Office of Solid Waste
           Hyannls Regency Inn
           Hyannis, Massachusetts
           December 8 and 9, 1986

The materials presented here have been reviewed by personnel from
the United States Environmental Protection Agency. They do not, how-
ever, necessarily reflect United States Environmental Protection Agency
policy. The materials were prepared primarily by:
Lexington, Massachusetts
Washington, D.C.

Office of Solid Waste
Hyannis Regency inn
- Hyannis, Massachusetts
December 8 and 9, 1986

TO: Participants in the Office of Solid Waste’s Case Study on
Risk and Decision Making
RE: Purpose of the Case Study and Your Role
Risk assessment is becoming an increasingly important compo-
nent of regulatory decision making within EPA. This is true for
a number of EPA offices, including the Office of Solid Waste.
Even so, the components and results of a risk assessment are
often not well understood, and the specific ways in which risk
assessment can be used in a particular situation are not well
defined. The result is confusion and ultimately frustration
among those who must carry out or are affected by the regula-
Risk assessments, however, need not be overwhelming and can
provide guidance in t hinking about an environmental problem.
The purpose of this workshop is to help individuals in the EPA
Regions understand the basis of risk assessment and to develop a
common base of knowledge and terminology. The workshop is not
intended, however, as a step—by—step “how to” on risk assessment.
Rather, we are trying to explain the concepts of risk assessment
in the context of a hypothetical case study. With any risk
assessment, there are many uncertainties and issues, and often no
clear “right” answers. As you proceed through the case, you will
be asked to consider those issues. Some of the issues you
normally would not confront in your day—to-day activities, and
some of the terms may be new. But, regardless of your back-
ground, we hope you will address those issues and develop your
own conclusions. By helping you understand the issues, we hope
to make you more informed consumers of Information on risks and
increase your understanding of both the potential and the limita-
tions of risk assessments. In addition, we hope to encourage
discussion of the unique circumstances involved in developing
risk assessments for the site—specific, localized problems that
confront individuals dealing with Resource Conservation and
Recovery Act (RCRA) issues.
The workshop case study will focus on a hypothetical site—
specific problem that EPA regional staff might encounter in their
day—to-day work under RCRA. You will have to decide what actions
should be taken at a site regulated under RCRA.

The Company
Electrobotics was formed 15 years ago as a privately held
company. Its two owners have lived in the community for many
years. Electrobotics manufactures electronic components for the
computer industry. In the past few years, the bulk of the com-
pany’s sales has been in parts for personal computers, particu-
larly the popular Bananachrome personal computer.
Electrobotics has had a rocky history and has been close to
bankruptcy several times. However, with the recent growth in
demand for personal computers, its performance has improved.
Last year Electrobotics had revenues of $7.5 million, compared
with $1.5 million five years ago. Even so, the company was only
marginally profitable, with after—tax profits of less than
Electrobotics employs about 150 people and has a reputation
for treating its employees well. It has never laid off an
employee, even during difficult periods.
Electrobotics is situated in a sparsely populated region. A
residential development was recently built near the facility’s
western boundary, and approximately 80_ op1e live in2O_homes
there. In addition, the town of j t 1a—lies a little more than
1 mile east of the facility. The area between the facility and
— — - -
the town has few homes, none closer than three quarters of a mile
to the plant’s eastern boundary. There has been some discussion
about building housing on the property, but no definite plans
exist at this time. Utopia relies o gx.Qun&. ater for its public
water_system and has 40 wells in a nearby well field. The welF
— — ---.
field supplies including those in
the development west of Electrobotics. The ground water from the
Electrobotics site flows toward the public weTrTiird. mrtr i
Electrobotics site would affect only_three—of—the-_p..ublic_wells.
(Figure 1 provides a schematic of the Electrobotics site aiW€he
surrounding area.)

Figure 1
Site Plan
— — — ROAD
1000 ft.— ’
L .1
7.000 ft. - 0’
Direction of
(Not to Scale)
Nature of the Problem
About five years’ ago, E].ectrobotics changed its production
process as it introduced a new product. The process required
the use of two industrial solvents-—dinitrochickenwire (DNC) and
SOLVALL. Wastewater containing the spent solvents is stored in a
flow equalization lagoon that is part of the Electrobotics waste—
water treatment plant (see Figure 1). After treatment, the
wastewater is discharged to the local publicly owned treatment
works. Electrobotics’ treatment plant uses an activated sludge
process. As a result, no concentrations of DNC or SOLVALL.we.r
found during initial
ment facility,_ and no DNC or SOLVALL concentrations were foundii
tE ai T i’ Tde the treatment plant.
EPA has classified the two solvents as hazardous wastes.
Information on the carcinogenic risks from SOLVALL was published
in 1981. Studies on the carcinogenic risks from DNC, however,
were just recently presented. These will be discussed in more
detail as you assess the risks at the site.
Water Supply

The hazardous waste regulations developed under RCRA require
that owners and operators of hazardous waste facilities, like
Electrobotics’ storage lagoon, utilize design features and con-
trol measures to prevent the leaking of hazardous waste into
ground water. Furthermore, all regulated units (a regulated
unit, such as the storage lagoon, is a facility that received
hazardous waste after July 26, 1982) are subject to monitoring
and corrective action requirements if a ground-water problem is
identified. The ground-water protection standards require the
Regional Administrator to establish in the facility permit, for
each hazardous constituent entering the ground water from a regu-
lated unit, a concentration limit beyond which degradation of
ground-water quality is not allowed. The concentration limits
determine when corrective action is required.
Three possible concentration limits can be used to establish
the ground-water protection standards:
• Background levels of the hazardous constituents
• Maximum concentration limits (MCLs) established by
• Alternate concentration limits (ACL5)
Background levels and MCLs are established in the facility permit
unless the facility owner or operator applies for an PCL. The
background levels of DNC and SOLVALL are zero, and no MCLs exist
for the two solvents.
In October 1985, the owners of Electrobotics submitted to
EPA, as required under the RCRA regulations, a Part B application
for an RCRA permit. This application provides the Regional
Administrator with information necessary to evaluate the safety
of the site. It generally includes:
• A description of the facility
• Chemical and physical analyses of the hazardous waste
to be handled
• Information from a hydrogeological investigation of the
site -
• The potential for the public to be exposed to hazardous
wastes or hazardous constituents through releases
related to the unit, including identification of the

potential pathways of human exposure and the magnitude
and nature of the human exposure resulting from such
In addition, Electrobotics’ owners have been conducting
ground—water monitoring as required under the regulations.
The results presented in the Part B application and from
other sources indicate that both DNC and SOLVALL were found in
th ground. wfer.—be-l-ow---t-he_ lagoon and in the air . The initial
monitoring wellswere locate ETh ii dThEčëd’ge of the
lagoon, referred to as the point of compj jan e. ” Additional
monitoring wells have been irii alled to characterize the plume,
and results indicate that it has moved to the eastern edge of the
facility boundary.
You, as the EPA representative responsible for the Electro—
botics site, will evaluate the available information on the risks
posed by DNC and SOLVAt 1 L and decide whether to issue a permit and
what, if any, corrective actions should be taken at the
Part I
During Part I, you wish to determine whether and to what
extent the DNC and SOLSIALL found at the Electrobotics plant
endanger the public health. Thus, you have decided to conduct a
risk assessment . Your staff has prepared a document summarizing
much of the information you will need for assessing the risks.
This document, attached as Part I, reviews the potential risks
from DNC and SOLVALL.
The first section, which contains toxicological data on the
two solvents, constitutes the hazard evaluation .
The second section of Part I contains a summary of data on
the exposure of various population groups to DNC and SOLVALL.
Several issues arise concerning the interpretation and use of
this information, and it will be necessary for you to formulate
appropriate conclusions.

The relationship between exposure to DNC and SOLVALL and the
risk of adverse health effects is determined by a dose—response
evaluation . In the third section of Part I, you must review
possible approaches to defining this relationship for the two
solvents. There may be several plausible options for describing
this relationship in the region of human exposure. Normally, you
would not examine the hazard evaluation data and the dose-
response information; these results would be provided by EPA
headquarters. However, in this instance you have asked your
staff to provide the material for your review because you feel it
is important to your understanding of the problem.
In the final section of Part I, you must present your con-
clusions regarding the human health risks posed by DNC and
SOLVALL from the Electrobotics facility, and the uncertainties in
your knowledge. You must characterize the risks .
Part I will be completed during the first day of the
Part II
Once you have assessed the risks from DNC and SOLVALL, you
must decide what actions should be required by Electrobotics’
owners. You must manage the risks . Part II of the case is
currently being prepared by your staff. It will be given to you
at the end of the first day of the workshop, when you have
completed your assessment of the risks, and will be discussed the
next morning. The new document will contain information on the
options for cleaning up the storage lagoon at the Electrobotics
site. In particular, you will have an approach proposed by the
owners of Electrobotics and two alternatives identified by your
For each of the four options, you will be presented with
information describing the approach, predicting the effect of the
option on the risks identified in Part I, and estimating the
At each of the steps in Part I and Part II, issues and data
will be presented and alternative conclusions listed. After
discussion, you may select the conclusion that seems most appro-
priate; if none seems appropriate you should offer your own.
Your review and evaluation will take place within a working
group of 10 to 12 people. After you discuss the issues with the
other members, your group should attempt to reach a consensus on
what regulatory action should be taken. If you cannot reach a

consensus, present the alternative views. You should note,
however, that you must ultimately decide what actions will be
required of Electrobotics’ owners. You will be meeting with the
Regional Administrator at the end of your session and must
present your recommendation to him at that time.

