Toxicity of mixtures of nephrotoxicants with similar or dissimilar mode of action

The toxicity of mixtures of chemicals with the same target organ was examined in rats using nephrotoxicants with similar or dissimilar modes of action. In a 4-wk feeding study, lysinoalanine, mercuric chloride, hexachloro-1,3-butadiene and d-limonene, each affecting renal proximal tubular cells but through different modes of action, were administered simultaneously at their individual lowest-observed-nephrotoxic-effect level (LONEL), no-observed-nephrotoxic-effect level (NONEL) and NONEL/4. Combined exposure at the LONEL resulted in increased growth depression and increased renal toxicity in male but not in female rats. Co-exposure at the NONEL produced only weak signs of toxicity (slightly retarded growth and increased renal weight), and rats co-exposed at the NONEL/4 did not show any treatment-related changes. The absence of an obviously increased hazard on combined exposure at the NONEL suggested absence of synergism and probably also of additivity. In a subsequent study the additivity assumption (dose addition) was tested using the similarly acting nephrotoxicants tetrachloroethylene, trichloroethylene, hexachloro-1,3-butadiene and 1,1,2-trichloro-3,3,3-trifluoro-propene. The compounds were given to female rats by daily oral gavage for 32 days either alone, at the LONEL and NONEL ( = LONEL/4), or in combinations of four (at the NONEL and LONEL/2) or three (at the LONEL/3). Relative kidney weight was increased on exposure to the individual compounds at their LONEL and, to about the same extent, on combined exposure at the NONEL or the LONEL/3. As assessed by this endpoint, the renal toxicity of the mixtures corresponded to the effect expected on the basis of the additivity assumption. The other endpoints were not (or hardly) affected on combined exposure.