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Phenoxy acid herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxyacetic acid (MCPA) have been found to induce proliferation of peroxisomes in the liver cells of rodents in the same manner as the hypolipidemic drug clofibrate. Both phenoxy acid herbicides and clofibrate (ethyl-alpha-p- chlorophenoxyisobutyrate ) are suspected carcinogens. The present study reports the effect of these agents on the induction of sister chromatid exchange (SCE) in the blood lymphocytes of exposed rats (100 mg/kg with 2,4-D and MCPA, 200 mg/kg with clofibrate for 2 weeks in one intragastric dose/day), in the bone marrow cells of exposed Chinese hamsters (100 mg/kg, treatments as above), and in Chinese hamster ovary (CHO) cells in vitro (10(-5), 10(-4), and 10(-3) M, for 1 h). In the experiments in vitro, the effects of purified 2,4-D and MCPA phenoxy acids were studied, in addition to those of the commercial herbicide formulations and clofibrate. No increase of SCE frequency was observed in the blood lymphocytes of the exposed rats in comparison with the controls. In the bone marrow cells of the exposed Chinese hamsters, a slight increase of SCE was found in the group treated with MCPA but not in the groups treated with 2,4-D or clofibrate. A slight increase in the number of SCEs was characteristic of all the treated CHO cell cultures, both with and without a rat liver microsomal activation system (S9 mix). No clear dose-related effects, however, could be discerned with any of the compounds, and no differences in the SCE induction were observed between the commercial herbicide products and the purified phenoxy acetic acids. The present results support the data which indicate that 2,4-D, MCPA, and clofibrate do not act as direct DNA-damaging agents.

An increase in either the size or amount of peroxisomes was obtained in the liver cells of Chinese hamsters after the animals were exposed to the phenoxy herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) or 4-chloro-2-methylphenoxyacetic acid (MCPA). At the dose level studied, 2,4-D was found to be more potent than MCPA in increasing the number of peroxisomes. A phenoxy acid derivative, clofibrate, one of the peroxisome proliferators known to possess carcinogenic properties in rodents, appeared to be still more potent in inducing peroxisome proliferation than either of the herbicides studied. Further investigations are warranted to clarify the significance of peroxisome proliferation to the toxicity of phenoxy herbicides.

Male Wistar rats were treated daily by gavage with two phenoxy herbicides, 2,4-dichlorophenoxyacetic acid (2,4-D)(100-200 mg/kg body wt) and 4-chloro-2-methylphenoxyacetic acid (MCPA) (100-200 mg/kg body wt), and with the chemically different glyphosate N-phosphonomethyl glycine (300 mg/kg body wt) 5 days per week for 2 weeks. A hypolipidemic drug, clofibrate [ethyl-2-(4-chlorophenoxy)-2-methylpropionate], which is structurally related to phenoxy acids, was used as a positive control (200 mg/kg body wt). 2,4-D and MCPA had several effects similar to those of clofibrate: all three compounds induced proliferation of hepatic peroxisomes, decreased serum lipid levels, and increased hepatic carnitine acetyltransferase and catalase activities. 2,4-D and MCPA, but not clofibrate, decreased lipoprotein lipase activity in the adipose tissue to about a third of the control value but did not change the lipoprotein lipase activity in the heart muscle. The data suggest that these compounds cause hypolipidemia not by enhancing the storage of peripheral lipids in adipose tissue but by preferentially increasing lipid utilization in the liver. Glyphosate caused no peroxisome proliferation or hypolipidemia, suggesting that these effects are associated with the structural similarity between phenoxy acid herbicides and clofibrate.

The effects of phenoxyacetic acid herbicides were investigated on the induction of chromosome aberrations in human peripheral lymphocyte cultures in vitro and in lymphocytes of exposed workers in vivo. Pure 2,4-dichlorophenoxyacetic acid (2,4-D; 0.125, 0.150, 0.200 and 0.350 mM) did not increase the number of aberrations, whereas the commercial 2,4-D formulation (0.125, 0.250, 0.500, 1.000 and 1.250 mM, with respect to phenoxyacetic acid concentration) significantly increased the number of chromosome aberrations in vitro (without exogenous metabolic activation). The phenoxy acid levels in the breathing zone of the workers varied between 0.3 and 0.4 mg/m3, and the concentrations of phenoxyacetic acids in the urine of the workers after exposure varied from 0.000 to 0.055 mmol/l. There were no increases in chromosome aberrations in peripheral lymphocytes of the exposed subjects.

The induction of sister chromatid exchanges (SCEs) was studied in the peripheral lymphocytes of workers spraying foliage in forestry with phenoxy acid herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-methyl-4-chlorophenoxyacetic acid (MCPA) or their mixtures. In order to follow possible exposure-related changes in the frequencies of SCEs, three successive blood samples were taken from 50 male sprayers during the spraying season of July-October, 1981. In addition, 15 control subjects not working with herbicides were included in the study. The actual exposure levels of the exposed subjects were estimated by measuring the concentrations of 2,4-D and MCPA in the urine of the sprayers. Enough cells for the SCE analysis were obtained from 35 herbicide workers and 15 control subjects. The concentrations of 2,4-D and MCPA in the urine samples after exposure varied from 0.00 to 10.99 mg/l. No significant differences in the frequencies of SCEs were observed in samples taken before, during, or after the exposure. Furthermore, the means of SCEs in a nonexposed control group of 15 subjects fell in the same range as those of the exposed subjects. A difference in the means of SCEs was observed between nonsmokers and smokers, smokers having significantly higher mean values than nonsmokers. The results of the present study add support to the earlier data indicating that 2,4-D and MCPA do not act as direct DNA-damaging agents.