Toxicology of Industrial Compounds

18
Neurotoxicity Testing of Industrial Compounds:
in vivo Markers and Mechanisms of Action
KORNELIS J.VAN DEN BERG, 1 JAN-BERT
P.GRAMSBERGEN, 2 ELISABETH M.G.HOOGENDIJK, 1
JAN H.C.M.LAMMERS, 1 WILLEM S.SLOOT 1 and
BEVERLY M.KULIG 1
1 TNO Nutrition and Food Research Institute, Rijswijk; 2
Erasmus University, Rotterdam
Introduction
Neurotoxicity assessment is designed to provide an answer to the question
of whether or not a particular chemical is able to evoke some form of
adverse effect specifically associated with the nervous system. The
development of risk assessment procedures is a long-term goal in view of
the complexity of the target organ involved, e.g. the nervous system. As
risk identification is a first step in the risk assessment paradigm of
chemicals (NAS, 1983), for neuro-toxicity this translates at present into
procedures and methods aimed at characterization of altered
neurobehaviour of exposed experimental animals and abnormalities in the
morphology of the nervous system. It has been suggested that risk
assessment procedures may take more the approach of ‘exposuredoseresponse’
(Andersen, 1991) in which mechanisms play an important role at
various levels, e.g. from disposition of the chemical through the body to
target tissues, via biochemical interactions at the molecular level to a toxic
response as altered behaviour. Understanding the mechanisms involved in
this sequence of events is helpful to arrive in the future at quantitative risk
assessment procedures, for instance biologically-based modelling (Borghoff
et al., 1991). In addition, a better knowledge of the mechanistic principles
of neuro-toxic agents may lead to the development of specific biomarkers
that would further improve the efficiency of procedures for neurotoxicity
screening, given the magnitude of the number of potentially neurotoxic
compounds (NRC, 1992).
Only for a small select group of industrial chemicals are mechanisms of
neurotoxic action more or less characterized. Perhaps the oldest examples
are the class of organophosphate (OP) pesticides where the molecular
targets have been identified as acetylcholinesterase (AChE) and neuropathy
target esterase (NTE), the latter being associated with organophosphate-