-------
                                                                 Jjft Systems, Jnc.
Table 7-2 - continued
       104.      alpha-BHC
       105.      bata-BHC

       106.      delta-BHC
       107.      ganna-BHC (Lindana)
       108.      Haptachlor
       109.      Aldrin
       110.      Haptachlor apoxlda

       111.      Endosulfan I
       112.      Dieldrin
       113.      4.4'-DDE
       114.      Endrln
       115.      Endosulfan II

       116.      4,4'-DDD
       117.      Endrln aldahyda
       118.      Endosulfan sulfata
       119.      4,4'-DDT
       120.      Endrln katona

       121.      Mathoxychlor
       122.      Chlordana
       123.      Toxaphana
       124.      Ar odor-1016
       125.      Aroclor-1221

       126.      Aroclor-1232
       127.      Aroclor-1242
       128.      Aroclor-1248
       129.      Aroclor-1254
       130.      Aroclor-1260
 Chemical Abstract
Service (CAS) Number

    319-84-6
    319-85-7

    319-86-8
    58-89-9
    76-44-8
    309-00-2
    1024-57-3

    959-98-8
    60-57-1
    72-55-9
    72-20-8
    33213-65-9

    72-54-8
    7421-93-4
    1031-07-8
    50-29-3
    53494-70-5

    72-43-5
    57-74-9
    8001-35-2
    12674-11-2
    11104-28-2

    11141-16-5
    53469-21-9
    12672-29-6
    11097-69-1
    11096-82-5
                                      7-7

-------

                                                                  £ife Systems, JHC.
When sampling is employed to obtain quantitative data on atmospheric
contamination It wist b« recognized that the distribution of a wind-borne
chemical varies over time with down-wind distance from the source.  Therefore,
sampling may have to be conducted over extended time periods and distances.

Air quality data should provide adequate temporal as well as spatial resolu-
tion of air pollutant concentrations.  An air sampling survey designed to
provide good temporal resolution should include samples having a short enough
averaging time to measure the effects resulting from a variety of possible
combinations of source strength and meteorological phenomena.  Obtaining
samples averaged over a short interval requires either continuous sampling or
frequent grab samples and results in a large quantity of data.  Monitoring
long enough to sample all variations of source strength and meteorology may
take as long as one year.  Continuous monitoring for one year usually assures
that samples are taken during each season, on all days, and during all hours.
Such sampling provides the best data describing the temporal distribution of
toxic chemical concentrations.  The cost, however, may be unreasonably high
for maintaining and operating monitoring stations.  There is also a long lag
time between initiation of the monitoring program and receipt of the final
results.  A compromise is often made between the two situations, using the
best available methodology and ensuring that the sampling schedule Includes
the time period expected to yield the highest toxic chemical concentrations.

7.1.2.2   Surface Water/Groundwater Contamination

Runoff and overland flow of toxic chemicals (from leaks, spills, etc.) are the
most likely sources of surface water contamination at hazardous waste sites.
Leaching of toxic chemicals from contaminated soils and the vertical migration
of toxic chemicals from lagoons are the most likely sources of groundwater
contamination at'hazardous waste sites.

Quantitative estimations of the degree of contamination of surface waters are
often derived by the application of mathematical models designed to provide
information on runoff releases and overland flow of toxic chemicals.  These
models require data on the sorptlon partition coefficients for contaminants of
concern (sorptlon partlon coefficients may be derived from octanol-water
partition coefficients).  A model also exists for the rapid estimation of the
extent of groundwater contamination.  This model requires data on various
site-specific and chemical-specific characteristics and provides order-of-
magnitude estimates of groundwater contamination.

Surface and groundwater contamination data may also be obtained via sampling.
As with air quality data, water sampling data should provide adequate temporal
and spatial description of water-borne chemical concentrations.  The variation
of chemical concentrations in groundwater samples will generally be less than
chemical concentrations in surface water.  Of particular concern when dealing
with water samples is the stability (Integrity) of the sample.  Complete
preservation of a sample is nearly impossible since biological, chemical or
physical changes in the sample will usually occur.  However, to the extent
possible, adequate integrity of samples must be maintained.
                                       7-8

-------
                                                                  &fc Systems, JMC.
7.1.2.3   Soil Contamination

Sources of surface soil contamination at hazardous waste sites include spills,
lagoon falluret contaminated runoff or intentional placement of waste on or in
the ground.  Toxic chemicals can also be leached from surface soils to
subsurface layers.  Generally* the substances of concern at uncontrolled
hazardous waste sites are non-polar and will bind (adsorb) strongly to organic
soil particles as a result of their hydrophobic properties.

No modeling methods are currently available to estimate toxic chemical concen-
trations in surface soils and direct sampling must be conducted to obtain data
on surface soil contamination.  Analyses of toxic chemical concentrations in
subsurface soils may be performed by means of modeling, sampling* or a combi-
nation of both.

7.1.2,4   Contamination of Biota

In addition to assessing concentrations of toxic chemicals in air, water and
soils, performance of an exposure assessment requires the collection of data
on the occurrence of toxic chemicals in the tissues of plants and animals that
may be consumed as food by other organisms.  Of special concern are organisms
(such as fish or shellfish) which are consumed by humans.  The quality of
results in assessing toxic chemical concentrations in food depends entirely on
the method of sampling and sample preparation.  Since even processed foods are
not homogeneous in quality, the design, sampling and interpretation of the
results requires extra care due to possible interactions between chemical,
food and nutrients.  Important factors that must be considered in the sampling
and analysis of biota include both the characteristics of the chemical of
concern and the food of concern.  Significant characteristics of chemicals-
include the physical/chemical properties and sources of release.  The food
characteristics that are important include the potential for contamination,
consumption data (regional patterns) and dynamics of food consumption.

7.1.2.5   Data Validation and Interpretation

In the collection of occurrence data for use in an exposure assessment, the
first task is to obtain relevant data that are complete, accurate and repre-
sentative of the actual situation and conditions.  The measurements should be
comparable and maintained in consistent units.  After collection of data,  the
next task is to verify and validate the data values.  This Involves removing
erroneous and irrelevant measurements, testing for outliers (extremely high or
low values) and testing data for accuracy, precision and representativeness.
A detailed explanation should be given to justify the removal or inclusion of
questionable data values in the final data set.  A decision must be made on
how to handle values below the detection limit or data reported with negative
values.  The final task is to perform statistical tests which will allow for
Interpretation of the data.  Since the statistical methods employed are
usually based on the assumption of the normality of the data values, appro-
priate tests should be performed and transformations (such as logarithmic)
should be used if needed.  The accuracy and precision of the estimates should
be reported in the form of standard deviation, coefficient of variation and
confidence limits.
                                       7-9

-------

                                                                  £ifc Systems, JKC.
7.1.2.6   Collection of Occurrence Data—A Hypothetical Example

In order to illustrate the nature of the data required In evaluating the
occurrence of a toxic chemical in the environment, the following  hypothetical
example is presented.

Prior to initiating an enforcement action at a hazardous waste site  pursuant
to Section 106 of CERCLA, an endangerment assessment is required.  One  of  the
first steps performed in preparing the endangerment assessment is an evalua-
tion of the history of the site.  In evaluating the history of a  particular
site it is determined that the waste present In the largest quantity is
1,1,2,2-tetrachloroethylane (perchloroethylene).

Results of the site history analysis Indicate that the perchloroethylene was
disposed of in steel drums buried in deep, unlined pits.  The site is located
several thousand feet from a reservoir which is a popular fishing location and
which also serve's as the drinking water supply for several nearby towns.
Available toxicological information on perchloroethylene indicates that this
compound is mutagenic, carcinogenic and hepatotoxic.  There is, therefore,  a
high level of concern regarding the presence of this chemical at  the site.   A
review of data on the physical and chemical characteristics of perchloro-
ethylene reveals that the chemical is expected to be mobile in groundwater
and, therefore, could be expected to migrate to the reservoir if  released  from
the buried drums.  A sampling plan, is subsequently devised to obtain data on
concentrations of perchloroethylene in the groundwater between the site and
the reservoir, and in the reservoir itself.  Sampling is also scheduled for
game fish species present in the reservoir because of the potential  for human
exposure through ingestion of contaminated fish.  Air sampling is not Included
in the initial sampling plan since the depth of burial of the waste-filled
drums reduces concern for volatilized emissions.  Similarly, soil sampling is
not scheduled because of the depth of waste location and because  no  human
exposure through contact with potentially contaminated soils is expected due
to the nature of the site (on relatively inaccessible private property  and
fenced in).

When sampling is concluded and valid occurrence data for perchloroethylene are
available, the data can be used to calculate predicted human exposure levels
for the two expected exposure routes (drinking water and ingestlon of
contaminated biota).

7.1.3     Legal Requirements

•It is not always possible to know in advance whether or not monitoring  data in
general, and exposure monitoring data in particular, may be used  in  enforce-
ment actions.  Therefore, it is good practice to make the assumption, when
collecting monitoring data, that the data may be used in enforcement actions.
Accordingly, there are certain policies and procedures which should  be
followed in order to ensure that the collected monitoring data will  be  accept-
able as evidence in a court of law.  The purpose of this section  is  to  present
a brief summary of some of the more important factors which must  be  taken  into
consideration so that monitoring data may be acceptable for use in enforcement
cases.  For more detailed information on this topic, the reader is referred to
the list of publications at the end of this chapter.


                                      7-10

-------
                                                                 &fc Systems, Jnc.
Prior to th« collection and analysis of samples, a draft sampling/analysis
plan should b« prepared and circulated to appropriate technical and legal
personnel for review and comment.  The final sampling/analysis plan should
then formally Incorporate or rebut all contents received.  The final plan
should also detail the sampling project's objectives, survey methods,
personnel and equipment requirements, safety program and equipment, custody
procedures, quality assurance procedures and report schedules.

Once samples have been collected they should be appropriately marked with tags
and maintained under Chain-of-Custody procedures.  Possession of all samples
must be traceable from the time they are collected until they are introduced
as evidence in legal proceedings.  Samples are accompanied by a Chain-of-
Custody Record, and all transfers between individuals must be documented by
signatures and records of the dates and times of transfer.  Samples are
shipped (if by mail, registered with return receipt requested) to an appro-
priate laboratory for analysis, with a separate custody record identifying the
sample contents accompanying each shipment.

At the receiving laboratory, a designated sample custodian accepts custody of
the samples and verifies that the information on the sample tags matches that
on the Chain-of-Custody Record.  After assigning a unique laboratory
identification number to each sample tag, the sample custodian enters the
sample tag data into a bound logbook arranged by project code and station
number.  The sample custodian then distributes samples to appropriate analysts
who also maintain a record to show the Chain-of-Custody for each sample or
sample aliquot.  All laboratory observations and calculations relevant to a
sample are recorded by the analysts in serialized logbooks.  The logbooks must
contain information sufficient to allow the analysts to recall and describe
succinctly each step of the analyses performed.  Moreover, sufficient detail
is necessary to enable others to reconstruct the procedures followed should
the original analyst be unavailable for testimony.  Any irregularities
observed during the analytical process need to be noted.

After an organization has completed its work for a particular project, all
documents generated should be assembled in the organization's files.  The file
then becomes accountable.  Any records taken from the file must be signed out.

Using proper Chaln-of-Custody procedures, data obtained from the analyses of
samples are returned to the Sampling/Analysis Project Leader for use in the
preparation of a draft project report.  In preparing reports, the ability to
substantiate and defend the contents is of foremost Importance.  All draft
reports should be dated and numbered and be accountable.  All draft copies of
the report must be returned to the Sampling/Analysis Project Leader after
review.  Once comments have been incorporated and the final report is avail-
able, all draft copies should be disposed of properly.

The following is a list of documents which provide more detailed information
on the procedures which should be followed to ensure that sampling data will
be acceptable as evidence in a court of law.
                                      7-11

-------
                                                                 &fe Systems, JHC.
     1.   The EPA1 a "Handbook for Analytical Quality Control in Water and
          Wastewater Laboratories" (Booth 1979) addresses In datall the
          following areaa:  laboratory facilities* instruaents, glassware
          requirements, and reagents.  It further deals with analytical
          performance* data handling* and data reporting.  Separate chapters
          are devoted to the special requirements for trace organic analysis,
          water and wastewater sampling, microbiology* aquatic biology* and
          safety.

     2.   The "Quality Assurance Guidelines for Biological Testing" (Stanley
          1978) discusses the following elements of quality assurance: quality
          assurance policy and objectives* design and analysis of experiments*
          sampling, precision and assurance of tests, physical environment of
          research, chemicals and reagents, control of performance* and data
          handling and reporting.

     3.   The "Handbook for Sampling and Preservation of Water and Wastewater"
          (Berg 1982) is not an official EPA manual* but is a reference to be
          used as an input to EPA manuals and guidelines.  The report presents
          general considerations for sampling; sample preservation and hand-
          ling methods, sampling methods for wastewaters, surface waters, and
          bottom sediments; methods for collection of microblal samples, and
          statistical analysis methods.

     4.   The "Quality Assurance Guidelines for IERL-C1 Project Officers"
          (Stratton and Bonds 1979) is designed for use, as the title Implies,
          by EPA project officers.  The report provides quality assurance
          guidelines for procurement of projects requiring sampling and
          analysis, guidelines for monitoring such projects and auditing
          procedures.  The document should assist in providing an
          understanding of what EPA project officers expect in terms of
          quality assurance.

     5.   Another source of EPA quality assurance procedures is the "Manual of
          Analytical Quality Control for Pesticides and Related Compounds in
          Human and Environmental Samples" (Sherma 1977).  A general
          description of pesticide residue analytical procedures is provided
          following a discussion on inter- and intra-laboratory quality
          control.  Also covered are procedures for analysis of samples
          including extraction, Isolation, and gas chromatography. Although
          the manual deals primarily with pesticides, many of the procedures
          and recommendations apply to the analysis of any organic chemical.

7.2       Identification and Analysis of Exposed Populations

The identification and analysis of exposed human populations generally
involves four distinct steps, each of which requires unique information.  In
the first step, population data are compared with occurrence data in order to
quantify the population that will actually or potentially come into contact
with contaminated air, water, soil or food.  The second step, population
characterization, involves determining whether any groups within the exposed
population may experience a greater risk than the average population as a
                                      7-12

-------
                                                                  &fe Systems, Jnc.
result of exposure.  High risk groups might include women  of  childbearing age,
the chronically ill, infants* children or the elderly.  The third  step*
activity analysis, involves an examination of the activities  in which a
potentially or actually exposed population engages.  The final  step,
development of exposure coefficients, yields information critical  to  the
calculation of exposure levels.  Each of these steps is discussed  in  further
detail below.  The analysis of nonhuman populations is also discussed.

7.2.1     Population Identification and Enumeration

The first step in identifying and analyzing exposed populations is to
determine the number of individuals exposed and the routes of exposure.    For
humans, the Census of Population (most recently conducted  in  1980)  can be
accessed to determine the size, distribution and demographic  characteristics
of a geographically defined population.  Census data are especially useful in
quantifying populations exposed as a result of their presence in a specific
locale (e.g., those exposed to toxic chemicals in ambient  air or. soil).   For
example, identification/enumeration of populations exposed to airborne
toxic chemicals may be accomplished by overlaying an laopleth map  of
chemical concentrations around a source on census maps.

In the analysis of populations that may be exposed to chemicals present in
surface or groundwater, all persons in the service area of a  water  supply
system that draw water from a contaminated source must be  considered  as
potentially exposed through ingestion and dermal exposure  while bathing.
Information concerning local drinking water sources and populations served can
usually be obtained from the local Department of Public Works,  Planning
Department or Health Department.  Information on public departments or private
drinking water treatment companies that use groundwater as their raw  water
supply, as well as the number of households drawing water  from  private wells,
will also generally be available from these sources.  Swimmers  in contaminated
waters may also comprise a portion of the exposed population.

Dermal exposure to contaminated soils could constitute an  exposure  route  for
individuals who work outdoors or for children playing outdoors.  In addition,
children sometimes Ingest toxic chemicals contained in soil through pica
behavior (eating soil).  Direct soil exposure is, in most  cases, minor in
magnitude when compared to other routes, and it Is often difficult  to quantify
the actual level of transmission of soil-absorbed toxic chemicals across  skin.
Exposure to airborne contaminated soil particulates and substances
volatilizing from soil may, however, be quite significant,  and must be
considered as an Integral component of the overall site air contamination/
exposure analysis.

Human exposure to contaminated food will usually be associated with fruit and
vegetables grown in home gardens, or with fish or game residing in
contaminated areas.

7.2.2     Population Characterization

After exposed populations have been identified and enumerated, they should be
characterized by age and sex factors since the physiological parameters that
determine dose (e.g., breathing rate, skin surface area,  food and  water
                                      7-13

-------
                                                                  tifc Systems, JHC.
ingestion) are often age- or sex-specific.  Also, from a toxicity standpoint,
subpopulations defined by age or sex may be especially susceptible to toxic
chemicals.  Thus, characterization of exposed populations permits the
determination of exposure distributions within the population at large, and
the delineation of specific high-risk subpopulations.

7.2.3     Activity Analysis

Activities engaged in by members of a given population or subpopulation can
dramatically affect the level of exposure to environmental chemicals.  For
example, persons whose .lifestyle or employment involves frequent strenuous
activity will ventilate larger volumes of air per unit time than will those
living a less strenuous life and will, therefore, experience a greater level
of exposure to airborne chemicals.  Another example would be if activities
take persons away from the source of the exposure such as weekends in the
country.  Also seasonal factors can affect exposure levels, e.g., dermal
contact with contaminated soil is considerably reduced during freezing
weather.

Key activity-related exposure determinants to be quantified in the activity
analysis phase for each exposure mechanism are:

     e Ingestion:        amount of contaminated food or water ingested
                         (per unit time).
     e Inhalation:       length of time (frequency and duration) spent in each
                         related activity; nature of the activity in terms of
                         light, medium, heavy, or maximum exertion (per unit time)
     e Dermal exposure:  length of time (frequency and duration) spent in
                         each related activity (per unit time).

7.2.A     Development of Exposure Coefficients

The final component of the identification and analysis of exposed human
populations is the development of exposure coefficients.  An exposure coeffi-
cient is a term which combines information on the frequency, mode and magni-
tude of contact with each contaminated medium to yield a quantitative value of
the amount of contaminated medium contacted per day.  Exposure coefficients
are developed for each exposure route and are used in calculating exposure
levels.  Developing an exposure coefficient requires that certain assumptions
be made regarding intake of air, food and water.  Some standard intake
assumptions are provided in Table 7-3.

7.2.5     Nonhuman Population Analyses

Nonhuman populations are generally more difficult to quantify and characterize
than are human populations because less Information is available and the data
that are available are often measured in units other than numbers of
organisms.  Populations may, for example, be expressed as herds or biomass.
The adequacy and sources of nonhuman population data vary considerably,
depending on the organism.  As might be expected, most research effort has
been invested in plant and animals species that have economic significance.
                                       7-14

-------
                                                                 &fe Systems, Jnc.
               TABLE 7-3  STANDARD INTAKE ASSUMPTIONS FOR HUMANS


                  . v           Adult        Adult          Child
  Respiratory Rate^ '           Male         Female        (10 yrs)

Resting (L/mln)                 7.5            7.0           4.8
Light Activity (L/mln)         20.0           19.0          13.0

Fluid Intake
Milk (L/day)                    0.30           0.20          0.45
Tap Water (L/day)               0.15           0.10          0.20
Other (L/day )( .                1.50           1.10          0.75
Total (L/day) lc;                1.95           1.40          1.40


Food Consumption           1,500 g/day          —            —
(a) Adapted from Callahan et al. (1983)
(b) Adapted from International Commission on Radiological Protection (IRCP)
    (1975).
(c) EPA usually uses 2 L/day as total fluid consumption for adults and 1  L/day
    for children.
                                     7-15

-------
                                                                 JCife Systems, JHC.
In most cases, it is necessary to gather the data from diverse sources to
enumerate nonhuman populations.  The major sources of data Include journal
articles and other publications, Federal and state agencies, and selected
private agencies.  When data from these sources are not available, field
surveys may be required.

