Adequacy of required regulatory hazard testing for the detection of potential hormonal activity of crop protection chemicals.

The capacity of some synthetic chemicals, the so-called "endocrine-disrupting chemical," to alter hormonal activity, as well as the adequacy of the testing of chemicals to evaluate this capacity, has been called into question. Among the chemicals indicted have been certain crop protection agents or pesticides. Crop protection chemicals rank among the most closely regulated and thoroughly tested chemicals in use in both the human health and environmental hazard areas. However, it has been proposed that in vitro and in vivo screening tests be used to identify potential endocrine-active chemicals and to supplement or replace required regulatory bioassays. In vitro tests, such as receptor binding, examine a single chemical event, do not measure toxicity, post-receptor-mediated biological response, or the absorption, distribution, metabolism, and elimination of a chemical. Therefore, data derived solely from such a limited testing technique should not be used as a basis for selection of chemicals for making regulatory decisions. In vivo screening tests, such as the uterotrophic assay, which promise to provide a rapid answer to a targeted question, do not capture the complexity of the biological response. As in the case with in vitro tests, results from a single in vivo test, such as a change in uterine weight, should not be used as a basis for regulatory decision making. Further, it has been suggested that such a screening battery should be put into place for ecotoxicity testing. Yet it is well recognized that endocrine-active chemicals that affect fish and wildlife in their natural habitat have been shown to cause similar adverse effects in laboratory test animals. Therefore, these screening tests do not add value to the current regulatory test battery. Evidence is presented that demonstrates that the regulatory safety assessment paradigm has a low likelihood of missing potential endocrine-active chemicals and has served society well.

Chronic toxicity and carcinogenicity studies with the insecticide endosulfan in rats and mice.

The insecticide endosulfan was evaluated for chronic toxicity and carcinogenicity in long-term feeding studies in both Sprague-Dawley rats and NMRI mice. Dietary concentrations of the test substance were administered to rats at 0, 3, 7.5, 15 and 75 ppm and to mice at 0, 2, 6 and 18 ppm for 24 months each. In the rat study, only the treatment with the highest dose caused a significant reduction of body weight gains of the males and females at 75 ppm. The increased incidence of enlarged kidneys seen at autopsy at 75 ppm in females, and the slightly increased incidence of progressive glomerulonephrosis and slightly increased incidence of renal aneurysms seen histopathologically in the 75 ppm males, make the kidney the target organ in rats. On the basis of these findings a dietary concentration of 15 ppm is considered to be the no-observed-effect level (NOEL) in rats, equivalent to a daily test substance intake of 0.6 mg/kg body weight in males and 0.7 mg/kg body weight in females. In the mouse study, the treatment with 18 ppm caused a significant increase of mortality in the females and a slight (in the first third of the study, significant) reduction of body weight gain in males. Since there were no other substance-related findings, the dietary concentration of 6 ppm is considered to be the NOEL in mice, equivalent to a daily test substance intake of 0.84 mg/kg body weight in males and 0.97 mg/kg body weight in females. An evaluation of all relevant tumour data gained in both studies revealed no differences between control and treated groups. It was concluded, therefore, that endosulfan has no carcinogenic potential.

Glufosinate ammonium--some aspects of its mode of action in mammals.

The broad-spectrum herbicide glufosinate ammonium is a structural analogue of glutamate and acts in plants by inhibition of glutamine synthetase leading to a complete breakdown of ammonia metabolism. Owing to the structural analogy of glufosinate ammonium to glutamate, its effect on various glutamate-utilizing systems needed to be investigated in mammals. Although in laboratory animals glufosinate ammonium causes an inhibition of glutamine synthetase activity in different tissues, this inhibition led to slight increases of glutamate and ammonia levels at high sublethal and lethal doses only. After oral administration for 28 days, glufosinate ammonium had no effect on glutathione and carbohydrate metabolism and no effect on biosynthesis of non-essential amino acids in rats and dogs. Glufosinate ammonium does not interfere with various neurotransmitter receptors in vitro and does not influence the catecholamine neurotransmitter tissue concentrations after iv application. The results of these studies show that--in contrast to the plant metabolism--in mammals the inhibition of glutamine synthetase activity in various tissues does not lead to a breakdown of ammonia metabolism. The mammalian metabolism obviously compensates for this inhibition of glutamine synthetase activity by various other metabolic pathways. It is concluded that under the conditions of recommended use of glufosinate ammonium as an active ingredient in herbicides, a detrimental effect on the health of both users and consumers is extremely unlikely.

Toxicology and hazard potential of trifluralin.

This paper reviews the results of toxicity studies conducted in laboratory animals to evaluate the safety of the herbicide trifluralin (TFL). The data show that TFL is slightly toxic following single oral exposure. Testing for embryotoxicity in rats and rabbits indicated no teratogenic potential, and many different mutagenicity tests showed that TFL was non-genotoxic. Subchronic and chronic toxicity testing in rats, mice and dogs indicated that TFL was haematotoxic (anaemia and methaemoglobinaemia), particularly in the dog, and slightly hepatotoxic. No-observed-effect levels of 4.8 and 41 mg/kg body weight/day, respectively, were determined in dogs and rats exposed chronically to TFL. Oncogenicity studies in rats and mice revealed no carcinogenic potential. Since the data for TFL indicated no mutagenic or other special toxicological risks, it is suggested that a safety factor of 100 could be used for the determination of the acceptable daily intake of TFL, which would be 0.05 mg/kg body weight/day.

Summary of safety evaluation toxicity studies of glufosinate ammonium.

This article reviews the results of toxicity studies to evaluate the safety of the herbicide glufosinate ammonium (GLA) and its formulation (200 g/litre) in laboratory animals. The data show that GLA and its formulation are slightly toxic following oral exposure. In addition, the formulation induced GLA and its formulation are slightly toxic following oral exposure. In addition, the formulation induced slight dermal toxicity and eye irritation. Testing for teratogenicity in rats and rabbits indicated no teratogenic potential, and numerous mutagenicity tests showed GLA to be non-genotoxic. Chronic toxicity testing in rats and dogs yielded no-observable-effect levels of 2 and 5 mg/kg body weight/day, respectively. Oncogenicity studies in rats and mice revealed no carcinogenic potential. On the basis of these toxicity data it is concluded that this herbicide is safe under conditions of recommended use.

The feasibility of sensitization studies using fewer test animals.

The possibility of reducing the number of animals in sensitization studies (maximization method) is discussed on the basis of results from 20 sensitization tests. It appears that the number of test animals in sensitization studies may be reduced to ten treated animals and five control animals without prejudice to the quality of the test.

Subacute toxicity studies of selected organic colorants.

The results of subacute toxicity studies on eight selected colorants of low acute oral toxicity (LD50 greater than 2000 mg/kg) are reported. These eight colorants, selected from widely differing chemical structural types, were administered as 22 daily doses over a period of 30 days (no weekend dosing) at 1000 mg/kg body weight/day by gavage to female and male rats. Animals treated with the vehicle served only as controls. In most cases the treatment period was followed by a 15-day recovery period. Even at this high dose level all products were tolerated without irreversible signs of toxicity. The survey of data available indicated that the substances investigated exhibited a very low cumulative toxicity.