Part I

A. Ground-Water Modeling Calculations and
Associated Assumptions
B. Human Dose Calculations and Associated

Dinitrochickenwire (DNC )
• Solvent used to degrease fabricated metal parts
• Impurities: commercial product contains trace amounts
of trinitrochickenwire
• Physical state: liquid, slight to moderate volatility
• Stability: degrades very slowly in aqueous environ-
• Solubility: moderately soluble in water
SOLVALL (dichioropentagon )
• Solvent used in the production of microchips
• Physical state: liquid, moderate to high volatility
• Stability: degrades very slowly in aqueous environ-
men t s
• Solubility: highly soluble in water

Normally, you would not review information on the
hazards of specific chemicals; the results would probably be
provided to you by EPA toxicologists. But by working through
the material in this section, you will develop an understand-
ing of the nature and quality of information used by the
toxicologists. You will not become toxicologists, but we
hope you will become more informed users of the information
they provide.

• The purpose of hazard evaluation is to identify the
types of adverse health effects that may be associated
with exposure to DNC and SOLVALL, and to characterize
the quality and strength of evidence supporting this
• The specific hazard of concern in this review is
• Epidemiological studies in exposed human populations
are generally considered the best source of inforatatiori
for hazard identification. Unfortunately, they are not:
available for most substances. Moreover, establishing
firm causal links between exposure and chronic human
disease (such as cancer) is very difficult.
• Studies with experimental animals also provide useful
information for hazard identification. Such studies
can be controlled, and thus can more easily establish
causality. Results from such studies suffer from the
obvious limitation that experimental animals are not
the species of ultimate interest.
• With one possible exception (arsenic), all known human
carcinogens are also carcinogenic in one or more
species of experimental animals. Most animal carcino-
gens have not been established as human carcinogens.
In most cases, the lack of adequate epidemiological
data means that no decision about human carcinogenicity
can be made.
• Biological data support the proposition that responses
- in experimental animals should be mimicked in humans.
For some agents, however, species differences in
response can be substantial.
• The specific sites of tumor formation in humans may
differ from those observed in experimental animals.
• Data obtained by administering a substance by the same
route of exposure experienced by humans are considered
more predictive than data obtained by a different
route. If tumors form at internal body sites, however,
the route of exposure may not be important.

• In general, a varied response in experimental animals——
tumor formation in several species and both sexes, at
different exposure levels with increasing response at
increasing exposure, and at multiple body sites——
provides more convincing evidence of potential human
carcinogenicity than does a response limited to a
single species or sex, or to body sites at which tumors
commonly occur in untreated animals (e.g., liver tumors
in untreated female mice).
The toxic properties of DNC were first investigated in the
1940s and 1950s. In most of these tests, small groups of experi-
mental animals were exposed to very high amounts of DNC to iden-
tify the exposure conditions that would cause death. Animals
received either a single exposure, or exposures covering only a
fraction of their lifetime.
During the 1950s and l960s, more extensive animal toxicity
tests were conducted, although none involved DNC exposures last-
ing more than about one—sixth of a lifetime. These tests
revealed the range of doses that produced toxicity (the principal
site of toxic action was the liver) and the exposure level below
which no form of toxicity was identified.
Information available in 1970 showed that the most highly
exposed humans received a daily DNC intake several hundred times
lower than the “no—observed toxic effect” intake identified in
the animal tests. Because the liver toxicity produced by DNC was
of a type likely to occur only ‘after a minimum threshold exposure
was exceeded, it was concluded that the most highly exposed
humans were protected from DNC toxicity by a wide safety margin;
that is, use of DNC presented no risk to the public health.
At least until 1980, no data had been published on the
effects of DNC on exposed humans.
The Frankenstein Study
In late 1985, an article titled “Chronic Toxicity of Dini—
trochickenwire in Rats and Mice” appeared in a respected scien-
tific journal (Frankenstein, V., 1. Environ. Tox.) . The Franken-
stein paper presented data on the effects of lifetime exposure to
DNC in two species of rodents. These data revealed a form of
toxicity——carcinogenicity——that had not been seen before. The
design of the Frankenstein experiment and the major findings are
presented in Tables 1 and 2.

Remarks on the Frankenstein Study
1. As far as can be determined from the published article, the
Frankenstein study was carefully conducted, and there is no
reason to doubt the accuracy of the reported data.
2. DNC increased the incidence of tumors (percentage or propor-
tion of animals with tumors) in certain groups of animals.
Not all animals in a group receiving DNC developed tumors.
Tumor incidence is a measure of the risk (probability) of
tumor development. Data in Table 2 can be interpreted as in
the following example: the lifetime risk of stomach cancer
in male rats exposed by gavage to the high dose of DNC
daily, for their full lifetimes, is 0.40.
3. Rats developed spleen and liver tumors after both inhalation
and gavage exposures. Lung tumors were produced only by
inhalation, and stomach tumors only by gavage. Females of
both species showed fewer tumors than males, and mice showed
fewer tumors than rats.
4. The stomach tumors appeared at the point where DNC contacted
the stomach when introduced by stomach tube. This point is
in the rodent forestomach, an anatomical feature not present
in humans.
5. Severe irritation was observed in the areas of the rodents’
stomachs that were exposed to high doses of DNC delivered by
stomach tube. No signs of irritation were observed in low—
dose control animals. Dr. Frankenstein believes that the
stomach tumors arose as a result of the severe toxic insult
caused by the direct stomach exposure.

Table 1
Number of
Groups Animals Amount of
Species end Receiving — ONC Received Duration of
Route of Exposure DNC Male Fesale Each Day 1 Exposure (weeks) 2
Rat, inhalation Control 60 60 0 104
Lowdose 60 60 30 104
Highdass 60 60 60 104
Rat, gavsge 3 Control 60 60 0 104
Losdose 60 60 50 104
Highdoee 60 60 100 104
Mouse, gavege 3 Control 60 60 0 78
Londose 60 60 60 78
Highdoee 60 60 120 78
t Nilliqreme of OMC per kilogres of the animal’s body weight. The concentration
of OMC in the air in the inhalation experiment has been converted to a unit of
weight so it can be compared with the unite in the gavege study.
2 Approiuaate lifeepane of the animals under laboratory conditions.
3 Gevage is sdunistration of a substance by means of a stomach tube.
Table 2
Following are the only groups in which a statistically eignificent excess
of tumors was found. Nearly 40 possible sites of tumor formation were
examined in each sex of both apecies.
Percentage of
Animals with Tumors
(incidence rate)
Tumors — — — — —
Study Group Sex Found Control Low Dome High Dose
Rat, inhalation Male Lung 3 25
Ret, inhalation Male Spleen 0 2
Rat, Inhalation Male Liver 3 7 l2
Rat, gavage Male Stomach 0 0 433
Rat, gavage Female Stomach 0 0
Rat, gavage Male Liver 3 7 15 a
Rat, gavage Male Spleen 0 33
Mouse, gavmge Male Liver 5 30 a
Mouse, gavags Male Stomach 0 0
9 A statistically significant excees of tumors relative to untreated
control animals. This means it is unlikely that the difference in tumor
incidence between the treated and control animals is due to chance.
Because the only difference between the control end treated animals was
the presence of DNC, it is likely that the excess tumor incidence is due
to this compound. Tumors were found at other sitee in both control and
treated animals, but no other tumors occurred in statistically
significant excess.

Issues to Be Considered
1. How do these data conform (or not conform) to the
principles laid out on pages Il—i and 11—2——particu-
larly the last principle?
2. In view of these principles, is there any reason to
conclude that DNC is not carcinogenic in rats of both
sexes (by inhalation and gavage exposures) and in male
mice (by gavage)?
3. Should the stomach tumors be considered relevant to
low—exposure risks to humans?
4. Should the data obtained by gavage treatment be
considered relevant to human exposure?
5. Is there any reason to believe that humans would not be
at risk of developing the various tumors, assuming
exposure to DNC?
6. Is there any way to determine, from the data given,
whether responses in humans are likely to be similar to
those of rats or mice? Males or females?

