TOXICITY OF MIXTURES OF NEPHROTOXICANTS WITH SIMILAR OR DISSIMILAR MODE OF ACTION

The toxicity of mixtures of chemicals with the same target organ was e xamined 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 proxima l tubular cells but through different modes of action, were administer ed simultaneously at their individual lowest-observed-nephrotoxic-effe ct level (LONEL), no-observed-nephrotoxic-effect level (NONEL) and NON EL/4. Combined exposure at the LONEL resulted in increased growth depr ession 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 th e NONEL/4 did not show any treatment-related changes. The absence of a n obviously increased hazard on combined exposure at the NONEL suggest ed absence of synergism and probably also of additivity. In a subseque nt study the additivity assumption (dose addition) was tested, using t he similarly acting nephrotoxicants tetrachloroethylene, trichloroethy lene, hexachloro-1,3-butadiene and 1,1,2-trichloro-3,3,3-trifluoroprop ene. 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 combin ations of four (at the NONEL and LONEL/2) or three (at the LONEL/3). R elative kidney weight was increased on exposure to the individual comp ounds at their LONEL and, to about the same extent, on combined exposu re at the NONEL or the LONEL/3. As assessed by this endpoint, the rena l toxicity of the mixtures corresponded to the effect expected on the basis of the additivity assumption. The other endpoints were not (or h ardly) affected on combined exposure. Copyright (C) 1997 Elsevier Scie nce Ltd.