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6
Volatile Organic Compounds
.
(VOCs): Risk Assessment Of
Mixtures of Potentially
; , . ~ . . i
Carcinogenic Chemicals
Drinking water can contain a wide array of toxic substances, including
substances known to be carcinogenic or potentially carcinogenic to humans,
including benzene, vinyl chloride, carbon tetrachloride, 1,2-dichloroethane,
trichloroethylene, chloroform, and other trihalomethanes and other volatile
organic chemicals (VOCs). In its approach to mixtures of carcinogens at
doses associated with a risk of less than 10-3, EPA (1985) assumes that the
upper-bound risk estimates for each of the carcinogenic chemicals can be
added. This chapter addresses risk assessment methods for mixtures of low
concentrations of carcinogens and draws heavily on a National Research
Council (NRC, 1988) report that discussed ways to test the toxicity of com-
plex mixtures and concluded that both exposure and pharmacokinetics are
important considerations.
For the known and probable human carcinogens, such as those listed in
the paragraph above, maximum contaminant level goals (MCLGs) are set at
zero by EPA. Practical considerations might at times make the attainment
of zero levels impossible, however, so alternative maximum contaminant
levels (MCLs) are set. MCLs are based on technical feasibility and other
factors, as well as toxicity. Risk assessment methods can be applied to the
individual contaminants to estimate the upper bounds of health risk for al-
ternative hypothesized exposures. The methods used by EPA (1980) apply
the linearized multistage (nonthreshold) model.
Table 6-1 lists the MCLs for several compounds. The table also gives
estimated lower bounds for drinking water concentrations associated with
estimated increases in lifetime risk of developing cancer of 10-6. Exposure
at these concentrations is assumed to be constant throughout a lifetime.
162
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Volatile Organic Compounds (VOCs) 163
TABLE 6-1 Maximum Contaminant Levels and "Virtually Safe Doses" for
Selected Volatile Organic Chemicals (VOCs) Regulated in Drinking Water
MCL, VSD,
Substance mg/litera mg/literb
Tr~chloroethylene 0.005 0.0026
Carbon tetrachlonde 0.005 0.00027
1,2-Dichloroethane 0.005 0.00038
Vinyl chloride 0.002 0.000015
Benzene 0.005 0.0012
aFrom EPA, 1987.
bDose associated with lifetime risk of 10-6 of developing cancer.
Comparison of these sets of numbers with the measured concentrations in
drinking water reported in Table 5-3 shows that the MCL is sometimes
exceeded. If the MCL is satisfied, however, the increase in risk of cancer
is estimated to be less than 1O-5 for benzene and trichloroethylene. Because
the dose-response curve is typically assumed to be linear at low doses, the
risks associated with MCL exposures to carbon tetrachloride and 1,2-dich-
loroethane are less than 2 x 10-s. For vinyl chloride, the maximum risk
would be about 1.3 x 10-4.
RISK ASSESSMENT METHODS
Risk assessment is a means to estimate the probability and possible mag-
nitude of a health response associated with a given exposure. For carcinogens,
methods of using available data to estimate risk have been relatively well
delineated (EPA, 1984, 1986a,b; OSTP, 1984), although validation of the
estimates (and of the methods generally) is still seriously incomplete. Animal
bioassays are undertaken at rather high doses, where the response (if any)
is assumed to be more frequent than at low doses and hence more likely to
be observed in a small group of animals. It is then necessary to adopt some
mathematical model of the dose-response curve and to extrapolate the re-
sponse observed at high doses to an estimated response at exposures of
interest. The linearized multistage model is widely used to estimate cancer
risks associated with environmental exposures (EPA, 1987) and is said to
provide an upper-limit estimate of low-dose response. To some degree, the
model's wide use reflects its mathematical flexibility. However, biologic
support for the assumption of linearity at low doses remains largely inferential
and probably wrong in a high proportion of cases (Bailer et al., 19881.
The NRC report on complex mixtures (1988) concluded that, at doses for
which the relative risk is less than 1.01 and under the assumptions of the
multistage model, the excess risk associated with exposure to several car
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164 DRINKING WATER AND HEALTH
cinogens can be estimated by adding the excess risks associated with each
carcinogen. That report defined a low dose as one associated with an excess
risk no more than 1% and with a small relative risk of cancer in the exposed
group (no more than 1.011. That result was also inferred to hold for several
additional dose-response models used to estimate cancer risks, such as the
one-hit, Moolgavkar-Knudsen, linear, and multiplicative models. These in-
ferences are not, however, validated by direct evidence.
Under most circumstances, one would like to use the dose at the target
organs as the input to dose-response models. That would increase the pre-
cision and could decrease the bias of any risk estimate (Krewski et al. 1987;
Whittemore et al., 19861; however, the lack of validated pharmacokinetic
models to represent mixtures impedes this effort. Further development of
pharmacokinetic models should make possible their application to the indi-
vidual components of a mixture. For materials activated, say, in the liver or
detoxified in the kidney, dose at the liver or the kidney might be most
important.
The NRC report (1988) also described risk assessment methods for using
data from epidemiologic studies, but noted that the problems presented by
human heterogeneity, the potential for bias, the lack of a uniform study
design, and the variability in data quality lead to a flood of risk assessment
methods, as well as uncertainty about results. Studies based on occupational
exposures, which are rarely of known magnitude but can be significantly
higher than those of the general population, also present some extrapolation
problems. The dose-response models used with these data are often among
those for which response additivity is presumed to hold at low doses.
This chapter is related to EPA's existing guidelines for carcinogen risk
assessment (EPA, 1986a), inasmuch as the methods suggested here could
be applied by EPA in conduction with those guidelines. Understanding of
the biology underlying carcinogenic mechanisms is rapidly evolving and
already raises some questions about the need to improve models and as-
sumptions or substitute alternative ones. The adoption of alternative models
would necessarily require reexamination of the conclusions given here.
The MCLs for the VOCs and other carcinogens in drinking water are
generally below those associated with a 10-3 excess risk (see Tables 6-1 and
4-3) thus they satisfy the first criterion for defining low dose. For doses
associated with excess risks greater than 10 - 3, if the NRC approach is correct,
synergism might be important; in such cases, however, the dose of a single
carcinogen itself would also be of concern.
It is more complicated to demonstrate that the second criterion for low
dose namely, a low relative risk has been met. For many of the VOCs
that have been studied, evidence of carcinogenicity is largely from animal
studies, vinyl chloride and benzene being exceptions. Except for vinyl chlo-
ride, excess tumors are generally seen for the hematopoietic or lymphatic
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Volatile Organic Compounds (VOCs) 165
systems. For these lymphomas the background cancer risks for humans are
about 0.018 over a lifetime (Schneiderman et al., 19791. Hence, for the
relative risks to be less than 1.01, the incremental risks associated with
exposure to these VOCs must be less than 1.8 x 10-4 to satisfy the low-
dose criterion; exposure at the MCLs satisfies the criterion. An argument
can be made that there is not necessarily a strict correspondence across sites
of cancer for rodents and humans; hence, total cancer rate should be con-
sidered. Alternatively, one could consider other individual sites or groups
of sites in humans that might be related to sites of observed tumors in rodents.
In such an approach, the low-dose criterion is satisfied, because environ-
mental concentrations of the individual VOCs need only be such that the
risk of cancer associated with individual toxic compounds is less than 0.003
(0.01 x 0.33, which is the probability of developing cancer during one's
lifetime for all races and both sexes) (Schneiderman et al., 19791.
Vinyl chloride exposures in humans are associated with an excess of liver
angiosarcoma, a relatively rare cancer. Background incidence rates are not
available for that cancer, but for total liver cancers, the lifetime incidence
for both sexes is 0.0054 (J. Horme, National Cancer Institute, personal
communication, 1988~. If total liver cancers are considered, satisfaction of
the low-dose criterion requires that excess risks associated with the chemical
in drinking water be less than 5 x 10-5. If total cancers are considered,
however, the second criterion is much more easily satisfied for vinyl chloride.
The apparent paradox is due to the smallness of the background incidence
of liver angiosarcoma, compared with the total cancer incidence.
The subcommittee recognizes that the assumption of response additivity
at low doses does not have an extensive empirical foundation. Rather, it rests
on theoretical considerations and observations in limited epidemiologic stud-
ies. Regarding higher doses, responses greater than additive occur after hu-
man exposure to some mixtures of agents, such as cigarette smoke and
asbestos, at concentrations that produce a high incidence of effects separately
(NRC, 1988).
CONCLUSIONS AND RECOMM ENDATIONS
The acceptance of an underlying dose-response model allows estimates of
lifetime cancer risk to be made for individual carcinogens in drinking water.
