Hazard Assessment and Contaminated Sites - Dealing with Contaminated Sites: From Theory Towards Practical Application - page 523

Developmental toxicity studies are studies which examine the spectrum
of possible in utero outcomes for the conceptus, including death,
malformations, functional deficits and developmental delays (Tyl and Marr
1997 ). Exposure during sensitive periods may alter normal development
resulting in immediate effects, or may subsequently compromise normal
physiological or behavioural functioning later in life. Since some devel-
opmental processes can occur peri- or postnatally, protocols for devel-
opmental studies are being reviewed with the possibility of extending
the dosing period in developmental toxicity studies from the period cov-
ering major organogenesis to cover the perinatal and early postnatal
period.
Genotoxicity studies are designed to determine whether test contaminants can
perturb genetic material to cause gene or chromosomal mutations. A large
number of assay systems, especially in vitro systems, have been devised to
detect the genotoxic or mutagenic potential of contaminant. Most authorities
consider that a minimum set of data is required to define a mutagen/non-
mutagen. These data usually consist of gene mutations in bacteria and
mammalian cells and in vitro and in vivo cytogenetics. Newer assays which
could provide additional information include the Comet assay, mutations in
transgenic animals, fluorescent in situ hybridisation and cell transformation
(IARC 1999 ).
12.3.2 Important Issues in Toxicity Testing and Assessment
12.3.2.1 Study Protocol and Design
Dosing Regimen
The purpose of toxicity studies is the detection of valid biological evidence for any
toxic and/or oncogenic potential of the contaminant being investigated. Therefore,
protocols should maximise the sensitivity of the test without significantly altering
the accuracy and interpretability of the biological data obtained. The dose regimen
has an extremely important bearing on these two critical elements.
Since the determination of dose responses for any observed effects is one of the
objectives of repeat-dose studies, at least three dose levels are normally required, as
well as controls. US EPA guidelines allow a limit dose of 1,000 mg/kg in chronic
and sub-chronic studies. If this dose produces no observable toxic effects and if tox-
icity is not expected, based upon data on structurally-related contaminants, then a
full study using three dose levels might not be considered necessary. Ideally, the
dose selection should maximise the detection of potential dose-response relation-
ships and facilitate the extrapolation of these to potential hazards for other species
including humans. The largest administered dose should not compromise biological
interpretability of the observed responses. For example, it is generally considered
that the upper dose should not: