Differential toxicity of monochloroacetate, monofluoroacetate and monoiodoacetate in rats

doi:10.1016/0041-008X(73)90089-6

Toxicology and Applied Pharmacology

Volume 26, Issue 1, September 1973, Pages 93-102

https://doi.org/10.1016/0041-008X(73)90089-6 Get rights and content

Abstract

Acute lethality and mechanisms of toxicity of monochloroacetate (MCA), monofluoroacetate (MFA) and monoiodoacetate (MIA) were compared in rats. MCA, MFA and MIA were administered to rats, and the number of dead was determined. LD90 doses of the haloacetates were administered to rats, and the time of death (LT) was noted. The effect of haloacetates on in vitro [¹⁴C] acetate oxidation in liver homogenates was determined, and Hofstee plots were used to estimate reaction kinetics. MCA binding of in vivo and in vitro sulfhydryl (SH) groups was examined as a possible mechanism of toxicity. Tissue distribution of [¹⁴C] haloacetates, LD90 dose, and of [¹⁴C]MCA, LD1 dose, was determined. The 24-hr LD50 for MFA, MIA and MCA were, respectively, 5, 60 and 108 mg/kg. The LT50 for MCA, MFA and MIA were, respectively, 130, 310 and 480 min. Reaction parameters for [¹⁴C]acetate oxidation were, V_max = 30.5 × 10²dpm¹⁴CO₂min⁻¹, apparent K_m = 2.4 × 10⁻⁶, m. MCA and MFA inhibited [¹⁴C]acetate oxidation: MCA apparent K_i = 9.1 × 10⁻⁷, m, and MFA apparent K_i = 11.0 × 10⁻⁷, m. MCA and MIA reduced the SH concentration in the kidney and liver but MCA did not reduce cysteine SH concentration in vitro. [¹⁴C]MCA and [¹⁴C]MIA distributed primarily to liver and kidney, but [¹⁴C]MFA had relatively higher plasma concentrations. It was concluded that MCA, MFA and MIA produce acute toxicity by dissimilar mechanisms.

References (16)

G.R. Bartlett et al.
The effect of fluoroacetate on enzymes and on tissue metabolism. Its use for the study of the oxidative pathway of pyruvate metabolism
J. Biol. Chem.
(1947)
I.M. Chaiken et al.
Reaction of the sulfhydryl groups of papain with chloroacetic acid
J. Biol. Chem.
(1969)
W.H. Lawrence et al.
Toxicity profile of chloroacetaldehyde
J. Pharm. Sci.
(1972)
J. Sedlak et al.
Estimation of total, protein-bound and non-protein sulfhydryl groups in tissue with Ellman's reagent
Anal. Biochem.
(1968)
T. Akera et al.
The interaction between chlorpromazine free radical and microsomal sodium- and potassium-activated adenosine triphosphatase from rat brain
Mol. Pharmacol.
(1969)
M.B. Chenoweth
Monofluoroacetic acid and related compounds
Pharmacol. Rev.
(1949)
M.B. Chenoweth et al.
Factors influencing fluoroacetate poisoning
J. Pharmacol. Exp. Ther.
(1951)
F. Dickens
Interaction of halogenacetates and SH compounds
Biochemistry
(1933)

There are more references available in the full text version of this article.

Cited by (49)