The kind of models also indicate that the risks associated with simultaneous
exposure to two or more carcinogens can be added when their concentrations
are low, as they are when drinking water standards are satisfied. Hence, in
the models advocated in the current EPA guidelines (EPA, 1986a), any
potential for more than additivity is ignored in risk assessments of carcinogens
present at low doses. Additional research should be conducted to provide a
firmer empirical base for those models, so that the techniques for the risk
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166 DRINKING WATER AND HEALTH
assessment of mixtures can be improved and refined. The present effort is
an early step; periodic reevaluation will be necessary.
Any summation of cancer risk estimates must be made with care, because
different sets of assumptions can lead to different results. Different models,
for example, have been applied to epidemiologic data and animal toxicologic
data. In addition, the exposures in epidemiologic studies, although rarely
known with any accuracy, are a fortiori in the range of past human exposures
and often much closer to environmental exposures of current concern than
are those of animal studies.
If upper-bound risk estimates are used, even more caveats need to be
applied in the summation exercise. It is true that the sum of the upper bounds
is an upper bound of the sum, but the sum of the upper 95% confidence
limits is not such a limit for the sum. Moreover, the calculations of these
upper bounds for the multistage model (EPA, 1986a) are heavily influenced
by the linearity of the underlying dose-response data. Relatively linear data
give rise to relatively tight confidence limits; nonlinear data generally do
not, because data at the higher doses become less and less informative about
lower doses as curvature over the intervening range of doses increases.
For carcinogens, the most important research needs are those associated
with the development of better estimates of dose-response relationships and
risks for individual carcinogens in drinking water. Additional research also
needs to be directed toward a better understanding of the mechanisms of
carcinogenesis and the development of improved risk assessment models that
better reflect the underlying biology. The replacement of existing models
with improved models could alter the conclusions about the assumption of
response additivity at low doses.
REFERENCES
Bailar, J. C., E. C. C. Crouch, S. Rashid, and D. Spiegelman. 1988. One-hit models of
carcinogenesis: Conservative or not? Risk Anal. 8(4):485-497.
EPA (Environmental Protection Agency). 1980. Chloromethane and chlorinated benzenes pro
posed test role; amendment to proposed health effects standards. Fed. Regist. 45(140):48524-
48566.
EPA (U.S. Environmental Protection Agency). 1984. Proposed guidelines for carcinogen risk
assessment. Fed. Regist. 49(227):46294-46301.
EPA (U.S. Environmental Protection Agency). 1985. Proposed guidelines for the health risk
assessment of chemical mixtures. Fed. Regist. 50(6):1170-1176.
EPA (U.S. Environmental Protection Agency). 1986a. Guidelines for carcinogen risk assess
ment. Fed. Regist. 51(185):33992.
EPA (U. S. Environmental Protection Agency). 1986b. Guidelines for the health risk assessment
of chemical mixtures. Fed. Regist. 51(185):34014-34025.
EPA (U.S. Environmental Protection Agency). 1987. National primary drinking water regu
lations Synthetic organic chemicals; monitoring for unregulated contaminants; final rule.
Fed. Regist. 52(130):25690-25717.
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Volatile Organic Compounds (VOCs) 167
Krewski, D.' D. J. Murdoch, and J. R. Withey. 1987. The application of pharmacokinetic
data in carcinogenic risk assessment. Pp. 441-468 in Drinking Water and Health. Vol. 8.
Pharmacokinetics in Risk Assessment. Washington, D.C.: National Academy Press.
NRC (National Research Council). 1988. Complex Mixtures: Methods for In Vivo Toxicity
Testing. Washington, D.C.: National Academy Press. 227 pp.
OSTP (Office of Science and Technology Policy). 1984. Chemical carcinogens; Notice of
review of the science and its associated principles. Fed. Regist. 49(100):21594-21661.
Schneiderman, M. A., P. Decoufle, and C. C. Brown. 1979. Thresholds for environmental
cancer: Biologic and statistical considerations. Ann. N.Y. Acad. Sci. 329:92-130.
Whittemore, A. S., S. C. Grosser, and A. Silvers. 1986. Pharmacokinetics in low dose
extrapolation using animal cancer data. Fundam. Appl. Toxicol. 7:183-190.
Representative terms from entire chapter:
low doses
