Hepatotoxicity databases

Zhu X, Kruhlak NL (2014) Construction and analysis of a human hepatotoxicity database suitable for QSAR modeling using post-market safety data. Toxicology 321, 62-72. 

As discussed in the introduction to Section 2.1, there are a number of limitations in the human database for most health effects, the data are inadequate to assess the potential for humans having a particular effect. Because the human data are incomplete, hazard and risk must be extrapolated across species. A large number of adverse effects have been observed in animals, and most have been observed in every experimental animal species tested, if the appropriate dose is administered. This is illustrated in Table 2-8 for 8 major effects associated with CDD toxicity (acute lethality, hepatotoxicity, wasting syndrome, chloracne, immunotoxicity, reproductive toxicity, developmental toxicity, and cancer). With the exception of acute lethality in humans, positive responses have been observed in each tested species, when a response has been investigated. Despite the similarities in hazard response between different species, large species differences in sensitivity have been observed. Comparisons of species sensitivity demonstrate that no species is consistently sensitive or refractory for all effects and, for some effects,... 

Mendrick, P. Higgs, B.W. Porter, M.W. Castle, A.L. Orr, M.S. Using gene markers identified from a large database built with primary rat hepatocytes for prediction of human hepatotoxicity. Toxicologist 2003, 72 (SI), 244. 

The authors noted that two other patients in the Australian adverse reactions database also appeared to have had hepatotoxicity related to entacapone. In response, representatives of the manufacturers (Novartis) strongly contested the conclusion that any of the three reported cases demonstrated entacapone-induced hepatotoxicity, and concluded that two of the three patients had cholestasis, which is unlikely to be related to entacapone, while the third had no real evidence of hepatic dysfunction (10). These arguments were in turn rebutted by the original authors, and the possible hepatotoxicity of entacapone remains a matter of debate, although there can be no doubt that it is safer than tolcapone. 

In silico tools make a significant contribution to the SAR-based early identification of potential toxicity. An increasing volume of published preclinical and clinical toxicity data are collected and used to build structure-related searchable databases. These expert knowledge databases can analyze chemical structures and match them with potential mechanisms of toxicity. DEREK for Windows (Lhasa Ltd.)39 is one of such broadly used knowledge-based expert systems to provide toxicology alerts for new compounds. Although certainly not comprehensive, numerous efforts have been made to predict hepatotoxicity. Recently,... 

The database incorporates information about 54 nosological entities pertaining to chemical-produced acute intoxications, which give rise to hepatotoxic effects of any type of severity, with manifestations presented by 455 signs. The differential diagnosis within a definite disease class is predominantly based on clinical features of an individual disease, i.e. etiopathogenesis. 

The Subcommittee on Permissible Exposure Levels for Military Fuels judged that, on the basis of available data, DOD s PEL of 350 mg/m3 for the fuel vapors is adequate to protect the health of naval personnel exposed to them occupationally (NRC 1996). However, because of uncertainties in the database, the PEL should still be considered interim until further research has been completed. The subcommittee recommended that data be obtained on exposures during operational procedures, including exposure to respirable aerosols of unburned fuels that studies be conducted on the possible effects of high-level acute and low-level chronic exposure to fuel vapors on the central nervous system and that research be conducted on the effect of fuel vapors on hepatotoxicity in experimental animals to help to identify a no-observed-adverse-effect level for JP-8 with greater confidence. 

The US EDA Human Liver Adverse Effects Database (HLAED) is one of many usefnl sonrces for model development (Rodgers et al., 2010). This data set is composed of 490 compounds, and the hepatotoxic drngs are... 

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