7.3       Calculation of Exposure

Calculation of doses of contaminants incurred by exposed populations is
accomplished by integrating the results of the collection of chemical
occurrence data (described in section 7.1) with the results of exposed
population analyses (described in section 7.2).

To calculate the dose incurred, the concentration of the chemical in an
environmental medium is first multiplied by the appropriate exposure
coefficient.  This calculation provides an estimate of the total amount of
each chemical to which the population is exposed on a daily basis.  However,
this value must be adjusted to account for the extent to which each chemical
Is transferred across the membranes of the exposed organism (i.e., the extent
of absorption).  This adjustment is accomplished by multiplying total daily
exposure values by an absorption factor.  Usually, absorption factors cited in
the toxicological literature are employed in this calculation.  When empiri-
cally derived absorption factors are not available, an absorption factor of
unity is applied, thereby generating a conservative (worst-case) estimate of
the dose incurred.  Finally, this whole-body dose estimate (mg/day) is
converted to terms of mg of contaminant/kg of body mass/day by dividing it by
the body mass representative of the receptor population.

Sample Calculation

The following hypothetical example illustrates the procedure for calculation
of dose incurred:

A factory is located near a toxic dump site which has improperly disposed of
large quantities of carbon tetrachloride (CC1,).  The factory draws water for
drinking and industrial uses from a well whicn Is found to contain 1.6 mg/L of
CC1,, and average air concentrations are 0.1 ppm (0.63 mg/m ).  The factory
employs adult males who work 8-hour shifts doing light physical labor.

Calculation of Exposure Coefficient:

Since the adult males spend about one-half of their waking hours In the
factory, the amount of water they consume may be estimated to be one-half of
average total water consumption for adults (2 L/day/2 » 1 L/day).  The
Inhalation exposure coefficient is calculated as follows:

                (20 L/min) (60 min/hr) (8 hr/day) - 9,600 L/day

Converting to more convenient units, this becomes:

                    (9,600 L/day) (10~3 m3/L) - 9.6 m3/day
                                      7-16

-------
                                                                   Jjfe Systems, JHC.
Absorption Coefficients:

Inspection of published toxicokinetic information on CC1, reveals  that
gastrointestinal absorption is about 90Z and absorption in the lung is  about
30Z, so the absorption coefficients are 0.90 and 0.30, respectively.

Dose Calculation:

     A.   Daily Dose via Water - (Exposure Coefficient) (Water Concentration)
                               - (1 L/day)(1.6 mg/L)
                               • 1.6 ing /day

          Daily Dose via Air • (Exposure Coefficient) (Air Concentration)
                             - (9.6 nT /day) (0.63 tag/nT)
                             • 6.0 mg/day

     B.   Absorbed Dose - (Daily Dose) (Absorption Coefficient)
                    For Water:  (1.6 mg/day) (0.90) - 1.4 mg/day
                      For Air:  (6.0 mg/day) (0.30) - 1.8 mg/day
          Total Absorbed Dose:  1.4 mg/day +1.8 mg/day "3.2 mg/day

     C.   Conversion to mg/kg basis for adult (70 kg):
It is Important in all caculations of exposure levels that assumptions
regarding body weight, water and air intake, food consumption, etc., be
clearly identified as such, to distinguish assumed average values from actual
measured values.

7.4       Estimation of Past Exposure

In some instances, it may be desirable to obtain estimates of past exposure
levels to certain chemicals.  This can sometimes be accomplished by measuring
the concentration of the chemical in body fluids or tissues of exposed
organisms .

Following the absorption of a chemical by a particular organism, the
chemical distributes throughout the organism and may accumulate in various
parts of the organism.  The site of accumulation may or may not be the major
site of toxic action.  When a chemical accumulates at a site other than the
site at which it produces toxic action, the site of accumulation may be
referred to as a "storage site."  The accumulation in this storage site may
serve as a protective mechanism, whereby the concentration of the chemical in
the storage site keeps the concentration of the chemical in a vulnerable organ
at a low level.  However, the concentration of the chemical in the storage
site is in equilibrium with the chemical in blood, and therefore it is slowly
released into the circulation at a rate equal to the rate at which the
chemical is excreted or removed from the blood.  This tends to maintain the
chemical in the blood for long periods of time.  Some of the major storage
areas for chemicals include plasma proteins, liver, kidney, fat and bone.
                                      7-17

-------
                                                                  £ife Systems, Jnc.
Therefore* measurements of toxic chemical concentrations In these storage
areas are the most useful In terms of estimating past exposure levels.

It should be noted that this means of estimating past exposure levels has a
major limitation.  Not all chemicals accumulate to the same extent.  There-
fore* estimation of past exposure levels by measuring accumulated chemical
concentrations is useful only for those chemicals that tend to accumulate.
This method provides no useful information on past exposure to chemicals that
are efficiently cleared from the body.

7.5       Prediction of Future Exposure

In order to predict future exposure scenarios* it is necessary to generate
estimates of the direction of travel and future ambient concentrations of
toxic chemicals within all environmental media.  Some Important physical /chemi-
cal properties of chemicals that may influence their environmental fate are
presented in Table 7-4.  Some important site characteristics that may influ-
ence environmental fate are presented in Table 7-5.  Whenever mathematical
models are employed to calculate expected future exposures* it is Important to
identify calculated values as such (to avoid confusion with measured values)
and to cite the model employed*  Population predictions* such as future popu-
lation characteristics and distribution patterns, are also necessary so that
they can be compared with future chemical distribution/concentration data In
order to predict future exposure scenarios.
                                                     »
7.5.1     Environmental Stability

In analyses of the environmental fate of chemicals* all processes that are
likely to lead to transformation of chemicals In various environmental media
must be identified.  In conducting environmental fate analyses* each
transformation process is assessed and* when possible* rates of all processes
are quantified.  Usually, information regarding the significance and rates of
transformation processes in various media is available In the technical
literature.  Some transformation processes likely to be important in assessing
the fate of chemicals are described below.

Photolysis is the degradation of a chemical caused by exposure to light.  This
process may be important to chemicals in the atmosphere, in surface water of
sufficient clarity for penetration of light* and on the surface of the soil.
Photolysis typically results in the degradation of chemicals through rupture
of covalent bonds.  Factors determining the rate of photolysis include:  flux
of photons to the substrate media* chemical-specific light adsorption
coefficients* and reactor yield constants (i.e., the efficiency of the
degradation process with available photon energy) .

Examples of photolysis include the splitting of hydrogen iodide by the
reaction:

                            2HI
and the splitting of ketene  (CH.CO) into carbon monoxide (CO) and carbene
(methylene)  (CH2) .
                                      7-18

-------
                                                  &fe Systems. JHC.
TABLE 7-4  PHYSICAL AND CHEMICAL PROPERTIES  THAT
        MAT INFLUENCE ENVIRONMENTAL FATE
        Adsorption Coefficient

        Blodegradation Rate

        Boiling Point

        .Henry's Law Constant

        Hydrolysis Rate

        Melting Point

        Molecular Weight

        Octanol/Water Partition Coefficient

        Photolysis Rate

        Vapor Pressure

        Volatilization Rate

        Water Solubility
                      7-19

-------
                                                   ttfe Systems, Jnc.
TABLE 7-5  SITE CHARACTERISTICS THAT HAT INFLUENCE
                ENVIRONMENTAL FATE
         Ambient Moisture

         Ambient Humidity Levels

        .Ambient Temperatures

         Ambient Wind Velocity and Direction

         Geologic Characteristics

         Hydrologic Characteristics

         Soil Characteristics

         Topographic Features of Site and Surrounding Area

         Vegetative Cover of Site and Surrounding Area

         Watershed/Land Use Characteristics
                       7-20

-------
                                                                  £ife Systems, Jnc.
Indirect photolysis is an  important  transformation process  for many chemicals.
This process involves intermediate compounds present  in the environmental
medium which undergo direct photolytic transformation and thereby become
reactive with a toxic chemical  (usually as a strong oxidizer).  These
intermediates subsequently react with a chemical,  effecting its  trans-
formation.  Indirect photolysis rates are governed by the concentration and
light adsorption coefficient of the  intermediate compound and the rate of its
subsequent reaction with the toxic chemical.

Oxidation is the process of removing electrons from a chemical.   These are
accepted by another chemical (an oxidizing agent) .  Chlorine in  drinking water
and ozone in the atmosphere are two  important oxidizing agents.   Oxidation by
oxygen is also important*  and occurs in .air, surface  water,  groundwater and
soil.  The rate of oxidation is determined by the  concentration  of the
oxidizing agent, and its reaction rate constant with  respect to  the chemical.

For example, cupric ion* is the  oxidizing agent in  the following  reaction:

                             Fe + Cu2"1" * Fe2+ + Cu

Here, two electrons are transferred  from the Fe atom  to the  Cu atom.   Thus,
the Fe atom is oxidized (becomes positively charged by the  loss  of two
electrons) while the Cu atom receives the two electrons and  becomes neutral
(is reduced) .

Hydrolysis is the splitting of  a chemical bond by  insertion  of water.
Hydrolysis may occur in the air, surface water, groundwater  or soil.
Hydrolysis is most important for organic chemicals which contain as part of
their structure one or more easily polarized, electronegative  groups
covalently bonded to carbon atoms.   Covalent inorganic chemical  compounds  also
undergo hydrolytic transformation, usually at rapid rates.   Hydrolysis is
highly pH-dependent , and can be acid- or base-catalyzed.

The hydrolysis of an organic cyanide (nitrile) is shown below  as  an example of
this type of reaction:

                                 2HO
                           RC2N - ~> RCO H + NH,
Chemical Speciation.  Metallic chemical compounds undergo a wide range of
transformation processes, forming and breaking down complexes with inorganic
or organic Uganda present in the substrate medium.  These processes, referred
to collectively as speciation, can occur in all environmental media.  The
final speciation of a metal in a given environment (i.e., its degree of
association with various complexing agents) affects its bioavailability,
solubility, volatility and sorption properties.  For example, lead chloride
(PbCl ) is a fairly soluble form of lead (Pb  ) , and could easily dissolve in
grounawater and escape from a toxic dump site.  However, if the soil were rich
in carbonates (CO ~ ) , the lead would form lead carbonate (PbCO.) , which is
much less soluble!

                         PbCl2 + C032" + PbC03 + 2Cl"


                                      7-21

-------
                                                                   Jttfe Systems, JHC.
Bioconcentration and blotransformation are processes mediated by organisms.
Bloconcentration is the uptake and accumulation of a chemical within the
tissue of exposed organisms (fish, plants* birds, etc.), often within specific
tissues or organs.  Bioconcentration rates are a function of the uptake and
excretion rates of the exposed organisms and the lipophilic properties of the
chemical.  Biotransformation is a collective term for the various reactions
that occur as a result of metabolism by organisms such as soil bacteria.
Biotransformation commonly causes the degradation and detoxification of toxic
organic chemicals.  Both bioconcentration and blotransformation are dependent
on the metabolic rates of the organisms which, in turn, are functions of
various environmental parameters, including the availability of nutrients,
sunlight, moisture, ambient temperature, and pH.  These transformation
processes occur in the water, soil, groundwater and, to a limited extent, in
the air.

An example of a biodegradation pathway is illustrated by the microbial
degradation of the insecticide parathion.  In this pathway, Pseudomonas
stutzeri initially converts parathion to p-nitrophenol which is subsequently
utilized by Pseudomonas acruginosa.

          P_. stutzeri               P_. aeruginosa
Parathion —	> p-Nitrophenol —	> Further Degradation Products

Table 7-6 presents some information on the environmental stability
(persistence) of selected chemicals from Table 7-2.

7.5.2     Environmental Mobility

The movement of chemicals in the environment is determined by the physical and
chemical properties of the chemicals themselves and by the characteristics of
the environment.  Chemicals may move both within media (intramedia transport)
and from one environmental medium to another (intermedia transport).

7.5.2.1   Intramedia Transport

Atmospheric transport of chemicals is governed by diffusion and by
meteorological variables such as air currents (wind speed and direction),
humidity, particulate concentrations and air temperature differentials.  The
size of the particle to which a toxic chemical is adsorbed is an important
determinant of the extent to which it will be transported through the
atmosphere.

In water, diffusion through the water and currents within the water are the
principal routes of transport.  Aquatic transport processes are, therefore,
dependent on whether the water body is a lake, slow river, swift stream,
estuary or ocean.  For example, tidal movement is the overriding transport
mechanism within an estuary, while thermal stratification may control movement
within a deep lake or reservoir.

Chemicals are transported within soil principally by water flow.  Aside from
the rate of water flow, the key parameter is the interaction (sorption and
                                       7-22

-------
                                                                  &{e Systems, Jnc.
            TABLE 7-6  ENVIRONMENTAL PERSISTENCE OF SOME COMPOUNDS
                    THAT MAT OCCUR AT HAZARDOUS WASTE SITES
        Chemical
Volatiles;

Vinyl chloride

Chloroform


1,1,1-Trichloroethane



Carbon tetrachloride

Dibromochloromethane

Bromoform

Chlorobenzene

Semi-Volatiles;

bis(2-Chloroethyl) ether

2-Chloropheno1

2,4-DlmethyIphenoL


2,4-Dichlorophenol

Hexachlorocylcopentadiene

2,4,6-Trichlorophenol

2-Chloronaphthalene

2,4-Dinitrophenol


2,6-Dinltrotoluene

Benzidine
       Environmental  Persistence
Half  life: 25 minutes

Half  life in bluegill:  1 day
Half  life in water:  15  months

Hydrolysis half life:
  freshwater: 5-9 months
  marine    : 39 months

Half  life in bluegill:  1 day

Half  life projection: 274 years

Hydrolysis half life: 686 years

Half  life in water:  5.8 hours
Half life in bluegill: 4-7 days

Half life in bluegill: 1 day

Complete biodegradation: 2 months
Half life: less than 1 day

Half life in aerated water: 8-9 days

Half life: 11 days

Half life in rat blood: 20 hours

Biomagnifled in water

No significant microbial degradation
  In 64 days

Greater than 64 days

Half life in dogs and rats: 68-88 hours


                    continued-
                                      7-23

-------
                                                                 tife Systems, Jnc.
Table 7-6 - continued





        Chemical



Semi-Volatilea (continued):



3,3*-Dichlorobenzidine



Pesticides;



Dieldrin



Chlordane
                                              Environmental Persistence
                                       Long life in soil







                                       Half life in water: 723 days



                                       Very persistent
Adapted from McNeils et  al.  (1984)
                                     7-24

-------
                                                                  Jtife Systems, Jnc.
desorption) of the chemical with soil particles.  Sorption is controlled by
the characteristics of the chemical and by the type  (i.e., organic content) of
the soil.  Site-specific information on soil composition should be used
whenever possible to characterize soil transport when disposal sites or other
areas of soil contamination are identified by location.

7.5.2.2   Intermedia Transport

The physical and chemical properties of a particular chemical typically have
the greatest Impact on intermedia transport.  Transport from air to water is
dominated by two process: (1) scavenging via liquid deposition (rain, snow),
and (2) gravitational settling (dry deposition).  Transport from water to air
is mediated by air-stripping, aerosol formation and volatilization.  Air-
stripping and aerosol formation are most Important under agitated conditions.
The importance of volatilization for a chemical can be evaluated by assessing
the chemical's solubility in water, vapor pressure, Henry's Law Constant,
molecular weight and activity coefficient.

Transport from ground to air may also occur through volatilization from soil.
Volatilization of organic chemicals from soil is strongly influenced by
sorption phenomena and local frequency of precipitation.  Volatilization from
soil may also be influenced by seasonal differences in air and ground tem-
peratures; volatility from soil is enhanced when the land is warmer than sur-
rounding air.  The other major ground-to-air transport process, resuspension
of dusts, also is affected by precipitation as well as by wind speed.
Chemicals are transported from air to ground by dry and wet deposition.

Transport between water and land is, to a large extent, controlled by the
solubility and leachability of a chemical and the affinity of the chemical for
the organic content of soil and sediment.  Soil particles upon which
chemicals are sorbed are washed into water bodies by surf-ace runoff; once the
chemical is in the water, equilibrium partitioning between water and suspended
solids is established.

7.5.3     Environmental Partitioning

Partitioning refers to the relative distribution of a chemical among environ-
mental compartments.  Partitioning analysis is essentially a qualitative
effort that is undertaken when the time or financial resources do not allow
for a detailed analysis of the environmental transport and transformation of a
chemical.  A partitioning analysis may be based on examination of a
chemical's physical and chemical properties, analogy with other chemicals
whose fate is fairly well documented or mathematical modeling.

Examination of a chemical's physical and chemical properties can often permit
an estimate of its environmental partitioning.  The following are the most
useful parameters for estimating the relative partitioning of a chemical:

     e  Vapor pressure is indicative of a chemical's ability to volatilize to
        the atmosphere.
                                      7-25

-------
                                                                   £ifc Systems, Jnc.
     •  Water solubility of a chemical is indicative of its ability to be dis-
        tributed by the hydrologic cycle.  Water solubility also affects other
        degradation pathways (e.g., photolysis, hydrolysis, oxidation) and
        specialized transport pathways (e.g., volatilization from solution and
        washout from the atmosphere by rain).

     e  Octanol/water partition coefficient (K  ) is indicative of a chemical's
        tendency to partition itself between an organic phase (e.g., fish,
        soil) and an aqueous phase.  It is particularly important for esti-
        mating bioconcentration factors for aquatic life.

     e  Boiling point, in addition to serving as an indicator of the physical
        state of a chemical, provides an indication of its volatility.

     •  Henry's Law Constant is indicative of an organic chemical's tendency
        to volatilize from water to air.

     •  Adsorption coefficient (K  ) is indicative of the extent to which a
        chemical partitions between solid and solution phases (e.g., water-
        saturated or unsaturated soil, runoff water, and sediment).
        Adsorption potential to soil/sediment is indicative of a chemical's
        environmental mobility.

Qualitative analysis of the fate of a chemical can also be made by analogy
with other chemicals whose fate is well documented.  If the chemical under
study is structurally similar to a*previously studied chemical, some parallel
can be drawn to the environmental fate of the analogue.

A more detailed mathematical modeling analysis of partitioning may also be
undertaken when resources permit and where environmental loadings (i.e.,
emission) data are available.

7.5.4.    Population Predictions

As noted in section 7.2, performing an exposure assessment requires a
characterization of exposed populations (number, age, sex, race, activities,
etc.).  Generally, predictions regarding future exposure scenarios require the
same types of information on exposed populations as assessments of present
exposures.  That is, potentially exposed populations must be identified, enum-
erated and characterized, an activities analysis must be performed and
exposure coefficients must be estimated.  (Section 7.2 of this handbook
provides descriptions of these aspects of exposed population analyses.)  Based
on this Information, predictions regarding future exposure levels can be made.

7.6       Key Guidance and Implementation Documents

In 1984, the EPA proposed guidelines for use in conducting exposure
assessments (49 FR 46304).  These guidelines, which will be revised by EPA as
necessary to reflect the benefit of experience, provide a general approach and
framework for carrying out exposure assessments for specified pollutants.  In
some cases these guidelines may be useful only as a rough template; in other
cases -they may serve as a model which can be closely followed.
                                      7-26

-------
                                                                  &fe Systems, Jnc.
According to the guidelines, the five major topics to be addressed in most
exposure assessments include:

        sources
        exposure pathways
        monitored or estimated concentration levels and duration
        exposed population(s)
        integrated exposure analysis

These five topics are appropriate for exposure assessments, whether the
assessments are of a global, national, regional, local, site-specific or
workplace-related nature.  The topics are also appropriate for exposure
assessments on new or existing chemicals and radionuclides.  They are also
applicable to both single media and multimedia assessments.

In general, the guidelines should be followed, to the extent possible, when an
exposure assessment is conducted as a required element in a regulatory process
or when an exposure assessment is conducted on a  discretionary basis to
support regulatory or programmatic decisions.  Application of these guidelines
to the conduct of exposure assessments results in a number of advantages
including the following:

     1.   While there will usually be gaps in the data required to perform an
          exposure assessment, the use of the guidelines should help avoid
          inadvertent errors of omission.

