Archives of toxicology. Supplement. = Archiv fur Toxikologie. Supplement最新文献

In summary, a number of studies have shown that not only estrogenic and androgenic steroids and their antagonists influence sexual differentiation of the mammalian brain but also drugs which stimulate or inhibit the adrenergic, the serotoninergic, or the cholinergic system in the developing brain. The present knowledge on the possible participation of neurotransmitter systems in sexual differentiation of the brain and their mode of interaction in this process perinatally with gonadal steroids is still rather limited. Sexual differentiation of the central nervous system is a complex integrated process, which relies on proper chronological and quantitative interactions of various endocrine and neuroendocrine mediators. Any disturbance of this delicate endogenous hormonal balance during ontogenetic development, e.g. by means of environmental influences, can result in permanent manifestation of anatomic and functional sexual deviations. A large number of man-made chemicals that have been released into the environment have the potential to disrupt the endocrine system of animals and humans. They do so because they mimick the effects of natural hormones or neurotransmitters by recognizing their binding sites, or they antagonize the effects of endogenous hormones or neurotransmitters by blocking their interaction with their physiological binding sites. Interaction of environmental endocrine disruptors with animals or humans during ontogeny may have deleterious effects on the differentiation of reproductive structures and functions, rendering the individuals in question permanently incapable to reproduce and, thus, endangering survival of the species.

People differ in their susceptibility to particular cancers and in their sensitivity to certain carcinogens. Differences in sensitivity to environmental carcinogens are determined by variations in genetic background--genetic polymorphism. Susceptibility or sensitivity factors can act at any stage in the multistage process of carcinogenesis, from exposure to carcinogens to the clinical appearance of cancer. This paper addresses the use and limitations of studies on human polymorphism for carcinogen metabolizing enzymes and their relevance for cancer control. The practical use of susceptibility and sensitivity markers in cancer control is not yet clear. Some of the potential dangers of their use are job discrimination and genetic exculpation--the 'blame the victim' attitude. Furthermore, an imprudent focus on genetic predisposition could shift the attention from carcinogens in the environment to biological 'defects' in the individual. Although carcinogens act in predisposed subjects, this should not overshadow the fact that most cancers are due to environmental factors, in both susceptible and unsusceptible individuals, and are therefore preventable. Even if individuals differ in their sensitivity to carcinogens, the primary option in cancer control must be to reduce exposure in order to include and protect the most sensitive fraction of the population.

Variability among individuals in their responses to toxic chemicals arises from several sources, the most important of which are genetic differences, environmental influences (including maternal effects and historical factors) and measurement error. Effective risk assessment requires that estimates of toxicant response (e.g., LD50, EC50, LOEC, NOEC) are precise--that is, have narrow confidence limits-, repeatable--that is, different laboratories must obtain the same or very similar result-, and accurate--that is, they must provide a reasonable approximation of the effects of toxicants on real ecological systems. Determining which of the above-mentioned sources of variability has the greatest influence on toxicant response has implications for both the design and interpretation of ecotoxicological tests. If, for example, genetic influences are of overriding importance, controlling genotype (by using clones or inbred strains) can lead to greater precision but at the expense of accuracy when the objective is to estimate toxicant response for the species as a whole. Likewise, if environmental influences are of primary importance in controlling the response to toxicants, performing experiments under a standard temperature, light, and food regime may provide highly repeatable test results that have little relevance to the responses of populations in nature. Although there is little doubt that the development of standard ecotoxicological test guidelines (e.g., by the OECD), that control genetic and environmental sources of variability, has led to improvements in the practice of risk assessment, further advances will require a more sophisticated approach for dealing with these sources of uncertainty. There is a need for more systematic approaches for quantifying the sources of variability in toxicant response and for formally combining the error associated with each source in key risk assessment endpoints.