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OCR for page 101
1
~ ntroduction
In light of the task before the U. S . Environmental Protection Agency (EPA)
of regulating exposure to toxic chemicals, its Office of Drinking Water asked
the Safe Drinking Water Committee of the National Research Council's Board
on Environmental Studies and Toxicology to hold a small workshop, with
each participant addressing some aspect of the methodology for assessing
the risk associated with exposure to mixtures of chemicals found in drinking
water. This report is the product of that workshop, held in October 1987 in
Washington, D.C., and of the deliberations of the Subcommittee on Mixtures
in a followup meeting.
This chapter briefly describes the background of the workshop, defines
concepts and terms, and suggests ways of grouping chemicals for estimating
their combined risk.
BACKGROUND OF THE STUDY
More than 6 million chemicals have been listed and given identifying
numbers by the Chemical Abstracts Service of the American Chemical So-
ciety. Most have not been adequately tested for toxicity (NRC, 1984) either
individually or in combinations. Some 67,000 of them are registered with
federal regulatory agencies for use as industrial chemicals; as pesticide, food,
drug, and cosmetic ingredients; or for other commercial purposes. Industrial
discharges or nonpoint discharges, such as runoff from hazardous-waste sites
or agricultural application, might cause many of those chemicals to appear
in surface water or groundwater and hence in drinking water. One consumer
advocacy group (Center for Study of Responsive Law) has compiled a list
101
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102 DRINKING WATER AND HEALTH
of some 2,000 contaminants in drinking water as detected in surveys con-
ducted since 1974 (Duff Conacher and Associates, 19881. Contaminants and
their concentrations vary with site, time, and temperature, and many (in-
cluding the by-products of disinfection) have not been characterized or even
identified (NRC, 19871. Because of the variability of drinking water com-
position and because the relatively low concentrations of the chemical con-
taminants in water would require large lifetime studies to reveal long-term
effects, regulatory authorities and theoretical scientists have attempted to
model the effects of mixtures by using the results of tests of the individual
components of the mixtures, often for shorter periods at higher doses (Bingham
and Morris, 1988; NRC, 19881. The National Toxicology Program has ini-
tiated short-term and subchronic studies of a mixture of 25 groundwater
contaminants at concentrations actually encountered (Yang and Rauckman,
19871; however, almost nothing is known about how chemicals interact when
they are ingested by humans as mixtures or with substances from other
sources, including medications. The potential for interactions that could have
adverse health consequences must be considered in any assessment of the
quality of drinking water. A recent study showed a statistically significant
association between the ingestion of chlorinated surface water and human
bladder cancer (Cantor et al., 1987~. Although the specific components re-
sponsible for that association remain unidentified, the by-products of chlorine
disinfection are currently the prime suspects.
CONCEPTS AN D DEFI N ITIONS
Exposure to two or more chemicals simultaneously can produce interac-
tions that qualitatively or quantitatively differ from biologic responses that
would be predicted from the actions of the individual chemicals separately
(Murphy, 1980; NRC, 1980, 19881. When the response is greater than that
predicted on the basis of adding the separate responses, the interaction is
said to be synergistic. When the response is less than that predicted on the
basis of additivity, the interaction is said to be antagonistic.
There is a contrast between dose additivity and response additivity that
needs to be addressed. If two (apparently different) toxic materials lead to
the same type and severity of toxic effect, they might be considered as one
material in the effect they produce. When there is no threshold and the dose-
response curve is essentially linear (at least across some modest range of
doses), a response-additive model is reasonable. Under such circumstances,
a response-additivity model and a dose-additivity model will give the same
answer for the same range of doses.
However, if some minimum dose must be reached before toxicity is man-
ifest (i.e., if there is a threshold), then the response-additivity model can be
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Introduction 103
misleading. At subthreshold doses, each of the materials in a mixture will
produce zero response separately. A response-additivity model would predict
that the sum of any number of zero responses will be a zero response.
However, if the sum of the doses is above the threshold, then a response
can occur and lead to an appearance of synergism i.e., greater than response
additivity. For a more technical definition and more detailed models of
synergism, see Elashoff et al. (1987) and Fears et al. (1988, 19891.