Epidemiological Data
After the Frankenstein report was published, three DNC manu-
facturers decided to submit reports to EPA on their investiga-
tions into employee health. The information from these three
reports is summarized below.
Manufacturer A
Manufacturer A had been producing DNC for 45 years, but none
of the 161 employees in the mortality study had been exposed for
more than 20 years; most were exposed for 10 to 15 years. Al-
though employee exposure data were not extensive, they suggested
that past exposures were relatively high, sometimes approaching
the inhalation levels that produced an excess of tumors in
animals. (Although the concentrations of air in the workplace
approached those used in the animal experiment, the workers were
exposed to these high levels for only a fraction of their life-
By January 1979, 35 of the 161 workers had died. No
increase in cancers of any type was noted among these workers
(3 cases observed, 3.8 expected in a population of the same size,
sex, and age). Malignant neoplasms of the digestive system were
elevated (2 cases observed, 0.7 expected), but this elevation was
not statistically significant (i.e., it is not possible to say
the observed difference was not due simply to chance). The
woricers were also exposed to several other chemicals, at least
two of which are known animal carcinogens.
Manufacturers B and C
Reports from Manufacturers B and C are similar to the report
of Manufacturer A. No cases of malignant neoplasms of the
stomach were reported by either manufacturer. Both manufacturers
reported slight elevations in lung cancer, but neither elevation
was statistically significant. No data on worker smoking habits
were available. Manufacturer C reported 33 deaths among 290

Issue to Be Considered
Should the information from the DNC manufacturers alter
earlier conclusions about the inferences to be drawn from
the animal data? If so, how? If not, why not?

EPA’S Risk Assessment Guidelines
The Office of Health and Environmental Assessment (OHEA)
within EPA’S Office of Research and Development has developed
guidelines for carcinogen risk assessment. These guidelines
discuss weighing the evidence that a substance is a carcinogen
and classifying the chemical into one of five groups:
Group A-—Human carcinogen
Group B-—Probable human carcinogen
Group C-—Possible human carcinogen
Group D——Not classified as to human carcinogenicity
Group E-—Evidence of noncarcinogenicity for humans
OHEA developed an illustrative categorization of substances
based on animal and human data, as shown in Table 3.
Table 3
Animal Evidence
Hunan - No
Evidence Sufficient Limited Inadequate No Data Evidence
Sufficient A A A A A
Limited Bi Bi Bi 81 81
Inadequate 82 C D D D
Nodata 82 C 0 D E
No evidence 82 C D D E

Some Possible Conclusions
About DNC Carcinogenicity
1. DNC is a human carcinogen (Group A). There is suff i—
cient evidence from epidemiological studies to support a
causal association between DNC exposure and cancer.
2. DNC is a probable human carcinogen (Group B2). There is
sufficient animal evidence of carcinogenicity as demon-
strated in the increased incidence of tumors at several
sites in multiple species (rats and mice), in multiple
experiments involving different routes of administration
(inhalation, gavage), and at different dose levels.
There is inadequate evidence of carcinogenicity from
epidemiological studies.
3. DNC is a possible human carcinogen (Group C). There is
limited animal evidence of carcinogenicity because the
data obtained when DNC was administered by stomach tube
may not be relevant to any route of human exposure.
Thus, DNC resulted in increased tumors in only one
species (rat) and in one experiment involving only the
inhalation route of exposure. There is inadequate
evidence of carcinogenicity from epidemiological
4. DNC is not classifiable as to human carcinogenicity
(Group D). Because of the extreme conditions under
which tumors were produced in the animal experiments,
there is no reason to believe that DNC is a possible
human carcinogen. There is inadequate evidence of
carcinogenicity from epidemiological studies.
5. Other (formulate your own conclusion).

SOLVALL is a chemical that has received widespread accep-
tance as an industrial solvent because it is relatively inexpen-
sive and has excellent solvent characteristics. Since the 1930s,
however, a number of reports have appeared in scientific litera-
ture that document SOLVALL’s depressant action on the central
nervous system. They include cases where humans were exposed
accidentally for short periods to very high air concentrations of
SOLSIALL, as well as the results of acute vapor exposures to
SOLVALL in laboratory animals.
Additional data on the toxicity of SOLVALL appeared in
scientific literature during the 1960s. Several investigators
reported the results of subchronic (one to three month) experi-
ments in mice and rats. These tests revealed the range of dose
levels that produced central nervous system depression and
adverse hepatic (liver) effects. These effects. are believed to
have a minimum threshold below which they will not occur.
Environmental sampling data from industrial operations in which
SOLVALL was heavily used indicate human exposure levels, at least
1,000 times lower than the minimum level resulting in central
nervous system or hepatic toxicity in laboratory animals. It was
therefore concluded that workers in such operations, believed to
be the most highly exposed human population, were not at risk of
developing adverse health effects.
EPA’s Carcinogen Assessment Group (CAG) recently reviewed
the available data on the carcinogenic potential of SOLVALL. One
item was a cancer bioassay conducted in 1970 by the National
Cancer Institute that was considered to be of adequate quality.
In this lifetime inhalation exposure study, statistically signif-
icant increases of kidney tumors were observed in male and female
mice administered 150 or 300 mg/kg/day SOLVALL. In addition,
statistically significant increases in liver tumors were observed
in male and female mice and in female rats in this study. (No
effect was observed in the 75 mg/kg/day group).
Only one epidemiological study is available of solvent-
distribution workers who were exposed to SOLVALL in addition to a
number of other potentially carcinogenic chemicals. When these
workers were compared with the adult male population of the
United States, they were found to have a slightly increased rate
of lung cancer, which was not statistically significant. The
study did not control for smoking or for-the other chemical
exposures of these workers.

On the basis of these data, EP concluded that SOLVALL was a
probable human carcinogen (Group 82). The animal data were con-
sidered sufficient because there was a statistically significant
increase in tumors in two species, with tumor incidence increas-
ing as dose levels increased. The evidence from the human study
was considered inadequate because while it showed evidence of an
association, it did not exclude chance, bias, or confounding
factors. A causal interpretation of these results in humans was
therefore not judged credible.

Issues to Be Considered
On the basis of your evaluation of DNC, what questions
would you ask the toxicologists about the hazards of

• The purpose of exposure evaluation is to identify the
magnitude of human exposure to DNC and SOLVALf , the
frequency and duration of that exposure, and the routes
by which humans are exposed. It may also be useful to
identify the number of exposed people along with other
characteristics of the exposed population (e.g., age,
• Exposure may be based on measurement of the amount of
DNC and SOLVALL in various media (air, water) and
knowledge of the amount of human intake of these media
per unit of time (usually per day) under different
conditions of activity.
• Some individuals may be exposed by contact with several
media. It is important to consider total intake from
- all media in such situations.
• Because only a limited number of samples of various
• media can be taken for measurement, the representative—
ness of measured values of environmental contaminants
is always uncertain. If sampling is adequately
planned, the degree to which data for a given medium
are representative of that medium can usually be
• Sometimes air and water concentrations of pollutants
can be estimated by mathematical models. Although some
of these models are known to be predictive in many
cases, they are not thought to be reliable in all
• Standard average values and ranges for human intake of
various media are available arid are generally used,
unless data on specific agents indicate that such
values are inappropriate.
As discussed earlier, the Electrobotics Company, which manu-
factures parts for Bananachrome personal computers, operates a
production facility in eastern Massachusetts. The facility

employs 150 workers and includes a wastewater treatment plant and
equalization lagoon (surface impoundment). (The site plan is
illustrated in Figure 2.) Wastewater from the manufacturing
plant operations contains high concentrations of DNC and SOLVALL
and is periodically discharged to a flow equalization lagoon,
which is located within 200 feet of the western facility
boundary. There are rio other potential sources of DNC or SOLVALL
releases in the surrounding area. Adjacent to this boundary is a
residential area of 20 houses in which 80 individuals reside.
The area between the Electrobotics facility and the threatened
water supply wells to the east is undeveloped and contains few
residences. There has been some discussion about building
housing on the property, but rio definite plans exist at this
The equalization lagoon maintains a regular flow to an
on—site a jy , dsu&g. wastewater treatment facility. The
equalization lagoon is maintained at an average fluid depth of
10 feet and measures 10,000 square feet.
Figure 2
Slte Plan and Points of Compliance and Exposure
— — ROAO —
7,000 ft.
Characterization Wells
Water Supply
Direction of
I Ground-Water
Point of
(Not to Scale)