     2.   Use of the guidelines should promote consistency among various
          exposure assessment activities.  For example, use of the guidelines
          should result in consistency with respect to common physical,
          chemical and biological parameters and with respect to assumptions
          about typical exposure situations.  Consistent presentation of the
          possible range estimates will enhance the comparability of results
          and allow for improvement of exposure assessment procedures through
          the sharing of common data and experiences.

     3.   The primary objective of most exposure assessments is to provide
          reliable data and/or estimates for subsequent use in conducting a
          risk assessment.   The guidelines provide a common approach to
          format which simplifies the process of reading and evaluating
          exposure assessments, thereby facilitating the integration of the
          exposure and hazard assessments.

In addition to EPA's proposed exposure assessment guidelines, a number of
other documents provide valuable information regarding the performance of
exposure assessments.  These documents are listed below.
                                         i
     1.   Superfund Exposure Assessment Manual (Versar 1984)—This document
          presents an integrated methodology designed to guide the execution
          of the major components of qualitative and quantitative exposure
          assessments for hazardous waste sites.
                                      7-27

-------
                           &{c Systems, JHC.
     2.   Exposure Assessment Methodologies for Hazardous Waste Sites (McNeils
          et al. 1984)—This document presents a uniform approach to the
          estimation of exposures to important receptors from defined
          hazardous waste constituents via all Important exposure pathways.
          The efficient use of available or historical Information and the
          need for exploratory programs is emphasized.  Applicable theoretical
          and empirical models which are accessible are described in
          sufficient detail to facilitate decisions regarding their use in
          designing and conducting an exposure assessment program.

     3.   Remedial Investigations Guidance Document (JRB 1984)—This document
          provides a detailed structure for field studies involving data
          collection for remediation decisions pertaining to hazardous waste
          sites.

7.7       Background References

Anderson E, Browne N, Duletsky S, Warn T.  1984.  GCA Corporation.
Development of statistical distributions or ranges of standard factors used in
exposure assessments.  Revised draft final report.  Washington, DC:  U.S.
Environmental Protection Agency, Office of Health and Environmental
Assessment, Exposure Assessment Group.  Contract No. 68-02-3510.

Berg EL.  1982.  Handbook for sampling and sample preservation of water and
wastewater.  Cincinnati, OH: U.S. Environmental Protection Agency.
EPA-600/4-82-029.

Booth RL.  1979.  Handbook for analytical quality control in water and waste-
water laboratories, Cincinnati, OH:  U.S. Environmental Protection Agency.
EPA-600/4-79-019.

IRCP.  1975.  International Commission on Radiological Protection.  Report of
the task group on reference man. No. 23.  Oxford, England: Pergamon Press.

JRB.  1984.  Remedial investigations guidance document.  Washington, DC:  U.S.
Environmental Protection Agency. Contract No.: 68-03-3113.

McNeils DN, LBarth DS, Khare M, LaPolnt TW, Yfantis EA.  University of Nevada,
Las Vegas.  1984.  Exposure assessment methodologies for hazardous waste
sites.  Las Vegas, Nevada:  Environmental Monitoring Systems Laboratory,
Office of Research and Development.  Cooperative Agreement No. CR 810550-01.

Sherma J.  1977.  Manual of analytical quality control for pesticides and
related compounds in human and environmental samples,.  Research Triangle Park,
NC: U.S. Environmental Protection Agency.  EPA-600/If79-008.

Stanley RE.  1978.  Quality assurance guidelines for biological testing.  Las
Vegas, Nevada:  U.S. Environmental Protection Agency.  EPA-600/4-78-043.

Stratton CL, Bonds JD.  1979.  Quality assurance guidelines for IERL-CI
project officers.  Cincinnati, OH:  U.S. Environmental Protection Agency.
EPA-600/9-79-047.
7-28
                                            I

-------
                                                                 J&fc Systems, Jnc.
USEPA.  1984.  U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment.  Proposed guidelines for exposure assessments;
request for comments.  Fed. Regist., Nov. 23, 198A, 49 46304.

Versar.  1984.  Superfund exposure assessment manual.  Washington. DC: U.S.
Environmental Protection Agency.  Contract Nos.:  68-01-6271, 68-03-3149.
Whitmore RW.  1984.  Research Triangle Institute.   Methodology for
characterization of uncertainty in exposure assessments.  Washington,  DC:
U.S. Environmental Protection Agency, Office of Health and Environmental
Assessment, Exposure Assessment Group.  Contract No.  68-01-6826.
                                      7-29

-------

-------
                                                                  fife Systems, JHC.
8.0       RISK ASSESSMENTS  '

Risk assessments are invaluable scientific tools for hazardous waste site
investigations.  Management decisions regarding the regulation of chemicals
present at hazardous waste sites require a thorough assessment of the
potential risk to human health and the environment resulting from exposure to
the chemicals present.  Hazardous waste site risk assessments may be utilized
for many purposes including:

     e Screening and determining response priorities.

     e Ranking the relative toxicities of a large number of chemicals at a
       site.

     e Estimating risk associated with various clean-up alternatives.

     e Supporting the assertion that an enforcement action is warranted under
       CERCLA.

This chapter will discuss the structure of the overall risk assessment process
and explain how. information developed during the toxicity assessment and
exposure assessment processes is combined to determine the magnitude of the
problem (i.e. probability of risk) at a site.  This chapter will also
introduce some specific applications of risk assessment at hazardous waste
sites, such as the Hazard Ranking System, Endangerment Assessments and
Feasibility Studies.
                                                        *
8.1       Risk Assessment Process

In the simplest sense, population risks from toxic chemicals are a function of
two measurable factors:  toxicity and exposure.  In order to cause a risk to
humans, a chemical must be (1) toxic, (2) present in the environment at some
significant level and (3) accessible for human exposure.  Risk assessment is
an evaluation and interpretation of the available scientific evidence on these
points, providing a Judgment and, if appropriate, an estimate of the
probability that risk exists.

The risk assessment process consists of one or more of the following four
steps:

     e Toxicological Evaluation

     e Dose-Response Evaluation

     e Exposure Assessment

     e Risk Characterization

The toxicological evaluation and dose-response evaluation collectively
comprise the toxicity assessment process at a hazardous waste site.   The risk
assessment process is usually initiated by performing a toxicological
evaluation and a. preliminary exposure assessment on the chemical(s)  of
                                      8-1

-------
                           J&fe Systems. Jnc.
                                             i
concern.  If the result* of either are negative (i.e., the chemical is not
toxic or is not present at some significant level), then it is not necessary
to proceed with the risk assessment.

Figure 8-1 provides an overview of the risk assessment process.

8.1.1     Toxicologieal Evaluation

The toxicological evaluation should answer the question "Does the chemical
have an adverse effect?1*  It is a qualitative evaluation of the scientific
data to determine the nature and severity of actual or potential health
hazards associated with exposure to a chemical substance.  This step involves
a critical evaluation and interpretation of toxicity data from
epidemiological, clinical, animal and in vitro studies.  Factors that should
be considered during the toxicological evaluation for each contaminant include
routes of exposure, types of effects, reliability of data, dose, mixture
effects and the strength of evidence supporting the conclusions of the
toxicological evaluation.  The toxicological evaluation should also identify
any known quantitative indices of toxicity (e.g., NOAEL, LOAEL, carcinogenic
risk factors, etc.).  The elements of the toxicological evaluation are
discussed in detail in Chapters 3.0, 4.0 and 5.0 of this handbook.

8.1.2     Dose-Response Evaluation

Once the toxicological evaluation indicates that a chemical is likely to cause
a particular adverse effect, the next step is to determine the potency of the
chemical.  The product of the dose-response' evaluation is an estimate of the
relationship between the dose of a chemical and the incidence of the adverse
effect in the human population.

The dose-response evaluation for non-carcinogenic chemicals provides an
estimation of the NOAEL or LOAEL and the margin of safety associated with the
conditions of exposure of the human populations at potential risk.

The dose-response evaluation for carcinogenic chemicals provides an estimation
of the probability or range of probabilities that a carcinogenic effect will
occur under the conditions of exposure of the human populations at risk.
These estimates of probability are derived using mathematical models of the
dose-response relationship.

The dose-response relationship is introduced in chapter 3.0 of this handbook
and discussed in detail in chapter 6.0.

8.1.3     Exposure Assessment

The exposure assessment describes the likely degree of human exposure to a
chemical of concern at a hazardous waste site.  The objectives of a
site-specific exposure assessment are to identify actual or potential routes
of exposure, characterize the population exposed and determine the extent of
the exposure at a site.  The product of the exposure assessment process, as
detailed in chapter 7.0, is an estimation of exposure levels or doses incurred
for chemicals of concern at the site.
8-2

-------
                                                                 &fe Systems, fac.
   Toxldty Assessment
Does the chemical cause an
     adverse effect?
 (lexicological Evaluation)

  What is the relationship
 between the dose and the
 adverse effect in humans?
(Dose-Response Evaluation)
 Exposure Assessment
What are the current and
projected exposure levels
     at the site?
                            Risk Characterization
                            What is the estimated
                           incidence of the adverse
                          effect in a given population?
    FIGURE 8-1  RISK ASSESSMENT PROCESS  AT HAZARDOUS WASTES SITES
      The risk assessment process  at hazardous waste sites Is  an
      evaluation and interpretation of the available scientific
      evidence on  the toxicity and exposure potential for a
      chemical of  concern.  The  results of the Toxicity and
      Exposure Assessments are integrated to yield a complete
      characterization of risk at  the site.
                                   8-3

-------
                                                                  £ift SystemsJnc.
8.1.4     Risk Characterization

The final step in risk assessment, risk characterization, is the process of
estimating the incidence of an adverse health effect under the conditions of
exposure described in the exposure assessment.  It is performed by Integrating
the information developed during the toxiclty assessment  (toxicological
evaluation and dose-response evaluation) and the exposure assessment to yield
a complete characterization of risk for a given hazardous waste site.

The final risk assessment should include a summary of the risks associated
with a site and such factors as the weight of evidence associated with each
step of the process, the estimated uncertainty of the component parts, the
distribution of risk across various sectors of the population and the
assumptions contained within the estimates.

8.2       Risk Characterization at Hazardous Waste Sites

This section discusses the characterization of risk at hazardous waste sites
In greater detail.  Two discrete steps are required to fully characterize
potential risks from exposure to toxic chemicals at hazardous waste sites:

     1.   Characterize noncarcinogenic risks.
     2.   Characterize carcinogenic risks.

Typically, human populations are exposed to a mixture of chemicals at a
hazardous waste site rather than a single chemical.  This phenomenon occurs
when a series of unrelated chemicals are placed in the same area for disposal
or storage, eventually come in contact with each other, and are released as a
mixture to the environment.  The EPA has published "Proposed Guidelines for
the Health Risk Assessment of Chemical Mixtures" (USEPA 1985) which provides
guidelines for assessing the effects of multiple toxicant or multiple
carcinogen exposures.  The following discussion of risk characterization at
hazardous waste sites is consistent with these proposed guidelines.

8.2.1     Characterization of Noncarcinogenic Risks

Risk assessment for single noncarcinogenic compounds at a site generally
results in the derivation of an exposure level that is considered acceptable
or is not expected to cause adverse effects.  This exposure level may be
expressed in a variety of ways such as the Acceptable Daily Intake (ADI), an
Ambient Air Standard, or Water Quality Criteria.  The term "acceptable level"
(AL) will be used here to indicate any derived criteria, health standards or
advisories.

Characterizing risks from noncarcinogenic compounds involves comparing the
expected exposure level (E) to the AL.  The resultant ratio (referred to as
the hazard index, HI - E/AL) is a numerical Indicator of the transition
between acceptable and unacceptable exposure levels.  When making this
comparison It Is Important to ensure that the units for the exposure level and
acceptable level are the same.  It may be necessary to apply a scaling factor
or exposure coefficient to the estimated exposure level, as appropriate, to
                                       8-4

-------
                             ERRATA (PAGES 8-4, 8-5)


Page 8-4, Section 8.2.1, Paragraph 2

Change the first sentence to read:  "One method that toxicologists use to
characterize noncarcinogenic risks involves comparing the expected exposure
levels (E) to the "acceptable level" (AL) (DSEPA 1985)."

Page 8-5, Paragraph 2

Add this paragraph immediately before Section 8.2.2:  "This method of character-
izing noncarcinogenic risks has not been adopted as official EPA policy.  This
is an oversimplification of the procedures used to estimate noncarcinogenic
risks associated with exposure to multiple chemicals.  There are many assump-
tions made in developing these calculation procedures which the user should be
aware of.  These assumptions are detailed in the proposed mixture guidelines
(USEPA 1985)."                '                     :

-------

-------
                                                                  £ife Systems, M:
standardize the units In the ratio.  When HI > 1 there Is a potential health
risk to the human populations associated with exposure to that chemical.
Therefore, the HI of a mixture may be defined as:

                      HI - EI/ALI + E2/AL2 + . . . + E±/ALI

where:

     E. - exposure level to the 1   toxic chemical
     AC, - maximum acceptable level for the 1   toxic chemical

The EPA guidelines assume dose additivity for exposure to multiple
noncarcinogens .  This assumption of additivity is most properly applied to
chemicals that induce the same effect by the same mechanism.  Thus* it may be
desirable to group the chemicals by type of adverse effect and derive a
separate HI for each chemical group to avoid overestimating risk.  As with
single chemicals, when HI approaches unity, the potential for 'risks increases.

8.2.2     Characterization of Carcinogenic Risks

Carcinogenic risks are estimated as the probability or range of probabilities
that a specific adverse effect will occur under the conditions of exposure of
the human population at risk.  One way of expressing this numerical estimate
of risk is as a carcinogenic potency factor or "unit cancer risk" which is
defined as the excess risk due to a continuous lifetime exposure to one unit
of carcinogen concentration.  This carcinogenic potency factor can be used to
convert estimated intake directly to Incremental risk.  This relationship may
be defined as:

     P - dB

where:

     P - incremental risk
     d - exposure level (mg/kg/day)            _.
     B - carcinogenic potency factor (mg/kg/day~ )
      •
For multiple compounds, the above equation may be generalized to:
Total incremental risk at the site is then equal to P.  + P. + ... + P

This equation is based on the following assumptions:

     e Individual intakes are small.
     e Actions by several carcinogens in mixture are Independent (i.e., not
       synergistic or antagonistic).
     e Route-specific cancer risks are additive.
     e Total risk for the site is additive.
                                      8-5

-------
                                                                 ttfe Systems, JHC.
Therefor*, characterizing the potential risks at a site from carcinogenic
chemicals involves determining the incremental risk associated with exposure
to each potential carcinogen at the site and summing the incremental risks to
determine the total risk at the site.

For a detailed discussion of the uncertainties* assumptions and limitations
associated with risk assessments of chemical mixtures refer to the proposed
EPA guidelines (USEPA 1985).

8.3       Application of Risk Assessment at Hazardous Waste Sites

Risk assessments at hazardous waste sites may be performed for many reasons.
Examples of some different applications of risk assessment are briefly
described below.  The Hazard Ranking System, which is described in Appendix A
of the National Contingency Plan, is a risk assessment approach to screen
hazardous waste sites for inclusion on the National Priorities List.

The Public Health Assessment component of the Remedial Investigation and
Feasibility Studies at Superfund sites prescribes an initial risk assessment
methodology for selecting indicator chemicals at a site.  Chemicals are
screened and assigned an "indicator score" based on concentrations present at
the site and their toxiclty.  Chemicals with the top scores are designated as
"Indicator chemicals" for all-analyses at the site.  This allows subsequent
analyses at the site to focus on five to ten "indicator chemicals" rather than
potentially thousands of individual chemicals that may be present at a site.

The goal of the Feasibility Study at a Superfund site is to develop and
evaluate alternative remedial actions.  This evaluation involves an analysis
of the effectiveness (i.e., risk assessment) of each proposed alternative at
reducing potential public health risks at the site.

Finally, any time EPA initiates an enforcement action against a responsible
party at a hazardous waste site, it must support and justify its actions with
an endangerment assessment.  The endangerment assessment, which is a type of
risk assessment, evaluates the magnitude and probability of actual or
potential harm to public health and welfare or the environment from the actual
or threatened release of hazardous substances from a site.  A more detailed
discussion of the endangerment assessment process can be found in the
Endangerment Assessment Handbook (ICAIR 1985).

8.4       Key Guidance and Implementation Documents

ICAIR, Life Systems, Inc.  1985.  The endangerment assessment handbook.
Draft.  Washington, DC:  U.S. Environmental Protection Agency, Office of Waste
Programs Enforcement.  Contract No. 68-01-7037.

ICF Incorporated.  1985.  Superfund public health evaluation process
procedures manual.  Draft.  Washington, DC:  U.S. Environmental Protection
Agency, Office of Emergency and Remedial Response.  Contract No. 68-01-6872.
                                      8-6

-------
                                                                  J&fe Systems, Jm.
Schultz HL, Palmer WA, Dixon GH «t al.  Versar Inc.   1984.  Superfund exposure
assessment manual.  Final Draft.  Washington, DC:  U.S. Environmental
Protection Agency, Office of Toxic Substances, Office of Solid Waste and
Emergency Response.  Contract Kos. 68-01-6271 and 68-03-3149.

USEPA.  1985.  U.S. Environmental Protection Agency.  Office of Waste Programs
Enforcement.  Draft endangerment assessment guidance.  Memorandum from Jack W.
McGraw.  Washington, DC:  U.S. Environmental Protection Agency.  January  16,
1985.

USEPA.  1984.  U.S. Environmental Protection Agency.  Office of Pesticides and
Toxic Substances.  Chemical activities status report, fourth edition, volume
2.  Washington, DC:  U.S. Environmental Protection Agency.  EPA
560/TIIS-84-0016.

USEPA.  1982.  U.S. Environmental Protection Agency.  Office of Pesticides and
Toxic Substances.  Graphical exposure modeling system (GEMS) user's guide.
Draft.  Washington, DC:  U.S. Environmental Protection Agency.

Whitmore RW.  Research Triangle Institute.  Methodology for characterization
of uncertainty in exposure assessments.  Washington, DC:  U.S. Environmental
Protection Agency, Office of Health and Environmental Assessment, Exposure
Assessment Group.  Contract No. 68-01-6826.

8.5       Background References

ICF Incorporated. .1983.  Scientific support document:  The scientific basis
for the risk evaluation process.  Draft.  Washington, DC:  U.S. Environmental
Protection Agency, Office of Emergency and Remedial Response.

ICF Incorporated.  1983.  Superfund feasibility study guidance, chapter 4,
risk evaluation.  Washington, DC:  U.S. Environmental Protection Agency,
Office of Emergency and Remedial Response.

Morgan RC, Clemens R, Davis BD, et al. (No date).  Endangerment assessments
for superfund enforcement actions.  Washington, DC:  U.S. Environmental
Protection Agency, Office of Waste Programs Enforcement.

Schaum J.  1984.  Short course on integration of exposure and risk assessment.
Part 3.  Exposure assessment methods.  Paper presented at the Annual Meeting
of Society for Environmental Toxicology and Chemistry, Arlington, VA.

USEPA.  1985.  U.S.  Environmental Protection Agency.  Environmental Criteria
and Assessment Office.  Proposed guidelines for the health risk assessment of
chemical mixtures.  Fed. Regist., Jan. 9, 1985, 50 1170.

USEPA.  1984.  U.S.  Environmental Protection Agency.  Risk assessment and
management:  framework for decision making.  Washington, DC:  U.S.
Environmental Protection Agency.

USEPA.  1984.  U.S.  Environmental Protection Agency.  Office of Health and
Environmental Assessment.  Proposed guidelines for carcinogen risk assessment.
Fed.  Regist., Nov. 23, 1984, 49 46294.
                                      8-7

-------
                                                                 Jttfe Systems, JHC.
USEPA.  1984.  U.S. Environmental Protection Agency.   Office of Health and
Environmental Assessment.  Proposed guidelines for exposure assessment.  Fed.
Regist., Nov. 23, 1984, 49 46304.

USEPA.  1984.  U.S. Environmental Protection Agency.   Office of Health and
Environmental Assessment.  Proposed guidelines for mutagenicity risk
assessment.  Fed. Regist., Nov. 23, 1984, 49 46314.

USEPA.  1984.  U.S. Environmental Protection Agency.   Office of Health and
Environmental Assessment.  Proposed guidelines for the health assessment of
suspect developmental toxicants.  Fed. Regist., Nov.  23,  1984, 49 46324.
                                      8-8

-------
                                                                   &fc Systems, Jnc.
9.0       SUMMARY 07 TOXICOLOGICAL INFORMATION ON DIOXINS AND FURANS

This chapter provides a stannary of current toxicological information  on
dioxins and furans.  This class of compounds was chosen for consideration here
because of their high inherent toxicity and because they are often found as
contaminants at hazardous waste sites.  This chapter is similar  to the sort of
summary which might he prepared by a toxicologist for a hazard assessment, and
therefore it is somewhat more technical and detailed than chapters 1  to 8 of
this handbook.  A nontoxicologist would not be expected to prepare a  summary
of this sort, but should, on the basis of the information presented in
chapters 1 to 8 of the handbook, be able to understand and apply this
information.

9.1       Chemical Properties and Environmental Stability

Dioxins are a class of compounds characterized by a structure comprising two
benzene rings interconnected to each other through a pair of oxygen atoms
(dibenzo-p-dioxin)., Individual dioxins differ from each other with respect to
substituents present on the benzene rings.  Various chlorine-substituted
dioxins have been found to be highly toxic, the degree of toxicity depending
on the substitution pattern, iEspecially toxic is 2,3,7,8-tetrachloro-
dibenzo-p-dioxin (TCDD).

Dioxins are stable and highly persistent in the environment.  Under laboratory
conditions, soil samples incubated with 1, 10 or 100 ppm of dioxin contained
75Z to 85Z of the original material up to 160 days after treatment (Kearney et
al. 1972).  In another study (Young 1974), soil samples from areas sprayed
10 years earlier contained dioxin levels of 10, 11, 30 and 710 ppt (parts per
trillion).

Some studies indicate that dioxins are subject to photodecomposition or
biodegradation.  Crosby and Wong (1977) applied herbicide formulations
containing chlorodioxins to glass petri dishes, rubber plant leaves or to loam
soil. About 60Z to 702 of the compound was lost in approximately six hours.
Esposito et al. (1980) reviewed studies on the biodegradability of dioxins in
aqueous and soil environments.  However, due to problems of extracting dioxins
from test soils, it was concluded that such transformation has not been
conclusively established.  Chlorodioxins (e.g., TCDD, 2,7-DCDD and DCDD)
undergo photodecomposition in nonpolar solvents, but photodecomposition is
very slow In aqueous solutions or in wet or dry soils (Crosby et al.   1971).

Dioxins are produced as unwanted contaminants in the Industrial manufacture
of chlorophenols and their derivatives.  The primary sources of dioxins in the
environment are the manufacturing and disposal sites of these Industries.
Important exposure routes for dioxins include dermal contact or ingestion of
contaminated water or soil.  Dioxins are lipophilic and tend to bioaccumulate
in fatty tissue, so ingestion of fish (especially bottom-feeders) from
contaminated waters is a significant human exposure route.

Furans are class of polyhalogenated aromatic compounds which are similar to
dioxins.  For example, 2,3,7,8-tetrachlorodibenzo-furan (TCDF)  is similar  in
structure and toxicity to the chlorinated dioxin (TCDD) Isomer.   Very few
                                      9-1

-------
                                                                  £ift Systems, JHC.
pertinent studies on polychlorinated dibenzofurans (PCDFs), including TCDF,
have been located.  Summaries of the available studies are included in the
appropriate sections of this chapter* but several sections (i.e., Mutagenic
and Carcinogenic Studies, Quantitative Indices of Toxicity) have no specific
references to PCDFs.

9.2       Summary of Health Effects Data

Exposure to TCDD causes thynic atrophy* decreased body weight* liver damage,
skin lesions (chloracne), renal function Impairment, hematologic effects,
adrenal atrophy* reproductive system damage* immunosuppresslon, fetotoxic,
teratogenic and mutagenlc effects and cancer.  The chemical TCDD is an
extremely toxic substance* with an LD5Q value reported as low as 0.6 yg/kg
following oral administration.

The effects of greatest concern associated with exposure to TCDD are liver
damage* thymic atrophy* fetotoxic and teratogenic effects and carcinogenic
potential.

Reported manifestations of TCDF toxicity are similar, including general edema
(accumulation of fluid)* liver effects* tskin lesions (chloracne)* thymic
atrophy* immunosuppression and lethality.

9.2.1     .Honcareinogenie Studies

9.2.1.1   Acute Effects
         fe ^^•^^"•"^^^•WM^^^"^^^^^^
                                                             •
Various chlorodioxins have produced lethality following exposures for short
durations via oral administration in the rat* mouse, guinea pig* rabbit,
monkey and dog (Schwetz et al. 1973, McConnell et al. 1978a, 1978b).
Estimates of LD.Q values for guinea pigs and mice exposed to various
chlorodioxins range from 283.7 yg/kg to 5*000 yg/kg.  These values are
summarized in Table 9-1.  The most toxic chlorodioxin is TCDD* which has been
shown to Induce lethality in a variety of animals (rat; guinea pig* mouse* .
monkey* rabbit) at dose levels between 0.6 yg/kg and 190 yg/kg following oral
administration.  The dermal U>5fl value was 270 yg/kg.  Estimates of LD50
values for this compound througn various routes of exposure are summarized in
Table 9-2.

A summary of studies providing data on the sub-lethal effects of acute
exposure to TCDD is presented in Table 9-3.  The effects were reported to
occur following single exposures ranging from 0.1 to 300 yg/kg In four animal
species (rat* guinea pig, chicken* mouse).  Liver damage is the most
consistently reported effect in most species.  Rats receiving a single dose of
100 yg/kg of TCDD showed severe liver damage, thymic atrophy and jaundice
(Gupta et al. 1973).  In the same study* thymic and liver damage of lesser
severity occurred at lower dose levels (25 and 50 yg/kg).  In another study
(Greig et al. 1973)* rats exposed to TCDD (300 yg/kg) exhibited jaundice,
multinucleated parenchyma! cells of the liver and gastric hemorrhage.
Histopathologic liver changes were observed five weeks after single oral doses
                                       9-2

-------
                                                          JClfc Systems, JHC.
TABLE 9-1 ACUTE TOXICITIES
Chlorine
Positions
2,8
2,3,7
2,3,7,8
1,2,3,7.8
1,2,4.7,8
1,2,3,4,7,8
1,2,3,6,7.8
1,2,3,7,8,9
OF VARIOUS CHLORODIOXINS BY ORAL EXPOSURE
Guinea Pig
300,000
29,400
0.6-2.0
3.1
1,125
72.5
70-100
60-100
Mouse

3,000
284
337
5,000
825
1,250
1,440
Adapted from MeConnell et al. (1978b).
                                9-3

-------
                                                               Jdfe Systems, Jnc.
TABLE 9-2 ACUTE LETHALITY OF TCDD *
Species
Rat
Rat
Rat
Guinea Pig
Rabbit
Mouse
Mouse
Monkey
Sex
M
M,F
F
M
M,F
M,F
M,F
M
M
F
Route
of Exposure
Oral
Oral
Oral
Oral
Oral
Dermal
Intra-
perltoneal
Oral
Oral
Oral
LD.M. UK/kg
22
100
190
0.6
115
272
252
114
283.7
<70
Reference
Schvetz et al. (1973)
Harris et al. (1973)
Greig et al. (1973)
Schvetz et al. (1973)
Schvetz et al. (1973)
Vos et al. (1974)
McConnell et al. (1978b)
McConnell et al. (1978a)
.*•'
Adapted from Esposito et al.  (1980) and DTP (1982a,b).
                                    9-4

-------
                                                                                                      Jttfc Systems, JHC.
               cn
                          cn
                                      cn
         2
         0
         V4
cn
2
X
H
H
               CO
               4J
               Pk
                  0

                  cd
                  4J
                  O.
            4)

            60
            •H

            2
            o
                                                                       cn    en    »*
                                                                       r-    r-    *-*   /-s
                                                                       ON    ON         eo
                                                                       -*    -*    C   r-
                                                                                   ••W    *^ "

                                                                              •    «3    *•"
                                                                             H    O
                                                               0
                                                               CD
                                                              •H

                                                               e
                                                                                  l
                                                                                         0

                                                                                         M
                                                                                         0
<

z
CO
                            • O
         CO
         4J
         U




         H
               (X
               8
               U    fH
               •H    CO
O
I
en
H
W


tn

O>

fti
               60
               CO .
                     §
            0
            U
            •H


            1
                                       0 .—>
                                       60 01
                                       CO  0

                                      •52
                  H fH        0

                  «IM  >,   *  CO
                     O  W     U fH
                  fH     vl    "H  9
                     SC  fH     M fH
                     O  CO    W fH
                  0 «H  *J     CO  0
                  M 4J  14     CO  O
                  •O  0  O     «)'-'

                  "ft8      -0
                   • 0  M     Cfl  60
                  v *o  o     to  CB
ft 0  •       *O U
 M tH «    W    -H
 ** 9 fi    .CUT)
 o fH at    6o 0 e
 g fH 60    i-l > 3
 0 0 I-    0 «rt CO
a: o o    ft 
-------
                                                                  £1 ft Systems, Jnc.
of TCDD as low as 50 Ug/kg were administered to male and female CD    rats*
and one week after a single dose of 50 Ug/kg was administered to female
CD-I    mice (Harris et al. 1973).  Increased liver weights were found in male
Wistar rats seven days after single intraperitoneal doses of 0.1 Ug/kg
(Cunningham and Williams 1972).

Acute exposure to TCDF appears to cause effects similar to, but less severe
than, the effects caused by TCDD.  A summary of the effects of acute exposure
to TCDF is presented in Table 9-4.

Acute toxicity studies show that TCDF is toxic in chickens and guinea pigs.
McKinney et al. (1976) reported that Leghorn chickens given 5 Wg/kg TCDF
showed fluid accumulation, enlarged hearts and reduced size of thymuses and
spleens.  The compound also caused lethality.

Harltey guinea pigs administered TCDF showed oral LD_Q values of 5 to
10 ug/kg, with a mean time to death of 11 days.  As a comparison, TCDD was
lethal to 50Z of the test guinea pigs following administration of 2.0 ug/kg.
Death occurred within 20.6 days (Moore et al. 1976).

Mice and rats were found to be resistant to TCDF (Moore et al. 1976).  Rats
administered TCDF at a dose of 1,000 Ug/kg failed to show any toxic effects.
Male mice administered a single oral dose of TCDF up to 6,000 ug/kg did not
exhibit adverse effects, except for mild effects on the liver.  Mice
administered subcutaneous injections of TCDF (6,000 Ug/kg) showed an increase
in liver weights as well as liver-to-body-weight ratio.  In contrast, TCDD
caused adverse effects at levels of 0.2 Ug/kg in mice (Kociba et al. 1976) and
0.1 Ug/kg in rats (Vos et al. 1974).

9.2.1.2   Subchronlc and Chronic Effects

Longer exposures to TCDD reportedly cause effects similar to those following
acute exposure including thymic atrophy, liver damage, renal function
impairment, hematological effects, hormonal alterations, immunosuppression,
nervousness and irritability.  A summary of major studies providing
dose-response effects is presented in Table 9-5.  Those studies providing
dose-response data indicating the greatest sensitivity to TCDD are described
below.

Doses as low as 0.1 ug/kg/day caused a slight degree of liver degeneration in
rats in a subchronic 13-week (5 doses per week) study (Kociba et al. 1976).
Dose levels of 1.0 ug/kg/day increased levels of serum bilirubin and alkaline
phosphatase and caused pathologic changes in the livers of rats.  A NOAEL of
0.01 ug/kg TCDD was reported for rats.
                                                                                   i
 (a) A series of letters, numbers or a combination of both indicates a specific
    strain  (i.e., a race or stock) of animals that all have common hereditary
    characteristics.
                                      9-6
-------
                                                                                         J&fe Systems, Jnc.
               VO
               r»
               ON
                       ^o   ^o
                       r*.   i-.
                       Ov   Ot
           8
          4
U
3
8
2
                        01    01

                        01    01

                        o    o
0)    01

0)    0)

o    o
u
e
u
c
o


H
           u
           V
                0)
                N
               •O
                01
                u
                w  e
                h  0)
                             (0

                             u
                   X
                   o
                                       M
                                       3
                        00 O
                        •H «H
                        01  4J



                        *  I
tfc
Q
f»-
O
                                       ^ ^1

                                  £        « J
                eo a
   I    o
   £»    m
                                  •H
                                  iH

                                  •O
                       s
     S-f
     e  o
                                                         (M
                                                         QO
                                                         ON
M
U-
ON

M
          I
                                       9
                                       U
                                         o
                                         00
           00



           00
           01
           (0
                in
        o


        o   §
        4J   O

        in   —i
                                  o
                                  0
                                  o
                                                         01

                                                         o
                                                         CO
                                                         o
                                                         o.
           0)

           «H
           U

           £
 e
 0)

 u
•H
                        00
                       •H
                       (Xi

                        CO
                        0)

                       •H

                       3
                                  o
     01
     (0
                                                         a-
                                                9-7
-------
                                                                                  £fe Systems, Jnc.

                                                                                                       i





0
6
2 0
O «M
&
M
§
06
5

p



^N
\O
•-4
^
tH
01
0

.0
•H
O

tot

CM
00
Ol
••4
,
i-4
4J
I *
^^ O •
*•* CO
a, 3
H O


^

O^
^
h
0
0
£
•o
8

00
^4
M




^
0»
s^
•
y*N iH
5 •
00 U
2 0
*-» B

iS f^
Z •<
^
eft
r*.
»
P4

•
00
2
>^
•
t-t
0

^Q
^
04

z








/^
o
00
v4
s^
04
£4
3S
            *e
OS

O Q
gen"
CM
                             o
                              •
                             o
                                  o
                                   •
                                  o
                                                  CM
                                                    8   §
                                                      •    •
                                                    o   o
   tf
  •o
   oc
  J<

  ^
                             ^^     »•
                        I*.   O     ^^
                        O   O      P
                                                              8
                                                               •
                                                              o
O M
W H
9 M
i

II
I
z


1
M
             O

            •8*
            c§
                 §
                 9
               >» eo   -H   A        «
              •o o   w    p.      • ct
               O rH   >H    M      00


              •QUO.          OJ 0

                 SO.   A    0      U
                           4J •      •
               0 »4   U    « *H   X M
               H 0   -H    > 0   4J 0
               U >   M    0 >   ** >
               0 -H   O   ^0   «J -H
              Q i-l   H   H *H   fc i-4
                                                       a
                                                       •H

                                                       O

                                                       U 14
                                                                    O
                                                                   •o
                                                  •H
                                                   B
                                                       9 0   
                                                       .-s   ^   §
                                         s
                                         (U
   0

cS
5S,
4J  &
          **
             U
             0
             a
            to
               0
               0
0    0
.    .


-------
                                                                 &fc Systems, Jut
Increased mortality was observed In female Sprague-Dawley rats maintained for
2 years on a diet that provided a TCDD dose of 0.1 Ug/kg/day, while no
increased mortality was observed in male rats at this dose or in animals
receiving doses of 0.01 or 0.001 Ug/kg/day (Kociba et al. 1978, 1979).  At
termination of the study, gross and histologic examination indicated that the
liver was the most severely affected organ, with degenerative, necrotlc and
inflammatory changes observed.  Increases in urinary excretion rates of the
metabolites, coproporphyrin and uroporphyrin, in the high and middle dose
females were consistent with the observed liver damage.  Primary liver injury
was dose-related with the lowest dose representing a NOAEL.

When TCDD was administered by gavage (by stomach tube) in corn oil-acetone
(9:1) at dose levels of 0.0, 0.5, 0.05 or 0.01 Ug/kg/week, toxic hepatitis was
observed in male Osborne-Mendel rats at incidences of none out of 74 tested
(0/74), 14/50, 0/50 and 1/50 and in female rats at incidences of 0/75, 32/49,
1/50 and 0/50 (NTP 1980a).  No other non-neoplastic lesions were observed,
even though extensive histologic examinations were performed.  The two
preceding studies support a NOAEL for rats of aO.OOl yg/kg/day, with a LOAEL
of 0.05 yg/kg/day, and a frank effect level (PEL) for liver injury and
possibly decreased survival of 0.5 yg/kg/day.

Non-neoplastic effects of chronic exposure to TCDD in mice were described in
studies investigating the carcinogenic potential of TCDD.  In a National
Toxicology Program (NTP) (1980a) bioassay, histologic examinations were
performed on B6C3F1C   mice treated biweekly with TCDD by gavage in corn
oil-acetone (9:1) for 104 weeks followed by an additional 3-week observation
period.  The doses for male animals were 0.0, 0.01, 0.05 and 0.5 ug/kg/week,
and for female animals, 0.0, 0.04, 0.2 and 2.0 ug/kg/week.  The only
non-neoplastic adverse effect was toxic hepatitis, which occurred in males at
Incidences of 0/73, 5/49, 3/49 and 44/50, and in females at incidences of
0/73, 1/50, 2/48 and 34/47, respectively, in the control, low, medium and high
dose groups.  In another study, weekly dosing by stomach tube of TCDD at doses
of 0.0, 0.007, 0.7 or 7.0 yg/kg/week for one year resulted in amyloidosis
(deposition of amyloid) of the kidney, spleen and liver, and dermatitis at the
time of death in male Swiss mice (Toth et al. 1978, 1979).  The incidences of
these effects in the control, low, medium and high dose groups, respectively,
was 0/38, 5/44, 10/44 and 17/43.  In the high dose group, the amyloidosis was
extensive and considered to be the cause of early mortality.  Severe toxic
effects were observed at doses of 1 yg/kg/day (early mortality) and 0.28 to
0.07 yg/kg/day (toxic hepatitis), while a LOAEL for dermatitis and amyloidosis
of 0.001 yg/kg/day was reported.

Several epidemiologic studies and case reports involving dioxin exposure in
human subjects have been reported (Esposito et al. 1980).  Effects observed
include skin lesions (chloracne, prophyria cutanea tarda), liver function
impairment and neurological disorders (polyneuropathy, peripheral nerve
damage).  An International Agency for Research on Cancer (IARC 1982)
evaluation of human exposure data concluded that these studies are inadequate
since they involve multiple chemical exposures.
                                      9-9
-------
                                                                   Jttfe Systems, JHC.
The chemical TCDD has been reported to be fetotoxic and teratogenic when
administered alone or in combination with other chemicals.  Various studies
have been identified in the available literature based on TCDD exposure alone.
Effects observed were kidney anomalies, intestinal hemorrhage* general edema*
cleft palate and fetal death.  Adverse effects on reproduction were also
reported.

Intestinal hemorrhage, general edema and a reduction in fetal weights were
reported in rats following the administration of 0.125 ug/kg/day in studies by
Sparschu et al. (1971).  In the same studies* the number of fetuses was
reduced and fetal death increased at 0.5 vg/kg/day.  No structural
malformations were reported at 0.03 ug/kg/day.  Courtney and Moore (1971)
reported cleft palate and kidney abnormalities in offspring from mice
administered TCDD at doses of 1.0 ug/kg or 3.0 ug/kg.  Similarly, kidney
malformations were reported by the same authors in offspring from rats which
received subcutaneous injections of 0.5 ug/kg/day on day 9, 10, or 13 and 14
of gestation. .

Murray et al. (1979) completed a three-generation reproduction study using
Sprague-Dawley rats fed TCDD continuously in the diet (at levels of 0, 0.001,
0.01, and 0.1 ug/kg/day).  Significant decreases, were observed in fertility,
litter size, gestation survival, postnatal survival, and postnatal body weight
for the 0.01 and 0.1 ug/kg groups.  No apparent adverse effect on reproduction
was seen at the 0.001 Ug/kg dose level.

