interest that would serve as the basis for upcoming ATSDR/RIVM cooperative projects. The aim for both agencies is a better understanding of the issues related to children's health, and the improvement of scientifically based (chemical) risk assessment in children. Topics discussed included clinical trials/toxicity studies, testing in juvenile animals, PBPK modeling in children, and children's risk assessment.

Public health assessment of hexachlorobenzene.

Recently, hexachlorobenzene (HCB) was proposed for inclusion in the system of toxicity equivalency factors (TEFs) currently used for dioxin-like compounds. In this paper, we explore the practical implications of the proposition to the Agency for Toxic Substances and Disease Registry (ATSDR) programs by comparing respective health guidance values for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and HCB (expressed as total toxicity equivalents [TEQs]), reviewing possible interactions between HCB and dioxin-like chemicals, and by providing information on actual co-existence of HCB and dioxin-like chemicals at hazardous waste sites. We found a good correlation between the TEF-adjusted oral exposure guidance values for HCB and guidance values for TCDD. The combination of HCB and other dioxin-like compounds was not found in soil, air, or water media at hazardous waste sites. Based on this fact, it is not necessary to include HCB in the total TEQ count at hazardous waste sites at this time.

Breast-feeding exposure of infants to selected pesticides: a public health viewpoint.

In this paper, we provide an overview of the public health implications of exposure to some pesticides via breast milk and provide health-based guidance. The presence of organochlorine pesticides in breast milk has been documented in many studies around the world. Included in our review are aldrin/dieldrin, chlordane, 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane (DDT)/1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), endrin, hexachlorobenzene (HCB), and hexachlorocyclohexane (HCH). Toxicological and environmental data on these chemicals are compiled in toxicological profiles published by the Agency for Toxic Substances and Disease Registry (ATSDR). Based on the data, ATSDR derives chemical-specific minimal risk levels (MRLs) that assist in evaluating public health risks associated with exposure. MRLs are health-based guidance values designed to protect the most sensitive populations, including breast-fed infants. We compare MRLs and projected intakes from the breast milk for the listed pesticides, explore the possibilities of toxicological interactions, and provide health-based recommendations.

Site-specific consultation for a chemical mixture.

The Agency for Toxic Substances and Disease Registry (ATSDR) uses the weight of evidence methodology to evaluate interactions of chemical mixtures. In the process, toxicity, toxicokinetics, and toxicodynamics of chemical components of the mixture are carefully examined. Based on the evaluation, predictions are made that can be used in real-life situations at hazardous waste sites. In this paper, health outcomes were evaluated for a mixture of eight compounds that were found at a specific site. These eight chemicals were identified and possibly associated with human exposure. The health assessors could consider similar thought processes when evaluating chemical mixtures at hazardous waste sites.

Reducing uncertainty in the derivation and application of health guidance values in public health practice. Dioxin as a case study.

We were requested by the U.S. Environmental Protection Agency (EPA) to clarify the relationships among the minimal risk level (MRL), action level, and environmental media evaluation guide (EMEG) for dioxin established by the Agency for Toxic Substances and Disease Registry (ATSDR). In response we developed a document entitled "Dioxin and Dioxin-Like Compounds in Soil, Part I: ATSDR Interim Policy Guideline"; and a supporting document entitled "Dioxin and Dioxin-Like Compounds in Soil, Part II: Technical Support Document". In these documents, we evaluated the key assumptions underlying the development and use of the ATSDR action level, MRL, and EMEG for dioxin. We described the chronology of events outlining these different health guidance values for dioxin and identified the areas of uncertainty surrounding these values. Four scientific assumptions were found to have had a great impact on this process; these were: (1) the specific uncertainty factors used, (2) the toxicity equivalent (TEQ) approach, (3) the fractional exposure from different pathways, and (4) the use of body burdens in the absence of exposure data. This information was subsequently used to develop a framework for reducing the uncertainties in public health risk assessment associated with exposure to other chemical contaminants in the environment. Within this framework are a number of future directions for reducing uncertainty, including physiologically based pharmacokinetic modeling (PBPK), benchmark dose modeling (BMD), functional toxicology, and the assessment of chemical mixture interactions.