For computational purposes for distinguishing between possible additivity
and multiplicativity of responses, a dose that leads to a relative risk of 1.01
or less is called a "low" dose. That does not, in any way, imply that such
a dose is "acceptable" or "safe." For example, if the overall age-adjusted
mortality from cancer in 1 year in the United States is 200 x 10-s, a dose
leading to a 1% increase would imply an excess mortality of 2 x 10-s,
which is generally considered to be unacceptable, although the relative risk,
(202 x 10-/200 x 10-s), equals 1 .01, an increase (as defined) of "only"
1%. Exposure to two materials, each at such a dose, would, if results were
strictly response-additive, produce a relative risk of 1.02 (i.e., 1 + 0.01 +
0.011. If results were multiplicative, the relative risk would be (1.011~1 .01)
= 1.0201 implying an excess over an additive risk that is extremely un-
likely ever to be measured or even measurable.
Synergistic interactions between chemicals have been suspected of causing
health effects in humans that could not be predicted by simply adding the
expected effects of the component chemicals. One such case was the incident
of mass organophosphorus insecticide poisoning among field workers in
Pakistan in 1976 (Baker et al., 19781; two of the pesticide formulations
contained contaminants, which could well have increased the toxicity attrib-
uted to the designated active pesticidal ingredient, malathion, by inhibiting
its detoxification (see Chapter 41.
The present approach for regulating organic chemicals in drinking water
(EPA, 1987) is to establish a maximum contaminant level goal (MCLG) and
a maximum contaminant level (MCL) for each organic compound, except
that trihalomethanes (THMs) as a class are regulated by a single MCL (EPA,
1979~. That exception is based on the "potential" carcinogenicity of chlo-
roform in humans and the similarities of chloroform to less-studied THMs;
chloroform is assumed to be representative of a class (the THMs) that is
ubiquitous in treated drinking water in the United States and whose members'
concentrations can be reduced simultaneously. All other EPA standards are
established after the toxicologic data, treatment capabilities, and occurrence
data are interpreted and evaluated for each chemical. The single-chemical
approach is scientifically appealing, but it could pose major problems, be-
cause it ignores both the possibility of interaction and the presence of many
unidentified chemicals (NRC, 1987) in treated drinking water.
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104 DRINKING WATER AND HEALTH
GROUPING CHEMICALS FOR ESTIMATION OF COMBINED RISK
Methods for assessing health risks associated with mixtures have not changed
substantially in recent years (EPA, 1985, 1986; Murphy, 1980; NRC, 1980,
19881. Lack of toxicologic information and the complexity of a mixture can
impede and complicate the application of any method, and considerable
reliance is still placed on knowledge of the toxicity of individual chemicals
in approaching the regulation of mixtures. Because of the substantial backlog
in testing and regulation, regulatory agencies need to explore carefully some
ways to group chemicals so as to facilitate their control in the absence of
complete toxicologic information. Grouping could be used to establish prior-
ities for testing, to formulate rules for testing, or to develop standards for
allowable concentrations of contaminants in drinking water.
The subcommittee did not consider either the complete universe of clas-
sifications that might be devised or the regulatory consequences of imple-
menting standards for classification. It did, however, review options and
suggested the following four types of grouping for consideration by EPA:
1. Contaminants can be grouped on the basis of their being carcinogenic.
According to the currently preferred dose-extrapolation models (EPA, 1986;
NRC, 1987), the risk of one end point associated with exposure to a mixture
of carcinogens at low concentrations can be theoretically approximated as the
sum of risks associated with the individual carcinogens; i.e., additivity of re-
sponse or risk is usually assumed for carcinogens associated with relative risks
of less than 1.01. However, the subcommittee recognizes that this assumption
of low-dose additivity of response does not have much empirical foundation.
Rather, it rests on theoretical considerations and observations from limited
epidemiologic studies, and it might not apply for carcinogens at doses yielding
high relative risks or when alternative dose-extrapolation models are considered.
For exposures at higher concentrations, synergistic interactions appear to occur
in humans exposed to combinations of several kinds of agents such as cigarette
smoke, asbestos, and alcoholic beverages (NRC, 19881. The assumption of
low-dose additivity needs to be carefully assessed in future research.
