Combined Actions and Interactions of Chemicals in Mixtures

1 Introduction
Prepared by John Chr. Larsen
1.1 Background
All living organisms are constantly and unavoidably exposed to foreign chemicals
(xenobiotics) through food, air, water, and dermal contact. The list of possible
exogenous compounds and their combinations is endless. Chemicals produced and
used by intention include industrial chemicals, food additives, pesticides and drugs.
As a result of industrial and other human activities (i.e. combustion, traffic) a large
number of pollutants are unintentionally released to the environment and may
subsequently contaminate air, food and water. Well-known examples are
polychlorinated dibenzo-p-dioxins and dibenzofurans (dioxins), polychlorinated
biphenyls (PCBs), metals, pesticides and polycyclic aromatic hydrocarbons (PAH).
Other contaminants are formed during processing, storage or cooking of food. In
addition, a wealth of naturally occurring compounds such as alkaloids, other
secondary plant metabolites and toxins produced by moulds, plants and animals,
are constantly being ingested by humans.
Following the current practices, health assessments of exposure to chemicals and
the subsequent regulatory measures, e.g. classification and labelling, establishment
of limit values such as MRLs, etc. are generally based upon data from studies on
the individual substances. However, humans are simultaneously exposed to a large
number of chemicals that potentially possess a number of similar or different toxic
effects. Consequently, not only opponents against the use of chemicals but also the
consumers at large are increasingly challenging the authorities to consider that this
“chemical cocktail” or “total chemical load” does not produce unforeseen health
effects. This question was even more highlighted in 1996 when the US Congress
passed the US Food Quality Protection act (FQPA). This act requires that the US
EPA consider the effects of exposure to all pesticides and other chemicals that act
by a common mechanism of toxicity when tolerances for pesticide use in crops are
derived. Therefore the aspect of combined actions of chemicals needs to be
addressed to a greater extent in the risk assessment process. A major obstacle in
doing so is the lack of data from studies on chemical mixtures employing generally
accepted toxicological methods, such as short-term and long-term animal studies.
Thus, about 95 % of all resources in toxicology are used to study single chemicals
or the effects of pre-treatment with one chemical on the effects of another (Yang
1994). In addition, data on human exposures to chemical mixtures are in general
very inadequate. Thus, the regulatory agencies are faced with the situation that they
cannot always reliably predict whether the simultaneous exposure to foreign
chemicals in the environment and food constitutes a real health problem. As the
possible combinations of chemicals are innumerable and experimental testing of all
such mixtures is not feasible from obvious reasons, there is a need for science
based advise on how exposure to mixtures of chemicals can be dealt with in the
risk assessment.
1.2 Objectives and Scope of the Report
The objectives of the report are to summarise and evaluate the current knowledge
about the combined toxicological effects that may occur from exposures to
different chemicals in mixtures. When justified from a scientific point of view, the
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