Agency for Toxic Substances and Disease Registry's 1997 priority list of hazardous substances. Latent effects--carcinogenesis, neurotoxicology, and developmental deficits in humans and animals.

In support of Superfund re-authorization legislation, the Division of Toxicology of the Agency for Toxic Substances and Disease Registry (ATSDR) prepared a chemical-specific consultation document for Congress that identified those chemicals with carcinogenic, neurological, or developmental adverse effects having a latency period longer than 6 years. The review was limited to the top 50 substances listed on ATSDR's 1997 Priority List of Hazardous Substances (Priority List). Among the top 50 chemicals, a review of the technical literature indicated that 38 (76%) were classified as "reasonably anticipated," "possibly," or "probably" capable of causing cancer in humans, based either on human and animal data. Eight chemicals (16%) had well-established cancer latency periods in humans of 6 years or more following exposure. Three substances (6%)--arsenic, creosote, and benzidine--had data indicating latency periods longer than 6 years. The technical literature review likewise confirmed the potential for neurological and developmental effects with a latency of 6 years. Twenty-seven (54%) of the top 50 substances caused acute and/or chronic neurotoxic effects; a number of these also caused neurological effects that persisted beyond 6 years (or the equivalent in animal studies) such as: behavioral problems, neurological deficiencies, reduced psychomotor development, cognitive deficiencies, and reduced IQ. Twenty-eight substances (56%) caused adverse developmental effects in offspring of exposed individuals or animals including increased fetal and infant mortality, decreased birth weights and litter sizes, and growth delays. Latency periods for related chemicals are expected to be similar due to structural and toxicological similarities.

Health effects classification and its role in the derivation of minimal risk levels: developmental effects.

Agency for Toxic Substances and Disease Registry (ATSDR) utilizes chemical-specific minimal risk levels (MRLs) to assist in evaluating the public health risk associated with exposure to hazardous substances. The MRLs are derived based on the health effects data compiled from current literature searches and presented in ATSDR's toxicological profiles. Health effects are categorized according to their degree of severity (e.g., serious, less serious, minimal, and not adverse). This evaluation is important, because each respective category can be assigned a different amount of uncertainty, thus affecting the final value of the calculated MRL. From the total of 272 MRLs derived as of December 1997, 21 were based on developmental effects. ATSDR's ranking of developmental health effects as described in the Guidance for Developing Toxicological Profiles and specific examples of how the categorized health effects were used in MRL derivations are provided in this paper.

Public health implications of environmental exposures.

The Agency for Toxic Substances and Disease Registry (ATSDR) is a public health agency with responsibility for assessing the public health implications associated with uncontrolled releases of hazardous substances into the environment. The biological effects of low-level exposures are a primary concern in these assessments. One of the tools used by the agency for this purpose is the risk assessment paradigm originally outlined and described by the National Academy of Science in 1983. Because of its design and inherent concepts, risk assessment has been variously employed by a number of environmental and public health agencies and programs as a means to organize information, as a decision support tool, and as a working hypothesis for biologically based inference and extrapolation. Risk assessment has also been the subject of significant critical review. The ATSDR recognizes the utility of both the qualitative and quantitative conclusions provided by traditional risk assessment, but the agency uses such estimates only in the broader context of professional judgment, internal and external peer review, and extensive public review and comment. This multifaceted approach is consistent with the Council on Environmental Quality's description and use of risk analysis as an organizing construct based on sound biomedical and other scientific judgment in concert with risk assessment to define plausible exposure ranges of concern rather than a single numerical estimate that may convey an artificial sense of precision. In this approach biomedical opinion, host factors, mechanistic interpretation, molecular epidemiology, and actual exposure conditions are all critically important in evaluating the significance of environmental exposure to hazardous substances. As such, the ATSDR risk analysis approach is a multidimensional endeavor encompassing not only the components of risk assessment but also the principles of biomedical judgment, risk management, and risk communication. Within this framework of risk analysis, the ATSDR may rely on one or more of a number of interrelated principles and approaches to screen, organize information, set priorities, make decisions, and define future research needs and directions.

