Wayland J. Hayes

The 90-dose LD50 and a chronicity factor as measures of toxicity

A 90-dose LD50 (or ED50) and a chronicity factor are proposed to help communicate the results of tests involving repeated doses of compounds. To determine the oral 90-dose LD50, groups of animals are fed appropriate dietary levels of a compound for 90 days and then held long enough for any sick survivors to die or recover. Food consumption is recorded and doses are expressed as milligrams of compound per kilogram of body weight per day. Statistically, the 90-dose LD50 is determined in the same way as the 1-dose LD50 using logarithms of doses and percent mortality expressed as probits. A ratio of the 1-dose LD50 and 90-dose LD50 of a compound is a measure of its cumulative effects and is termed the chronicity factor. The largest one found so far is more than 500 times the smallest. These factors permit objective comparison of different classes of compounds, but whether the smaller distinctions within a class are significant, remains to be learned. Since 90-day feeding tests are already widely used, it is suggested that-in addition to parameters conventionally reported-the results be reported in the form of 90-dose LD50 and ED50 values. By the use of these values and the chronicity factors calculated from them and from the corresponding 1-dose LD50 and ED50 values, it may be hoped that the study of long-term toxicity may be made more quantitative. By plotting the logarithm of time in days necessary to kill half of each group of animals against the logarithm of the daily dose necessary to produce this effect, one may predict from a brief test the 90-dose LD50 of some compounds with acceptable accuracy but only a much smaller, limiting value for other compounds. In addition to its limited predictive value, the log-time, log-dose relationship has considerable theoretical interest. The complete curve, exemplified by that for warfarin, shows 3 distinct segments corresponding to (1) an inherent delay in the action of the compound even when given at high dosages, (2) a gradual increase in the time necessary for intermediate dosages to produce their effect, and (3) the failure of sufficiently small dosages to produce an effect even when continued for the lifetime of the animal. Curves for many compounds lack 1 or even 2 of these segments.

Mortality from pesticides in the United States in 1973 and 1974

Abstract All 1973 and 1974 death certificates in six main categories in which accidental deaths associated with pesticides have been reported were reviewed. For each death in which a pesticide was not definitely excluded by the cause stated on the certificate, a letter was written to the signer of the certificate, to the hospital where the death occurred, or to both. Most accidental deaths from pesticides were classified properly, but some were reported in categories other than the one (E865) specifically established for this class of poisons. A few deaths probably unrelated to poisoning were attributed to pesticides. Some apparent suicides and murders carried out with pesticides were listed as accidents. As in the past, most poisonings in 1973 and 1974 were nonoccupational and involved gross carelessness; a disproportionate number involved males and nonwhites. However, the number of accidental deaths associated with pesticides was greatly reduced. In 1961 and earlier, there were 100 or more such deaths per year in the United States, but the numbers reported in Category E865 were 56 in 1969, 32 in 1973, and 35 in 1974. Counting all categories, the numbers judged to be clear-cut accidents were 97, 62, 45, and 33 in 1961, 1969, 1973, and 1974, respectively. The reduction of deaths from pesticides was accompanied by a reduction in the proportion involving children and an increase in the proportion from very small towns and rural areas. No new example of death caused by an aerosol without wilful misuse was found.

Distribution of dieldrin following a single oral dose.

Abstract Two groups of investigators have used the classical model for the distribution of thiopental following iv injection to predict the distribution of dieldrin following accidental ingestion. They concluded that the concentration of dieldrin in the brain is reduced first by redistribution to muscle and only later by redistribution to fat. The model as originally designed for thiopental had been evaluated by analysis of samples from persons undergoing surgery under thiopental anesthesia. Since it is not appropriate to give large doses of dieldrin to humans or to collect samples of muscle and various vital organs from them, the distribution of dieldrin was studied in rats. Dieldrin dissolved in corn oil was administered to these animals by stomach tube. The highest concentration of dieldrin in the brain was reached in 4 hr, and the concentration decreased gradually thereafter. The concentration in muscle remained essentially steady during the interval from 4 to 48 hr. There was no peak for muscle that could be interpreted as replacing a peak for brain. The concentration of dieldrin in fat was already slightly higher than that in the brain at 1 hr, very much higher at 4 hr when the concentration in the brain was maximal, and the concentration in the fat continued to increase during the first 24 hr. Either on the basis of concentration or on the basis of the total amount in each organ, no reason was found to assign any special importance to muscle as a sink into which dieldrin is redistributed from the brain. The fat appears to be far more important in this regard. The results indicate the danger of applying a mathematical model to a new situation without checking the results experimentally.

ETHICAL CONSIDERATIONS INVOLVING STUDIES OF PESTICIDES AND OTHER XENOBIOTICS IN MAN

Abstract The existence of species differences means that the safety of a compound cannot be known until it has been studied in man. These human studies may involve poisoned patients, treated patients, workers, or volunteers. The four different kinds of study in man offer different advantages and present different constraints. For nontherapeutic compounds, studies in volunteers are the only kind that can reveal a clear relationship between effects and dosages likely to be encountered in practical use. Much valuable information can be obtained from studies of workers, but their dosage is not predetermined and must be estimated by more or less indirect methods. This means that for nontherapeutic compounds there is real scientific advantage in studies in volunteers that cannot be matched by any other kind of study. At least 92 pesticides or related compounds have been studied in volunteers. Of these, 26 also have been used therapeutically, and 26 additional pesticides have been administered as drugs. It is unfortunate that the number of studies of pesticides in volunteers has declined relentlessly since about 1973. Potential benefit to the individual patient is the oldest objective of studying new compounds in man. The development of modern scientific medicine required a new objective: benefit to future patients or to the community in general. In the absence of personal benefit, participation in a study requires altruism. The doctrine of informed consent is societys affirmation of the ethical right of a volunteer to undertake an act of altruism. Many constraints on investigators, including the requirement for consultation or group review, ensure that the risks will be minimal, even though the limitations of human knowledge make it impossible to exclude risk absolutely. The codes for conducting studies in man that have been propounded since 1803 and especially since 1901 are characterized by their consistency. The only thing new is consideration of the application of the recognized codes to the special problems of developing countries. The most neglected part of the ethical fabric is the responsibility of toxicologists to ensure the best possible evaluation of the safety of all the compounds used by our society. Toxicologists should insist much more on the ethical requirement that new compounds be introduced or old compounds be given significantly new uses only under conditions that guarantee and facilitate their scientific study in man.

Factors limiting injury from pesticides

Factors are discussed that may limit injury from pesticides whether the victims are exposed occupationally, through other intentional uses, or simply accidently. Emphasis is placed on choice of methods fitted to the problems revealed by dependable vital statistics for each country. In general, good labeling of pesticides is the most important single factor in their safe use. Regulation of use combining agricultural advice to the farmer with surveillance of his practices in the handling of pesticides often is the best way to minimize occupational poisoning and restrict residues on crops brought to market. To be successful, these and other aspects of education must be directed toward the improvement of human health. International organizations may be the best source of practical solutions simply because of the range of their experience.