The equalization lagoon is underlaid by a compacted natural
clay liner with a hydraulic conductivity (a measure of the rate
at which it transmits water) of 3 x l0 cm/sec, which is
designed to provide substantial containment of the wastewater.
The uppermost geologic formation beneath the site is composed of
approximately 75 feet of stratified glacial outwash, which con-
sists of layered sand and gravel with some silt. These unconsol-
idated sediments form a productive aquifer that is a source of
potable water to the surrounding area. A well field is located
approximately 1.5 miles to the east (downgradient) of the site
and provides approximately 3 million gallons per day (mgd) of
potable water to its 50,000 customers. The well field contains
40 separate wells, each pumping 75,000 gallons per day (gpd).
The hydraulic conductivity of the aquifer has been estimated
at 40 feet per day, based on field tests in the area. However,
there may be thin continuous layers of significantly lower or
higher hydraulic conductivity within the glacial outwash. The
water table is located about 10 feet below the bottom of the
lagoon at the site. The hydraulic gradient (a measure of the
slope of the water table), based on the best available potentio—
metric head measurements, is estimated at 0.005 feet/feet toward
the community well field.
The site is located in a humid area. The wind direction is
seasonal; however-, according to a wind rose from a local ineteoro—
logical station (which describes wind direction and frequency),
the wind blows west, across the site toward the 20 homes adjacent
to the lagoon approximately 30 percent of the time.
The owners of Electrobotics conducted extensive analysis of
the lagoon in preparing their Part B application. The nature of
the materials stored in the lagoon and the meteorological and
hydrogeological conditions in the vicinity have resulted in some
concern by EPA about possible exposure of workers at the facility
and residents in the vicinity to DNC and SOLVALL via inhalation
of air, as well as possible exposure of the community via con-
tamination of drinking water supplies. In an attempt to be
responsive to the regulations and concerns of EPA staff, the
owners undertook a program of air and ground—water monitoring.
Measurements of concentrations of DNC and SOLVALL on the
site are described in the next section. A ground-water monitor-
ing program has been undertaken to comply with regulations
promulgated under the Resource Conservation and Recovery Act
(RCRA). Electrobotics is monitoring contaminants in ground water
at the downgradient limit of the waste management unit, termed
the “point of compliance.” The point of compliance in this case
is at the eastern limit of the berm around the lagoon. Three
monitoring wells have been installed at this point, and one well
was installed upgrádient (see Figure 2). This conforms to the

regulatory minimum. No DNC or SOLVALL was found in the sample
from the upgradient well. The nearest downgradient property
boundary is to the east, about 1,000 feet from the lagoon.
Because DNC and SOLVALL have been detected at the downgrad-
ient compliance—monitoring wells, a ground—water assessment has
been initiated, and additional monitoring wells have been con-
structed at the eastern property boundary to monitor chemical
concentrations. Further downgradient, the public well field
represents a point of potential human exposure. Three of the
40 wells are located directly downgradient of the lagoon. The
relative locations of the point of compliance, eastern regulatory
boundary, and actual point of exposure are shown in Figure 2.
Measurements of DNC and SOLVALL concentrations in air along
the western site boundary, outdoors at the facility adjacent to
the lagoon, and indoors within the treatment plant have been made
during- a single air—sampling program. The sampling program was
conducted for a period of one week, during
concentrations were measureftă E he western property boundary,
adjacent. to the equalization lagoon and within the treatment
plant. During the period of measurement, wind was blowing gen-
erally west across the lagoon toward the residential area. The
mean, standard deviation, and range of measured chemical concen—
trations in air are shown in Table 4. Air measurements that were
made concurrently inside the wastewater treatment plant did not
detect measurable concentrations of either solvent. Within the
treatment plant, all treatment units are closed and vapor—
controlled to limit any fugitive air-emissions.
Table 4
Detection Standard Standard
Nediup Location Level Mean Deviation Range - Mean Deviation Range
Air Ineide treatment plant ( Lg/in 3 ] ND 1 — — pu I — —
Air At weatern boundary of mite iug/m 3 1 11 4 2—17 153 10 130—160
Air l 1—site Iug/m 3 ] 47 20 30—120 700 22 650—1 000
Ground water Point of compliance (ug/l] 332 30 290—350 1,000 168 000—1,250
Ground water Eastern property boundary 90L 2 0012
Ground watar Municipal water supply ND’ — ND’
‘Not detected at 1 ppb.
2 Trace concentretiona. below detection limit at 1 ppb.

The ground water has been periodically sampled and tested
for DNC and SOLVALL both at the point of compliance, the monitor-
ing wells on the eastern boundary, and at the water treatment
plant at the community water system, which draws water from the
aquifer for the municipal supply. The concentrations of chemi-
cals in monitoring wells at the point of compliance are indicated
in Table 4. The concentrations detected at the compliance point
indicate contamination of the aquifer. Trace concentrations of
SOLVALL have also been detected at the eastern boundary in the
most recent water tests, but at concentrations less than the
method—detection limit of 1 part per billion (ppb or ig/l). The
municipal water supply has been tested, and no detectable concen-
trations of DNC or SOLVALL were found. However, the detection
limit for both chemicals offered by available analytical methods
for ground water is 1 ppb.
Available information suggests that the chemical plume may
not yet have migrated beyond the eastern property boundary, but
without corrective action the concentrations are expected to
increase in time in this vicinity, eventually affecting offsite
ground water.
A mathematical model of the contaminant plume movement in
the aquifer has been constructed to estimate future concentra—
tions in the aquifer. A summary of the modeled environmental
concentrations in ground water is presented in Table 5. Appen-
dix A contains the calculations and the associated assumptions
that were applied in modeling these environmental concentra-
Table 5
Location DNC (ag/i) SOLVALL (ag/i )
Eastern property boundary 275 770
Actual paint of exposure 5.5 9.3

The environmental concentrations summarized in Tables 4 and
5 are the starting point for the calculation of estimates of
human exposure to DNC and SOLVALL.
The medium in which a substance is present will determine
the potential route of human exposure. For example, substances
present in water may be ingested. Contaminated water may also
lead to inhalation exposure when water is used for cooking or
showering, although this exposure route is likely to be minor
unless the contaminant is present at high concentrations in the
water and is highly volatile. Exposure by inhalation of contam-
inated water or by the derma]. route during bathing or showering
vlas considered insignificant because of the low concentrations of
these substances in the municipal water supply. Doses resulting
from these exposure routes were therefore not calculated. Sub-
stances present in air will be inhaled. Finally, substances
present in soil may be ingested, absorbed through the skin,
inhaled, or taken up by plants with human exposure resulting if
these plants are used as food or if these plants are fed to
livestock, the various products of which are used as food.
Human exposure to contaminated soil, however, was considered
insignificant at this site because soils potentially contaminated
by ground water are located at least 10 feet below the land sur-
f ace. Consequently, doses resulting from potential human expo-
sure to soil were not calculated.
In order to estimate human exposure, or dose of the consti-
tuent from each contaminated medium, certain data and assumptions
were applied. These data and assumptions relate to the extent
and frequency of human contact with these media and the degree of
absorption of chemicals for each route of exposure. When the
constituent is ingested, a certain fraction will be absorbed
through the gastrointestinal wall; when it is inhaled, a certain
fraction will be absorbed from the lungs.
The method of dose calculation depends on the route of expo-
sure. Certain standard values have been developed to estimate
contact with and intake of certain media. For drinking water,
the EPA and other scientific groups generally assume that adults
drink 2 liters of water per day. It is also generally assumed
that the average adult inhales 23 cubic meters Cm 3 ) of air per
day. It should be noted, however, that the data and assumptions
required for estimation of dose from most other routes of
exposure are not as readily standardized.

The assumptions and calculations required to estimate DNC
dose to the 80 neighboring residents resulting from inhalation of
DNC—contaminated air are presented below to illustrate the ele-
ments of dose estimation. A complete set of calculations and
associated assumptions for both chemicals and the critical
pathways is shown in Appendix B.
Inhalation of DNC—Containinated
Air by Neighboring Residents
• An adult inhales 23 m 3 /day of air.
• Based on wind direction analysis, the duration of
exposure is 30 percent of the time on an annual average
• The body weight of an adult is 70 kg.
• The inhalation absorption factor for DNC is 0.75.
• The adult lives in the home throughout his lifetime.
0.011 mg
(average DNC air concentration at boundary)
m 3
23m 3 1
x x x 0.3 (human intake factor)
day 70 kg
x 0.75 (inhalation absorption factor)
= 8.1 x l0 mg/kg/day
Table 6 presents a summary of all the exposure calculations
performed to estimate doses from the contaminated media to the
identified exposed population groups.

