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.

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.

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.

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.