Safety evaluation of 8 drug degradants present in over-the-counter cough and cold medications.

Although the United States Food & Drug Administration (FDA) has provided guidance on the control of drug degradants for prescription drugs, there is less guidance on how to set degradant specifications for FDA OTC monograph drugs. Given that extensive impurity testing was not part of the safety paradigm in original OTC monographs, a weight of evidence (WOE) approach to qualify OTC degradants is proposed. This approach relies on in silico tools and read-across approaches alongside standard toxicity testing to determine safety. Using several drugs marketed under 21 CFR 341 as case studies, this research demonstrates the utility of a WOE approach across data-rich and data-poor degradants. Based on degradant levels ranging from 1 to 4% of the maximum daily doses of each case study drug and 10th percentile body weight data for each patient group, children were recognized as having the highest potential exposure relative to adults per body mass. Depending on data availability and relationship to the parent API, margins of safety (MOS) or exposure margins were calculated for each degradant. The findings supported safe use, and indicated that this contemporary WOE approach could be utilized to assess OTC degradants. This approach is valuable to establish specifications for degradants in OTCs.

The 2022 world health organization reevaluation of human and mammalian toxic equivalency factors for polychlorinated dioxins, dibenzofurans and biphenyls.

In October 2022, the World Health Organization (WHO) convened an expert panel in Lisbon, Portugal in which the 2005 WHO TEFs for chlorinated dioxin-like compounds were reevaluated. In contrast to earlier panels that employed expert judgement and consensus-based assignment of TEF values, the present effort employed an update to the 2006 REP database, a consensus-based weighting scheme, a Bayesian dose response modeling and meta-analysis to derive "Best-Estimate" TEFs. The updated database contains almost double the number of datasets from the earlier version and includes metadata that informs the weighting scheme. The Bayesian analysis of this dataset results in an unbiased quantitative assessment of the congener-specific potencies with uncertainty estimates. The "Best-Estimate" TEF derived from the model was used to assign 2022 WHO-TEFs for almost all congeners and these values were not rounded to half-logs as was done previously. The exception was for the mono-ortho PCBs, for which the panel agreed to retain their 2005 WHO-TEFs due to limited and heterogenous data available for these compounds. Applying these new TEFs to a limited set of dioxin-like chemical concentrations measured in human milk and seafood indicates that the total toxic equivalents will tend to be lower than when using the 2005 TEFs.

Updated systematic assessment of human, animal and mechanistic evidence demonstrates lack of human carcinogenicity with consumption of aspartame.

Aspartame has been studied extensively and evaluated for its safety in foods and beverages yet concerns for its potential carcinogenicity have persisted, driven primarily by animal studies conducted at the Ramazzini Institute (RI). To address this controversy, an updated systematic review of available human, animal, and mechanistic data was conducted leveraging critical assessment tools to consider the quality and reliability of data. The evidence base includes 12 animal studies and >40 epidemiological studies reviewed by the World Health Organization which collectively demonstrate a lack of carcinogenic effect. Assessment of >1360 mechanistic endpoints, including many guideline-based genotoxicity studies, demonstrate a lack of activity associated with endpoints grouped to key characteristics of carcinogens. Other non-specific mechanistic data (e.g., mixed findings of oxidative stress across study models, tissues, and species) do not provide evidence of a biologically plausible carcinogenic pathway associated with aspartame. Taken together, available evidence supports that aspartame consumption is not carcinogenic in humans and that the inconsistent findings of the RI studies may be explained by flaws in study design and conduct (despite additional analyses to address study limitations), as acknowledged by authoritative bodies.

Benefit-risk of coffee consumption and all-cause mortality: A systematic review and disability adjusted life year analysis.