Micronuclei induction and chromosomal aberrations in Rattus norvegicus by chloroacetic acid and chlorobenzene
2006, Ecotoxicology and Environmental Safety
Chloroacetic acid (CAA) and chlorobenzene (CB) have been evaluated for in vivo mutagenic potential in Rattus norvegicus, employing the following criteria : (i) chromosomal aberrations (CAs) such as breaks, gaps, exchanges, rings, and multiple aberrations and (ii) micronuclei (MN) induction. Three sublethal doses, 0.008, 0.01, and 0.012 mg/g b. wt. of CAA and 0.75, 1.0, and 1.25 mg/g b. wt. of rat of CB were administered and the bone marrow cells evaluated in each of the three treated groups at 12, 24, and 48 h, respectively. Mean MN frequencies of 4.40±0.2 and 5.42±0.3, obtained respectively for CAA and CB. The higher induction of MN by CAA and CB was dose- and time-dependent. Most significant impact (P<0.05) for either of the compounds was observed at 24 h post administration, when the recorded mean frequency of CAs was maximum for CAA (4.33±0.6) as well as for CB (4.66±0.5).
The traditional categories of fluoroacetate poisoning signs and symptoms belie substantial underlying similarities
2004, Toxicology Letters
Sodium monofluoroacetate (Compound 1080) has been widely used around the world as a vertebrate pest control agent. Following ingestion of 1080 there is a latent period, during which the compound is metabolised into a toxic form, before the onset of symptoms. The timing of this period varies significantly between species as does the median lethal dose. Traditionally different species have also been classified into groups depending on the primary organ system involved in 1080 toxicosis (cardiac, nervous, or mixed signs/symptoms). However, general acceptance of this method of classification has obscured the fact that several signs of fluoroacetate poisoning are common to most vertebrate species. This paper reviews five decades of literature on the signs/symptoms of fluoroacetate poisoning in vertebrates and concludes that there is little justification for the division of animals poisoned by fluoroacetate into symptomatic groups.
Trichloroacetic acid (TCA) and trifluoroacetic acid (TFA) mixture toxicity to the macrophytes Myriophyllum spicatum and Myriophyllum sibiricum in aquatic microcosms
2002, Science of the Total Environment
Trichloroacetic acid (TCA) and trifluoroacetic acid (TFA) have been detected together in environmental water samples throughout the world. TCA may enter into aquatic systems via rainout as the degradation product of chlorinated solvents, herbicide use, as a by-product of water disinfection and from emissions of spent bleach liquor of kraft pulp mills. Sources of TFA include degradation of hydrofluorocarbons (HFCs) refrigerants and pesticides. These substances are phytotoxic and widely distributed in aquatic environments. A study to assess the risk of a binary mixture of TCA and TFA to macrophytes in aquatic microcosms was conducted as part of a larger study on haloacetic acids. M. spicatum and M. sibiricum were exposed to 0.1, 1, 3 and 10 mg/l of both TCA and TFA (neutralized with sodium hydroxide) in replicate (n=3) 12 000 l aquatic microcosms for 49 days in an one-way analysis of variance design. Each microcosm was stocked with 14 individual apical shoots per species. The plants were sampled at regular intervals and assessed for the somatic endpoints of plant length, root growth, number of nodes and wet and dry mass and the biochemical endpoints of chlorophyll-a, chlorophyll-b, carotenoid content and citric acid levels. Results indicate that there were statistically significant effects of the TCA/TFA mixture on certain pigment concentrations immediately after the start of exposure (2–7 days), but the plants showed no signs of stress thereafter. These data suggest that TCA/TFA mixtures at environmentally relevant concentrations do not pose a significant risk to these aquatic macrophytes.
Trichloroacetic acid fate and toxicity to the macrophytes Myriophyllum spicatum and Myriophyllum sibiricum under field conditions
2002, Aquatic Toxicology
Trichloroacetic acid (TCA) has been detected in rain, snow, and river samples throughout the world. It may enter into natural water systems via herbicide use, as a by-product of water disinfection, from emissions of spent bleach liquor of kraft pulp mills, and as a natural fungal product. This compound is phytotoxic and likely to accumulate in aquatic environments. A study to assess the fate of TCA in semi-natural aquatic environments and the toxicity of TCA to rooted aquatic macrophytes was conducted. The experiment involved exposing three replicate 12 000 l aquatic microcosms at the University of Guelph Microcosm Facility to 0.05, 0.5, 3, and 10 mg/l of TCA for 35 days in a one-way analysis of variance design. Each microcosm was stocked with 14 individual 5 cm apical shoots of Myriophyllum spicatum and M. sibiricum. The plants were sampled at regular intervals and assessed for the somatic endpoints of plant length, root growth, number of nodes and wet and dry mass and the biochemical endpoints of chlorophyll-a and chlorophyll-b, carotenoid content, and citric acid levels. TCA half-lives in the microcosms ranged from 190 to 296 h depending on the initial concentration of TCA. Myriophyllum spp. results indicate that while there were some statistically significant differences from controls, there were no biologically significant effects of TCA for any of the endpoints examined. These data suggest that TCA does not pose a significant risk to these macrophytes up to 10 mg/l, which typically exceeds environmentally relevant concentrations by several orders of magnitude.
The role of time in toxicology or Haber's c x t product
2000, Toxicology
It happened exactly 100 years ago that Warren established for the first time a quantitative link between dose and time while studying the toxicity of sodium chloride in Daphnia magna (Straus). During this century many toxicologists in different contexts returned to this idea, which has become known as Haber’s rule of inhalation toxicology. Most attempts to explore this relationship ended in frustration because of the supposed occurrence of exceptions. Thus, toxicologists concentrated on the quantitative relationship between dose and effect under mostly isotemporal conditions while time took a back seat and was assigned such arbitrary, semiquantitative designations as acute, subacute, subchronic and chronic. Time itself as a quantifiable variable of toxicity was seldom studied and when it was studied, it was often not under isodosic (steady state) conditions as required by theory. A recent analysis of toxicological time indicated the impact of three independent time scales (toxicokinetic, toxicodynamic, exposure frequency/duration) in toxicological studies, which interact with dose and effect to yield the enormous complexity known to every toxicologist. Based on prototypical examples when toxicokinetic (dioxins), toxicodynamic (nitrosamines, benzene) or exposure frequency (methylene chloride, chloroacetic acid, HgCl₂, CdCl₂, etc.) represent the critical time scale, the general validity of the c×t=k concept will be discussed as a starting point for a theory of toxicology. As endpoints of toxicity, (delayed) acute toxicity, blood dyscrasias and cancer will be used to illustrate the critical conditions needed to demonstrate the validity of this theory.
Sodium monochloroacetate poisoning of greenfinches
1992, Forensic Science International
A large number of passerine birds, mainly greenfinches, were found dead or dying in a hedgerow close to a field of onions recently sprayed with sodium monochloroacetate (SMCA). An analytical method is described for isolating monochloroacetic acid from bird tissues, as its potassium salt, by ion exchange chromatography. The ion exchange eluate is evaporated to dryness, acidified, extracted with ether and the ethereal extract methylated with diazomethane. The concentration of the methyl ester of monochloroacetic acid is determined using the Mass Selective Detector in the Selected ion mode. Chemical analysis confirmed the exposure of the birds to SMCA. It is calculated that 50 μl of spray contained the lethal dose of SMCA for a greenfinch.

View all citing articles on Scopus

View full text

Differential toxicity of monochloroacetate, monofluoroacetate and monoiodoacetate in rats

Abstract

J. Biol. Chem.

J. Biol. Chem.

J. Pharm. Sci.

Anal. Biochem.

The interaction between chlorpromazine free radical and microsomal sodium- and potassium-activated adenosine triphosphatase from rat brain

Mol. Pharmacol.

Monofluoroacetic acid and related compounds

Pharmacol. Rev.

Factors influencing fluoroacetate poisoning

J. Pharmacol. Exp. Ther.

Interaction of halogenacetates and SH compounds

Biochemistry