Nisbet and Paxton (1982) reevaluated the data of Murray et al. (1979) using
different statistical methods.  From this reevaluation it was concluded that
TCDD significantly reduced the gastational index, decreased fetal weight, and
increased liver-to-body weight ratios and the Incidence of dilated renal
pelvis in both lower dose groups.  Nisbet and Paxton (1982) concluded that the
dose of 0.001 Ug/kg/day was not a NOAEL but a LOAEL in this study.

Luster et al. (1980) examined bone marrow, immunelogic parameters, and host
susceptibility in B6C3F1    mice following pre- and postnatal exposure to
TCDD.  Doses of 0, 1.0, 5.0 or 15.0 ug/kg TCDD/body weight were given to dams
on day 14 of gestation and to offspring on days 1, 7 and 14 following birth.
Neonatal body, liver, spleen, and thymus weights were decreased and bone
marrow toxicity occurred in the 5.0 and 15.0 ug/kg groups.  Red blood cell
counts, hematocrits, and hemoglobin were decreased at the highest dose tested.

Oishi et al. (1978) studied the subchronic toxicity of polychlorinated
dibenzofurans  (PCDFs) in rats.  Test animals were fed diets containing 1 or
10 ppm PCDF for four weeks.  The PCDF markedly depressed normal body weight
gain.  In rats fed diets containing 10 ppm of PCDF, significantly decreased
thymus, ventral prostate, and seminal vesicle weights were found, and the
animals developed chloracne-like lesions on the ears within three weeks.
Hemoglobin and hematocrit values (percentage of the volume of a blood sample
occupied by cells) were decreased in rats fed either diet.

9.2.2     Mutagenic and Carcinogenic Studies

Studies on the mutagenicity of TCDD have produced conflicting results.  The
chemicals TCDD reportedly produces mutagenic effects in various bacterial
                                      9-10
-------
                                                                  £ife Systems, JHC.
systems.  However, results were negative In tests employing other indicator
test systems, including cytogenetic (chromosome analysis) tests and dominant
lethal assays.  Hussaln et al. (1972) reported that TCDD  (2 yg/mL) increased
the incidence of reverse mutations in Escherichia coli.   Similarly, TCDD  (dose
not specified) was reported to be mutagenic ..without metabolic activation  in
Salmonella typhimurium test strain TA 1532.  '  Green et  al. (1977) gave  0.25,
0.5, 1.0, 2.0, or 4.0 vg/kg TCDD (dissolved in 1 part acetone: 9 parts corn
oil) by gavage to male and female Osborne-Mendel rats twice weekly for 13
weeks and. observed an increased incidence of chromosomal  breaks in female rats
dosed with 4 ug/kg and in males dosed with 2 vg/kg or 4 yg/kg.

Mutagenic effects (with or without metabolic activation)  were not detected
when Geiger and Neal (1981) examined the mutagenicity of  TCDD (up to
20 yg/plate) using the S. typhimurium test strains^ ' TA1535, TA100, TA1538,
TA98, and TA1537.

The carcinogenic potential of TCDD has been studied extensively.  A summary of
the results of selected comprehensive studies is presented in Table 9-6.  The
results of these studies show that TCDD-exposed animals exhibited malignant
lesions involving multiple organ systems including accessory digestive organs
(liver), endocrine (thyroid, adrenal), renal, reproductive (testes), and  nasal
structures.  Representative studies are described below.

Groups of ten male Sprague-Dawley rats were fed a diet containing TCDD for 78
weeks at dose levels ranging from 1 ppt to 500 ppt or 1 ppb to 1,000 ppb  (Van
Miller et al. (1977).  These dose levels represent approximate weekly dose
levels of 0.0003 to 0.1 ug/kg or 0.4 to 500 ug/kg.  Animals exposed at 5  ppt,
50 ppt, 500 ppt or 5 ppb showed an overall incidence of neoplasm of 38Z
(23/60).  No neoplasms were reported or observed following exposure to 1  ppt
TCDD.  In the 5 ppt group, 5/10 animals had six neoplasms (earduct carcinoma,
lymphocytic leukemia, adenocarcinoma, malignant histiocytoma (with meta-
stases), angiosarcoma and Leydig-cell adenoma).  Neoplasm were also observed
in the following groups:  at 50 ppt, three in 3/10; at 500 ppt, four in 4/10;
at 1 ppb, five in 4/10; at 5 ppb, ten in 7/10.  Neoplasms were not observed in
the controls.  Rats administered TCDD at 50, 500 or 1,000 ppb exhibited 100%
mortality by the fourth week.

In another study (Kociba et al. 1978), groups of 100 Sprague-Dawley rats  (50
males and 50 females) received diets containing TCDD at 0, 22, 210, or
2,220 ppt (equivalent to 0.0, 0.001, 0.01 and 0.1 yg TCDD/kg/day) for two
years .  Administration of 0.01 yg/kg/day increased the incidence of
hepatocellular hyperplastic nodules (female: 18/50 versus 8/86 controls)  and
focal alveolar hyperplasia in the lungs (P<0.05).  Dietary intake of
0.1 yg/kg/day increased the incidence of hepatocellular carcinomas (female:
11/49 versus 1/86) and squamous cell carcinomas of the lung (female: 7/49
versus 0/86), hard palate/nasal turbinates (male: 4/50 versus 0/85; female:
4/49 versus 0/86), and tongue (male: 3/50 versus 0/85) (F<0.05).  Also
increased in frequency by the 0.1 yg TCDD/kg/day were adenoma of the adrenal
cortex (male) and hepatocellular hyperplastic nodules (female).
                                     9-11
-------
                                                                                 £fe Systems. JHC,
              JJ
              «
              gs
                                                                         .0
                                                                         CM
                                                                         00
                                                                                00
CO
H
w
cj
                                                  1
                                                  •I
                                                  a
                                                  s
                                                  8
                                                  o
                                               «-    K .   .
                                               «    0 W «H
                                               OO.fi
                                               (3    C «W  *
                                               0)    « O  S/-K
                                               o    o    w m

                                               h    h B IH  •

                                               !    llsl
                                               •H    «p| «H  C8 04
                                               tJ    |J O  C »-*
                                                                                              •a
                                                                                              1
                                                                                              o
                                                                                              u
                                                                         O 00   « >-*
                                                                         h «w   r-l      4J
                                                                         «      9 'O   «n  •
                                                                         CO B   Of!   « ON
                                                                         O O   »   O JS   « -*
                                                                         Cu (0   (k< w   Z ^
                                                  •
                                                 •H
                                                 O
                                                                                60
                                                                                «


                                                                                u
                                                                                       at
                                                                                       oo
                                                                                       to
                                                  2
                                                 CM
                                                                         n
                                                                         •B
                                                                               I
          a
          o
          O
               §:
                      a.
                      o.
                     o
                     o
                            I

                            •7
     a    oo
s   -    *
o   o    -«
                                                                        J
                                                                         00
                                                                         O
                                                                          •
                                                                         o
                               00
                              Jri

                              *ob
                                      00
 X

CO /-«.
•^. M
 
                                               9-12
-------
                                                                         £fe Systems, Jnc.
         0
         I
             N

             00
                      o

                      CO
         co
         w
         o
         0
         H
««^
W  C Pn
« .
             0 -* <£>
             as '<-"«'
                 CM   iH
         M tft
         CO >^
         •H O
         <-l W
         ^ >%
         O A
         to w
             M
             CO
         0
         00




         C9
                 ^
                  «
                 «

                 00
         §
         «0
         M


         O
                 o
                 00
                 Ox
         0
         CO
I
e
o
o
C*
0
CO
H
60



O


-------
                                                                  £ifc Systems, Jnc.
                                                                                    i
The NTP has performed a chronic bioassay in both Osborne-Mendel rats and
B6C3F1 mice to determine the carcinogenicity of a mixture containing 31Z
1,2,3,6,7,8-HCDD and 67Z 1,2,3,7,8,9-HCDD (NTP 1980).  Other dioxins,
including di-, tri-, tetra-, pentachlorodibenzo-p-dloxin, and
bromopentachlorodibenzo-p-dioxln, were present at less than 0.09Z.  The
mixture was administered to the test animals in corn oil-acetone  (9:1) by
gavage two times/week.  The male and female rats, and the male mice received
doses of 0.0* 1.25* 2.5 or 5 ug/kg/week, and the female mice received doses of
0.0, 2.5, 5.0 or 10 pg/kg/week.  Treatment was continued for 104 weeks
followed by a 3-4 week observation period.  In both test species, exposure to
HCDD produced a dose-related "toxic hepatitis" and an increased incidence of
hepatocellular nodules or tumors (adenomas and carcinomas).  Liver tumor
incidence was statistically significant in both male and female mice and in
female rats.

The NTB /1982a) conducted a study for 104 weeks using Osborne-Mendel rats and
B6C3F1    mice.  The rats and male mice were administered TCDD at 0, 0.01,
0.05 or 0.5 Pg/kg/wk by gavage in two divided doses, and the female mice were
given 0, 0.04, 0.2, or 2.0 Vg/kg/wk.  Incidences of folllcular cell thyroid
adenomas in male rats (PO.001) and of neoplastic nodules in livers of female
rats (P-0.006) increased significantly.  TCDD Increased the numbers of
hepatocellular carcinomas in male mice (P-0.002) and in females (P-0.014).
The total liver tumors (carcinomas and adenomas) were increased in males
(P<0.001) and females (P-0.002).  In addition, female mice had increased
incidence of follicular cell thyroid adenomas.  These studies indicate that
TCDD is an animal carcinogen.

Epldemlologic studies on industrial workers and herbicide applicators are
consistent with the conclusion from animal studies that TCDD is a carcinogen.
However, since TCDD is usually a contaminant of phenoxy acids and/or
chlorophenols, human exposure is always to multiple chemicals.  Therefore, the
evidence for human carcinogenicity from these studies is only suggestive due to
the .difficulty of evaluating the risk of TCDD exposure in the presence of the
confounding effects of the other chemicals (DSEPA 1984).

9.3       Quantitative Indices of Toxlclty

9.3.1     Noncarcinogenlc Effects

Recommended exposure limits to TCDD to ensure human safety have been
established by many agencies.  The National Academy of Sciences (NAS 1977),
before TCDD was considered to be a carcinogen, suggested an ADI of 0.0001 pg/
TCDD/kg/day based on a 13-week feeding study in rats (Kociba et al. 1976).
The reported NOEL in that study  (0.01 Pg/kg) was divided by an uncertainty
factor of 100 to determine the ADI.  The NAS then calculated a suggested-
no-adverse-effeet-level in drinking water of 0.0007 Pg/L, based on the average
weight of a human adult (70 kg) and an average daily intake of water of 2 L,
with water representing 20Z of total intake.

The USEPA (1984) has calculated an ADI of 10   ug/kg/day, using a LOAEL, based
on toxic effects and reduced fertility, of 0.001 pg/kg/day and employing an
uncertainty factor of 1,000.  Using a bioaccumulation factor of 5,000, and
                                      9-14
-------
                                                                   JCife SystemsJHC.
assuming a daily consumption of 6.5 g of fish, a water concentration of
2.0 x 10~  yg/L was derived.  It was noted that this value may not be
sufficiently low to protect against the carcinogenic effects of TCDD (USEPA
1984).

9.3.2     Carcinogenic Effects

Since there is no recognized safe concentration for a human carcinogen, and
TCDD is a suspected human carcinogen, the recommended concentration of TCDD in
water is zero (USEPA 1984).  Assuming daily consumption of 2 L of water and
6.5 g of fish and shellfish, the concentrations of TCDD in water that
correspond to excess cancer risks of 10  , 10   or 10   were calculated to be
1.3 x 10  , 1.3 x 10"8 or 1.3 x 10~* yg/L, respectively (USEPA 1984).  Because
of the tendency for aquatic organisms to bioconcentrate TCDD, most of this
risk is due to consumption of the fish or shellfish.  If no contaminated fish
or shellfish were eaten, the water-concentrations corresponding to-excess
cancer risks of 10  , 10   and 10   would be 2.2 x 10  , 2.2 x 10   and 2.2 x
10**  ug/L, respectively.  These criteria are below the limit of detection of
TCDD in water (approximately 3 x 10~  yg/L) by current analytical methods.

The Food and Drug Administration (FDA) issued a health advisory stating that
fish with residues of TCDD ^50 ppt should not be consumed, but fish with
residues of < 25 ppt pose no serious health concern (USEPA 1984). The Centers
for Disease Control (CDC) has established 1 ppb TCDD as a level of concern in
residential soils.

9.4       Special Concerns

The special concerns related to TCDD are its extreme toxicity and persistence
in the environment.  It is possibly, on a molecular basis, the most poisonous
synthetic chemical known (Esposito et al. 1980).  It is resistant to
biodegradation and has a high affinity to soil, especially soil with a
significant organic content.

The data from animal studies suggest that fetuses and newborns may be at
greater risk from TCDD exposure than the general population.

9.5       References

Allen JR, Barsotti DA, Van Miller JP, Abrahamson LJ, Lalich JJ.  1977.
Morphological changes in monkeys consuming a diet containing low levels of
TCDD.  Food Co sine t. Toxicol. 15:401.

Anaizi NH, Cohen J.  1978.  The effects of TCDD on the renal tubular secretion
of phenolsulfonphthalein.  J. Pharmacol. Exp. Ther. 207(3):748-755.

Courtney KD, Moore JA.  1971.  Teratology studies with 2,4,5-T and
2,3,7,8-TCDD.  Toxicol. Appl. Pharmacol. 20:396-403.

Crosby DG, Wong AS, Plimmer JR, Woolson EA.  1971.  Photodecomposition of
chlorinated dibenzo-p-dioxins.  Science 173:748-749.

Crosby DG, Wong AS.  1977.  Environmental degradation of
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).  Science 195:1337-1338.

                                     9-15
-------

                                                                   £fe Systems, Jnc.
Cunningham HM, Williams DT.  1972.  Effect of 2,3,7,8-tetrachloro-
dibenzo-p-dioxin on growth rat* and the synthesis of lipids and proteins in
rats.  Bull. Environ. Contam. Tozicol. 7(1):45-51.

Esposito MP, Tiernan TO, Dryden FE.  1980.  Dioxins.  Industrial Environmental
Research Laboratory, Office of Research and Development.  EPA 600/2-80-197,
187-306.

Gelger LE, Meal RA.  1981.  Mutagenicity testing of 2,3,7,8-tetrachloro-
dibenzo-p-dioxin in histidine auxotrophs of Salmonella typhimurium.  Toxicol.
Appl. Fharmacol. 59(1):125-129.

Goldstein JA, Linko P, Bergman H.  1982.  Induction of porphyria in the rat by
chronic versus acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Biochem. Pharmacol. 31(8):1607-1613.

Green S, Moreland F, Shen C.  1977.  Cytogenetic effects of 2,3,7,8-TCDD on
rat bone marrow cells.  Food and Drug Administration Bylines 6:292-294.

Greig JB, Jones G, Butler WH, Barnes JM.  1973.  Toxic effects of
2,3,7,8-TCDD.  Food Cosmet. Toxicol.  11:585-595.

Gupta BN, Vos JG, Moore JA, Zinkl JG, Bullock BC.  1973.  Pathologic effects
of 2,3,7,8-tetrachlorodibenzo-p-dloxin in laboratory animals.  Environ. Health
Perspect. 5:125-140.

Harris MW, Moore JA, Vos JG, Gupta BN.  1973.  General biological effects of
TCDD in laboratory animals.  Environ. Health Perspect. 5:101-109.

Hook JB, et al.  1978.  Renal effects of 2,3,7,8-TCDD.  Environ. Sci. Res.
12:381-388.

Hussain SL, Ehrenberg L, Lofroth G, Gejvall T.  1972.  Mutagenic effects of
TCDD on bacterial systems. Ambio. 1:32-33.

IARC.  1982.  International Agency for Research on Cancer.  IARC monographs on
the evaluation of carcinogenic risk of chemicals to humans.  Suppl 4. IARC
Lyon. France.

Kearney PC, Woolson EA, Ellington CP.  1972.  Persistence and metabolism of
chlorodioxins in soils.  Environmental Sci. Tech. 6(12):1017-1019.

Ring ME, Roesler AR.  1974.  Subacute intubation study on rats with the
compound 2,3,7,8-tetrachlorodioxin.  United States Environmental Protection
Agency.  NTIS PB-257-677, p 27.

Rociba RJ, Reeler PA, Park CN, Gehring PJ.  1976.  2,3,7,8-tetrachloro-
dibenzo-p-dioxin (TCDD)-Results of a 13-week oral toxicity study in rats.
Toxicol. Appl. Pharmacol. 35:553-574.

Rociba RJ, Reyes DG, Beyer JE, et al.  1978.  Results of a two-year chronic
toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin In
rats.  Toxicol. Appl. Pharmacol. 46(2):279-303.
                                     9-16
-------
                                                                   £ife Systems. Jnc.
assuming a daily consumption of 6.5 g of fish, a water concentration of
2.0 x 10~  jig/L was derived.  It was noted that this value may not be
sufficiently low to protect against the carcinogenic effects of TCDD (USEPA
1984).

9.3.2     Carcinogenic Effects

Since there is no recognized safe concentration for a human carcinogen,  and
TCDD is a suspected human carcinogen, the recommended concentration  of TCDD in
water is zero (USEPA 1984).  Assuming daily consumption of 2 L of water  and
6.5 g of fish and shellfish, the concentrations of TCDD in water that
correspond to excess cancer risks of 10** , 10**  or 10**  were calculated  to  be
1.3 x 10  , 1.3 x 10   or 1.3 x 10   yg/L, respectively (USEPA 1984).  Because
of the tendency for aquatic organisms to bioconcentrate TCDD, most of this
risk is due to consumption of the fish or shellfish.  If no contaminated fish
or shellfish were eaten, the water7concentrations corresponding to7excess
cancer risks of 10  , 10   and 10   would be 2.2 x 10  , 2.2 x 10    and  2.2 x
10**  ug/L, respectively.  These criteria are below the limit of detection of
TCDD in water (approximately 3 x 10   Ug/L) by current analytical methods.

The Food and Drug Administration (FDA) issued a health advisory stating  that
fish with residues of TCDD ^50 ppt should not be consumed, but fish  with
residues of < 25 ppt pose no serious health concern (USEPA 1984). The Centers
for Disease Control (CDC) has established 1 ppb TCDD as a level of concern  in
residential soils.

9.4       Special Concerns

The special concerns related to TCDD are its extreme toxicity and persistence
in the environment.  It is possiblyj on a molecular basis, the most  poisonous
synthetic chemical known (Esposito et al. 1980).  It is resistant to
biodegradation and has a high affinity to soil, especially soil with a
significant organic content.

The data from animal studies suggest that fetuses and newborns may be at
greater risk from TCDD exposure than the general population.

9.5       References

Allen JR, Barsotti DA, Van Miller JP, Abrahamson LJ, Lalich JJ.  1977.
Morphological changes in monkeys consuming a diet containing low levels of
TCDD.  Food Co sine t. Toxicol. 15:401.

Anaizi NH, Cohen J.  1978.  The effects of TCDD on the renal tubular  secretion
of phenolsulfonphthalein.  J. Pharmacol. Exp. Ther. 207(3):748-755.

Courtney KD, Moore JA.  1971.  Teratology studies with 2,4,5-T and
2,3,7,8-TCDD.  Toxicol. Appl. Pharmacol. 20:396-403.

Crosby DG, Wong AS, Plimmer JR, Woolson EA.  1971.  Photodecomposition of
chlorinated dibenzo-p-dioxins.  Science 173:748-749.

Crosby DG, Wong AS.  1977.  Environmental degradation of
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).  Science 195:1337-1338.

                                     9-15
-------
                                                                   Jdfc Systems, Jnc.
Cunningham HM, Williams DT.  1972.  Effect of 2,3,7,8-tetrachloro-
dibenzo-p-dioxin on growth rate and the synthesis of lipids and proteins in
rats.  Bull. Environ. Contaa. Toxicol. 7(1):45-51.

Esposito MP, Tiernan TO, Dryden FE.  1980.  Dioxlns.  Industrial Environmental
Research Laboratory, Office of Research and Development.  EPA 600/2-80-197,
187-306.

