Steven J. Broderius

Acute toxicity of organic chemical mixtures to the fathead minnow

Abstract The acute joint toxicity of industrial organic chemicals to the fathead minnow was determined for binary and equitoxic multiple chemical mixtures. Results from binary tests were used to define isobole diagrams. The degree of joint toxic action was determined among 27 chemicals from seven different chemical classes. The slopes of the acute concentration response relationships were quite similar for all test chemicals. This suggests that the mode of acute toxic action for these chemicals is alike though it may not be identical. Intoxication signs of fish exposed to nearly all test chemicals were also similar and indicative of an anesthetic like effect. The results of isobole diagrams for binary mixtures, with 1-octanol as the reference chemical, demonstrated a near concentration additive acute joint action over a wide range of mixture ratios for each chemical from 7 different classes. Tests conducted with mixtures containing equitoxic levels of two to 21 chemicals also displayed a concentration additive acute joint action. All test chemicals can be modeled by a structure-toxicity relationship characteristic of a narcosis type of toxic action. These results are consistent with those of other investigators and are of particular importance when one realizes that numerous industrial chemicals are likely to cause lethality to aquatic organisms through similar toxic action.

Structure-Toxicity Relationships for Industrial Chemicals Causing Type (II) Narcosis Syndrome

Several structure-activity relationships have been published for estimating the lethality of nonpolar nonelectrolytes to fish. The vast majority of non-reactive industrial chemicals produce toxicity symptoms consistent with narcosis. However, we have found that many chemicals which appear to produce narcosis, are substantially more toxic than the published structure-toxicity relationship predicts. We observed that these chemicals are more polar and often have acidic hydrogen bond donor functional groups. The data are consistent with the “polar” narcotic class proposed by Ferguson five decades ago.

A QSAR study of the toxicity of amines to the fathead minnow.

Simple and multiple linear regressions were applied to the development of fish toxicity QSAR models for the 96-h LC50 to the fathead minnow, Pimephales promelas. The data on unbranched saturated primary alkylamines as well as the complete data set were well-fitted to linear QSAR models using log P or the valence first-order connectivity index (1XV) as descriptors. Although adding data on other subclasses of amines in this data set yield acceptable QSARs, only the tertiary amine subclass provided a poor fit with both of these descriptors. The amines include both acyclic and cyclic derivatives, either with no additional functional groups, or with the hydroxyl, keto, methoxy, and propargyl moieties. The molecular mechanism for fish toxicity of these amines as well as the outliers in the study were investigated. Based upon the calculated log P value of -1.40, tripropargylamine has an apparent excess toxicity of 84 times; in contrast, the measured shake-flask log P for this compound was subsequently found to be 1.26, giving a predicted LC50 consistent with the observed value. An upward curvature of the QSAR plot for the most hydrophilic compounds suggests a shift in mechanism for the lowest members of the series.

Influence of Cytochrome P450 Mixed-Function Oxidase Induction on the Acute Toxicity to Rainbow Trout (Salmo gairdneri) of Primary Aromatic Amines

The influence of enzyme induction on the acute toxicity of aniline and 4-chloroaniline to rainbow trout (Salmo gairdneri) was investigated. For these two xenobiotics, bioactivation reactions are known to occur in mammals. Induction of cytochrome P450 mixed-function oxidase was obtained by intraperitoneal (ip) injection of trout with a mixture of polychlorinated biphenyls (Aroclor 1254). Five days after ip injection with three different doses of Aroclor 1254 (50, 100, and 200 mg/kg), benzo[a]pyrene hydroxylase activity in trout liver microsomes increased five- to sixfold. Cytochrome P450 concentrations in the microsomes were slightly, but significantly, enhanced in two of the three dose levels. The 96-hr LC50s of aniline and 4-chloroaniline were not affected by pretreatment with Aroclor 1254, suggesting that metabolic activation does not necessarily play a role in the acute toxicity of aromatic amines to fish.

A comparison of the lethal and sublethal toxicity of organic chemical mixtures to the fathead minnow (Pimephales promelas)

The joint toxic effects of known binary and multiple organic chemical mixtures to the fathead minnow (Pimephales promelas) were defined at both the 96-h 50% lethal effect concentration (LC50) and sublethal (32-d growth) response levels for toxicants with a narcosis I, narcosis II, or uncoupler of oxidative phosphoralation mode of toxic action. Experiments were designed to define the degree of additive joint toxicity for mixtures of specific xenobiotics that are believed to act through a similar or different primary mode of toxic action. Our results support the general conclusion that concentration addition is expected for the joint toxicity of similarly acting toxicants. When chemicals were thought to act by a dissimilar mechanism, the combined effects we observed at both of the response levels tested were less than predicted by concentration addition, but usually more toxic than that predicted by the independent action/response addition model. It was demonstrated in multichemical mixtures that several toxicants can act together in a nearly additive fashion to produce effects even when they are present at concentrations below their individual no-observed-effect concentration. Concentration-response relationships for test chemicals at both the lethal and sublethal responses were defined for each of the three modes of toxic action studied. When normalized for potency, it was observed that one relationship could be defined to predict lethality to juvenile fathead minnows when exposed to individual chemicals with either a narcosis I, narcosis II, or uncoupler mode of toxic action. These sublethal relationships were similar for the narcosis I and narcosis II test chemicals, but a steeper response was observed for tests conducted with uncouplers.

Comparison of the susceptibility of daphnids and fish to benzene derivatives

Abstract A battery of acute toxicity tests with a variety of aquatic organisms may represent a valid approach for preliminary hazard assessment. As the difference in sensitivity among species can be very large, it is fundamental that the test organisms are properly selected. The paper compares the sensitivity of three aquatic species — Ceriodaphnia dubia, Daphnia magna , and Pimephales promelas (fathead minnow) larvae — to acute effects of toxicants. The comparison is based on data for nine compounds; namely, benzene and eight monosubstituted benzenes (MBs) expected to span a sufficiently wide range of toxicity. The results of acute toxicity tests with Ceriodaphnia dubia and fish larvae showed that the two organisms have a very similar susceptibility towards the tested chemicals, with the major exception of aniline, which was more toxic to daphnids than to fish (the actual LC 50 s differing by more than two orders of magnitude). Toxicity data for Daphnia magna , available from a previous study, show a trend similar to that observed with Ceriodaphnia dubia , but, at the same time, suggest that this species is equally or more sensitive than Ceriodaphnia dubia and fathead minnow.

Predicting modes of toxic action from chemical structure

CHRISTINE L. RUSSOM,*y STEVEN P. BRADBURY,z STEVEN J. BRODERIUS**,y DEAN J. HAMMERMEISTER,y ROBERT A. DRUMMOND**,y and GILMAN D. VEITH**y yUS Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Office of Research and Development, Duluth, Minnesota, USA zUS Environmental Protection Agency, Office of Pesticide Programs, Office of Chemical Safety and Pollution Prevention, Washington, DC, USA