2. Systemic contaminants that have similar toxic end points, such as those
resulting in specific organ toxicity or peripheral nerve damage, can be grouped
and treated as having additive effects under most conditions. A general
description of this approach is given in Chapter 3, and the anticholinesterases,
which have similar toxic consequences, are examined in detail as a biolog-
ically based class in Chapter 5. Materials that are assumed to have thresholds
for response require special attention to the biologic mechanisms leading to
a toxic response. As indicated earlier, where the mechanisms of toxicity of
two or more toxicants are the same, combining below-threshold doses (i.e.,
doses that produce a zero response) could lead to an above-threshold dose,
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Introduction 105
(i.e., a dose that produces a response). Thus, dose additivity should be
considered for materials that yield the same toxic end point. Furthermore,
in some cases in which toxicity information is limited and exposure concen-
trations are high, an uncertainty factor could be applied to accommodate the
possibility of synergism; this is discussed in Chapter 3.
3. Dissimilar chemical compounds might be physiologically transformed
into similar metabolites with similar reactivity and stability. For the purposes
of assessing combined risk, chemicals can be grouped on the basis of this
kind of similarity. A caution to keep in mind is that materials that appear to
have similar metabolites might nonetheless at times have different toxic end
points (see Chapter 54.
4. Contaminants can be grouped according to structural similarity, which
might imply similar biologic responses.
In grouping chemical mixtures by whatever method, a "toxic-equiva-
lence" approach can be considered assigning numerical potency values to
individual mixture components that are representatives of specific classes,
estimating potencies of other class members that are present relative to those
of the appropriate representative chemicals, and then summing the products
of the relative potencies and concentrations of all the chemicals present across
all end points. Risks associated with exposure to polycyclic aromatic hydro-
carbons (Clement Associates, 1988) and the chlorinated dibenzo-p-dioxins
and dibenzofurans (Berlin and Barnes, 1987) have been estimated by this
method. Again, the concept of dose additivity is inherent in the consideration
of toxic equivalents and relative potency; this approach implies that one
material is operationally a dilution (in effect) of the other material.
Volatile halogenated hydrocarbons including carbon tetrachloride, te-
trachloroethylene, trichloroethylene, and 1,2-dichloroethane are frequently
found in drinking water, and several could be placed into more than one of
the above groups (e.g., into the group of carcinogens or into a group of
chlorinated compounds). These substances have similar physical and chem-
ical properties, they are metabolized in the liver, and similar methods are
used in treating drinking water to reduce their concentrations. The highest
recommended concentrations for these compounds are all set within a rather
narrow range (2-5 ~g/liter), because their parallel toxicologic properties are
similar and it is feasible to control them together (EPA, 19871. The chemicals
could be evaluated together with an additivity formula or with a single
standard for a mixture of them. Combining the carcinogenic potentials of
such chemicals is discussed in Chapter 7.
STRUCTU R E OF TH E R EPORT
Chapter 2 explains the importance of pharmacokinetics to an estimation
of the health risks associated with multiple-chemical exposures. Appendix
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106 DRINKING WATER AND HEALTH
A gives examples of the use of physiologically based pharmacokinetics to
determine the risk to humans of exposure to volatile synthetic organic com-
pounds by extrapolating data from inhalation studies performed on laboratory
animals. The current EPA approach for assessing health risks related to
noncarcinogens is reviewed in Chapter 3, which suggests modifications of
the approach. A simple illustrative mathematical model that supports some
of the modifications is given in Appendix B. Appendix C discusses dose
addit~vity and response additivity. Chapter 4 considers issues of exposure,
with emphasis on the organophosphates, carbamates, and volatile organic
compounds. Chapter 5 reviews the biologic mechanisms of and interactions
among anticholinesterases. Chapter 6 shows how the assumptions inherent
in EPA's risk assessment methods for carcinogens can be used to combine
the estimated risks associated with individual carcinogenic components in a
mixture. Although the workshop led to an affirmation of current methods
for the risk assessment of mixtures in drinking water, attempts at developing
a firmer empirical base and reevaluation should continue. Chapter 7 rec-
ommends research to facilitate further improvement.
Because there are so many chemicals and so many possible mixtures to
which humans could be exposed, the absence of toxicity data might result
in human exposure to chemicals or mixtures that are not being studied by
regulatory agencies. More research is needed on the scientific basis for
grouping chemicals for testing and regulation. Specific research proposals
are given in Chapters 2-6 and summarized in Chapter 7.
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and W. R. Teeters. 1978. Epidemic malathion poisoning in Pakistan malaria workers. Lancet
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Bellin, J. S., and D. G. Barnes. 1987. Interim Procedures for Estimating Risk Associated
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Introduction 107
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Representative terms from entire chapter:
chemical mixtures