Geiger LE, Neal RA.  1981.  Mutagenicity testing of 2,3,7,8-tetrachloro-
dibenzo-p-dioxin in histidine auxotrophs of Salmonella typhimurium.  Toxicol.
Appl. Pharmacol. 59(1):125-129.

Goldstein JA, Linko P, Bergman H.  1982.  Induction of porphyria in the rat by
chronic versus acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Biochem. Pharmacol. 31(8):1607-1613.

Green S, Moreland F, Shen C.  1977.  Cytogenetic effects of 2,3,7,8-TCDD on
rat bone marrow cells.  Food and Drug Administration Bylines 6:292-294.

Greig JB, Jones G, Butler WH, Barnes JM.  1973.  Toxic effects of
2,3,7,8-TCDD.  Food Cosinet. Toxicol.  11:585-595.

Gupta BN, Vos JG, Moore JA, Zinkl JG, Bullock BC.  1973.  Pathologic effects
of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals.  Environ. Health
Perspect. 5:125-140.

Harris MW, Moore JA, Vos JG, Gupta BN.  1973.  General biological effects of
TCDD in laboratory animals.  Environ. Health Perspect. 5:101-109.

Hook JB, et al.  1978.  Renal effects of 2,3,7,8-TCDD.  Environ. Sci. Res.
12:381-388.

Bussain SL, Ehrenberg L, Lofroth G, Gejvall T.  1972.  Mutagenic effects of
TCDD on bacterial systems. Ambio. 1:32-33.

IARC.  1982.  International Agency for Research on Cancer.  IARC monographs on
the evaluation of carcinogenic risk of chemicals to humans.  Suppl 4. IARC
Lyon. France.

Kearney PC, Woolson EA, Ellington CP.  1972.  Persistence and metabolism of
chlorodioxins in soils.  Environmental Sci. Tech. 6(12):1017-1019.

Ring ME, Roesler AR.   1974.  Subacute intubation study on rats with the
compound 2,3,7,8-tetrachlorodioxin.  United States Environmental Protection
Agency.  NTIS PB-257-677, p 27.

Rociba RJ, Reeler PA, Park CN, Gehring PJ.  1976.  2,3,7,8-tetrachloro-
dibenzo-p-dioxin (TCDD)-Results of a 13-week oral toxicity study in rats.
Toxicol. Appl. Pharmacol. 35:553-574.

Rociba RJ, Reyes DG, Beyer JE, et al.  1978.  Results of a two-year chronic
toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in
rats.  Toxicol. Appl. Pharmacol. 46(2):279-303.
                                     9-16
-------
                                                                   Jttfe Systems, JHC.
Kociba RJ, Reyes DG, Beyer JE, Carreon KM, Gehrlng PJ.  1979.  Long-term
toxicologic studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in
laboratory animals.  Ann. NY Acad. Science. 320:397-404.

Luster MI, Boorman GA, Dean JH, et al.  1980.  Examination of bone marrow,
immunologic parameters and host susceptibility following pre- and postnatal *
exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).  Int. J.
Immunopharmacol.  2(4):301-310.

McConnell EE, Moore JA, Dalgard DW.  1978a.  Toxicity of 2,3,7,8-tetrachloro-
dibenzo-p-dioxin in rhesus monkeys (Macacas mulatta) following a single oral
dose.  Toxicol. Appl. Pharmacol. 43:175-187.

McConnell EE, Moore JA, Baseman JR, Harris MW.  1978b.  The comparative
toxicity of chlorinated dibenzo-p-dioxins in mice and guinea pigs.  Toxicol.
Appl. Pharmacol. 44:335-356.

McRinney JD, Chae R, Gupta GN, Moore JA, Goldstein JA.  1976.  Toxicological
assessment of hexachlorobiphenyl isomers and 2,3,7,8-tetrachlorobenzofuran in
chicks.  I.  Relationships of chemical parameters.  Toxicol. Appl. Pharmacol.
36:65-80.

Moore JA, Gupta BN, Vos JG.  1976.  Toxicity of 2,3,7,8-tetrachlorodibenzo-
furan - preliminary results.  Proc. Natl. Conf. PCB's, November, 77-80.

Murray FJ, et al.  1978.  Three generation reproduction study of rats
ingesting TCDD.  Toxicol. Appl. Pharmacol. 41:200-201.

Murray FJ, Smith FA, Nitschke RD, Humiston CG, Rociba RJ, Schwetz BA.  1979.
Three-generation reproduction study of rats given 2,3,7,8-tetrachloro-
dibenzo-p-dioxin (TCDD) in the diet.  Toxicol. Appl. Pharmacol. 50:241-251.

NAS.   1977.  National Academy of Sciences.  Drinking water and health.
Washington, DC:  National Academy of Sciences.

Nisbit ICT, Paxton MB.  1982.  Statistical aspects of three-generation studies
of the reproductive toxicity of TCDD and 2,4,5-T.  Am. Stat. 36:290-298.

NTP.  1982a.  National Toxicology Program.  Carcinogenesis bioassay of
2,3,7,8-tetrachlorodibenzo-p-dioxin in Osborne-Mendel rats and B6C3F1 mice
(Gavage Study).  Tech. Rpt. Ser. No. 209.  NIH.  Pub. No. 82-1765.

NTP.  1982b.  National Toxicology Program.  Carcinogenesis bioassay of
2,3,7,8-tetrachlorodibenzo-p-dloxin in Swiss-Webster mice (dermal study).
Tech. Rpt. Ser. No. 201.  NIH Pub. No. 82-1757.

NTP.  1980.  National Toxicology Program.  Bioassay of 1,2,3,7,8- and
1,2,3,7,8,9-hexachlorodibenzo-p-dioxin (gavage) for possible carcinogenicity.
DHHS Publication No. (NIH) 80-1754.  Carcinogenisis Testing Program, NCI, NIH,
Bethesda, MD and National Toxicology Program, RTF, Box 12233, NC.
                                     9-17
-------
                                                                   &fc Systems, JHC.
Olshi S, Morita M, Fukuda H.  1978.  Comparative toxicity of polychlorinated
biphenyls and dibenzofurans in rats.  Toxicol. Appl. Pharmacol. 43:13-22.

Schwetz BA, Norris JM, Sparschu GL, et al. 1973.  Toxicology of chlorinated
dibenzo-p-dioxins.  Environ. Health Perspect. 5:87-99.

Sparschu GL, Dunn FL, Rowe VK.  1971.  Study of the teratogeniclty of
2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat.  Food Cosmet. Toxicol.
9:405-412.

Toth R, Somfai-Relle S, Sugar J, Bence J.  1979.  Carcinogenicity testing of
herbicide 2,4,5-trichlorophenoxyethanol containing dioxin and of pure dioxin
in Swiss mice.  Nature (Lond).  278(5704):548-549.

Toth K, Sugar J, Somfai-Relle S, Bence J.  1978.  Carcinogenic bioassay of the
herbicide, 2,4,5-trichlorophenoxyethanol (TCPE) with different
2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) content in Swiss mice.  Prog.
Biochem. Pharmacol. 14:82-93.

USEPA.  1984.  United States Environmental Protection Agency.  Ambient water
quality criteria for 2,3,7,8-tetrachlorodibenzo-p-dioxin.  Washington, DC:
Office of Water Regulations and Standards.  U.S. Environmental Protection
Agency. EPA 440/5-84-007.

Van Miller JP, Lalich JJ, Allen JR.  1977.  Increased incidence of neoplasms
in rats exposed to low levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Chemosphere 6:537-544.

Vos JG, Moore JA, Zinkl JG.  1974. Toxicity of 2,3,7,8-TCDD in C5781/6 mice.
Toxicol. Appl. Pharmacol. 29:229-241.

Weissburg JB, Zinkl JG.  1973.  Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin
upon hemostasis and hematologic function in the rat.  Environ. Health
Perspect. 5:119-123.

Young AL.  1974.  Ecological studies on a herbicide-equipment test area
(TA-C-52A).  Elgin Air force Armament Laboratory.  Technical Report
AF ATL-TR-74-12.
                                      9-18
-------
                                                                  &fe Systems. JHC.
10.0      SUMMARY OF TOXICOLOGICAL INFORMATION ON TRICHLOROETHYLENE

This chapter provides a summary of current toxicological Information on
trichloroethylene.  This compound was chosen for consideration here because  of
its high inherent toxicity and because it is often found as a contaminant at
hazardous waste sites.  This chapter is similar to the sort of summary which
might be prepared by a toxicologist for a hazard assessment, and  therefore it
is somewhat more technical and detailed than chapters 1 to 8 of this handbook.
A nontoxicologist would not be expected to prepare a summary of this sort, but
should, on the basis of the information presented in chapters 1 to 8 of the
handbook, be able to understand and apply this information.

10.1      Chemical Properties and Environmental Stability

Trichloroethylene (TCE) is a nonflammable, colorless liquid used  primarily as
a solvent, in metal degreasing, in drycleaning operations and in  refrigerants
and fumigants.  In the past, TCE has also been used as an anesthetic and as  an
extractant in food processing.  Trichloroethylene has a sweet odor, resembling
that of chloroform.  Trichloroethylene is practically insoluble in water, but
highly soluble in llplds.

Although TCE can be formed during the water chlorination process, the major
source of environmental levels of this chemical is volatilization of TCE
during manufacturing.  Trichloroethylene is widely distributed in the environ-
ment; however, there is no Indication that it is persistent or that it bioac-
cumulates'ln the food chain.  Trichloroethylene has .been detected in air,
food, human tissues and in groundwater.  Concentrations in groundwaters range
from 18 to 22,000 ppb.  An EPA finished water survey of ten cities reported
TCE in half the supplies tested (levels ranged from 0.1 to 0.5 Vg/L (USEPA
1975).

10.2      Summary of Health Effects Data

Exposure to TCE can produce CNS depression (e.g., unconsciousness, numbness,
incoordlnation), minor liver damage, kidney necrosis (death of kidney cells),
painful breathing and cardiac arrhythmia.  The most critical endpoint for
toxicological evaluation, however, is the carcinogenic potential  of TCE.

The most Important routes of exposure to TCE are Inhalation and ingestion.
Trichloroethylene is readily absorbed both orally and in the lungs.  In mice
and rats 95Z and 98Z, respectively, of an orally administered dose of TCE was
absorbed from the gastrointestinal tract within 72 hours (Dekart et al.  1984).
Human data concerning TCE absorption has been obtained using the inhalation
route of exposure.  Stewart et al. (1962) reported TCE concentrations of
4.5 to 7 mg/L in blood within two hours of exposure to a time-weighted average
concentration of 1,420 mg/m .  Estimates of retention In the lung have ranged
from 28% to 24Z.  Dermal absorption is also rapid, but in most cases the
opportunity for this route of exposure is Insignificant.

The metabolism of TCE is an Important factor in its toxicity.   Trichloro-
ethylene is metabolized to active intermediates (e.g., 2,2,3-trichloroxirane,
dichloroacetic acid) that may be responsible for some of  the long-term effects
of TCE.  Additionally, there are Important differences in the  metabolism among


                                     10-1
-------
                                                                  Jttfe Systems, JHC.
different species, making interspecies comparisons difficult.  Trichloro-
ethylene does not appear to be teratogenic.  Available evidence concerning
mutagenicity is nixed.  Trichloroethylene was mutagenlc in two microbial
nutagenlcity assays (an Ames test and a host-mediated assay in mice).
However* exposure of mouse sperm cells to TCE had no significant effect on
litter size (dominant lethal assay).

10.2.1    Honcareinogenic Studies

10.2.1.1  Animal Studies

Trichloroethylene* like most other chlorinated aliphatic hydrocarbons,
produces depression of the CSS and inhibits cardiac function in animals
following acute exposure.  At higher doses liver damage occurs.  Evidence
indicates that repeated acute exposures are no more harmful to laboratory
animals that a single, acute exposure (i.e., there is no accumulation).

Grandjean (1960) exposed male rats to 200 and 800 ppm TCE vapor for 4 to
11 weeks.  After a single three-hour exposure the animals were tested in  a
previously trained rope-climbing experiment.  The number of spontaneous climbs
to receive a reward was significantly increased in comparison to controls.
The observed effect* attributed to TCE-induced excitability, was, however, not
dose dependent.  In a subsequent study Grandjean (1963) exposed rats to 400 or
800 ppm TCE for six hours and measured swimming performance and motor
activity.  At 400 ppm performance was retarded slightly; at 800 ppm
performance was significantly adversely affected.  One hour after termination
of exposure no significant changes were observed.

Adams et al. (1951) exposed several species to various levels of TCE vapor
7 hours/day, 5 days/week for 6 months.  The authors determined iM-«-»m««i
no-effect levels of 400 ppm in monkeys, 200 ppm in rabbits and rats and
100 ppm in guinea pigs.  Prendergast et al. (1967) subjected rats, rabbits,
guinea pigs, monkeys and dogs to either 730 ppm TCE (5 days/week, 8 hours/day
for six weeks) or 35 ppm (continuously for 90 days).  In both these
experiments, the only effects of TCE exposure observed were occasional, slight
body weight loss or below normal body weight gain.

Klmmerle and Eben (1973) exposed male rats to 55 ppm TCE vapor for 15 weeks
(8 hours/day, 5 days/week).  The only observable effect seemed to be increased
liver weights.  Clinical hematologlcal values were within normal ranges.

Tucker et al. (1982) exposed male and female CD-I mice to TCE in drinking
water at concentrations of 0, 100, 1,000, 2,500 or 5,000 mg/L for six months.
The 100-mg/L dose produced no observed effects in the mice.  The 1,000-tng/L
dose produced an increase in the ratio of liver weight to total body weight in
males only.  At the 2,500-mg/L dose males exhibited Increased ketone (an
indication of diabetes) and protein levels In the urine and Increased relative
liver weights.  These effects were not observed in the females.  The highest
dose produced decreased body weights, Increased liver and kidney weights  and
increased urinary ketone and protein levels.
                                      10-2
-------
                                                                  J&fe Systems, JHC.
Stott et al.  1982 administered various doses of TCE to mice  and  rats  by gavage
(5 days/week) for three weeks.  At 250 mg/kg minimal hepatotoxic effects were
observed in the mice.  Doses of 500 mg/kg/day or greater produced
centrilobular hypertrophy  (swelling of the middle of the lobe) in the mouse
livers.  In contrast, a dose of 1,000 mg/kg/day resulted in  no liver  damage  in
the rats.

10.2.1.2  Human Studies

In humans, acute exposure  to high levels of TCE results in CNS depression  such
as incoordination and unconsciousness.  Although there have  been incidences  of
acute exposure, clinical analysis of these incidents rarely  establishes
clear-cut exposure limited to only TCE.  Chronic exposure of humans to  TCE in
occupational settings has  resulted in few reports of liver damage.

Single oral doses of TCE ranging from 7.6 to 35 g have been  reported  to produce
adverse symptoms and eventual recovery.  Feldman (1970) reported on a person
exposed to TCE vapors from an overheated, degreasing unit (exposure level  not
reported).  Symptoms included nausea, vomiting, blurred vision and facial
numbness.  An 18-month recovery period resulted in restoration of facial
sensation and motor function.  In fatal cases of acute TCE exposure,  no tissue
abnormalities were observed at autopsy (Kleinfeld and Tabershaw  1954).

Epidemiological evidence has been generally reported on workers  exposed
occupationally.  These studies rarely include an unexposed control group.
Demographic characteristics of the exposed group are not always  provided.
Another serious flaw includes lack of information about possible exposures to
other chemicals in the workplace.

Bordodej and Vyskocil (1956) examined 75 persons occupationally  exposed  to TCE
in drycleaning or degreasing establishments.  The TCE concentration varied
from 50 to 630 ppm; workers had been exposed from six months to  25 years.
Symptoms including alcohol intolerance, shivers, giddiness, anxiety and
cardiac abnormalities and  sleep disturbances were found to be significantly
correlated with the duration of exposure.

Takamatsa (1962) studied 50 males and female factory workers exposed  to TCE
for approximately 2.5 years.  Airborne TCE concentrations ranged  from 25 to
250 ppm.  Workers exposed  to less than 50 ppm TCE showed no apparent  ill
effects.  Six workers In a degreasing room (150 to 250 ppm TCE)  reported
headaches, dizziness, giddiness, drunken feeling, flushing of the face,
burning throat and fatigue.

10.2.2    Mutagenic and Carcinogenic Studies
                             I
10.2.2.1  Animal Studies     i

A number of carcinogenic studies have been performed In rats and mice that
indicate the carcinogenic potential of TCE.  Experimental details for these
studies are provided In Table 10-1.  The National Cancer Institute (NCI)
(1976) conducted a 78-week carcinogenic study in rats and mice.  Five-week-old
                                     10-3
-------
                                                                Jdfe Systems. JHC.
  1
  fc
  0
976
NC
982
982
Henschler
et al.
(1980)
                ~  -8
occurr
11/47
umo
e) and
reated
with 0/20
(P<0.05
t
s
the
ared
atocellular
4/50 (low-d
e) of
s comp
emale
ev
gh
ra
gh
a
f
hi
(

Hep
in
(hi
fem
con
were
for the

No effects





0 •
•0 -H CO
i • a
5 • o
J3 0 0
•STJ
:ss
iH «H O
SO
** 0
0 0
0 5 >o
«a u 0
O -H
Tias
•ftU
-------
                                                                                             JCife Systems, JHC.
                    0
                    u
                    M

                    VM

                    OS
                              KUM00
                          H 0    «y«w0H0-Hca
                                                        0 O
                    X
                    01
                    M
                        pu fe PM to   P* te (M
Species
(strain
                                  co
                          8/-»
                          U
                        9 «
                        0 M
                        8 vx
                                  >>
                                00
                                U «-l
                             M  0. »
                             « CO 5
                             h «-* Q
tLJ fi
 o "
                    1
                  «W M
                  e« «
                         a
                        us
       1


       i
!
                  4J 0
                  0 0
                  M M
                  9 H
                  Q
                                          cd 0
                                         •o «
        fa a ao h a eo
          §>»-< 9 >>-*
          0    00
       JC -O M J3 •« fa
            O     O
                           • o
                      fa
                      o
                                                      M »
                                      I*
                                                      14 • o
            --8
          •o
          !
          g
          u
0
a
o
Q
§.0.
a. a.
o o
0 0
•* m
§.§,
a. o,
•^ m
§,§.§.
O. PU ft.
o o o
m m in
•— < -*
1; I g.
Cb CU ftl
o o o
m in m
                                                           10-5
-------
                                                                  J&fe Systems, Jnc.
mice and seven-week-old rats were gavaged 5 days/week with TCE with a high or
low dose.  No treatment-related effects were observed in rats.  There was  a
significant increase in hepatocellular carcinomas in the male mice  at both
doses and in the females of the high-dose group.  Due to suspected  contamina-
tion of the original test material with eplchlorohydrln (a known  carcinogen),
the bioassay was repeated.  In the repeat bioassay, rats (F344/N)     and mice
(B6C3F1)W of both sexes were administered TCE by gavage for 103 weeks.   Rats
received doses of 500 or 1,000 mg/kg; mice were administered 1,000  9g/fcg*
Trichloroethylene was not found to be carcinogenic in female F344/N   rats.
The experiment with male rats was considered to be inadequate, since these
rats received dose levels of TCE that exceeded the maximum tolerated dose.
Trichloroethylene was demonstrated to be carcinogenic in both sexes of
B6C3F1^   mice, producing hepatocellular carcinomas.

The NTP (1982) completed a bioassay using Fisher 344(a) rats and  B6C3Fl(a)
mice.  Trichloroethylene was administered by gavage at doses of 500 or
1,000 mg/kg in rats and 1,000 mg/kg in mice for 103 weeks.  High-dose male
rats exhibited a significant increase In kidney tubular adenocarcinomas.   A
dose-related reduction in survival was noted in male rats.  Toxic nephrosis
(degeneration of the cells in the kidney tubules) was found in treated rats
dying during the course of the study.  In the treated mice, body weights and
survival were reduced in males.  In both sexes there was a significant
increase in the incidence of hepatocellular carcinomas.

