Hazard Assessment and Contaminated Sites - Dealing with Contaminated Sites: From Theory Towards Practical Application - page 554

12.5.8 Inter- and Intra-Species Considerations
The material in this section is from WHO ( 1999 , p. 20) with slight adaptation.
The strains and species of laboratory animals exposed in toxicity studies have
been selected to show minimum inter-individual variability. Compared to laboratory
animals, humans represent a very heterogeneous population with both genetic and
acquired diversity.
Sources of inter-species and inter-individual variations in toxicokinetics include:
differences in anatomy (e.g., gastrointestinal structure and function); physiologi-
cal function (e.g., cardiac output, renal and hepatic blood, glomerular filtration rate
and gastric pH); and biochemical differences in, for example, enzymes involved in
xenobiotic metabolism.
In some cases, it may be possible to conclude that effects detected in animals are
unlikely to be relevant to humans. In other cases, there may be data to indicate that
humans are likely to be more or less sensitive than animal species; this information
is important for consideration in the selection of critical effects.
In extrapolating between species, three aspects need to be considered: (1) dif-
ferences in body size, which require dose normalisation or scaling (often done by
expressing the dose per kg body weight); (2) differences in toxicokinetics, partic-
ularly bioactivation and/or detoxification processes; and (3) the nature and severity
of the target for toxicity.
The greater potential variability in heterogeneous human populations must be
addressed in Risk Assessment. Sources of inter-individual variability in human pop-
ulations include, for example, variations in genetic composition, nutrition, disease
state and lifestyle.
12.5.9 Mixtures
While important, currently there is no agreed international approach to assessing
mixtures of contaminant. Where data (including mechanistic data) are available
on the interaction of contaminant this should be taken into account in the Risk
Assessment.
The Agency of Toxic Substances and Disease Registry (ATSDR) in the US uses
one approach that includes performing a critical synthesis of relevant data and
then identifying generalisable rules that can be used in site-specific assessments
of health risk following exposure to mixtures. This approach allows research to:
identify what contaminant mixtures may affect public health; evaluate the potential
for exposure of human populations to contaminant mixtures; study the pharmacoki-
netic behaviour of contaminant mixtures; identify various end points that would be
affected; study the mechanism of action, progression and repair; and identify (both
generic and specific) that would allow the determination of the health of the organ-
ism and develop qualitative and quantitative health assessment methods so as to
assess multiple health effects (Hansen et al. 1998 )