A multi-tiered hierarchical Bayesian approach to derive toxic equivalency factors for dioxin-like compounds.

In 2005, the World Health Organization (WHO) re-evaluated Toxic Equivalency factors (TEFs) developed for dioxin-like compounds believed to act through the Ah receptor based on an updated database of relative estimated potency (REP)(REP2004 database). This re-evalution identified the need to develop a consistent approach for dose-response modeling. Further, the WHO Panel discussed the significant heterogeneity of experimental datasets and dataset quality underlying the REPs in the database. There is a critical need to develop a quantitative, and quality weighted approach to characterize the TEF for each congener. To address this, a multi-tiered approach that combines Bayesian dose-response fitting and meta-regression with a machine learning model to predict REPS' quality categorizations was developed to predict the most likely relationship between each congener and its reference and derive model-predicted TEF uncertainty distributions. As a proof of concept, this 'Best-Estimate TEF workflow' was applied to the REP2004 database to derive TEF point-estimates and characterizations of uncertainty for all congeners. Model-TEFs were similar to the 2005 WHO TEFs, with the data-poor congeners having larger levels of uncertainty. This transparent and reproducible computational workflow incorporates WHO expert panel recommendations and represents a substantial improvement in the TEF methodology.

Use of acceptable daily intake (ADI) as a health-based benchmark in nutrition research studies that consider the safety of low-calorie sweeteners (LCS): a systematic map.

BACKGROUND: It is well-recognized that consumers face many challenges in understanding and applying nutritional guidance for low-calorie sweeteners (LCS). Thus, this research aims to (1) assess how benchmarks for safe levels of consumption of LCS are utilized by researchers, and (2) understand how varying use of such benchmarks may contribute to challenges in understanding and applying nutritional guidance for LCS consumption. METHODS: A systematic mapping exercise was employed to characterize when and how acceptable daily intake (ADI) values are used as health-based benchmarks in nutrition research studies that consider the safety of LCS. RESULTS: Based on results from charting 121 studies, our findings demonstrate that comparisons of LCS intake to an ADI derived by an authoritative body have been made in a diverse set of published literature, varying widely in their objectives, approaches, and populations of interest. The majority of studies compared the ADI to intake in a population under study; these represent the type of comparison that is most consistent with the intent of the ADI. Other applications of the ADI included use as a benchmark in experimental studies, risk-benefit analyses, and metabolism studies. CONCLUSION: Although most instances of ADI use were reasonable within the context of the individual studies' objectives, the diversity in use by original-study authors amplifies the continued need for development of "best practices" regarding the use and interpretation of the ADIs in current research. Using comparisons to the ADI can be a helpful way to provide context to research findings. However, in doing so, it is important that researchers utilize the value in a manner specific with its intent, as the ADI is a metric that represents an estimate of the amount of a substance that can be consumed daily over a lifetime without presenting an appreciable risk to health.

A systematic approach to evaluate plausible modes of actions for mouse lung tumors in mice exposed to 4-methylimidozole.

The National Toxicology Program (NTP) reported that chronic dietary exposure to 4-methylimidazole (4-MeI) increased the incidence of lung adenomas/carcinomas beyond the normally high spontaneous rate in B6C3F1 mice. To examine plausible modes of action (MoAs) for mouse lung tumors (MLTs) upon exposure to high levels of 4-MeI, and their relevance in assessing human risk, a systematic approach was used to identify and evaluate mechanistic data (in vitro and in vivo) in the primary and secondary literature, along with high-throughput screening assay data. Study quality, relevance, and activity of mechanistic data identified across the evidence-base were organized according to key characteristics of carcinogens (KCCs) to identify potential key events in known or novel MLT MoAs. Integration of these evidence streams provided confirmation that 4-MeI lacks genotoxic and cytotoxic activity with some evidence to support a lack of mitogenic activity. Further evaluation of contextual and chemical-specific characteristics of 4-MeI was consequently undertaken. Due to lack of genotoxicity, along with transcriptomic and histopathological lung changes up to 28 and 90 days of exposure, the collective evidence suggests MLTs observed following exposure to high levels of 4-MeI develop at a late stage in the mouse chronic bioassay, albeit the exact MoA remains unclear.

An updated mode of action and human relevance framework evaluation for Formaldehyde-Related nasal tumors.

Formaldehyde is a reactive aldehyde naturally present in all plant and animal tissues and a critical component of the one-carbon metabolism pathway. It is also a high production volume chemical used in the manufacture of numerous products. Formaldehyde is also one of the most well-studied chemicals with respect to environmental fate, biology, and toxicology-including carcinogenic potential, and mode of action (MOA). In 2006, a published MOA for formaldehyde-induced nasal tumors in rats concluded that nasal tumors were most likely driven by cytotoxicity and regenerative cell proliferation, with possible contributions from direct genotoxicity. In the past 15 years, new research has better informed the MOA with the publication of in vivo genotoxicity assays, toxicogenomic analyses, and development of ultra-sensitive methods to measure endogenous and exogenous formaldehyde-induced DNA adducts. Herein, we review and update the MOA for nasal tumors, with particular emphasis on the numerous studies published since 2006. These new studies further underscore the involvement of cytotoxicity and regenerative cell proliferation, and further inform the genotoxic potential of inhaled formaldehyde. The data lend additional support for the use of mechanistic data for the derivation of toxicity criteria and/or scientifically supported approaches for low-dose extrapolation for the risk assessment of formaldehyde.

Hexavalent chromium and stomach cancer: a systematic review and meta-analysis.

Hexavalent chromium [Cr(VI)] is known to cause lung cancer in workers of certain industries, but an association with stomach cancer is uncertain and widely debated. Systematic review and meta-analyses were conducted to assess the risk of stomach cancer mortality/morbidity in humans and experimental animals exposed to Cr(VI). In accordance with the protocol (PROSPERO #CRD4201605162), searches in PubMed and Embase®, and reviews of secondary literature bibliographies, were used to identify eligible studies. Critical appraisal of internal validity and qualitative integration were carried out using the National Toxicology Program's Office of Health Assessment and Translation (OHAT) approach; meta-analyses were conducted based on the occupational data (the only data suitable for quantitative assessment). Forty-seven publications (3 animal, 44 occupational, 0 non-occupational) met the eligibility criteria. Stomach cancer was only observed in one high risk of bias animal study, and in the low risk of bias studies no stomach cancer was observed. Thus, confidence in this evidence base is high. Environmental epidemiology studies did not meet eligibility criteria because exposure and outcome were not measured at the individual level. Meta-analyses of human data resulted in overall meta relative risks of 1.08 (95% CI: 0.96-1.21) including all studies and 1.03 (95%CI: 0.84-1.26) excluding studies associated with the highest risk of bias. Because most occupational studies have high risk of bias for confounding and exposure domains, the overall confidence in this evidence base is low to moderate. Combining the streams of evidence per the OHAT approach, Cr(VI) does not pose a stomach cancer hazard in humans.

Development of an oral reference dose for the perfluorinated compound GenX.

Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, also known as GenX, is a processing aid used in the manufacture of fluoropolymers. GenX is one of several chemistries developed as an alternative to long-chain poly-fluoroalkyl substances, which tend to have long clearance half-lives and are environmentally persistent. Unlike poly-fluoroalkyl substances, GenX has more rapid clearance, but has been detected in US and international water sources. There are currently no federal drinking water standards for GenX in the USA; therefore, we developed a non-cancer oral reference dose (RfD) for GenX based on available repeated dose studies. The review of the available data indicate that GenX is unlikely to be genotoxic. A combination of traditional frequentist benchmark dose models and Bayesian benchmark dose models were used derive relevant points of departure from mammalian toxicity studies. In addition, deterministic and probabilistic RfD values were developed using available tools and regulatory guidance. The two approaches resulted in a narrow range of RfD values for liver lesions observed in a 2-year bioassay in rats (0.01-0.02 mg/kg/day). The probabilistic approach resulted in the lower, i.e., more conservative RfD. The probabilistic RfD of 0.01 mg/kg/day results in a maximum contaminant level goal of 70 ppb. It is anticipated that these values, along with the hazard identification and dose-response modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for GenX.