Henschler et al. (1980).studied the effect of chronic inhalation of TCE on the
.tumor incidence in NMRI    mice, Wlstar rats and Syrian hamsters.   Groups  of
male and female animals of each species were exposed by Inhalation  to 100  or
500 ppm TCE for 18 months.  At 30 months (for mice and hamsters)  and 36 months
(for rats), no statistically significant increased tumor incidences were
observed in any group except for malignant lymphomas in female mice in both
treated groups.

Fukuda et al. (1983) examined the effect of chronic inhalation of reagent
grade TCE  (99.8% pure) on the tumor incidence in female ICR    mice and
Sprague-Dawley rats.  Groups of 49 to 51 animals of each species were exposed
to 0, 50,  150 or 450 ppm TCE for 104 weeks.  In mice, the incidences of
pulmonary adenocarcinomas in the 150 ppm group and the 450 ppm group were
significantly higher than that of controls.  The average number of  lung tumors
per mouse in groups exposed to 150 ppm TCE and 450 ppm TCE was more than three
times that of the controls.  No increased tumor incidences were observed in
rats.

10.2.2.2  Human Studies

Axelson et al.  (1978) conducted an epidemlological study of cancer  deaths
among a group of 518 men occupatlonally exposed to TCE.  Exposure was ;
 (a)  A series  of  letters,  numbers  or  a  combination  of both  Indicates a  specific
     strain (i.e.,  a  race  or  stock) of  animals  that all have common hereditary
     characteristics.
                                      10-6
-------
                                                                  £ ft Systems, Jnc.
estimated by measuring a  TCE metabolite,  trlchloroacetic acid (TCA), in the
urine.  A TCA  level of >100 mg/L was  considered to be high exposure,
corresponding  to more than 30  ppm in  air.  Close agreement was found between
observed and expected numbers  of cancer deaths based on national Swedish death
rates.  Since  the sample  was small, the authors hesitated to rule out an
increased cancer risk from TCE exposure,  especially from rare tumors.

10.3      Quantitative Indices of Toxicity

A number of estimates of  noncarcinogenic  indices of toxicity and estimates of
carcinogenic risk have .been calculated for TCE.  These are summarized in
Table 10-2.

10.3.1    Noncarcinogenic Effects
        •  ^^•••••^•^•"•^^^••^^^••^•••••^••^•^^•"^^^^•^^•fc^^"

There have been several risk estimates for TCE calculated with regard to
noncarcinogenic endpoints.   The National  Academy of Sciences (HAS 1980)
calculated a Suggested No-Adverse-Response Level (SNARL) of 105 mg/L of
drinking water based on observation that  the  lowest oral dose of TCE reported
to produce inebriation was approximately  300  mg/kg.  A 100-fold safety factor
was used in the calculation, recognizing  that the minimum effect level fo?
inhibition of  reflexes was undoubtedly lower  than 300 mg/kg.  It was assumed
that the sole  source of TCE was drinking  water and that a 70-kg human consumes
2 L/day.  A seven-day SNARL of 15 mg/L was also calculated by dividing the
one-day value  by 7.  A chronic minimum effect level was not established  due to
lack of appropriate, data.

The EPA Office of Drinking Water (USEPA 1979)  computed a one-day SNARL value
of 2 mg/L.  This value was based on a study in which human volunteers were
exposed via inhalation to 110  ppm of  TCE  for  an eight-hour period.   The
calculation considered the most sensitive subpopulation (children)  and used an
uncertainty factor of 100.   A  ten-day SNARL was conservatively estimated by
dividing the one-SNARL by 10 (200 Ug/L).   A chronic SNARL of 74 yg/L was
derived using  the minimum effect level of 55  ppm observed in the Kiamerle and
Eben (1973) study.

The EPA Office of Water Regulations and Standards (USEPA 1980)  established an
ADI of 38 mg/day based on the  noncarcinogenic  endpoints noted in the NCI
(1976) bioassay (dose-related  decreased survival,  chronic kidney disease).
The lowest dose (548 mg/kg/day,  time-weighted  average)  was considered a
LOEL.  Assuming daily consumption of  2 L  of water and 6.5 grams of
contaminated fish, the level that protects against the  toxic effects of  TCE
was calculated to be 18.3 mg/L.

The American Conference of  Governmental Industrial Hygienists (ACGIB 1980)
has recommended a Threshhold Limit Value  (TLV)  of  50  ppm and a  Short-Term
Exposure Limit (STEL) of  150 ppm.  These  levels are recommended to  provide
workers with adequate protection against  the toxic effects of TCE.   An
8 hour TLV of  100 ppm has been proposed by the National Institute for
Occupational Safety and Health (NIOSH)  (1973)  for  an  eight-hour workday.
                                     10-7
-------
                                                                 Jttfc Systems, Jnc.
                      TABLE 10-2  RISK ESTIMATES FOR TCE
       Organization
     Noncarcinogenic
HAS (1977)

HAS (1980)
USEPA (1979)
(Office of Drinking Water)
USEPA (1980)
(Office Water Regulations
and Standards)

ACGIH (1980)
NIOSH (1973)
105 mg/L (one-day SNARL)
15 mg/L (seven-day SNARL)

2 mg/L (one-day SNARL)
200 yg/L (ten-day SNARL)
74 yg/L (chronic SNARL)

38 ing/day (ADI)
18.3 mg/L (Ambient Water
Standard)

50 ppm (TLV)
150 ppm (STEL)

100 ppm (TLV, 8-hour)
10   Excess Cancer Risk

        6.3 yg/L

        3.0 yg/L
        2.7 yg/L
                                                                                  i
                                      10-8
-------
                                                                   £ife Systems, JHC.
10.3.2    Carcinogenic Effects

The IARC has performed an assessment of the degree of evidence for the
carcinogenicity of TCE to humans and experimental animals which was published
by the World Health Organization (WHO) (WHO 1982).  This assessment concluded
that TCE is a Group 3 chemical (inadequate evidence of carcinogenicity in
animals or humans).  Nonetheless, several carcinogenic risk assessments have
been performed.

A statistical assessment of human cancer risk associated with TCE in drinking
water was performed by NAS (1977) based on the NCI (1976) study.  For TCE at a
concentration of 1 yg/L, the estimated risk was calculated to be 0.36 to.
1.1 x 10" .  The concentration corresponding to a cancer frequency of 10~  is
9.1,to 27.7 ug/L.  The upper bound 95% confidence limit estimate was 1.6 x
10~  for 1 ug/L.  This corresponds,to a concentration of 6.3 yg/L for an
excess lifetime cancer risk of 10~ .  Using the data from NTF (1982), another
estimate was made using the multistage model (USEPA 1983).  Averaging both the
male and female data sets, the estimated upper 952 confidence estimate of
lifetime risk per yg/L was 3.3 x 10  .  The concentration corresponding to a
10   risk level is 3.0 yg/L.  The EPA Office of Water Regulations and
Standards (USEPA 1980), using the data from-NCI (1976), published a
recommended criterion of 2.7 yg/L for the 10~  risk level.

10.4      Special Concerns

Since the toxicity of TCE is highly dependent on its. metabolism, the
possibility exists that there will be age and sex differences and additional
risk in extrapolating results from one species to another.  Additionally,
there is the possibility of synergistic effects with alcohol.

10.5      References

ACGIH.  1980.  American Conference of Governmental Industrial Hygienists.
Threshold limit values for chemical substances and physical agents in the
workroom environment with intended changes for 1980.  Cincinnati, Ohio:
American Conference of Governmental Industrial Hygienists, p. 406.

Adams EM, Spencer NC, Rowe KU, McCollister DO, Irish DD.  1951.  Vapor
toxicity of trlchloroethylene determined by experiments on laboratory animals.
AHA Arch. Ind. Hyg. Occup. Med. 4:469.

Axelson 0, Andersson R, Hogstedt C, Holmberg B, Molina G, de Verdier A.  1978.
A cohort study on trichloroethylene exposure and cancer mortality.  J.  Occup.
Med. 20:194.

Bardodej Z, Vyskocil J.  1956.  The problem of trichloroethylene in
occupational medicine.  AMA Arch. Ind. Health 13:581.

Dekant W, Metzler M, Henschler D.  1984.   Novel metabolites of
trichloroethylene through dechlorination reactions in rats, mice and humans.
Biochem. Pharmacol. 33:2021-2027.
                                     10-9
-------
                                                                   & ft Systems, JHC.
Feldman EG, Mayer KM, Taub A.  1970.  Evidence for a peripheral neurotoxic
effect of trlchloroethylene.  Neurology 20:599-606.

Pukuda K, Takemoto K, Tsuruta H.  1983.  Inhalation carcinogenicity of
trichloroethylene in mice and rats.  Industrial Health 21:243-254.

Grandjean E.  1963.  The effects of short exposures to trichloroethylene on
swimming performances and motor activity of rats. Am. Ind. Hyg. Assoc. J.
24:376.

Grandjean E.  1960.  Trichloroethylene effects on animal behavior.  Arch.
Environ. Health 1:106.

Henschler D, Romen W, Elsasser HM, Reichert D, Ecler E, Radwan Z.  1980.
Carcinogenicity study of trichloroethylene by long-term inhalation in three
animals species.  Arch. Toxlcol. 43:237-248.

Klmmerle G, Eben A.  1973.  Metabolism, excretion and toxicology of
trichloroethylene after Inhalation.  I. Experimental exposure on rats.  Arch.
Toxicol. 30:115.

Kleinfeld M, Tabershaw IR.  1954.  Trichloroethylene toxicity.  AMA Arch. Ind.
Hyg. Occup. Med. 10:134.

HAS.  1980. . National Academy of Sciences.  Drinking water and health.  Vol.
III.  Washington, DC:  National Academy Press.

HAS.  1977.  National Academy of Sciences.  Drinking water and health.  Vol I.
Washington, DC:  National Academy Press.

NCI.  1976.  National Cancer Institute.  Carclnogenesis bioassay of
trichloroethylene.  U.S. Department of Health Education and Welfare, Public
Health Service.

NIOSH.  1973.  National Institute for Occupational Safety and Health.
Criteria for recommended standard occupational exposure to trichloroethylene.
HFM 73-11025.  Washington, DC:  U.S. Government Printing Office.

NTP.  1982.  National Toxicology Program.  Carcinogenesis bioassay
experimental and status report, March 1982.  National Toxicology Program:
Research Triangle Park, NC.

Prendergast JA, Jones RA, Jenkins LJ, Slegel J.  1967.  Effects on
experimental animals of long-term inhalation of trichloroethylene, carbon
tetrachloride,  1,1,1-trichloroethane, dichlorodifluoromethane, and
1,1-dichloroethylene.  Toxicol. Appl. Pharm. 10:270.

Stewart RD, et al.  1962.  Observations on the concentrations of
trichloroethylene in blood and expired air following exposure to humans.  Am.
Ind. Hyg. Assoc. J. 23:167.
                                      10-10
-------
                                                                 Jjfc Systems, Jnc.
Stott WT, Quast JF, Watanabe PG.  1982.  The pharmacoklnetics and
macromolecular interactions of trichloroethylene in mice and rats.  Toxicol.
Appl. Pharmocol. 62:137-151.

Takamatsa M.  1962.  Health hazards in workers exposed to trichloroethylene
vapor.  II.  Exposure to trichloroethylene during degressing operation in a
communicating machine factory.  Kumamoto Med. J. 15:43.

Tucker An, Sanders VM, Barnes DW, Bradshav TJ, White KL, Sain LE, GBorzelleca
JF, Munson AE.  1982.  Toxicology of trichloroethylene in the mouse.  Toxicol.
Appl. Pharmacol. 62:351-357.

USEPA.  1983.  United States Environmental Protection Agency.  Health
assessment document for trichloroethylene.  ECAO.  Research Triangle Park, NC.
December 1983 draft.
                 *
USEPA.  1980.  United States Environmental Protection Agency.  Ambient water
quality for trichloroethylene. . Washington, DC:  U.S. Environmental Protection
Agency.  EPA 440/5-80-077.

USEPA.  1979.  United States Environmental Protection Agency.  SNARL for
trichloroethylene.  Health Effects Branch, Criteria and Standards Division,
Office of Drinking Water, Washington, DC.

USEPA.  1975.  United States Environmental Protection Agency.  Identification
of organic compounds in effluents from industrial sources.

WHO.  1982.  World Health Organization.  IARC monographs on the evaluation of
the carcinogenic risk of chemicals to humans.  Chemicals, industrial processes
and industries associated with cancer in humans.  International Agency for
Research on Cancer Monographs.  Vol 1 to 29, Supplement 4.  Geneva:  World
Health Organization.
                                     10-11
-------

-------
                                                                  &{e Systems, Jnc,
11.0      SUMMARY OF TOXICOLOGICAL INFORMATION ON LEAD

This chapter provides a summary of current toxlcological  Information on
lead.  This compound was chosen for consideration here because  of  its high
inherent toxicity and because it is often found as a contaminant at  hazardous
waste sites.  This chapter is similar to the sort of summary which might be
prepared by a toxicologist for a hazard assessment, and therefore  it is
somewhat more technical and detailed than chapters 1 to 8 of this  handbook.  A
nontoxicologist would not be expected to prepare a summary of this sort, but
should, on the basis of the information presented in chapters 1 to 8 of the
handbook, be able to understand and apply this information.

11.1      Chemical Properties and Environmental Stability

Lead is a metallic element designated by the symbol Fb.   Contamination of the
environment with lead has increased dramatically since the industrial
revolution, due primarily to lead emissions into the air.  These emissions may
be inhaled directly, or may settle on soil or water and be ingested.   The
chemical form of lead emissions and its form in soil, water or  the food chain
varies considerably, but is nearly always some oxide, salt or complex of the
lead ion (Pb  ).  Lead oxides, salts and complexes may be altered  by
speciation reactions, but the lead ion itself is stable under normal
environmental conditions.

11.2      Summary of Health Effects Data

Lead exposure produces adverse effects on many systems of the body,  including
the hematopoietic, cardiovascular, nervous, endocrine, renal, reproductive and
digestive systems.  Acute lead intoxication in humans is  characterized by
encephalopathy (disease of the brain), abdominal pain, hemolysis (destruction
of red blood cells), liver damage, renal tubular necrosis, seizures,  coma and
cardiorespiratory arrest.  Severe poisonings of this sort are rare,  and most
concern regarding lead toxicity focuses on insideous Injury to the hema-
topoietic system, the nervous system and the cardiovascular system following
chronic exposure to low levels of lead.  Of particular concern are data that
suggest that some of these effects may not have a threshold value.

Lead-induced effects have been extensively investigated both in animals and In
humans.  Studies in animals are useful since dose levels and the chemical form
of administered lead are known, but they are limited by differences in  lead
absorption and metabolism between animals and humans.  Studies in humans are,
therefore, more directly useful, but accurate knowledge of exposure levels,
exposure routes or chemical form are rarely known.

One means of solving this problem is to assess human exposure to lead by
measuring the concentration of lead in the blood (FbB).  This value reflects
the magnitude of current or recent-past exposure to lead,  and it is possible
to calculate the exposure that produced the observed FbB value.   While  this
approach permits the use of human data in identifying NOAEL and LOAEL values
for lead, it is limited by the fact that the calculation of lead exposure from
measured FbB values may not be highly accurate.   Moreover, many of the toxic
                                     11-1
-------
                                                                  £ife Systems, Jnc.
effects of lead arc irreversible and current or recent-past exposure  levels
•ay not reflect exposure levels at the tine the injury actually occurred.

The following sections provide brief descriptions of some representative
studies of the key adverse health effects of lead in animals and humans.

11.2.1    Noncarcinogenic Studies

11.2.1.1  Effects of Lead on Henatopoiesis

Lead inhibits several key enzymes involved in heme  (a component of hemoglobin)
biosynthesis.  The activity of delta-aminolevulinic acid dehydratase  (ALA-D)
appears to be very sensitive to lead* and inhibition had been reported  at
quite low PbB values.  Hernberg and Nikkanen (1970) found that ALA-D  activity
was inversely correlated with PbB values in a group of subjects with  50Z
inhibition at a PbB level of 16 Mg/dL.  Other reports have.confirmed  these
observations across age groups and exposure categories.

The inhibition of ALA-D is reflected by increased levels of its substrate,
delta-aminolevulinic acid (ALA), both in urine and in whole blood or  plasma.
The toxicological significance of an increase in cellular or plasma ALA levels
is uncertain, but it appears that ALA can inhibit release of neurotransmitter
from nerve cells, even at ALA levels as low as 1.0 idi (Brennan and Cantrill
1979).

Another enzyme of heme biosynthesis that is inhibited by lead is
ferrochelatase.  This enzyme inserts ferrous ion (Fe  ) into protoporphyrin to
form heme.  In lead exposure, the porphyrin acquires a zinc ion in lieu of
ferrous ion, forming zinc protoporphyrin (ZPP).  A correlation between  PbB and
erythrocyte ZPP has been extensively documented, with a threshold value of
about 15 to 30 ug/dL (Reels et al. 1975, Plomelll et al. 1982).

One of the most characteristic effects of chronic lead intoxication is  anemia.
The mechanism of lead-associated anemia appears to be a combination of  reduced
hemoglobin production and shortened erythrocyte survival.  Reduced
hemoglobin production is a consequence of inhibition of heme synthesis  (as
described above), coupled with a decreased production of globin.  It  is also
clear that there is a hemolytic component to lead-induced anemia in humans,
owing to shortened erythrocyte survival (Hernberg et al. 1967, Leikin and Eng
1963).

Exposure to lead results in inhibition of heme biosynthesis not only  in
erythrocytes, but in other tissues as well.  This results in decreased
activity of a number of heme-containing enzymes, including cytochrome P-450
(which is important in metabolism of many drugs, chemicals and natural
compounds) and the renal enzyme 1-hydroxyglase (which mediates the final step
in the synthesis of the active form of vitamin D).  Inhibition of the latter
enzyme impairs biosynthesis of the active form of vitamin D, and this may
produce a series of adverse effects related to calcium absorption and cell
development.
                                      11-2
-------
                                                                  Oft Systems, Juc.
11.2.1.2  Effects of Lead on th« Nervous System

Studies In animals indicate that the perinatal period of ontogeny  is a time of
particular sensitivity of the nervous system to lead exposure.   In nursing
female rats, ingestion of water containing levels as low as 20 mg  Pb  /L
(2 mg/kg/day) causes effects on neurotransmitter metabolism in the offspring,
and higher exposure levels result in a number of morphologic, biochemical and
electrophysical changes (Govoni et al. 1980).

Grant et al. (1980) exposed rats indirectly to lead in utero and during
lactation through the mother's milk and, after weaning, directly through
drinking water.  There were delays in the development of surface righting and
air righting reflexes in subjects given water containing 50 or 250 mg Pb  /L
(5 or 25 mg/kg/day).  Generally similar results were obtained when suckling or
young rats were exposed to lead directly (as opposed to indirect exposure via
the mother).  Cory-Slechta and Thompson (1979) supplied weanling male
rats with drinking water solutions containing 25, 150 or 500 mg  Pb /L (2.5,
15 or 50 mg/kg/day).  Animals exposed to 50 ppm or 300 ppm lead  solutions
showed significantly higher response rates than matched controls during
conditioned response training.  Jason and Kellogg (1981) reported  a
developmental lag in activity around post-natal day (PUD) 15 to  18, as
measured in an automated activity chamber.  Rat pups were dosed  on PHD 2 to 14
with lead at 25 or 75 mg/kg.  A delay in the characteristic decrease in
activity that normally occurs in pups at that age was observed,  indicating
that lead-exposed pups were significantly more active than control subjects at
PHD 18.  These alterations in behavior are indicative of altered neural
functioning in the CNS.
      ^
Bushnell and Bowman (1979) investigated the effect of lead on learning in
rhesus monkeys.  Lead acetate was fed to the animals for 12 months, resulting
in PbB levels of '30 to 50 Ug/dL (versus 5 Vg/dL in controls).  Exposed
monkeys were significantly retarded in their ability to learn a  visual
discrimination task.

In conclusion, it appears that alterations in behavior and neural  development
in rats and monkeys occur as a consequence of oral exposure to lead.  These
alterations are presumably indicative of altered neural functioning,
especially in the CNS, but whether such alterations represent biologically
significant Impairment in overall functioning of the lead-exposed  subjects is
not yet clear.

