Carrol S. Weil

Range-Finding Toxicity Data: List VII

Abstract Acute toxicity and irritation data on about 200 compounds are presented, accumulated in a continuing program for screening potential commercial products.

Study of intra- and interlaboratory variability in the results of rabbit eye and skin irritation tests

Abstract Twenty-five laboratories supplied data for a joint study of the variability of test results. Each laboratory was to test skin and eye irritation by a reference and by a nonreference method for each of 12 materials.

Statistics vs safety factors and scientific judgment in the evaluation of safety for man

Abstract The extension of the information obtained in animal toxicology experiments to evaluate hazard and predict safety in the use of chemicals for man is discussed. Illustrations are presented of the inapplicability of exaggerated or improperly designed animal tests. The many factors that influence the slope or shape of dose-response curves are illustrated, primarily using cancer as the response. These include duration and regimen of dosing, type of resulting neoplasm, strain, sex, nutritional status and age of the animal. Variation in slope of dose-response curves, even in 1 experimental design, single peroral dose, is extreme. Extrapolation to an LD35, an interval close to the LD50 midpoint, while theoretically applicable, was illustrated to be highly inaccurate. Therefore, the establishment of the shape of the low-response end of a dose-response curve by the use of large numbers of animals, and the statistical extrapolation of this information to predict a safe level for man, is deprecated. However, the applicability of a suitably large safety factor, e.g., 1 5000 of the lowest-effect dose level for cancer, is recommended by the author when the use of a material is deemed important. The size of the safety factor and the potential use of a chemical should be established by properly informed, scientific judgment.

An exploration of joint toxic action: Twenty-seven industrial chemicals intubated in rats in all possible pairs

Abstract Prediction of the safety or hazard of various exposures to mixtures of chemicals must often be made in the absence of knowledge of the mode of their joint toxic action. The rat peroral LD50 was determined for 50% by volume mixtures of all possible pairs among 27 commercial organic chemicals. The results indicate that the harmonic mean formula for additive joint toxicity satisfactorily predicted the toxicity of a large proportion of the pairs. The soundest hypothesis for the joint action of untested pairs is that of additive toxic action. Pairs deviating most markedly from this mode of joint action are listed.

Range-finding toxicity data: List VIII

Abstract Acute toxicity and irritation data are tabulated for about 140 synthetic organic compounds, most of them tested before regular production, in a continuing program to predict potential acute hazards to health of accidental human contact with chemicals which may become commercial products.

Guidelines for experiments to predict the degree of safety of a material for man

Abstract Agreement with and suggestions for changes in 5 guidelines for animal experiments applicable in predicting hazards for man were collated from responses of scientists to a questionnaire. More complete statements are in the text, but a brief summary of the guidelines follows: 1. 1. Use, wherever possible, species that biologically handle the material as similarily as possible to man. 2. 2. Where practical, use several dose levels on the principle that all types of toxicologic and pharmacologic actions in man and animals are doserelated. 3. 3. Effects produced at higher dose levels are useful for delineating mechanism of action, but for any material and adverse effect, some dose level exists for man or animal below which this adverse effect will not appear. This biologically insignificant level can and should be set by use of a proper safety factor and competent scientific judgement. 4. 4. Statistical tests for significance are valid only on the experimental units (e.g., either litters or individuals) that have been mathematically randomized among the dosed and concurrent control groups. 5. 5. Effects obtained by one route of administration to test animals are not a priori applicable to effects by another route of administration to man. The routes chosen for administration to test animals should, therefore, be the same as those to be used in man. Thus, for example, food additives for man should be tested by admixture of the material in the diet of animals.

Current status of tests of carbaryl for reproductive and teratogenic effect

Abstract A 3-generation rat reproduction study with technical carbaryl (1-naphthyl methylcarbamate) added to the diet to provide daily doses up to 10 mg/kg resulted in no statistically significant, dose-related effect upon fertility, gestation, viability of pups or lactation. A rat teratogenic study with carbaryl added to the diet to provide daily doses up to 500 mg/kg resulted in no increase in teratogenic anomalies and no effect on fertility or gestation. Only at the highest dose was weight gain reduced; many pups in this group died before weaning from carbaryl-fed mothers. A rat reproduction study included groups receiving carbaryl in the diet at daily doses up to 200 mg/kg, while other groups concurrently received carbaryl by po intubation of doses up to 100 mg/kg/day. A dose of 100 mg/kg/day given by intubation before mating resulted in mortality, signs of cholinesterase inhibition and reduced fertility. None of these effects were seen in groups dosed in the diet. Reduction in growth at 100 mg/kg/day given by intubation was equivalent to that of 200 mg/kg/day given in the diet. Guidelines for an acceptable experimental design of studies to evaluate human risks are discussed in relation to published articles and unpublished reports on the effect of carbaryl on animal reproduction or teratology. Only 1 study other than the 3 reported here conformed to all the guidelines; in this study it was reported that no reproductive effects occurred in rats given 2000 ppm in the diet.