Table 6
N anber
Methtai DIC (ng/kqjday) SOLVALL (mq/kg/day) of Persons Exposed
Air, neighboring residents 8.1 * iO 1.1 x io.2 80
Air, workers 1.2 x 10 1.8 x 10.2 150
Ground water, point of compliance 9.5 * 1O 2.9 x ia. 2 0
Ground water, eastern property boundary 7.8 x i0 2.2 x LO.. . 2 0
Ground water, public well field 1.6 * 10 2.7 * 10 50,000
Remarks on Exposure Data
1. Ground water directly beneath and adjacent to the regulated
unit has been sampled and analyzed for the presence of DNC
and SOLV LL. Concentrations that have been measured have
remained relatively constant for the past two years (four
samplings) and indicate that both these chemicals have
leaked from the storage lagoon into the underlying aquifer.
Ground water moves toward a well field that provides drink-
ing water for a community of 50,000 people. DNC and SOLVALL
have not been detected in the water supply but may be pres-
ent at concentrations below the current method detection
limits, which are 1 ppb ( .tg/l) for both chemicals.
2. Both DNC and SOLVALL are unstable in the environment and
will decompose by biodegradation in shallow aquifer systems.
The decomposition of both chemicals in aquifers has been
demonstrated in aquifer restoration programs at other sites,
but the rates of decomposition are variable and have only
been quantified in laboratory experiments. The rate of
decomposition at concentrations less than 10 ppb is
3. Trace concentrations (less than 1 ppb) of chemicals have
been detected at the eastern facility boundary. A mathemat-
ical model has been used to predict future concentrations of
DNC and SOLVALL in ground water downgradient of the regu-
lated unit. The model prediction indicates that both chemi-
cals will migrate in ground water and degrade at a slow
rate. On the basis of the model prediction, concentrations
are expected to increase at the eastern property boundary if
no corrective action is taken. The degradation products are
not believed to be carcinogenic.

4. Estimates of future concentrations of both chemicals in
drinking water are based on analytical predictions from a
ground—water model. Appropriate adjustments regarding
ground—water dilution were made to estimate concentrations
at the tap.
5. Estimates of current exposure in air were based on analyti-
cal results obtained from measuring the air concentrations
in the facility and at the boundary over a single seven—day
period in April 1986. Twenty—four—hour composite samples
were taken each day over the sampling period. No other air
data are available.

Issues to Be Considered
1. The summary exposure data presented in Table 6 include
some current exposure estimates and some future expo-
sure estimates. Models are used to predict concentra-
tions of DNC and SOLVALL at some point in the future,
assuming that releases of the substance from the lagoon’
occur at the current rate. Should the two types of
exposure data (current and future) be treated the same
for purposes of characterizing human risk? How should
distinctions be reported?
2. Should the ground—water concentration estimates that
are based in part on modeling of a degradation process
be used at all? How should this be decided? If
modeled concentrations are not used, how should the
analyses of chemicals that are reported as “below
detection limit” or “not detected° in the water supply
system be represented in exposure estimates?
3. Is the mean concentration in the various media the
appropriate summary statistic to use to characterize
human exposure? Should the tipper range or statistical
upper confidence limit be used as an alternative?
4. Are the various assumptions about human intake and
average exposure to various media valid? Should others
be substituted or added?
5. Should other routes of exposure to the various contami-
nated media have been considered?
6. Should the total exposure and risk for the regulated
unit be represented by the sum of all incremental risks
for each chemical/pathway?
7. Was it appropriate to model the exposure based on an
adult population? Should other populations—at-risk
have been considered?
8. Should exposure and risk to workers at the facility be
considered in the same context as residents in the
surrounding community?

Some Possible Conclusions About
Human Exposure to DNC and SOLVALL
Which of the following conclusions best characterizes
the information you have seen?
1. None of the exposure estimates is adequate for use in
risk assessment. The risk assessment should describe
exposure in qualitative terms only. Such a qualitative
description is appropriate and adequate for character-
izing risk, which also can be done in qualitative terms
2. The exposure estimates presented in Table 6 for drink-
ing water and air are reliable and can be used for risk
assessment. However, no risks should be assessed until
appropriate data are obtained from other pathways of
3. Although the exposure estimates in Table 6 are based on
different data and assumptions, they are all adequate
and sufficient for assessing risks. The risk manager
should be made aware of the uncertainties in each of
the data sets, but a quantitative risk should be devel-
4. In addition to Conclusion 2, it should be noted that
all the exposures from various media should be added
for those people exposed to all sources of DNC and
5. Other (formulate your own).

Normally, you would not be involved in reviewing dose-
response information; the results generally would be pro-
vided to you. As discussed before, however, we hope that by
having you evaluate this information and address the key
issues here, you will be able to better use the dose—
response information you will receive.
We have given you the EPA approach to evaluating dose-
response relationships. In addition, we have identified
alternative approaches so that you develop an understanding
of how others may perceive the issue.

Because of the relative complexity of dose—response evalua-
tion, the following discussion is substituted for a statement of
key principles.
Animal data showing that DNC and SOLVALL are carcinogenic
were obtained in the high—exposure region of the dose—response
curve. Thus, animal exposures were in the 30—to—300—unit range
(see Table 1 for DNC), and these produced measurable risks in the
range of 10 to 50 percent (see Table 2 for DNC). Predictions of
human exposure, as discussed in Section III, are at much lower
levels. What can be said about risks in the range of human
At least three general approaches to this problem have been
proposed by various experts.
Approach 1
Based on general theories of how carcinogens act to produce
cancer (largely derived from experimental studies and epidemi-
ological data), all finite exposure levels will produce a finite
risk. The magnitude of the risk will decline as the magnitude of
exposure declines (clear even in the animal data). 1
If the quantitative relationship between exposure and risk
were known for all exposures, the risks to rodents exposed at
very low levels could be predicted from the measured exposure—
risk data. The risks to humans could be predicted at these very
low levels if the relationship between rodent and human suscepti-
bilities were known. Although these relationships cannot be
known with accuracy, a plausible upper limit on human risk can be
predicted with sufficient accuracy to be used as a guide to mak-
ing risk decisions. Actual human risk is not likely to exceed
the upper limit, and it may be less. This is the approach
generally adopted by EPA in evaluating the risk associated with
low—level exposure to carcinogens.
1 These two sentences are the proper formulation of the “no—
threshold” concept. It does not mean that all finite exposures
will cause cancer; rather, it means that all finite exposures
will increase the probability (risk) that cancer will occur.

Approach 2
The quantitative relationships between high—exposure and
low—exposure risks in rodents and between rodent and human risk
are not known with sufficient reliability to be used in risk
assessment. Moreover, there is no reliable theory on which one
can conclude with assurance that low—level human exposure (i.e.,
exposure below the range producing detectable risks) poses any
risk at al] .. As with other toxic effects, carcinogenicity will
not be initiated within an individual until a minimum threshold
of exposure is exceeded. In such circumstances, the only reason-
able course is to report the magnitude of the margin—of—exposure
(MOE) by which humans are protected. MOE is the maximum amount
of exposure producing no measurable tumorigenic response in ani-
mals divided by the actual amount of human exposure. MOE gives
the risk manager adequate information on which to decide whether
exposures must be reduced or eliminated to provide human protec-
tion. A relatively large MOE is desirable because it is likely
that the threshold for the entire human population is lower than
that observed in small groups-of experimental animals. This
approach is generally applied when evaluating the potential risk
of most noncarcinogenic effects.
Approach 3
Although there is adequate theory and some evidence to per-
mit the conclusion that humans are at finite risk at all finite
exposure levels, there is insufficient knowledge to allow predic-
tion of the risks in quantitative terms. The risk assessor
should simply attempt to describe risks qualitatively, perhaps
coupling this description with some information on the potency of
the compound and the magnitude of human exposure. This type of
presentation is adequate for the risk manager, who should nřt be
concerned with the quantitative magnitude of risk in any case. -
* * * * *
Each of these views, and perhaps others as well, has some
merit. The first approach is now used by most federal public
health and regulatory agencies, including EPA. These agencies
emphasize that the predicted numerical risks are not known to be
accurate, but because of the nature of the models used to predict
them, they are likely to be upper—bound estimates of human risk .
An upper—bound estimate is one that is not likely to be lower
than the true risk and is likely to exceed the true risk (which
could be zero). . -

For this exercise, we will estimate low—exposure risks using
the model currently used by EPA. A model is a mathematical for-
mula that describes the relationships between various measures.
Two models are needed to predict low—exposure risics:
• A high to low exposure extrapolation model is needed to
predict low—exposure risks to rodents from the measured
high—exposure, high-risk data (see Table 2 for DNC).
EPA currently uses a “linearized multistage model” for
this purpose. This model is based on general (not
chemical—specific), widely held theories on the biolog-
ical processes underlying carcinogenesis. Application
of the model to the rodent exposure risk data produces
an estimate of the lifetime risk for each unit of
exposure in the low—exposure region. This is called
the unit cancer risk. The linearized model is used to
ensure that the unit cancer risk is an upper—bound
estimate of risk.
• An interspecies extrapolation model is used to extra-
polate from rodent unit risks to human unit risks. EPA
assumes that rodents and humans are at equal risk at
the same exposure measured in milligrams of carcinogen
per square meter of body surface area per day. Inter-
species extrapolation models are commonly called
“scaling factors” because they are used to scale doses
between species.
EPA’S selection of these models is based on the agency’s
view that they are the best supported for purposes of deriving an
upper-bound estimate of risk. Alternative models are available
for both these forms of extrapolation, and several are equally
plausible. In most cases, but not always, use of plausible
alternative models will yield lower estimates of risk than those
predicted by the two described here. Differences can sometimes
be very large, but are generally relatively small when the models
are limited to those that are linear at low exposures.
Further discussions of various models and their plausibility
can be found in the handout “Principles of Risk Assessment: A
Nontechnical Review.”
In this exercise we determine the upper—bound estimate of
unit cancer risks predicted for DNC and SOLVALL using the models
currently preferred by EPA. The effect of using alternative,