Assessment of associations between inhaled formaldehyde and lymphohematopoietic cancer through the integration of epidemiological and toxicological evidence with biological plausibility.

Formaldehyde is recognized as carcinogenic for the portal of entry sites, though conclusions are mixed regarding lymphohematopoietic (LHP) cancers. This systematic review assesses the likelihood of a causal relationship between formaldehyde and LHP cancers by integrating components recommended by NASEM. Four experimental rodent bioassays and 16 observational studies in humans were included following the implementation of the a priori protocol. All studies were assessed for risk of bias (RoB), and meta-analyses were conducted on epidemiological studies, followed by a structured assessment of causation based on GRADE and Bradford Hill. RoB analysis identified systemic limitations precluding confidence in the epidemiological evidence due to inadequate characterization of formaldehyde exposure and a failure to adequately adjust for confounders or effect modifiers, thus suggesting that effect estimates are likely to be impacted by systemic bias. Mixed findings were reported in individual studies; meta-analyses did not identify significant associations between formaldehyde inhalation (when measured as ever/never exposure) and LHP outcomes, with meta-SMRs ranging from 0.50 to 1.51, depending on LHP subtype. No associations with LHP-related lesions were reported in reliable animal bioassays. No biologically plausible explanation linking the inhalation of FA and LHP was identified, supported primarily by the lack of systemic distribution and in vivo genotoxicity. In conclusion, the inconsistent associations reported in a subset of the evidence were not considered causal when integrated with the totality of the epidemiological evidence, toxicological data, and considerations of biological plausibility. The impact of systemic biases identified herein could be quantitatively assessed to better inform causality and use in risk assessment.

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.

Performance of preclinical models in predicting drug-induced liver injury in humans: a systematic review.

Drug-induced liver injury (DILI) causes one in three market withdrawals due to adverse drug reactions, causing preventable human suffering and massive financial loss. We applied evidence-based methods to investigate the role of preclinical studies in predicting human DILI using two anti-diabetic drugs from the same class, but with different toxicological profiles: troglitazone (withdrawn from US market due to DILI) and rosiglitazone (remains on US market). Evidence Stream 1: A systematic literature review of in vivo studies on rosiglitazone or troglitazone was conducted (PROSPERO registration CRD42018112353). Evidence Stream 2: in vitro data on troglitazone and rosiglitazone were retrieved from the US EPA ToxCast database. Evidence Stream 3: troglitazone- and rosiglitazone-related DILI cases were retrieved from WHO Vigibase. All three evidence stream analyses were conducted according to evidence-based methodologies and performed according to pre-registered protocols. Evidence Stream 1: 9288 references were identified, with 42 studies included in analysis. No reported biomarker for either drug indicated a strong hazard signal in either preclinical animal or human studies. All included studies had substantial limitations, resulting in "low" or "very low" certainty in findings. Evidence Stream 2: Troglitazone was active in twice as many in vitro assays (129) as rosiglitazone (60), indicating a strong signal for more off-target effects. Evidence Stream 3: We observed a fivefold difference in both all adverse events and liver-related adverse events reported, and an eightfold difference in fatalities for troglitazone, compared to rosiglitazone. In summary, published animal and human trials failed to predict troglitazone's potential to cause severe liver injury in a wider patient population, while in vitro data showed marked differences in the two drugs' off-target activities, offering a new paradigm for reducing drug attrition in late development and in the market. This investigation concludes that death and disability due to adverse drug reactions may be prevented if mechanistic information is deployed at early stages of drug development by pharmaceutical companies and is considered by regulators as a part of regulatory submissions.

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.