Comparative effect of carbarylon rat reproduction and guinea pig teratology when fed either in the diet or by stomach intubation

Abstract A 3-generation rat reproduction study, terminating with teratologic and mutagenetic studies included groups receiving carbaryl in the diet at maximum daily doses of 200 mg/kg while other groups concurrently received daily po intubation of carbaryl in doses as high as 100 mg/kg. A guinea pig teratology study was also run with maximum levels of carbaryl of 300 mg/kg in the diet or 200 mg/kg po. Previous publications of repeated po intubation reported rat reproduction effects from carbaryl at 2 mg/kg and guinea pig teratology at a maternal toxic level of 300 mg/kg. The concurrent study of administration of carbaryl by daily po administration or by dietary inclusion resulted in neither rat teratology or mutagenesis nor guinea pig teratology in the animals that received the maximum dosage levels. However, the maximum po groups had severe toxic effects in both studies as contrasted to little or no effect at the maximum dietary levels for rat or guinea pigs and no effect at 25 mg/kg po to rats or 100 mg/kg po to guinea pigs. These studies verify the differences that result by deviation from certain proposed guidelines for experimental design. There-fore, the importance of mode of administration was demonstrated, thus verifying that dosage-related responses must be considered if results are to be used to predict safety for man.

Relationship between single-peroral, one-week, and ninety-day rat feeding studies

Abstract To facilitate the planning of critical dosage levels for 90-day and longer-term feeding studies and to predict their probable outcome, 20 materials, predominantly pesticides and surfactants, were fed for 7-day periods in the diets of rats. The lowest dosage level that resulted in minimum effect (MiE) for this period was compared to the single dose peroral LD50 and the MiE for 90 days for each material. The relationship between the single-dose peroral LD50 and the corresponding 90-day or 2-year study MiE was inefficient as compared to the MiE 7-day MiE 90-day and MiE 90-day MiE 2-year ratios. The coefficients of rank correlation for these latter ratios were +0.943 and +0.946. Therefore, the following formulas may be used to predict the most probable (median) minimum effect dosage level limit for inclusion of a material in the diet of rats for 2 years, as well as the limit which is predicted to include the MiE 95 times in 100: Predicted upper limit to achieve a minimum effect level (MiE) Value For 90-day feeding study For 2-year feeding study Median MiE 7 3.0 MiE 90 1.8 or MiE 7 5.4 95th percentile MiE 7 6.2 MiE 90 5.7 or MiE 7 35.3

Results of feeding propylene glycol in the diet to dogs for two years

Abstract Groups of five male and five female beagle dogs were fed diets containing propylene glycol or dextrose, the latter as equicalorific controls, for 2 yr. Dosage levels used were 5·0 and 2·0 g propylene glycol/kg and 6·35 and 2·54 g dextrose/kg, and in addition a control group received neither compound. The criteria of effect included mortality, body-weight change, diet utilization and water consumption, micropathology, liver, kidney and spleen weights, and measurements of blood, urine and biochemical parameters. None of the criteria measured were significantly altered at 2 g propylene glycol/kg. The higher dose levels of propylene glycol and dextrose were maintained by the inclusion of approximately 20 and 25%, respectively, in the diets of the dogs. As both compounds provide calories available for conversion to adipose tissue, both groups gained somewhat more weight than the controls during the first part of the study. Propylene glycol, in high concentrations, increases the rate of erythrocyte haemolysis. When it was given at the 5-g/kg level, haemoglobin and haematocrit values and the total erythrocyte count were slightly low, while the incidence of anisocytosis, poikilocytes and reticulocytes was increased, findings indicative of erythrocyte destruction with accelerated replacement from the bone marrow. Even at a propylene-glycol concentration of 20% of the diet, this effect was not sufficient to result in any changes that appeared to be irreversible and there was no evidence of damage to bone marrow or spleen. The majority of parameters relevant to effects on the liver were similar in all dosage groups. In dogs consuming 5 g propylene glycol/kg there was a slight increase in total bilirubin. It is concluded that propylene glycol fed to dogs at a concentration of approximately 8% in the diet (2 g/kg/day) is utilized as a carbohydrate energy source without any adverse effects.