plausible models is also described, as are the animal data that
pertain to the second or third approaches described above for
dose—response evaluation (i.e., the MOE or qualitative
Estimates of Upper—Bound,
Lifetime Unit Cancer Risks
Using Current EPA Models
Application of the EPA models for high—to—low—dose and
interspecies extrapolation to the measured animal cancer data for
DNC (Table 2) and SOLVALL yields the results shown in Table 7.
The result of such extrapolations is the unit cancer risk. In
this exercise, one unit of exposure is equal to one milligram
(mg) of the carcinogen per kilogram (kg) body weight of the
animal (or human) per day throughout the lifetime of the animal
(or human). Thus, if the unit cancer risk for DNC is 0.0897
(8.97 x 10—2), the risk of developing cancer from 1 mg/kg/day of
lifetime exposure to DNC is 8.97 x 10—2 (a probability of about 9
in 100).
Table 7
Species, Sex Route of Exposure Tumor Site Unit Cancer Risk 1
DNC (based on Table 2)
Rat, male Inhalation Lung 0.0186 (1.86x10 2 )
Rat, male Inhalation Spleen 0.0126 (1.26x10 2 )
Rat, male Inhalation Liver 0.0168 (1.68x10 2 )
Rat, male Gavage Stomach 0.0054 (5.4x11r 3 )
Rat, female Cavage Stomach 0.0054 (5.4x1O 3 )
Rat, male Gavage Liver 0.0120 (1.2x10 2 )
Rat, male Gavage Spleen 0.0228 (2.28x1O 2 )
Mouse, male Gavage Liver 0.0897 (8.97x1O 2 )
Mouse, male Gavage Stomach 0.0096 (9.6x10 3 )
SOIVALL (as provided by EPA Carginogen Assessment Group)
Mouse, male Inhalation Pooled tumors 2 0.0018 (1.8x10 3 )
1 Risk for an average daily lifetime exposure of one unit. Units are the
same as those used earlier for describing the animal exposure (Table 1
for ONC), such that one unit = one milligram per kilogram body weic t
per day. Risk is obtained from unit risk by multiplying the latter by
the actual number of units of human exposure. For a given exposure,
the hi er the unit risk, the higher the risk.
2 The percent of animals with one or more tumor sites showing signif i—
cantly elevated tumor incidence.

This relationship is presented graphically in Figure 3. The
horizontal axis is the dose of DNC measured in mg/kg/day. The
vertical axis is the response and is a probability.
Figure 3
Dose—Response Relationship for DNC
(unit cancer
To obtain the risk from other levels of exposure, the unit
cancer risk is multiplied by the number of units of exposure.
Thus, if a person were exposed to 0.003 units of DNC throughout
his lifetime (0.003 mg/kg/day), the risk would be 0.003 units
times 0.0897/unit, or 0.00027 (2.7 x l0 ), a probability of 2.7
cases arising in 100,000 individuals exposed at this level.
Estimates of Lifetime Unit
Cancer Risks Using Other Models
Application of other models for high-to—low—dose extrapola-
tion yields unit risks equal to or slightly lower than (less than
fivefold) those in Table 7, as long as the other models incor-
porate the concept that risk increases in direct proportion to
exposure in the low—exposure region (linear models). Use of the
most plausible alternative interspecies extrapolation model (that
generally used by FDA) yields unit risks sixfold (for rats) and
thirteenfold (for mice) lower than those predicted in Table 7.
Thus, alternative models predict unit risks about 30 to 65 times
lower than those predicted using the EPA models.
Adoption of certain nonlinear models for high—to—low—dose
extrapolation predicts risks about 1,000 to 10,000 times lower
than those predicted by use of the EPA model. The nonlinear
models are not used by agencies charged with protecting human
health, but cannot be rejected on purely scientific grounds.

Dose—Response Evaluation not
Involving Formal Extrapolation
For those who believe formal extrapolation beyond the
measurable dose—response data should not be performed, it is
important to identify the exposures at which DNC and SOLVALL
produce tumors and those at which no tumor excess is found (the
“no observed effect level” or NOEL). Table 8 identifies NOELs
from data on DNC in Table 2. Note that this is not the approach
generally applied by EPA for carcinogenic substances. (The
Carcinogen Assessment Group consequently did not report NOELs for
Table 8
Study Group Sex Ti.sior - NOEL
ONC (based an Table 2)
Rat, inhalation Male Lung 30
Rat, inhalation Male Spleen 30
Rat, inhalation Male Liver 30
Ret, gevage Male Stomach 50
Rat, gavage Female Stomach 50
Rat, gavage Male Liver 50
Rat, gavage Male Spleen None found
Mouse, gevage Male Liver None found
Mouse, gevage Male Stomach 60
1 tjnits are identical to those in Tables 1 end 2.
“None found” means that a measurable excess of
tumors was found at both levels of exposure used
in the experiment.

Issues to Be Considered
1. If explicit estimates of unit risks are made, should
only EPA’S currently preferred models be used? Should
the results of applying other models also be displayed?
2. Which species/sex/tumor site data from Table 7 should
be used for unit risk assessment? All, shown individ-
ually as in Table 7? Only the data set yielding the
highest unit risk? A sum of all? Other?
3. Should the DNC stomach tumor data set be rejected
because there is no exact anatomical counterpart in
4. How should the uncertainties in use of models be
5. Are the observed NOELs true “no-effect” levels? Could
they simply reflect the fact that in experiments with
relatively small numbers of animals, the failure to
observe a statistically significant increase of tumors
is, an artifact of the experimental design, and not a
true absence of biological effect? How should this
uncertainty, if it is real, be taken into account?
6. EPA has adopted the first approach, using unit cancer
risks, to extrapolate from the high doses used in the
animal studies to the low doses at which humans are
exposed. How might you respond to someone who argues
for one of the other approaches?

IV- 9
Some Possible Conclusions About
Dose—Response Evaluation
Which of the following conclusions best characterizes
the information you have seen?
1. The unit cancer risks listed in Table 7 are true upper—
bound estimates. The true unit risk is not likely to
exceed those listed, may be lower, and could be zero.
2. The same as the first conclusion, but add: The use of
alternative, plausible models yields unit risks about
10 to 100 times lower than those in Table 7.
3. Unit risks should be reported for all plausible models,
and the full range of estimates should be reported
without bias.
4. There is no justification for calculating and reporting
unit risks. What is critical for understanding the
public health importance of low—level exposure to DNC
(and SOLVALL) is the margin of exposure (MOE). Estima-
tion of the MOE is based on the NOELs for its carcino-
genic effects; these figures are reported in Table 8.
5. Neither unit cancer risks nor NOELs are reliable indi-
cators of human risk, and neither should be considered
for risk assessment. Dose—response relations for the
human population are not known for DNC or SOLVALL; risk
should be described in qualitative terms only.
6. Other (formulate your own conclusion).

In the last step of risk assessment, the information col-
lected and analyzed in the first three steps is integrated to
characterize the excess risk to humans. In line with the alter-
native approaches for describing dose—response relationships, at
least three approaches to this step can be taken:
1. Provide an explicit numerical estimate of excess lifetime
risk for each population group by multiplying the unit risk
times the number of units of exposure experienced by each
Excess lifetime = (unit cancer risic) x (units of exposure)
In this equation, excess risk is unitless——it is a probabil-
2. Estimate the margin of exposure (MOE) for each group by
dividing the NOEL by the exposure experienced by that
3. Describe risks qualitatively for each population group.
Risk characterization might also include some combination of
all three approaches, along with a description of their relative
It is also essential that the statistical and biological
uncertainties in estimating the extent of health effects be
described in this step.
Table 9 presents the excess lifetime risks for each popula-
tion group using data from Tables 6 and 7. These risks are based
on the highest unit cancer risk for DNC and the unit risk deter-
mined by the Carcinogen Assessment Group for SOLVALL (Table 7).
If other unit risk figures from Table 7 had been used, excess
risks would be somewhat lower. And if unit cancer risks derived
from other dose response models had been used, the excess risics
shown in Table 9 would be 10 to 100 times lower. The risks in
Table 9 are thought to be upper—bound lifetime risks.
Table 9 also reports the MOE for each group. The MOE is not
an expression of risk, but the difference between the actual

human exposure and the highest exposure causing no observable
carcinogenic effect in the most sensitive animal species. (Use
of the MOE approach is not the policy of the EPA. These results
are presented, however, because this approach may be applied by
non—agency risk assessors.) -
Table 9
1 RIsk obtained by multiplying the highest unit cwieer risk Figure frow Table 7 (0.0897 for ONC and 0.0018 for SCLVALL) by the unite of exposure from
fable 6.
2 Tota l risk obtained by udding risks from air and aster exposures.
3 1U For ONC obtained by dividing the lowest NOEL (30 mg/kg/day) from Table 0 by the mis of ONC air and water exposures from Table 6. For SOLVALL,
HOE obtained by dividing 75 mg/kg/day (the loweet NOEL) by the mum of S .VALL air and water exposures from Table 6.
4 0btsined by multiplying total excess risk by thu ustisatud riuaber of people exposed.
Exposed Population
Upper —Oound
Estimate of Exceas
Chesics.l Risk from Air’
Excess Risk Cancer Cease
from Water 1 Total Excess Risk 2 Over a Lifetime 4
General population (50,000)
Nearby residents (80)
Workers (150)
Risks Based on Water Consumption at Pi 1ic Well Field
501 VA IL
DNC 7.3 x LO
S01VALL 2.0 x 1O
9.3 a l0
1.4 *