BACKGROUND: Recommendations and guidance from scientific bodies do not provide clear messages about potential health risks or benefits of coffee consumption. Numerous studies have demonstrated inverse (beneficial) effects of coffee consumption for many adverse outcomes such as cancer and cardiovascular disease; fewer studies demonstrate risks. However, the risk-benefit relationship has not yet been fully assessed using quantitative metrics preferred by policy makers (disability-adjusted life years [DALYs]). OBJECTIVE: Conduct a quantitative analysis of the risk-benefit for coffee consumption and all-cause mortality using the Benefit-Risk Analysis for Foods (BRAFO) framework and the DALY as a quantitative metric. METHOD: A systematic search and appraisal of meta-analyses investigating coffee consumption and all-cause mortality was conducted. Using the BRAFO framework, evidence was assessed in context of potential risks or benefits associated with the reference scenario - coffee consumption (assessed by varying the consumption level in three analyses) in adults aged 15+ versus the alternative scenario of no coffee consumption. DALYs were used to quantify risks and benefits based on risk ratios from meta-analyses with populations from the United States. RESULTS: Meta-analyses consistently report an inverse (beneficial) relationship between coffee consumption and all-cause mortality; subsequently, even while varying consumption amounts and prevalence of coffee consumption, DALYs calculated consistently demonstrated findings in the direction of prevention of healthy years of life lost with variable magnitude. More than 3.5 million DALYs, or ∼3.35% of estimated years of healthy life lost could be prevented by consuming one cup of coffee per day, up to 4.7% of estimated years of healthy life lost could be prevented at current consumption rates ranging from 1 to 8 cups/day, and even more benefit could be seen (prevention of an estimated 6% of years of healthy life lost) if consumers all drank 3 cups of coffee per day. IMPACT: Policy that directs consumers to avoid drinking coffee may be a detriment to the overall health of the population given the substantial potential benefits of coffee consumption on all-cause mortality for adults.

Review of potential risks associated with supplemental dietary exposure to nitrate-containing compounds in swine-a paradox in light of emerging benefits.

Calcium nitrate has been reported to benefit reproductive outcomes in sows and their offspring when administered via the feed (15 to 19 mg/kg-body weight [bw]/day) during the periparturient period. Traditionally, dietary nitrate had been considered a methemoglobinemia (MetHb) risk in swine. Similar hazard concerns have existed in humans, but a recent benefit/risk analysis established that nitrate levels associated with well-recognized health benefits outweigh potential risks. A similar benefit/risk perspective in swine was lacking and challenged by sparse published hazard data, often referenced within larger reviews related to all livestock. The objective of this review was to better characterize the potential for adverse health and performance effects reported in the literature for swine consuming nitrate and to provide metrics for evaluating the reliability of the studies reviewed. Supplemental exposure via feed or drinking water was considered for any life stage, dose, and exposure duration. More than 30 relevant studies, including case reports and reviews, examined calcium, potassium, sodium, or unspecified nitrate salts at doses up to 1,800 mg nitrate/kg-bw/day for exposures ranging from 1 to 105 d. The studies primarily evaluated weight gain, blood methemoglobin levels, or vitamin A homeostasis in sows or growing swine. An extensive review of the literature showed reports of adverse effects at low nitrate doses to be of low reliability. Conversely, reliable studies corroborate nitrate intake from feed or drinking water at levels equal to or greater than the European Food Safety Authority's no-observed-adverse-effect level (NOAEL) for swine of 410 mg nitrate/kg-bw/day, with no MetHb or other adverse effects on reproduction, growth, or vitamin A levels. Using a weight-of-evidence evaluation, we have moderate-to-high confidence that the NOAEL for nitrate supplementation in swine is likely between 600 and 800 mg/kg-bw/day. These levels are several-fold higher than dietary nitrate concentrations (19 mg/kg-bw/day) that are known to benefit birth outcomes in sows. This review elucidates the quality and reliability of the information sources historically used to characterize nitrate in swine feed as a contaminant of concern. Results from this evaluation can assist risk managers (e.g., regulatory officials and veterinarians) in consideration of proposed benefits as well as reassuring swine producers that low-level nitrate supplementation is not anticipated to be a concern.

Assessing the food safety risk of ochratoxin A in coffee: A toxicology-based approach to food safety planning.

Under the Food Safety Modernization Act (FSMA) and preventive controls (PCs) regulations, food manufacturers must consider whether PCs are needed for potential hazards present in food. The mycotoxin ochratoxin A (OTA) is considered a chemical hazard under FSMA. It is produced by several fungal species and can be present in various agricultural commodities, including coffee. OTA presents a unique scenario in food safety, because it is known to be a potential risk; because heating may destroy it, but not completely; and because the hazard profile suggests it is not acutely toxic at the occurrence levels in coffee, although at high exposure levels, it is potentially nephrotoxic and carcinogenic in animal models. In the absence of US compliance levels, it is important for the risk assessor and risk manager to determine whether PCs are warranted. To address this complex situation in the coffee industry, we combined food safety and toxicology risk assessment principles to examine the available information on OTA hazard and risk in coffee. Exposure and health-based benchmarks for OTA in coffee, established by reviewing peer-reviewed literature, food recall databases, and authoritative reviews, resulted in large margins-of-exposure for both single and repeated exposure scenarios. Furthermore, no evidence was identified from historical data to suggest OTA is acutely toxic in humans from coffee consumption or other exposure sources. Therefore, findings from this assessment indicate that no PC is warranted for US coffee manufactures, based on the low severity and likelihood of risk according to margin-of-exposure estimates and historical data.

Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.

Structured approaches like the adverse outcome pathway (AOP) framework offer great potential for depicting complex toxicological processes in a manner that can facilitate informed integration of mechanistic information in regulatory decisions. While this concept provides a structure for organizing evidence and facilitates consistency in evidence integration; the process, inputs, and manner in which AOPs and AOP networks are developed is still evolving. Following the OECD guiding principles of AOP development, we propose three AOPs for male reproductive tract abnormalities and derive a putative AOP network. The AOPs were developed using a fundamental understanding of the developmental biology of the organs of interest, paying close attention to the gestational timing of key events (KEs) to very specifically inform the domain of life stage applicability for the key event relationships (KERs). Chemical stressor data primarily from studies on low molecular weight phthalates (LMWPs) served to 'bound' the pathways of focus in this dynamic period of development and were integrated with the developmental biology data through an iterative process to define KEs and conclude on the extent of evidence in support of the KERs. The AOPs developed describe the linkage between 1) a decrease in Insl3 gene expression and cryptorchidism, 2) the sustained expression of Coup-tfII and hypospadias and 3) the sustained expression of Coup-tfII and altered Wolffian duct development/ epididymal agenesis. A putative AOP network linking AOP2 and AOP3 through decreased steroidogenic biosynthetic protein expression and converging of all AOPS at the population level impaired fertility adverse outcome is proposed. The network depiction specifies and displays the KEs aligned with their occurrence in gestational time. The pathways and network described herein are intended to catalyze collaborative initiatives for expansion into a larger network to enable effective data collection and inform alternative approaches for identifying stressors impacting this sensitive period of male reproductive tract development.

Overall lack of genotoxic activity among five common low- and no-calorie sweeteners: A contemporary review of the collective evidence.

Low- and no-calorie sweeteners (LNCS) are food additives that have been widely consumed for many decades. Their safety has been well established by authoritative bodies globally and is re-evaluated periodically. The objective herein was to survey and summarize the genotoxicity potential of five commonly utilized LNCS: acesulfame potassium (Ace-K), aspartame, saccharin, steviol glycosides and sucralose. Data from peer-reviewed literature and the ToxCast/Tox21 database were evaluated and integrated with the most recent weight-of-evidence evaluations from authoritative sources. Emphasis was placed on assays most frequently considered for hazard identification and risk assessment: mutation, clastogenicity and/or aneugenicity, and indirect DNA damage, such as changes in DNA repair mechanisms or gene expression data. These five sweeteners have been collectively evaluated in hundreds of in vivo or in vitro studies that employ numerous testing models, many of which have been conducted according to specific testing guidelines. The weight-of-evidence demonstrates overall negative findings across assay types for each sweetener when considering the totality of study design, reliability and reporting quality, as well as the lack of carcinogenic responses (or lack of responses relevant to humans) in animal cancer bioassays as well as observational studies in humans. This conclusion is consistent with the opinions of authoritative sources that have consistently determined that these sweeteners lack mutagenic and genotoxic potential.

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. Specific topics were discussed via case studies in small break-out groups. The group concluded that adverse outcome pathways provide an important framework to support mechanism-based assessment in environmental health. The process of their development has a few challenges that could be addressed with systematic methods and automation tools. Addressing these challenges will increase the transparency of the evidence behind adverse outcome pathways and the consistency with which they are defined; this in turn will increase their value for supporting public health decisions. It was suggested to explore the details of applying systematic methods to adverse outcome pathway development in a series of case studies and workshops.

Assessment of Mechanistic Data for Hexavalent Chromium-Induced Rodent Intestinal Cancer Using the Key Characteristics of Carcinogens.

