Regulatory Policy Implications of 1,4-Dioxane - Environmental Investigation and Remediation - page 464

concordance of only 57% between the overall rodent carcinogenicity classii cations from both
sources (Gottmann et al., 2001). However, repeating 1,4-dioxane carcinogenicity testing would be
extremely expensive, and the available bioassays are deemed sufi cient for deriving CSFs by most
regulatory toxicologists. The question then becomes whether the expense of additional or repeat
carcinogenicity assays is outweighed by the cost of cleaning 1,4-dioxane up to a threshold set too
low due to problems with extrapolating the nonlinear dose-response.
Even with improvements to reduce the uncertainty in PBPK models and better assays to determine
1,4-dioxane carcinogenicity and toxicity, the assessment of 1,4-dioxane's health effects may be lim-
ited because, like all other drinking water toxicity evaluations, the framework for assessing risk
focuses on 1,4-dioxane in isolation from the other chemicals occurring as co-contaminants. A number
of new approaches to evaluating the toxicity of chemical contaminants may impart a more compre-
hensive analysis of the effects of multiple contaminants through multiple exposure pathways by
providing mechanistic details of events at the cellular and molecular levels (Bhogal et al., 2005).
Regulators and regulated parties are best served by clearly delineated regulatory thresholds, for
which well-established toxicity values are needed. As described above, the road to human 1,4-dioxane
toxicity values are constrained by the limitations of the methods used; however, new developments
hold promise to remove these limitations and expand the toxicological database upon which regula-
tions are established. Some of these new toxicological methods may improve the evaluation of 1,4-
dioxane toxicity and are proi led in the following sections.
10.3.1 A DDRESSING S YNERGISTIC E FFECTS OF M ULTIPLE C ONTAMINANTS
Most toxicological testing is performed on single chemicals, yet human exposures are rarely limited
to single chemicals as contamination at hazardous waste sites generally involve multiple contami-
nants. In addition to the chemical of interest, people may also be exposed to chemicals they
consume in alcoholic drinks, tobacco smoke, medicines, and foods, and may involuntarily be
exposed to vehicle exhaust, drinking water disinfection byproducts, and chemicals in the work-
place. What is the net effect of exposure to mixtures of chemicals? Mixtures of chemicals, each of
which may be present at concentrations less than their respective regulatory thresholds, may cause
health effects due to additivity, interactions, or both. It is therefore important to make an exposure-
based assessment of the joint toxic action of chemical mixtures (Agency for Toxic Substances
Disease Registry [ATSDR], 2004).
The ATSDR published guidance on a semiquantitative screening process for the assessment of the
joint toxic action of chemical mixtures (ATSDR, 2004). Practical and accessible tools are needed to
facilitate assessment of this particularly complex challenge. Aspects of the complexity of the joint
toxic action of chemical mixtures include the combined action of different chemicals at different
concentrations, each with different dose-response relationships, different routes of exposure, differ-
ent potentials to produce toxic metabolic byproducts whose interactions must also be evaluated, dif-
ferent target organs, and combinations of carcinogenic and noncarcinogenic effects. The composition
of the mixture also changes with time and distance from the release point due to the differential fate
and transport of its constituent compounds (ASTDR, 2004).
The major mechanisms that must be considered for toxicant interactions are direct chemical-
chemical, pharmacokinetic, and pharmacodynamic mechanisms (ATSDR, 2004). Developing a
knowledge base of these mechanisms for binary mixtures and for classes of chemicals can support
the prediction of interactions for new combinations of chemicals. Chemical-chemical interactions
may include potentiation or synergism * such as the formation of carcinogenic nitrosamines from
* Potentiation : when a component that does not have a toxic effect on an organ system increases the effect of a second
chemical on that organ system. Synergism : when the effect of the mixture is greater than that estimated for additivity
based on the toxicities of the components (ATSDR, 2004).