PRINCIPLES OF TOXICOLOGY - Biology East Borneo

11.4 CURRENT RESEARCH CONCERNS 235• Given that the human diet contains high amounts of naturally-derived hormonally activeagents, is it feasible that synthetic chemicals with weak hormonal potency could adverselyaffect human endocrine functioning?• Do the dose-response curves of hormonally active agents lack a threshold for adverse effects?• Do toxic effects of high doses of hormonally active agents mask more subtle adverse effectsthat can only be detected at low doses using specialized assay systems?• Are hormonally active agents more prone to exhibiting interactive effects (synergism orantagonism) than chemicals that operate through other mechanisms?• Is it practical to regulate chemicals based on presumed mechanisms of action—i.e., on thebasis of a potential endocrine mechanism—rather than on production of adverse effects suchas reproductive or developmental impairment?The way that the scientific and regulatory communities answer these questions could have a profoundimpact on the risk assessment of hormonally active agents in the workplace and in the environment.Lead Poisoning and the Lowering of the ThresholdCurrently, a hot area of research is the sensitivity of the developing nervous system to low-dose leadexposure. Lead toxicity is apparent in a variety of organ systems. As mentioned above, lead effects onboth male and female reproduction have been investigated and the use of lead salts for inducing abortionreaches back to antiquity. The neurological system is recognized as one of the key targets for toxicresponses to lead. Some reports have recently suggested that the levels of environmental lead exposuresreceived by large populations, especially in urban areas, could be sufficient to produce adversecognitive effects. This has lead to substantial investigation of both lead toxicity mechanisms in animalsand the occurrence of cognitive deficits in children. Though reports of low-dose lead effects have struckparental and societal chords, the body of research on intelligence and cognitive outcomes does notsupport a consistent association with today’s common levels of environmental lead exposure.Rather than the traditional applied dose, lead exposure is typically considered on the basis of ameasured blood level. There is little dispute about the potential for lead toxicity in children whenchronic blood levels reach the 30–50 µg/dl range or higher. A standard regulatory criterion of concernis 10 µg/dl. However, there are suggestions that cognitive effects may accrue even at this threshold, orperhaps even up to 10-fold lower. Unfortunately, the endpoints of intelligence and verbal ability thathave been suggested as the most sensitive indicators are exceedingly difficult to measure in a repeatable,reliable, and objective manner. A further complication is the considerable plasticity in learningprocesses and the ability of children to “make up ground” as they develop.Scientific arguments rage over the verbal abilities of two-year olds and the meaning of IQdifferences of less than one or two points on the typical scale. Research has suggested that verbaldevelopment is a brain function particularly vulnerable to lead. However, despite claims of statisticalsignificance in some studies, the uncertainty associated with evaluating these endpoints, which is notcaptured statistically, clearly makes definitive conclusions impossible. The testing methods forassessing cognitive development and verbal ability in infants and toddlers are not generally regardedas sensitive enough to reliably distinguish between inter-individual variability and exposure-associatedeffects at the required levels.However, information from animal studies has begun to shed light on mechanisms by which leadcould affect brain development. There does appear to be a heightened sensitivity of fetal and neonatalbrain cells to lead effects compared to adults. This may relate to the much more active process offorming connections among neural cells and expansion of vascular, blood carrying elements duringfetal and neonatal stages. It is not clear what degree of change in this process must occur to representan adverse reaction to lead, however, since there is considerable variation and plasticity in the processanyway.