Assessing liver toxicity of organic compounds based on their physicochemical properties for the purpose of calculating occupational exposure limits

Introduction
Occupational exposure limits (OELs) are based on the no-observed-adverse-effect level ( NOAEL), lowest-observed-adverse-effect level (LOAEL) or benchmark dose (BMD) deriving from epidemiological and experimental studies. The aim of this study is to investigate to what extend the LOAEL values for organic compounds responsible for liver toxicity can be calculated based on their physicochemical properties.

Methods
Distribution coefficients from the air to the liver (log Kliver) were calculated according to the LFER equation proposed by Abraham et al. (2007). LOAEL values for early effects in the liver were obtained from the literature data.

Results
The descriptors for Abraham’s equation have been found for 54 compounds, which were divided into two groups: “non-reactive” (alcohols, ketones, esters, ethers, aromatic and aliphatic hydrocarbons, amides) and “possibly reactive” ( aldehydes, allyl compounds, amines, benzyl halides, halogenated hydrocarbons, acrylates).The correlation coefficients between log-log K and log LOAEL for non-reactive and reactive compounds were statistically significant (p<0002) and amounted to r = -0.748 and r = -0.838 respectively. The method of calculation of the LOAEL values was validated against already established OEL values. For this purpose LOAEL’s for 18 compounds, where liver was considered as critical organ for setting OEL’s , have been calculated on the basis of their log-log Kliver values according to the regression equations for reactive and non-reactive compounds. Correlation between the mean OEL values published by at least of 2 out of tree organizations ACGIH (2010), DFG (2010), CIOP-PIB (2010) and those calculated was very high ( r = 0.911, p<0000)

Discussion
The obtained results suggest that LOAEL’s can be predicted based on their logKliver values. In view of the tendency to limit the animal testing procedures, the method proposed in this paper can improve the practice of setting exposure guidelines for unstudied compounds.