PRINCIPLES OF TOXICOLOGY

• Given that the human diet contains high amounts of naturally-derived hormonally active
agents, is it feasible that synthetic chemicals with weak hormonal potency could adversely
affect 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 effects
that can only be detected at low doses using specialized assay systems?
• Are hormonally active agents more prone to exhibiting interactive effects (synergism or
antagonism) than chemicals that operate through other mechanisms?
• Is it practical to regulate chemicals based on presumed mechanisms of action—i.e., on the
basis of a potential endocrine mechanism—rather than on production of adverse effects such
as reproductive or developmental impairment?
The way that the scientific and regulatory communities answer these questions could have a profound
impact on the risk assessment of hormonally active agents in the workplace and in the environment.
Lead Poisoning and the Lowering of the Threshold
11.4 CURRENT RESEARCH CONCERNS 235
Currently, a hot area of research is the sensitivity of the developing nervous system to low-dose lead
exposure. Lead toxicity is apparent in a variety of organ systems. As mentioned above, lead effects on
both male and female reproduction have been investigated and the use of lead salts for inducing abortion
reaches back to antiquity. The neurological system is recognized as one of the key targets for toxic
responses to lead. Some reports have recently suggested that the levels of environmental lead exposures
received by large populations, especially in urban areas, could be sufficient to produce adverse
cognitive effects. This has lead to substantial investigation of both lead toxicity mechanisms in animals
and the occurrence of cognitive deficits in children. Though reports of low-dose lead effects have struck
parental and societal chords, the body of research on intelligence and cognitive outcomes does not
support 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 a
measured blood level. There is little dispute about the potential for lead toxicity in children when
chronic blood levels reach the 30–50 µg/dl range or higher. A standard regulatory criterion of concern
is 10 µg/dl. However, there are suggestions that cognitive effects may accrue even at this threshold, or
perhaps even up to 10-fold lower. Unfortunately, the endpoints of intelligence and verbal ability that
have 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 learning
processes 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 IQ
differences of less than one or two points on the typical scale. Research has suggested that verbal
development is a brain function particularly vulnerable to lead. However, despite claims of statistical
significance in some studies, the uncertainty associated with evaluating these endpoints, which is not
captured statistically, clearly makes definitive conclusions impossible. The testing methods for
assessing cognitive development and verbal ability in infants and toddlers are not generally regarded
as sensitive enough to reliably distinguish between inter-individual variability and exposure-associated
effects at the required levels.
However, information from animal studies has begun to shed light on mechanisms by which lead
could affect brain development. There does appear to be a heightened sensitivity of fetal and neonatal
brain cells to lead effects compared to adults. This may relate to the much more active process of
forming connections among neural cells and expansion of vascular, blood carrying elements during
fetal and neonatal stages. It is not clear what degree of change in this process must occur to represent
an adverse reaction to lead, however, since there is considerable variation and plasticity in the process
anyway.