1.4 a l0
1.4 x
4.9 a i0
1.4 a
1.4 x l0
4.9 a 10
1.4 x 10
1.4 a 1O
4.9 a l0
1.4 a
8.1 a
2.0 a
1.1 * ia— 4
1.2 a
3.2 a l0
1.5 a 10
1.1 a 10-4
3.2 a 10
1.4 a 10
1.9 a
3.0 a
3.1 a
6.8 a
2.2 a
4.0 a
Risks Based on Water Consumption at Eastern Property Bowidary
population (50,000)
501 VAIL
50 1. VAIL
7.0 a
7.0 a
4.0 •
3.8 a
3.5 a
i ’
10 ’
7.4 a
7.4 a
1.3 a
2.0 a

7.0 x
4.0 a
7.7 a
6.0 a

3.5 a
2.3 a
9.3 a
7.4 x
0.3 a
3.2 a
i —
4.0 a
i —

8.1 a
7.2 a
s. a
1.9 a
1.4a1 0
7.4xl O
8.Oxl O
Risks Based on Water Consumption at Point of
0. 0
population (50,000)
8.5 x
5.2 a
8.5 x
5.2 a
5.2 a
2.8 a
9.0 a
9.0 a
7.3 a
2.0 a
8.5 a
5.2 x
9.2 a
7.2 a
i —
2.9 a
1.9 a
9.3 a
9.0 a
9.9 a
1.1 a
3.2 a
8.5 *
5.2 a

9.6 a
0.4 a
2.0 a
1.6 a
1.4 x
9.0 a
i0 4
1.0 *

V- 3
Issues to Be Considered
1. Are the results reported in Table 9 an adequate characteriza-
tion of DNC and SOLVALL risks? What else should be added?
2. Risks are presented at three points: the point of compliance,
the eastern property boundary, and the public well field. What
are the advantages and disadvantages of using each? Which one
do you feel best represents the risks?
3. Should risks derived using other unit cancer risks reported in
Table 7 and unit risks obtained using alternative models also
be discussed? How would you. present these uncertainties?
4. The risks, MOE, and number of cases reported in Table 9 depend
on the assumption that the number of people exposed and their
level of exposure will remain constant over a lifetime. Is
this a plausible assumption? Can alternative assumptions be
5. Is it important to distinguish routes of exposure? Should unit
risks obtained from the gavage data be used for population
groups exposed by inhalation? Should gavage data be used at
6. The risks from DNC and SOLVALL are added together in Table 9.
Does this seem reasonable?
7. Is it appropriate to estimate the number of cancer cases by
multiplying risk times population size (last column of
Table 9)? Which is more important——risk to an individual, or
risk to a population?
8. Do you believe that animal data obtained from continuous, hf e—
time exposure should not be used to characterize the risk of
people exposed by certain routes intermittently, for a rela-
tively small fraction of their lifetime?

V- 4
Some Possible Conclusions
About DNC and SOLVALL Risks
Which of the following best characterizes the
information you have seen?
1. Upper—bound excess risks to humans exposed to DNC and
SOLVALL are those reported in Table 9. Although risks
obtained from the use of other models are lower, the
risks could be as high as those reported in the table.
There is no evidence that a threshold dose exists for
DNC or SOLVALL, so the MOE estimates have little
2. Same as Conclusion 1, except restrict estimates of
excess risks for inhalation exposure to unit risks
estimated from inhalation data, and restrict risks for
ingestion to gavage data.
3. The excess risks shown in Table 9 as well as those
obtained from all other plausible models and all the
various tumor site data should be reported, and all
estimates should be given equal weight. Such a
presentation affords the decision maker a view of the
uncertainty in the estimated risks.
4. Upper—bound estimates of excess lifetime risks to
humans are those reported in Table 9. Use of all
other animal data sets and alternative risk models used
by some other agencies would result in prediction of
lower risks, perhaps up to 65 times lower. These risks
are conditional on the assumption that DNC and SOLVALL
are probable human carcinogens, based on observations
of carcinogenicity in two species of experimental
animals. Uncertainties in the exposure and population
estimates are those described in the Exposure Assess-
ment section.
5. DNC and SOLVALL are probable human carcinogens, based
on observations of carcinogenicity in two animal
species. Exposures needed to produce animal
carcinogenicity are many times higher than those to
which humans are exposed. The margins of exposure by
which humans are protected are shown in Table 9.
Because a NOEL has not been identified for all the
various carcinogenic end points, a greater than usual
MOE should be employed to protect human beings.

V- 5
Some Possible Conclusions
About DNC and SOLVALL Risks (continued)
6. DNC is a probable human carcinogen, based on
observations of carcinogenicity in two species of
experimental animals. SOLS/ATJL is a probable human
carcinogen, based on strong evidence in two species of
experimental animals and suggestive evidence from
observations in exposed humans. Humane are exposed to
these chemicals through air and water. In general,
large numbers of people are exposed continuously to
very low levels of DNC and SOLVALL in drinking water,
and a few groups are exposed to relatively high levels
in air, some continuously, others intermittently. The
individual risk in the general (larger) population is
probably low, and this translates to a very small
number of cancer cases. The individual risk to nearby
residents is moderate, and this also translates to a
small number (<1) of excess cancer cases. The
individual risk to workers at the plant is slightly
higher than that of nearby residents, although because
of the relatively small number of workers, this again
translates to less than one excess cancer case expected
in this group.
7. Other? Some combination of the others?

Acceptable daily intake (ADI) . Estimate of the largest amount
of chemical to which a person can be exposed daily that is not
anticipated to result in adverse effects (usually expressed in
Carcinogen . A substance that increases the risk of cancer.
Control animals . Animals that receive identical treatment as
test animals, except exposure to DNC, for the purpose of observ-
ing the natural or background rate of cancer in that type of
Dose . Measurement of the amount received by the subject, whether
human or animal.
Dose—response evaluation . A component of risk assessment that
describes the quantitative relationship between the amount of
exposure to a substance and the extent of toxic injury or
Dose—response relationship . The quantitative relationship
between the amount of exposure to a substance and the extent of
toxic injury produced. -
Epidemiological study . Study of human populations to identify
causes of disease. Such studies often compare the health status
of a group of persons who have been exposed to a suspect agent
with that of a comparable unexposed group.
Exposure . To be accessible to the influence of a chemical or
chemical action.
Extrapolation . The estimation of a value beyond the known range
on the basis of certain variables within the known range, from
which the estimated value is assumed to follow.
Gavage . Type of exposure in which a substance is administered to
an animal through a stomach tube.
Hazard evaluation . A component of risk assessment that involves
gathering and evaluating data on the types of health injury or
disease (e.g., cancer) that may be produced by a chemical and on
the conditions of exposure under which injury or disease is

High—to—low—dose extrapolation . The process of predicting low-
exposure risks to rodents from the measured high—exposure,
high—risk data.
Human exposure evaluation . A component of risk assessment that
involves describing the nature and size of the population exposed
to a substance and the magnitude and duration of exposure. The
evaluation could concern past exposures, current exposures, or
anticipated exposures.
Human health risk . The likelihood (or probability) that a given
exposure or series of exposures may have or will damage the
health of individuals experiencing the exposures.
Incidence of tumors . Percentage of animals with tumors.
Interspecies extrapolation model . Model used to extrapolate from
results observed in laboratory animals to humans.
Linearized multistage model . Derivation of the multistage model,
where the data are assumed to be linear at low doses.
Margin of safety (MOS) . Maximum amount of exposure producing no
measurable adverse effect in animals (or studied humans) divided
by the actual amount of human exposure in a population. -
Microgram (JLg) . One-millionth of a gram (1 ,zg = 3.5 x 10—8 oz. =
0.000000035 oz.). -
Milligram (i g) . One-thousandth of a gram (1 mg = 3.5 x i0 oz.
= 0.000035 oz.).
Multistaqe model . Mathematical model based on the multistage
theory of the carcinogenic process, which yields risk estimates
either equal to or less than the one—hit model.
Neoplasm . An abnormal growth of tissue, as a tumor.
No—observed-effect level (NOEL) . Dose level at which no effects
are noted.
One—hit model . Mathematical model based on the biological theory
that a single “hit” of some minimum critical amount of a carcino-
gen at a cellular target——namely DNA-—can initiate an irrevers— -
ible series of events, eventually leading to a tumor.
Potency . Amount of material necessary to produce a given level
of a deleterious effect.

