POLYHALOGENATED ORGANOPHOSPHATE FLAME RETARDANTS AND DEVELOPMENTAL NEUROTOXICITY: A 21ST CENTURY PERSPECTIVE

Ubiquitous exposure to environmental chemicals has come to define contemporary life, although the role of these exposures has only recently been appreciated in the etiology of neurodevelopmental diseases. Organophosphate flame retardants are one such implicated group of chemicals, and as such have faced renewed regulatory scrutiny over the magnitude of risk they pose to the developing human brain. Large epidemiological studies of maternal exposure as well as direct exposures in school-aged children have consistently associated organophosphate flame retardants with clinical indicators of abnormal neurodevelopment. However, the dual challenges of incomplete understanding of these disorders and discordant data in conventional toxicological research has complicated efforts to determine a causal role for flame retardants in the etiology of neurodevelopmental disease. This investigation aims to determine whether organophosphate flame retardants classified by shared functional, structural, physicochemical, and biological properties exhibit sufficient concordance across a battery of developmental neurotoxicity assays in the human iPSC-derived BrainSphere model to justify a single assessment of human neurodevelopmental hazards for the entire subclass. Utilizing the subclass-based approach recommended by the National Academies of Sciences, Engineering, and Medicine, I exposed a 3-dimentional coculture of 4-week neuronal and glial cells to three flame retardants in the Polyhalogenated Organophosphate subclass (tris(2-chloroethyl) phosphate—TCEP, tris(1,3-dichloro-2-propyl)phosphate—TDCPP, and tris(2-chloropropyl) phosphate—Tris) for one week at concentrations found in human serum. The results indicate that these compounds impair neurite quality and elicit a minor upregulation of microtubule-associated (TUBB3, MAP2) and synaptic (PSD-95, GRIN1, GRIN2a) proteins. At 10 and 20 μM exposure, polyhalogenated organophosphate flame retardants do not appear to elicit as strong a toxic effect as BDE-47, the primary congener of polybrominated diphenyl ether (PBDE), which has been removed from the market due to its toxicity in the developing brain. While these findings should still be considered preliminary, evidence suggests that constituents of the PHOP subclass are both capable of perturbing key events in neurodevelopment and do so with a sufficiently similar magnitude and directionality to justify regulatory consideration of co-exposures in a cumulative human risk assessment

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