Regulatory Policy Implications of 1,4-Dioxane - Environmental Investigation and Remediation - page 465

noncarcinogenic nitrites and amines in the stomach (ATSDR, 2004). Pharmacokinetic interactions
include absorption, distribution, excretion, and metabolism. Pharmacodynamic interactions may
include interaction at same receptor site or target molecule, interaction at different sites on the same
molecule, or interaction among different receptor sites (ATSDR, 2004).
The ATSDR guidance uses variations of an old and simple approach called the hazard index to
address the joint toxic action of chemical mixtures. The hazard index assumes that the noncancer
health effects of the mixture can be estimated from the sum of the doses (weighted for potency) or
the effects of the individual components as described in the following equation:

n

E

Â

i

(10.2)

HI = ,

DL

i

i = 1

where E i is the dose or level of exposure to the i th chemical, and DL is the dei ned level of exposure
to that chemical, usually a toxicity threshold or regulatory threshold. This ratio is known as the
hazard quotient. For example, the hazard quotient for a single chemical exceeds unity when the
concentration exceeds the MCL; when the sum of the hazard quotients for a mixture exceeds unity,
the mixture is considered to be capable of causing adverse health effects. The hazard index approach
must account for each pathway and exposure duration of concern, with a separate hazard index for
each (ATSDR, 2004).
The simplistic basis of the hazard index accounts for noncancer effects only and does not account
for the mechanisms of carcinogenicity. Computational methods using databases of binary interac-
tions of carcinogens with tumor initiators, tumor promoters, and tumor inhibitors can be used to
develop more sophisticated models of the joint toxic action of chemical mixtures. Carcinogenesis is
a multistage process and is often modeled as a synergistic response between a tumor initiator and a
tumor promoter. The combination of a genotoxic contaminant that causes DNA damage combined
with another chemical that enhances cell proliferation would act synergistically, and the response
can be more than additive of the two chemicals' toxic effects taken independently. Integrating PBPK
modeling to assess the toxic effects of chemical mixtures can further address the modes of action
for mixtures of toxins. For mixtures of two chemicals, PBPK models for the individual chemical are
linked at the assumed point of interaction, frequently the hepatic (liver) metabolism term. Uncertainty
about the toxicological interaction of multiple chemicals is an impediment to regulation; therefore,
computational toxicology methods are needed to address the complexity of the joint toxic effects of
exposure to multiple contaminants (see Section 10.3.3 ).

10.3.2 T HE P ROMISE OF C ELL L INES TO A CCELERATE AND I MPROVE T OXICOLOGY A SSAYS
The i eld of environmental toxicology is undergoing a paradigm shift from a check-list approach
using animal testing ( in vivo ) to the use of new cell line methods ( in vitro ) and computational toxi-
cological methods ( in silico ). The new methods provide mechanistic details of events at the cellular
and molecular levels and are being developed primarily by pharmacologists and biotechnologists to
accelerate the development and testing of pharmaceuticals; however, they also have ready applica-
tion to the toxicological assessment of chemicals and chemical products. In vitro methods permit
the observation of specii c changes at the molecular level, rather than just the number of tumors,
deaths, or overt clinical changes observed in test animals using in vivo methods. Molecular-scale
changes observed in vitro include DNA alteration at a target organ site, and changes to proteins in
cell membranes and within cells (Bhogal et al., 2005).
The European Union's new REACH policy requires the assessment of tens of thousands of
chemicals. It will be unworkable to complete the task using conventional methods; therefore, new
innovative tools are required to allow high-throughput screening of chemicals (Bhogal et al., 2005).