Toxic effects of mixtures

Toxic effects of mixtures

Contaminants that exhibit similar modes of action can produce toxic effects

that are synergistic or antagonistic. Assessments that examine such compounds

independently could underestimate or overestimate risk. Several approaches are

being developed that attempt to address this deficiency in current risk assessment

methodology. Some of these approaches predict effects of mixtures based on

measured or modeled body burdens of particular classes of organic contaminants.

For example, narcosis theory predicts that nonpolar hydrophobic contaminants

will produce a narcotic effect on exposed organisms. This effect is thought to

occur when hydrophobic contaminants partition into the lipid phase of the

organism, including the lipid bilayer of the cellular membrane, and cause a

physical deformation or swelling or the membrane (van Wezel and Opperhuizen

1995). Acute narcosis has been demonstrated to occur in aquatic organisms at

whole body concentrations of 2 to 8 mmol total contaminant per kg wet weight

tissue (McCarty and Mackay 1991). Because the molecular size of most nonpolar

organic contaminants of concern does not vary considerably, this approach can

be used to predict narcotic effects of single contaminants or the molar sum of a

mixture of contaminants. Variability in the tissue concentration that produces the

toxic effect (2-8 mmol/kg) is reduced when concentrations of narcotics are

determined on a lipid normalized basis (van Wezel et al. 1995).

Another approach predicts the effects associated with body burdens of

dioxinlike compounds (Giesy, Ludwig, and Tillitt 1994). In this approach,

organic contaminants that are extracted from tissue are tested for dioxinlike

activity in a sensitive in vitro bioassay. The bioassay measures the induction of

cytochrome P450 enzyme activity in a cell line that is exposed to the tissue

extract. Induction of P450 activity has been shown in this bioassay to be an

indicator of exposure to dioxinlike compounds, such as some PCBs, dioxins, and

furans. In some cases, bioassay activity of tissue extracts from exposed

organisms has been shown to be strongly correlated with adverse reproductive

effects in birds (Tillitt et al. 1992, Auman et al. 1997).

In a related approach, tissue concentrations of dioxinlike compounds that are

measured by standard analytical techniques can be expressed in terms of their

potency in comparison to the most potent compound, 2,3,7,8-TCDD. Standard

conversion factors, called Toxic Equivalency Factors (TEF), have been

established for a variety of compounds and receptors. For example, the TEF for

1,2,3,4,7,8-hexachlorodibenzodioxin (HxCDD) in fish is 0.5, because this

compound has been shown to be half as potent as 2,3,7,8-TCDD in various

bioassays and toxicity tests. Separate TEFs have been established for

humans/mammals, fish, and birds on the basis of differences between taxa in

their response to these compounds (World Health Organization (WHO) 1997).1

Individual compounds have different levels of uncertainty associated with their

corresponding TEFs, but in general, uncertainty in the values of TEFs for

individual compounds are expected to be less than an order of magnitude

(Eastern Research Group (ERG) 1998).

World Health Organization. (1997). Draft report on the meeting on the derivation of

toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs and other dioxinlike

compounds for humans and wildlife. Stockholm, Sweden, 15-18 June 1977.

Chapter 5 Uncertainty in Tier IV Risk Assessments