. Parts per billion.
Parts per million.
Risk . Probability of injury, disease, or death under specific
Risk assessment . The scientific activity of evaluating the toxic
properties of a chemical and the conditions of human exposure to
it both to ascertain the likelihood that exposed humans will be
adversely affected, and to characterize the nature of bhe effects
they may experience.
Risk characterization . Final component of risk assessment that
involves integration of the data and analysis involved in hazard
evaluation, dose-response evaluation, and human exposure evalua-
tion to determine the likelihood that humans will experience any
of the various forms of toxicity associated with a substance.
Risk management . Decisions about whether an assessed risk is
sufficiently high to present a public health concern and about
the appropriate means for control of a risk judged to be
Route of exposure . Method by which the chemical is introduced
into the biological organism.
Safe . Condition of exposure under which there is a “practical
certainty” that no harm will result in exposed individuals.
Scientifically plausible . An approach or concept having substan-
tial scientific support but without complete empirical
Statistically significant . The difference in tumor incidence
between the treated and control animals that is probably not due
to chance.
Systemic effects . Effects observed at sites distant from the
entry point of a chemical due to its absorption and distribution
into the body.
Threshold dose . The dose that has to be exceeded to produce a
toxic response.
Total dose . Sum of doses received by all routes of exposure.

Unit cancer risk . Estimate of the lifetime risk caused by each
unit of exposure in the low—exposure region.
Upper—bound estimate . Estimate not likely to be lower than the
true risk.

Appendix A
Predicted Concentration of DNC
in Ground Water at Eastern Property
Boundary and Public Well Field
• Concentration in lagoon: 30 ppm (mg/i)
• Concentration measured at compliance point: 332 ppb
• Half—life of DNC in aquifer: 10 years = 3,650 days
——Degradation rate of DNC = 0.693/half—life
= 1.9 x l0 day 1
Distance from source to property boundary: 1,000 feet
• Travel time (T) from the source to property boundary:
(distance traveled] x (effective porosity]
(hydraulic conductivity] x (hydraulic gradient]
1,000ft x 0.2
= ___________________ = 1,000 days
40 feet/day x 0.005
• Steady-state concentration at property boundary:
(332 ppb] x exp ((—1.9 x day 1 ) x 1,000 days]
= 275 ppo
• Distance from source to public well field:
1.5 miles = 8,000 feet

• Travel time from the source to three threatened wells:
8,000 x 0.2
___________________ = 8,000 days
40 feet/day x 0.005
• Steady—state concentration at the three threatened
[ 332 ppb] x exp ((—1.9 x i0 day 1 ) x 8,000 days]
= 73 ppb
• Steady—state concentration at actual point of exposure
(drinking water supply):
The three threatened wells provide 7.5 percent of total
drinking water supply; therefore, the concentration at
the actual point of exposure (the drinking water
0.075 x 73 ppb = 5.5 ppb
Predicted Concentration of SOLVALL
in Ground Water at Eastern Property
Boundary and Public Well Field
• Source concentration in lagoon: 50 ppm
• Concentration measured at compliance point: 1 ppm
• Half-life of SOLVALL in aquifer: 7.3 years =
2,660 days
-—Degradation rate of SOLVALL = 0.693/Half—life
= 2.61 x i0 day 1
• Travel time from point of compliance to property
boundary = 1,000 days
• Steady—state concentration at property boundary:
(1 ppm] x exp [ (—2.61 x l0 day 1 ) x (1,000 days)]
= 770 ppb

A— 3
• Travel time from point of compliance to three
threatened wells = 8,000 days
• Steady—state concentration at three threatened wells:
(1 ppm] x exp ((—2.61 x i0 day -) (8,000 days)]
= 124 ppb
• Steady—state concentration at public well field
(drinking water supply):
The three threatened wells procride 7.5 percent of
drinking water supply; therefore, the concentration at
the actual point of exposure (in the water supply):
0.075 x 124 ppb = 9.3 ppb

Appendix B
Inhalation of DNC—Contaminated
Air by Neighboring Residents
• An adult inhales 23 m 3 /day of air.
• Based on wind direction analysis, the duration of
exposure is 30 percent of time on an annual average
• The body weight of an adult is 70 kg.
• The inhalation absorption factor for DNC is 0.75.
• The adult lives in the home throughout his lifetime.
0.011 mg
(average DNC air concentration at boundary)
m 3
23m 3 1
x x x 0.3 (human intake factor)
day 70 kg
x 0.75 (inhalation absorption factor) -
= 8.1 x l0 mg/kg/day
Inhalation of DNC—Contaminated
Air by Workers
• An adult inhales 23 m 3 /day of air.
• The body weight of an adult is 70 kg.
• The inhalation absorption factor for DNC is 0.75.

• The duration of exposure is 40 hours/week for a 30—year
work period, or 10.2 percent of an average lifetime.
0.047 mg
(average DNC air concentration on-site)
23m 3 1
x x x 0.10 (human intake factor)
day 70 kg
x 0.75 (inhalation absorption factor)
= 1.2 x mg/kg/day
Inhalation of SOLVALL—Contantinated
Air by Neighboring Residents
• An adult inhales 23 m 3 /day of air.
• Based on wind direction analysis, duration of exposure
is 30 percent of time on an annual average basis.
• The body weight of an adult is 70 kg.
• The inhalation absorption factor for SOLVALL is 0.75.
• The adult lives in the home throughout his lifetime.
0.153 mg
(average DNC air concentration at boundary)
m 3
23m 3 1
x x 0.3 (human intake factor)
x day 70kg
x 0.75 (inhalation absorption factor)
= 1.1 x 10-2 mg/kg/day

Inhalation of SOLVALL—Contazninated
Air by Workers
• An adult inhales 23 m 3 /day of air.
• The body weight of an adult is 70 kg.
• The inhalation absorption factor for SOLVALL is 0.75.
• The duration of exposure to workers is 40 hours/week
for a 30—year work period, equivalent to 10.2 percent
of an average lifetime.
0.7 mg
(average SOLVALL air concentration on—site)
m 3
23m 3 1
x x x 0.102 (human intake factor)
day 70kg
x 0.75 (inhalation absorption factor)
= 1.8 x 1O2 mg/kg/day
Ingestion of DNC-Contaminated
Drinking Water at Eastern
Property Boundary
• An adult consumes 2 liters of water per day.
• The body weight of an adult is 70 kg.
• Absorption is 100 percent.
• The water is consumed throughout the adultts lifetime.

B— 4
0.275 mg
(predicted DNC concentration in ground water
liter at eastern property boundary)
2 liters 1
x x (human intake factyr)
day 70 kg
x 1 (ingestion absorption factor)
= 7.8 x i0 3 mg/kg/day
Ingestion of DNC—Containinated
Drinking Water at Public Well Field
5.5 x i — mg
(predicted DNC concentration in ground
liter water at public well field)
2 liters 1
x x (human intake factor)
day 70 kg
x 1 (ingestion absorption factor)
= 1.6 x mg/kg/day
In estion of DNC—Contaminated
Drinking Water at Point of Compliance
3.32 x 10—1 mg
(measured DNC concentration in ground
liter water at point of compliance)
2 liters 1
x x (human intake factor)
day 70 kg
x 1 (ingestion absorption factor)
= 9.5 x mg/kg/day

Ingestion of SOLVALL-Contaminated
Drinking Water at Eastern
Property Boundary
• An adult consumes 2 liters of water per day.
• The body weight of an adult is 70 kg.
• Absorption is 100 percent.
• The water is consumed throughout the adult’s lifetime.
7.7 x 10—1 mg
______— (predicted SOLVALL concentration in
liter ground water at eastern property
2 liters 1
x x (human intake factor)
day 70 kg
x 1 (ingestion absorption factor)
= 2.2 x 10-2 mg/kg/day
Inyestion of SOLVALL-Contaminat
Drinking Water at Public Well Field
9.3 x 1O mg
(SOtIVALL concentration in ground water
liter at public well field)
2 liters 1
x x _ —__ (human intake factor)
day 70 kg
x 1 (ingestion absorption factor)
= 2.7 x l0 mg/kg/day

Ingestion of SOLVALL—Contaminated
Drinking Water at Point of Compliance
l.OxlO 0 mg
(measured SOLVALL concentration in
liter ground water at point of compliance)
2 liters 1
x x (human intake factor)
day 70 kg
x 1 (ingestion absorption factor)
= 2.9 x 10-2 mg/kg/day