Oral exposure to hexavalent chromium (Cr[VI]) induces intestinal tumors in mice. Mutagenic and nonmutagenic modes of action (MOAs) have been accepted by different regulatory bodies globally, the latter involving cytotoxicity-induced regenerative cell proliferation. However, concerns persist that all possible MOAs have not been fully considered. To address the potential for alternative MOAs, mechanistic data not represented in the existing two MOAs were evaluated. Relevant data were identified and organized by key characteristics of carcinogens (KCCs); literature related to epigenetics, immunosuppression, receptor-mediated effects, and immortalization were reviewed to identify potential key events associated with an alternative MOA. Over 200 references were screened for these four KCCs and further prioritized based on relevance to the research objective (ie, in vivo, oral exposure, gastrointestinal tissue). Minimal data were available specific to the intestine for these KCCs, and there was no evidence of any underlying mechanisms or key events that are not already represented in the two proposed MOAs. For example, while epigenetic dysregulation of DNA repair genes has been demonstrated, epigenetic effects were not measured in intestinal tissue, and it has been shown that Cr(VI) does not cause DNA damage in intestinal tissue. High-throughput screening data related to the KCCs were also evaluated, with activity generally limited to the two recognized MOAs. Collectively, no plausible alternative MOAs (or key events) were identified in addition to those previously proposed for Cr(VI) small intestine tumors.

Development of a Range of Plausible Noncancer Toxicity Values for 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Based on Effects on Sperm Count: Application of Systematic Review Methods and Quantitative Integration of Dose Response Using Meta-Regression.

Regulatory agencies have derived noncancer toxicity values for 2,3,7,8-tetrachlorodibenzo-p-dioxin based on reduced sperm counts relying on single studies from a large body of evidence. Techniques such as meta-regression allow for greater use of the available data while simultaneously providing important information regarding the uncertainty associated with the underlying evidence base when conducting risk assessments. The objective herein was to apply systematic review methods and meta-regression to characterize the dose-response relationship of gestational exposure and epididymal sperm count. Twenty-three publications (20 animal studies consisting of 29 separate rat experimental data sets, and 3 epidemiology studies) met inclusion criteria. Risk of bias evaluation was performed to critically appraise study validity. Low to very low confidence precluded use of available epidemiological data as candidate studies for dose-response due to inconsistencies across the evidence base, high risk of bias, and general lack of biological coherence, including lack of clinical relevance and dose-response concordance. Experimental animal studies, which were found to have higher confidence following the structured assessment of confidence (eg, controlled exposure, biological consistency), were used as the basis of a meta-regression. Multiple models were fit; points of departure were identified and converted to human equivalent doses. The resulting reference dose estimates ranged from approximately 4 to 70 pg/kg/day, depending on model, benchmark response level, and study validity integration approach. This range of reference doses can be used either qualitatively or quantitatively to enhance understanding of human health risk estimates for dioxin-like compounds.

Evaluation of potential human health risk associated with consumption of edible products from livestock fed ration supplemented with Red Lake Diatomaceous Earth.

Red Lake Diatomaceous Earth (DE) is a naturally occurring blend of diatomaceous earth and calcium bentonite that can be used as an anti-caking agent in animal feed and contains naturally occurring dioxins. A quantitative risk assessment was conducted to assess potential human health risk associated with consumption of edible tissues from livestock exposed to dioxins via feed containing Red Lake DE. Empirical data characterising the transfer of dioxins to eggs and other tissues in chickens demonstrate that resulting concentrations in eggs are lower than those found in the general food supply. These data also provided product-specific input for a risk assessment conducted both with default parameters and with media-specific input from the feed study. Results demonstrate that exposure to dioxins in edible tissue from livestock that consumed Red Lake DE in feed would not be associated with an increased risk to humans. Findings from this assessment highlight the utility and importance of accounting for bioavailability as part of health-based risk assessment and provide information critical to risk managers in determining the safe use of Red Lake DE as an anticaking agent in livestock and pet feed.

Systematic evaluation of mechanistic data in assessing in utero exposures to trichloroethylene and development of congenital heart defects.

