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4-Week oral toxicity study of a combination of eight chemicals in rats: Comparison with the toxicity of the individual compounds

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Author: Jonker, D. · Woutersen, R.A. · Bladeren, P.J. van · Til, H.P. · Feron, V.J.
Institution: Centraal Instituut voor Voedingsonderzoek TNO
Source:Food and Chemical Toxicology, 9, 28, 623-631
Identifier: 231290
doi: doi:10.1016/0278-6915(90)90170-R
Keywords: dioctyltin dichloride · hemoglobin · loperamide · lysinoalanine · metaldehyde · mirex · potassium nitrite · sodium metabisulfite · stannous chloride · unclassified drug · animal experiment · article · drug mixture · female · kidney mass · male · nonhuman · priority journal · rat · toxicity · Administration, Oral · Animal · Blood · Body Weight · Drug Synergism · Drug Toxicity · Eating · Female · Male · Organ Weight · Pharmaceutical Preparations · Rats · Rats, Inbred Strains · Support, Non-U.S. Gov't · Animalia · Rattus norvegicus


In a 4-wk oral toxicity study, 4-wk-old male and female Wistar rats were exposed to a combination of arbitrarily chosen chemicals comprising sodium metabisulphite, Mirex, Loperamide, metaldehyde, di-n-octyltin dichloride, stannous chloride, lysinoalanine and potassium nitrite. The dose levels used were based on the 'no-observed-adverse-effect level' (NOAEL) and the 'minimum-observed-adverse-effect level' (MOAEL) of the individual compounds obtained in similar studies with Wistar rats previously performed at TNO-CIVO, and comprised 0 (controls), 1/10 and 1/3 of the NOAEL, the NOAEL and the MOAEL. In comparison with the adverse effects of the individual compounds, both more severe and less severe adverse effects were observed at the MOAEL of the combined compounds, indicating interaction of effects at this exposure level. Slightly decreased haemoglobin content and slightly increased relative kidney weight were the only treatment-related adverse effects seen in the NOAEL group. In the 1/10 and 1/3 NOAEL groups no untoward effects were found that could be related to treatment. The present study clearly demonstrates absence of a simple additive effect, and provides some, but no convincing, evidence for an increased risk from exposure to a combination of chemicals when each chemical is administered at its own individual NOAEL. At lower dose levels no increased risk appears to exist. These generalizations may not be fully justifiable from a purely scientific point of view but are the most important practical lesson learnt from the present study. Chemicals/CAS: Pharmaceutical Preparations