Procedures to reveal 'immunotoxic' potentials of chemicals in animal experiments (mostly in rodents) have been recommended, but the selection of test systems is rather arbitrary. The predictive power of extrapolations to the possible situation in humans is unknown because human studies to confirm or to reject clues from animal data are largely lacking. End points selected in animal studies and those expected to be relevant in humans are not identical. Results of animal experiments are based on doses, generally ignoring the important species differences in pharmacokinetics. This unfavorable situation is especially pronounced when attempting to evaluate 'environmental chemicals'. Because much more information is available on many medicinal drugs, exposures can be defined and pharmacokinetic data are available or obtainable. The situation is even more complicated when attempting to assess possible adverse effects on the developing immune system: in addition to the problems mentioned, numerous different developmental periods with varying susceptibilities must be considered, and species differences in the immune response are superimposed with large differences in pre-, early post-, and later postnatal development. Simultaneously, the kinetic variables are continuously changing with time (with additional variability among species). Different results, even between rats and mice, are bound to occur. Extrapolation to the situation possibly relevant for human exposure will be almost impossible, especially from rodent data. The majority of such effects induced peri- or early postnatally may be expected to be reversible. It must also be assessed whether qualitatively different adverse effects are likely to be induced during 'development', which cannot be revealed (accepting quantitative differences) by more easily performed tests on the adult organism. Considering the intrinsic difficulties, the most promising approach would be to directly obtain data from human trials. This is feasible for medicinal drugs. Alternatively, data on nonhuman primates, the species phylogenetically closest to man, may provide useful information. The status quo for such a strategy and the possible pitfalls are discussed in this overview.

Adult↗

PubMedDate not supplied

Toxicity studies with cellular models of differentiation.

Recently a variety of models have been developed in several laboratories to allow the study of various types of tissue differentiation processes from species ranging from lower animals to mammals. If the use of in vitro systems is intended to reveal toxic effects, two main lines of application may be envisaged (a) toxic effects, for which some indication already exists, can be further characterized and the mode of their toxic action clarified ('secondary testing'), and (b) toxic effects, previously unknown, can be detected ('primary testing'). Primary testing is difficult, regarding not only the strategy to be used and the validation of the system, but also the extrapolation of data to the situation which possibly exists in man. Due to these reasons, this approach has so far not been successfully applied with any group of chemicals.

Aging↗

PubMedDate not supplied

Morphological and histochemical effects of 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) on marmoset (Callithrix jacchus) testes.

The testes of marmosets (Callithrix jacchus), which had been treated with a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.3 microgram to 10 micrograms/l kg body weight (BW)) were studied after 7 days using morphological and histochemical techniques. Light microscopic and electron microscopic examination revealed decreased intercellular contact in the germinal epithelium, as indicated first by enlarged intercellular spaces between the Sertoli's cells and between the Sertoli's cells and neighboring germ cells (i.e., spermatogonia and preleptotene spermatocytes), particularly in the basic compartment of the germinal epithelium. Second, decreased intercellular contact was indicated by the accumulation of premature spermatids and spermatocytes in the tubular lumen after TCDD treatment. The Sertoli's cells exhibited an increased amount of lipids, phagolysosomes, and vacuoles in their cytoplasm. Spermatids were frequently affected by TCDD, particularly during early spermiogenesis. These alterations included vacuolization of the cytoplasm and the development of additional germinal vesicles. This special effect on spermiogenesis became even more evident quantitatively by determination and counting of tubular stages in semithin sections. Tubular determination on the basis of the appearance of spermatids revealed that the ratio of tubular stages I to III became lower and that of stages V to VII became higher, dose dependently, indicating a maturation stop at the beginning of spermiogenesis caused by TCDD treatment. After TCDD treatment, Leydig's cells were morphologically unaffected, but histochemical investigations revealed decreased activity of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD). The sensitivity of the applied methods was different in view of the level of unaffection. The effect of Leydig's cells, as indicated by the decreased activity of 3 beta-HSD, had already been found at a dose of 1 microgram/kg BW TCDD, whereas clear-cut morphological and morphometrical effects were seen at 3 micrograms/kg BW for the first time. Moreover, with the special effect on spermiogenesis in marmoset monkeys, the findings demonstrate that the toxicity of TCDD on testicular morphology is species specific.

3-Hydroxysteroid Dehydrogenases↗

PubMedDate not supplied

Reflections on the assessment of the toxicity of "dioxins" for humans, using data from experimental and epidemiological studies.

"Dioxins" (polyhalogenated dibenzo-p-dioxins and dibenzofurans, PHDDs/PHDFs) have gained considerable scientific interest, and (unjustified or justified) also received tremendous political attention. The data pool available on sources, distribution in the environment, kinetics in animals and humans, and on biological and toxic actions in various species (including humans), is one of the largest among all environmental organic substances; but quality and predictive power of the data on possible effects in humans vary widely, from adequate to not acceptable. This fact is often ignorantly or perhaps even deliberately disregarded, and such divergent data are frequently given the same weight in attempted risk assessments. It must be stressed that the quality of the toxicological data on most "environmental compounds" in general is far below today's standards required for preclinical and clinical data on medicinal substances. The crucial question is whether humans constitute an especially vulnerable species for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or the other PHDDs/PHDFs. Since ample data on body burdens and some results of clinical and epidemiological studies on TCDD have become available, answering this question may now be attempted on the basis of a comparison of animal and human data. Quality of the data and the predictive power of the methods used must be considered, dose-response relationships must be critically evaluated, and body burdens achieved in humans and experimental animals must be taken into account. Pitfalls in attempts to extrapolate data from animal studies to humans and limitations of conclusions to be drawn from epidemiological data on humans are discussed in this presentation.

Animals↗