The hypothesis that in utero exposures to low levels of trichloroethylene (TCE) may increase the risk of congenital heart defects (CHDs) in offspring remains a subject of substantial controversy within the scientific community due primarily to the reliance on an inconsistent and unreproducible experimental study in rats. To build on previous assessments that have primarily focused on epidemiological and experimental animal studies in developing conclusions, the objective of the current study is to conduct a systematic evaluation of mechanistic data related to in utero exposures to TCE and the development of CHDs. The evidence base was heterogeneous; 79 mechanistic datasets were identified, characterizing endpoints which ranged from molecular to organismal responses in seven species, involving both in vivo and in vitro study designs in mammalian and non-mammalian models. Of these, 24 datasets were considered reliable following critical appraisal using a study quality tool that employs metrics specific to the study type. Subsequent synthesis and integration demonstrated that the available mechanistic data: 1) did not support the potential for CHD hazard in humans, 2) did not support the biological plausibility of a response in humans based on organization via a putative adverse outcome pathway for valvulo-septal cardiac defects, and 3) were not suitable for serving as candidate studies in risk assessment. Findings supportive of an association were generally limited to in ovo chicken studies, in which TCE was administered in high concentration solutions via direct injection. Results of these in ovo studies were difficult to interpret for human health risk assessment given the lack of generalizability of the study models (including dose relevance, species-specific biological differences, variations in the construct of the study design, etc.). When the mechanistic data are integrated with findings from previous evaluations of human and animal evidence streams, the totality of evidence does not support CHDs as a critical effect in TCE human health risk assessment.

A Framework for Systematic Evaluation and Quantitative Integration of Mechanistic Data in Assessments of Potential Human Carcinogens.

Recently, the key characteristics of carcinogens (KCC) have been proposed as an organizational approach for the evaluation of mechanistic data related to carcinogenicity. Our objective was to develop a framework to systematically and quantitatively integrate KCC data using elements that are important to risk assessment. Methods for developing the framework included: defining objectives, identifying and accommodating key considerations for components, input, and output of the framework, and operational development via iterative testing by a multidisciplinary team. The proposed framework involves 3 steps: (1) a structured, yet flexible, appraisal of individual studies and endpoints, (2) a structured and transparent evaluation of the body of evidence for each key characteristic, and (3) an evaluation of all of the KCC-relevant data relative to tumors and/or cancer types. In step 1, data are assessed and scored for reliability, strength, and activity. In step 2, a mathematical algorithm is used to integrate (and weight) the quality, relevance, and activity for each of the KCCs. These scores facilitate subsequent evaluations related to the overall body of evidence in step 3 in which KCCs can be linked, assessing potential adverse outcome pathways or networks, and finally, considered in the context of observed carcinogenic responses in animals and/or humans. The output is an overall conclusion regarding KCC activity as it relates to carcinogenic responses. The proposed framework provides a flexible solution to quantitatively integrate KCC data in a systematic and transparent manner that provides weighting of data most well-suited for the assessment of potential human carcinogenicity.

Estimating serum concentrations of dioxin-like compounds in the U.S. population effective 2005-2006 and 2007-2008: A multiple imputation and trending approach incorporating NHANES pooled sample data.

Dioxin-like compounds (DLCs) are monitored in the U.S. population using data collected with the National Health and Nutrition Examination Survey (NHANES). Until recently, participants' serum samples have been analyzed individually, and summary statistics defining reference ranges by age, gender, and race/ethnicity have served as the background by which other biomonitoring data can be evaluated. In the most recent NHANES DLC data, 2005-2006 and 2007-2008, participants' sera have been physically pooled prior to laboratory analysis, introducing major challenges to their utility as a reference population: variability among individuals and relations with covariates are lost, and individual design effects cannot be applied. Further, the substantial drop in limits of detection (LODs) in pooled sample biennials prevents reliable comparisons to individual data, and has complicated estimates of change over time. In this study, we address the drawbacks introduced by pooled samples by generating U.S. population reference ranges based on individual-level data adjusted to 2005-2006 and 2007-2008 levels. Using publicly available data, multiple imputation (MI) generated four NHANES biennials (2001-2008) of individual DLC data; we then trended the change over time in each DLC by demographic stratum. NHANES 2003-2004 individuals were adjusted by the trended change over time. Population estimates of toxic equivalency (TEQ) concentrations were calculated using traditional MI survey analysis methods and reference tables provided for 2005-2006 and 2007-2008 by age, race, and gender. Demographic differences in TEQ concentrations and trended change are reported, e.g. TEQ continues to drop in young adults aged 20-39, but distributions appear stable in older adults 60+; Mexican Americans have consistently lowest dioxins, furans, and PCBs, with non-Hispanic Blacks dropping to the same levels as non-Hispanic Whites in dioxins and PCBs and significantly below non-Hispanic Whites in furans by 2007-2008. Additionally, the ratio of 95th percentile to mean in DLC distributions was found to vary by age, between dioxins, furans, and PCBs, and across mean, making a simple ratio approach impractical for describing population concentrations using pooled samples. We discuss the practical implications of the pooled sample method, the performance of this trending solution in the context of other methods, and expected effects of distribution assumptions on variability and TEQ estimates, particularly in largely undetected congeners. These updated reference populations of individuals, along with information on trending, provide a common and valid basis for interpreting other individually sampled biomonitoring data.