Breast-feeding exposure of infants to cadmium, lead, and mercury: a public health viewpoint.

The purpose of this report is to provide an overview of the public health implications of exposure via breast milk to cadmium, lead, and mercury for nursing infants and to provide health-based guidance. Daily intakes were calculated and compared with guidance values used for public health assessments at hazardous waste sites. Cadmium, lead, and mercury under normal conditions are found in breast milk at concentration ranges of < 1 microgram/L, 2-5 micrograms/L, and 1.4-1.7 micrograms/L, respectively. Women exposed environmentally or occupationally can have higher levels in their breast milk. Concentrations of about 5 micrograms/L (cadmium), 20 micrograms/L (lead), and 3.5 micrograms/L (mercury) appear to be adequate screening levels. Many factors affect both the distribution of cadmium, lead, and mercury in breast milk and the health consequences to an infant. It is not clear what additional impact low-level exposure via breast milk may have on an infant born with a body burden to one of these metals. There is sufficient evidence to make the case that contaminated breast milk is a source of potential risk to infants in certain populations. Prevention strategies that include behavior modification and proper nutrition should be communicated to women at risk. Identification and elimination of exposure pathways and a critical analysis of the benefits of breast feeding versus heavy metal exposure are needed on a site-specific or individual basis. Research is required to better understand the impact of low-level exposure to heavy metals via breast milk. Breastfeeding should be encouraged under most circumstances.

Public health guidance values for chemical mixtures: current practice and future directions.

Agency for Toxic Substances and Disease Registry (ATSDR) utilizes chemical-specific minimal risk levels (MRLs) to assist in evaluating public health risks associated with exposure to hazardous substances. The MRLs are derived based on the data compiled from current worldwide literature searches and presented in ATSDR's toxicological profiles. These documents profile not only individual chemicals, but also groups of chemically related compounds and chemical mixtures. ATSDR took several approaches when developing MRLs for chemical mixtures. In some instances, toxicity equivalency factors were used to estimate the toxicity of the whole mixture; in other instances, the most toxic chemical was assumed to drive the health assessment for the whole mixture. Another approach was to treat the mixture as one entity and develop a health guidance value for the whole mixture. In yet another approach, each chemical of the mixture was evaluated separately and several health guidance values were developed. In the future, ATSDR will evaluate priority chemical mixtures found at hazardous waste sites. A weight-of-evidence approach, physiologically based pharmacokinetic modeling and bench-mark dose modeling, and quantitative structure-activity relationships will have an impact on the development of MRLs and the assessment of chemical mixtures.

Breast-feeding exposure of infants to environmental contaminants--a public health risk assessment viewpoint: chlorinated dibenzodioxins and chlorinated dibenzofurans.

Exposure of children to chlorinated dibenzodioxins and chlorinated dibenzofurans via breast-feeding has been well-documented in industrialized countries. Recent studies indicate a possible link between development of subtle health effects in children and their exposure to dioxin-like chemicals from maternal milk. Some examples of the effects are lower vitamin K levels, increased thyroxine levels, and mild changes in liver enzymes. The projected daily intakes of chlorinated dibenzodioxins and chlorinated dibenzofurans are compared with minimal risk levels for intermediate duration oral exposure (15-365 days) derived for these chemicals. Public health recommendations for future actions related to infant intake of chlorinated dibenzodioxin- and chlorinated dibenzofuran-contaminated breast milk are also addressed.