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Alternative acute inhalation toxicity testing by determination of the concentration-time-mortality relationship : experimental comparison with standard LC50 testing

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Author: Zwart, A. · Arts, J.H.E. · Berge, W.F. ten · Appelman, L.M.
Type:article
Date:1992
Source:Regulatory Toxicology and Pharmacology, 15, 278-290
Identifier: 78747
doi: doi:10.1016/0273-2300(92)90039-C
Keywords: Biology · Biology · Medicine · Geneeskunde · Pharmacology · Toxicology · Animal experiment · Article · Inhalation · Lc 50 · Nonhuman · Rat · Toxicity · Toxicity testing · Administration · Inhalation · Animal · Comparative Study · Environmental Exposure · Female · Lethal Dose 50 · Male · Mortality · Rats · Reference Values · Research Design · Support, Non-U.S. Gov't · Time Factors · Toxicology · Animalia

Abstract

A new design for acute inhalation toxicity testing was evaluated and compared with results obtained according to OECD guideline 403. The new design consists of a range-finding test, which is compatible with a conventional limit test, and can be followed by determination of a concentration-time-mortality relationship, enabling calculation of LC50 (50% mortality exposure concentration) values. By exposing pairs of rats for different periods of time to about four different test concentrations in a nose-only exposure unit, LT50 (50% mortality exposure time) values were obtained for five pairs of animals per concentration. The mortality data of the approximate 20 time-concentration combinations were used to calculate the probit relationship. Estimated mortality responses from these probit relations were compared with mortality figures obtained by exposing groups of five male rats and five female rats whole-body according to conventional toxicity testing. In general, there was good correspondence between the estimated and the observed mortality response. In our hands, the determination of the concentration-time-mortality relationship takes about the same number of animals (40-50) as the conventional LC50 procedure according to the OECD guideline 403. However, the new method has several additional advantages such as: (A) LC50 values are obtained over a 10-fold range in time, with the potential of decreasing the number of animals used when regulations require acute toxicity data for different periods of exposure. (B) The obtained relationship contains considerably more valuable information for risk assessment than the LC50 value. (C) The method is less sensitive to small fluctuations in test substance concentrations which is important especially for substances with steep concentration-response curves. The results of this investigation indicate the need for reconsideration and adaptation of the OECD guideline 403 on acute inhalation toxicity testing.