Development of linear and threshold no significant risk levels for inhalation exposure to titanium dioxide using systematic review and mode of action considerations.

Titanium dioxide (TiO2) has been characterized as a poorly soluble particulate (PSP) with low toxicity. It is well accepted that low toxicity PSPs such as TiO2 induce lung tumors in rats when deposition overwhelms particle clearance mechanisms. Despite the sensitivity of rats to PSPs and questionable relevance of PSP-induced tumors to humans, TiO2 is listed as a possible human carcinogen by some agencies and regulators. Thus, environmental toxicity criteria for TiO2 are needed for stakeholders to evaluate potential risks from environmental exposure and regulatory compliance. A systematic review of the literature was conducted to characterize the available data and identify candidate datasets upon which toxicity values could be derived. Key to this assessment, a survey of mechanistic data relevant for lung cancer was used to support quantitative inhalation risk assessment approaches. A total of 473 human studies were identified, 7 of which were epidemiological studies that met inclusion criteria to quantitatively characterize carcinogenic endpoints in humans. None of these studies supported derivation of toxicity criteria; therefore, animal data were used to derived safety values for TiO2 using different dose-metrics (regional deposited dose ratios, TiO2 particle surface area lung burden, and volumetric overload of alveolar macrophages), benchmark dose modeling, and different low-dose extrapolation approaches. Based on empirical evidence and mechanistic support for nonlinear mode of action involving particle overload, chronic inflammation and cell proliferation, a no significant risk level (NSRL) of 300 µg/day was derived. By comparison, low-dose linear extrapolation from tumor incidence in the rat lung resulted in an NSRL value of 44 µg/day. These toxicity values should be useful for stakeholders interested in assessing risks from environmental exposure to respirable TiO2.

A review of background dioxin concentrations in urban/suburban and rural soils across the United States: implications for site assessments and the establishment of soil cleanup levels.

Over the last several decades, dioxin releases have decreased >90%, leading to a corresponding decrease in human body burdens. In addition, the weight-of-evidence indicates that soil exposures have little impact on human body burdens of dioxin-like compounds (DLCs), with dietary sources being the greatest contributor. In spite of this, USEPA recently proposed substantially lower preliminary remediation goals (PRGs) for soil based on their new oral reference dose (RfD) for dioxin. As such, it is important to understand how these lower soil PRGs compare to background concentrations in urban/suburban and rural soils. The objective of this evaluation was to conduct a comprehensive review of available data concerning background levels of DLCs in U.S. soils. There was substantial variability in how the soil dioxin data were presented (e.g., raw vs. summary data, congener vs. toxic equivalency [TEQ] concentration, number of DLC congeners reported, etc.). In cases where TEQ estimates were based on outdated TEFs and congener-specific data was provided, TEQ concentrations were recalculated using the current WHO2006 TEFs. The data available for rural soils were generally more robust than for urban/suburban soils. Not surprisingly, background levels of DLCs in urban/suburban soils were higher and more variable than in rural soils: 0.1-186 vs. 0.1-22.9 ng/kg TEQ, respectively. In several cases, incomplete soil DLC data were available (e.g., DL-PCBs not included) and, as such, calculated TEQ concentrations likely underestimate actual background levels. Though the current data are somewhat limited, these findings indicate that background DLC concentrations in urban/suburban soils may exceed the USEPA's updated PRGs based on the oral RfD, and are expected to substantially exceed future PRGs to be developed based on the forthcoming dioxin cancer slope factor. This demonstrates a need to characterize anthropogenic background DLCs in non-rural areas across the US to avoid establishing soil screening levels and PRGs that are lower than background concentrations.