Combined Actions and Interactions of Chemicals in Mixtures

should be estimated for all endpoints of concern. This implies that a TTD should be
established for all relevant endpoints for each chemical using the same principles
as used in the “normal” derivation of the RfD/ADI/TDI and that “hazard quotients”
be calculated for the relevant effects of each chemical (for details see ATSDR
2002).
4.2.1.1 Weight-of-Evidence (WOE) modification to the hazard index
The hazard index method does not incorporate information on interactions among
components of the mixture (ATSDR 2002). Mumtaz and Durkin (1992) proposed a
weight-of-evidence (WOE) method to systematically address this need. The
method was designed to modify the hazard index to account for interactions, using
the weight of evidence for interactions among pairs of mixture components. Thus,
the basic assumption is that pair wise interactions will dominate in the mixture and
adequately represent all the interactions. For example, if chemicals A and B
interact in a certain way, the presence of chemical C will not cause the interaction
to be substantially different.
It should be noted that experience with the method has revealed that it is mainly
useful for a qualitative prediction as to whether the hazard may be greater or less
than indicated by the hazard index (ATSDR 2002).
The method evaluates the data relevant to joint actions for each possible pair of
chemicals in the mixture in order to make qualitative binary weight-of-evidence
(BINWOE) determinations for the effect of each chemical on the toxicity of every
other chemical. Two BINWOEs are needed for each pair: one for the effect of
chemical A on the toxicity of chemical B, and another for the effect of chemical B
on the toxicity of chemical A. The BINWOE determination indicates the expected
direction of the interaction, such as greater than additive, less than additive,
additive, or intermediate. It scores the data qualitatively by using an alphanumeric
scheme that takes into account mechanistic understanding, toxicological
significance, and relevance of the exposure duration, sequence, bioassay, and route
of exposure. The alphanumeric terms are finally converted into a single numeric
score. The BINWOE evaluations should be target organ specific. A more detailed
description and discussion has been provided by ATSDR (2002).
4.2.2 Point of Departure Index (PODI)
A scientifically more appropriate method of addition is summing the exposures of
each compound expressed as a fraction of their respective PODs instead of the ADI
or RfDs. These POD fractions (PODF) are reciprocals of the individual margin of
exposures (MOE) of each compound. This approach sums the exposures to the
compounds in terms of their relative potencies. In this example the ED10 (Table
4.2.1) are used as PODs:
PODI = 0.005 + 0.001 + 0.0004 + 0.002 = 0.0084 Risk units
The PODI can be converted into a “risk cup” unit by multiplying by an appropriate
group UF. For example, a group UF of 100 would result in a combined risk of 0.84
risk units.
4.2.3 Toxicity equivalency factors (TEF)
The TEF approach normalises exposures to common mechanism chemicals with
different potencies to yield a total equivalent exposure (TEQ) to one of the
chemicals, the “index compound”. TEFs are derived as the ratio of the POD of the
index compound to that of each member in the group. The exposure to each
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