There are many reports of lead-induced nervous system injury in humans.   Morgan
and Repko (1974) reported deficits in hand-eye coordination and reaction time
in an extensive study of behavioral functions in 190 lead-exposed workers.
Similar studies (Arnvig et al. 1980, Haenninen et al.  1978,  Valciukas et al.
1978) have found disturbances in visual motor performance, IQ test
performance, hand dexterity, mood, nervousness and coping in lead workers with
PbB values of about 50 to 80 yg/dL.

Seppalainen et al. (1975) measured nerve conduction velocity (NCV)  in 26 lead
workers whose PbB levels had been monitored regularly for several years.   Most
                                     11-3
-------
                                                                 J&ft Systems, Jnc.
                                                                                   n.
PbB values ranged between 35 and 60 Vg/dL with occasional values as low as 20
or as high as 70 Vg/dL.  There was a clear decrease in mean NCV in nerves of
the arm in exposed workers compared to controls (P<0.01).  The authors
emphasized that the data showed evidence of neurophysiological effects in
workers whose PbB values never exceeded 70 Vg/dL.

Melgaard et al. (1976) observed a clear association between lead exposure and
peripheral nerve dysfunction in 20 automobile mechanics exposed to tetraethyl
lead and other lead compounds in lubricating and high-pressure oils.  Half of
the workers had elevated PbB levels (60 to 120 Vg/dL) and showed definite
electromyographic deficits (abnormal electrical activity in skeletal muscles).
The mean blood lead level for the control group was 18.6 Vg/dL.

Thus, considerable evidence exists that peripheral nerve dysfunction occurs in
adults at PbB levels as low as 30 to 50 Vg/dL.  The question as to whether
these reflect mild, reversible effects or are true early warning signals of
progressively more serious peripheral neuropathies la still a matter of some
dispute.

As in experimental animals, the developing child appears to be especially
sensitive to lead-induced nervous system injury.  De la Burde and Choate
(1972, 1975) observed neurological dysfunctions Including fine motor
dysfunction, Impaired concept formation and altered profiles in 70 preschool
children exhibiting pica behavior (the tendency to eat dirt).  These children
displayed elevated PbB levels (30 to 100 Vg/dL, mean « 58 Vg/dL) in comparison
with 70 matched control subjects not engaging in pica.  Continuing CMS
impairment in the lead-exposed group, as assessed by a variety of
psychological and neurological tests, was observed when the children wsre
seven to eight years old, despite the observation that many of their PbB
levels had by then decreased significantly from the Initial study.

The relationship between low-lead exposure, psychometric function and
electrophysiological response In children aged 13 to 78 months was explored In
studies by Mllar et al. (1980, 1981), Otto et al. (1981) and Benlgnus et al.
(1981).  Psychometric evaluation revealed lower scores for children with PbB
levels of 30 Vg/dL or higher compared to children with PbB levels under
30 Vg/dL, but the observed IQ deficits were confounded by poor home caregiver
environment scores in children with elevated PbB levels.  Electrophysiological
assessments, Including analyses of slow potentials during sensory conditioning
and electroencephalogram (EEC) spectra, did provide evidence of CNS effects of
lead in the same children.  A significant linear relationship between PbB
(ranging from 7 to 59 Vg/dL) and slow wave (SW) voltage was observed (Otto et
al. 1981).  Analyses of quadratic and cubic trends in SW voltage did not
reveal any evidence of a threshold for this effect.

Seattle et al.  (1975) identified 77 retarded children and 77 normal children
matched for age, sex and geography.  Of 64 matched pairs, 11 of the retarded
children came from homes with high concentration of lead In the water.  By
contrast, none of the control children came from such homes.  In a follow-up
study, PbB values of the mental retardates, measured during the second week of
life, were found to be significantly higher than those of control subjects
(25.5 ± 8.9 versus 20.9 ± 7.9 Vg/dL) (Moore et al. 1977).  When compared with
                                      11-4
-------
                                                                  J&fe Systems, Jnc.
studies of children suffering neurobehavloral deficits  produced by direct
exposure to lead, these studies suggest  that  the brain  of  the fetus is
considerably more sensitive to the  toxic effects of  lead than the brain of the
young child.

11.2.1.3  Effects of Lead on Blood  Pressure

Several epidemlological studies have Indicated that  chronic  lead exposure may
be associated with increased blood  pressure in humans (Dingwall-Fordyce and
Love 1963, Beevers et al. 1980), although other studies have not detected such
an association  (Cramer.and Dahlberg 1966).

More recently, Harlan et al. (1985) examined  the relationship between PbB and
blood pressure by statistical analysis of the data base obtained during the
second National Health and Nutrition Examination Survey (NHANES-II).   This
survey collected Information on a representative cross-section of over 20,000
members of the U.S. population.  Using simple regression analysis,  a  direct,
nearly linear relationship was found between  PbB and blood pressure in both
men and women aged 12 to 74 years.  Since blood pressure is  known to  be
related to factors such as age and  body  mass,  multiple  regression analyses
were performed po separate confounding factors.  After  accounting for these
and other variables, PbB was found  to retain  a statistically significant
relationship to blood pressure in males  (P<0.05) but not in  females.   The
authors cautioned that causal inferences about effects  of  PbB on blood
pressure should not be drawn from this cross-sectional  survey,  although the
results obtained were consistent with a  direct effect.
                                    *                            •
Pirkle et al. (1985) employed the NHANES-II data base to perform a  detailed
statistical analysis of the relation between  PbB and blood pressure in white
males aged 40 to 59 years.   This sub-population was selected because,  in this
age range, the effects of age on blood pressure are  small, and  confining the
analyses to white males obviated the confounding effects of  sex and race.
Regression analyses correcting for  age and body mass indicated  that PbB values
correlated to both systolic and diastolic blood pressure.  Segmented
regression analyses Indicated there was  no threshold below which blood
pressure was not related to PbB.

11.2.2    Mutagenic and Carcinogenic Studies

Studies of cytogenetic (chromosome appearance) abnormalities  in persons
exposed to lead have yielded mixed results.  For example, O'Riordan and  Evans
(1974) reported no significant chromosomal damage in male workers with PbB
values from 40 to 120 Ug/dL.  However, Forni et al.  (1976)  found the  Incidence
of abnormal metaphases doubled (PS0.05)  In workers exposed for one month  to
air lead levels of about 0.8 mg/m .

A number of ingestion studies on the carcinogenic potential of various lead
salts in animals have been reported.  The most common observation was
increased frequency of renal tumors, although evidence of tumors In other
tissues has been noted.  The doses of lead producing these  effects were quite
high, generally 0.1Z to 1Z in the diet (equivalent to about 50 to
500 mg Pb/kg/day).  For example, Azar et al. (1973) reported dose-dependent
                                     11-5
-------
                                                                  £ife Systems, JHC.
increases in renal tumor frequency in male rats fed 500 to 2,000 ppm Pb  in  the
diet.  It should be noted that these doses are associated with moderate  to
severe non-carcinogenic effects in rats.

A number of epldemlologlcal studies.of industrial workers with elevated  lead
exposure have been conducted to evaluate the role of lead in the induction  of
human neoplasia (Cooper 1976, Dingwall-Fordyce and Lane 1963, Lane  1964,
McMichael and Johnson 1982).  In general, these studies made no attempt  to
consider the types of lead compounds to which workers were exposed, or to
determine probable routes of exposure.  While a number of these studies  found
an association between, lead exposure and the frequency of various cancer
types, no study was sufficiently free of confounding factors to permit a clear
conclusion.

The IARC has performed an assessment of the degree of evidence for  the
carcinogenicity of lead and lead compounds in humans and experimental animals
(WHO 1982).  This assessment concluded that lead and lead compounds are  Group
3 compounds (sufficient evidence for carcinogenicity of some lead salts  in
animals, but inadequate evidence for carcinogenicity in humans).

11.3      Quantitative Indices of Toxicity

Many studies in animals indicate that adverse effects occur in pups born to
dams exposed to doses of lead from 5 to 150 mg/kg/day.  Similarly,  studies  in
young animals exposed to lead directly indicate that doses of 5 to
500 mg/kg/day cause behavioral or neurological effects.
                                               €                             *

Studies in humans suggest that PbB values of around 25 yg/dL or higher are
associated with adverse effects in adults, and even lower values may be
associated with adverse effects in children.  Some effects may occur without a
threshold value.  Equations have been developed which describe the
relationship between PbB values and lead exposure via inhaled air and
Ingested food, water or soil.  While there is some variability between
different studies, application of these equations makes clear, that  daily
ingestion or inhalation of several hundred mlcrograms or less of Pb could
yield these PbB values.

The current MCL for lead in drinking water Is 50 Pg/L (USEPA 1976).  This
corresponds to a total ADI of 100 tig/day.  The present TLV for inorganic lead
compounds in inhaled air is 0.15 mg/m , and the STEL is 0.45 mg/m   (ACGIH
1980).  There is growing awareness that present exposure limits may not
provide an adequate margin of safety (e.g., see HAS 1977), and several
agencies are evaluating recent data on lead toxicity to determine if revisions
in existing guidelines and standards are appropriate.

11.4      Special Concerns

There are a number of special concerns associated with lead toxicity.  First,
most adverse effects develop only slowly, but are basically irreversible.
Thus, by the time injury is recognized, permanent harm may already have  been
done.  Second, the fetus in utero and the young child are especially
sensitive.  Third, as analytical techniques and testing protocols become more
                                      11-6
-------
                                                                  £ife Systems, Jnc.
powerful and sophisticated, adverse effects of lead are being detected at
levels previously thought to be safe.  Indeed* some researchers feel there nay
be no threshold for some lead-induced effects.

11.5      References

AGGIE.  1980.  American Conference of Governmental Industrial Hygienists.
Threshold limit values for chemical substances and physical agents in the
workroom environment with intended changes for 1980.  Cincinnati, Ohio:
American Conference of Governmental Industrial Hygienists, p. 243.

Arnvig E, Grandjean P, Beckmann J.  1980.  Heurotoxic effects of heavy lead
exposure determined with psychological tests.  Toxicol. Lett. 5:399-404.

Beattie AD, Moore MR, Goldberg A.  1975.  Role of chronic low-level lead
exposure in the aetiology of mental retardation.  Lance 1 (7907):589-592.

Beevers DG, Cruickshank JK, Yeoman WB, Carter GF, Goldberg A, Moore MR.  1980.
Blood-lead and cadmium in human hypertension.  J. Environ. Pathol. Toxicol.
4:251-260.

Benignus VA, Otto DA, Muller KE, Seiple KJ.  1981.  Effects of age and body
lead burden on CMS function in young children.  II:  EEC spectra.
Electroencephalogr. Clin. Neurophysiol. 52:240-248.
                                                                          *
Breennan MW, Cantrill RC.  1979.  Delta-aminolaevulinic acid is a potent
agonist for GABA autoreceptors.  Nature (London) 280:514-515.

Bushnell PJ, Bowman RE.  1979.  Reversal learning deficits in young monkeys
exposed to lead.  Pharmacol. Biochem. Behav. 10:733-742.

Cooper WC.  1976.  Cancer mortality patterns in the lead Industry.  Ann. N.Y.
Acad. Sci. 271:250-259.

Cory-Slechta DA, Thompson T.  1979.  Behavioral toxiclty of chronic
postweaning lead exposure in the rate.  Toxicol. Appl. Pharmacol. 47:151-159.

Cramer K, Dahlberg L.  1966.  Incidence of hypertension among lead workers:  a
follow-up study based on regular control over 20 years.  Br. J.  Ind. Med.
23:101-104.

De la Burde B, Choate MS, Jr.  1972.  Does asymptomatic lead exposure in
children have latent sequelae?  J. Pediatr. 81:1088-1091.

De la Burde B, Choate MS, Jr.  1975.  Early asymptomatic lead exposure and
development at school age.  J. Pediatr. 87:638-642.

Dingwall-Fordyce I, Lane RE.  1963.  A follow-up study of lead workers.  Br.
J. Ind. Med. 20:313-315.
                                     11-7
-------
                                                                 fife Systems, fac
Govonl S, Memo M, Lucchi L, Spano PF, Trabucchi M.  1980.  Brain
neurotransmltter systems and chronic lead Intoxication.  Pharmacol. Res.
Commun. 12:447-460.

Granick JL, Sassa S, Granick S, Levere RD, Kappas A.  1973.  Studies in lead
poisoning.  II:  Correlation between teh ratio of activated and inactivated
delta-amlnolevulinlc acid dehydratase of whole blood and the blood lead level.
Blochem. Med. 8:149-159.

Grant LD, Kimmel CA, Vest GL, Martinez-Vargas CM, Howard JL.  1980.  Chronic
low-level lead toxicity In the rat.  II.  Effects on postnatal physical and
behavioral development.  Toxicol. App. Pharmacol. 56:42-58.

Haennlnen H, Hernberg S. Mantere P, Vesanto R, Jalkanen M.  1978.
Psychological performance of subjects with low exposure to lead.  J. Occup.
Med. 20:683-689.

Harlan WR, Landis R, Schmounder RL, Goldstein NG, BarIan LC.  1985.  Blood
lead and blood pressure.  Relationship in the adolescent and adult U.S.
population.  J. Am. Med. Assoc. 253:530-534.

Hernberg S, Nikkanen J.  1970.  Enzyme inhibition by lead under normal urban
conditions.  Lancet 1 (7637):63-64*

Hernberg S, Hurmlnen M, Hasan J.  1967.  Nonrandom shortening of red cell
survival times In men exposed to lead.  Environ. Res. 1:247-261.

IARC 1980.  International Agency for Research on Cancer.  Lead and lead
compounds.  In:  IARC monographs on the evaluation of the carcinogenic risk of
chemicals to humans:  some metals and metallic compounds; October, 1979; Lyon,
France.  Geneva, Switzerland:  World Health Organizatlon/IARC; pp. 325-416.

Jason MK, Kellogg CK.  1981.  Neonatal lead exposure:  effects on development
of behavior and strlatal dopamine neurons.  Pharmacol. Biochem. Behav.
15:641-649.

Lane RE.  1964.  Health control in inorganic lead Industries:  a follow-up of
exposed workers.  Arch. Environ. Health 8:243-250.

Leiken S, Eng G.  1963.  Erythrokinetic studies of the anemia of lead
poisoning.  Pediatrics 31:996-1002.

Litman DA, Correla MA.  1983.  L-tryptophan:  A common denominator of
biochemical and neurological events of acute hepatic porphyries?  Science
222:1031-1033.

McMichael AJ, Johnson HM.  1982.  Long-term morality profile of
heavily-exposed lead smelter workers.  J. Occup. Med. 24:375-378.

Melgaard B, Clausen J, Rastogi SC.  1976.  Electromyographic changes In
automechanics with increased heavy metal levels.  Acta. Neurol. Scand.
54:227-240.
                                      11-8
-------
                                                                           JttfeSystems, Jnc.
         Milar CR, Schroeder SR, Mushak P, Boone L.   1981.  Failure  to  find
v        hyperactivity in preschool children with moderately elevated lead burden.   J.
v         Pediatr. Psychol. 6:85-95.

%        Milar CR, Schroeder SR, Mushak P, Dolcourt JL, Grant LD.  1980.  Contributions
         of the caregiving environment  to increased lead burden of children.  Am. J.
         Ment. Defic. 84:339-344.

         Morgan BB, Jr, Repko JD.  1974.  Evaluation  of behavioral functions  in workers
         exposed to lead.  In:  Xintaras C, Johnson BL, DeGroot I, eds. Behavioral
         toxicology:  early detection of occupational hazards.  Washington, DC:
         Department of Health, Education and Welfare; pp. 248-266.

         NAS.  1977.  National Academy  of Sciences.   Drinking water  and health.
         Washington, DC:  National Academy of Sciences.

         Otto DA, Benignus VA, Muller KE, Barton CN.  1981.  Effects of age and body
         lead burden on CNS function in young children.  I:  Slow cortical potentials.
         Electroencephalogr. Clin. Neurophysiol. 52:229-239.

         Pirkle JL, Schwartz J, Landis  JR, Harlan WR.  1985.  The relationship between
         blood lead levels and blood pressure and its cardiovascular risk Implications.
         Am. J. Epldem. 121:246-258.

         Piomelli S, Seaman C, Zullow D, Curran A, Davidow B.  1982.  Threshold for
         lead damage to heme synthesis  in urban children.  Proc. Natl. Acad.  Sci.
         U.S.A. 79:3335-3339.

         Roels HA, Lauwerys RR, Buchet  JP, Urelust MT.  1975.  Response of free
         erythrocyte protoporphyrin and urinary-d-aminolevulinic acid in men  and women
         moderately exposed to lead.  Int. Arch. Arbeitsmed. 34:97-108.

         Seppalainen AM, Tola S, Hernber S, Kock B.   1975.  Subclinical neuropathy at
         "safe" levels of lead exposure.  Arch. Environ. Health 30:180-183.

         USEPA.  1984.  U.S. Environmental Protection Agency.  Air quality criteria for
         lead.  Review Draft.  Research Triangle Park, N.C., EPA report No.
         EPA-600/8-83-028B.

         USEPA.  1976.  U.S. Environmental Protection Agency.  National interim primary
         drinking water regulations.  Washington, DC:  U.S. Gov. Printing Office, pp.
         69-75.

         Valciukas JA, Lilis R, Eisinger J, Blumberg WE, Fischbein A, Selikoff IJ.
         1978.  Behavioral indicators of lead neurotoxicity:  results of a clinical
         field survey.  Int. ARch. Occup. Environ. Health 41:217-236.

         WHO.  1982.  World Health Organization.  IARC monographs on the evaluation of
         the carcinogenic risk of chemicals to humans.  Chemicals, Industrial processes
         and industries associated with cancer In humans.  International Agency for
         Research on Cancer Monographs.  Vol. 1 to 29, Supplement.  Geneva:  World
         Health Organization.
                                              11-9
-------
                                                                & ft Systems, JHC.
Zielhuis RL.   1975.   Dose-response relationships for inorganic lead.  I.
Biochemical and haematological responses.  Int. Arch. Occup. Environ. Health         i
35:1-18.
                                     11-10
-------
                                                           £ifc Systems, Jnc.
                        SUBJECT INDEX
Subject
                                       Page
 acceptable  daily  intake*  example
   calculation. ...
 acute studies ................ .
 animal studies ..... ...
 bioassays
 carcinogen
              Subject
                                      Page
 cellular defense mechanisms ...........
 chain  of custody.... ..................
 chronic studies .......................
 clinical studies ......................
 detection limits ......................
 dioxln-f urans .........................
 dose ..................................
 dose,  conversions of ..................
 dose conversion, example. .............
 dose conversion  factors ...............
 dose-response  curves ..... . ........... .
^dose-response  models. ............ .....
  cotoxicological guidelines ...........
'ecotoxicological studies ..............
 ecotoxicological studies,  limitations.
 ecotoxicological study* example .......
                                  :....
     ctive concentration (EC) ..........
 effective dose (ED)... ................
 endangerment assessment ........... ....
 endpoints. .. ................. . ..... .. .
 endpoints, measuring  techniques .......
                        6-15
                        5-1
                        5-1
                        5-10
                        2-5 ,
                        4-8
                        3-1
                        7-11
                        5-4
                        5-4
                        2-1
                        9-1
                        2-5
                        6-2
                        6-6
                        6-7
                        3-1
                        6-10
                        5-12
                        5-10
                        5-14
                        5-11
 environmental fate/stability ..........
 environmental persistence .............
 epidemiological studies ......... . .....
 epidemiological studies,  limitations..
 exposure ..............................
 exposure assessments ......... ....... . .
 exposure calculation,  present ..... ....
 exposure coefficients .................
 exposure, duration of .................
 exposure estimation , past .............
 exposure prediction,  future ...........
 exposure, routes of ........ . ..........
 extrapolation, animals to  humans ......
 extrapolation, high to low dose .......
 extrapolation, mathematical models  of.
' aepatoxicity ..........................
 incremental risk ......................
 injection .............................
                        3-10
                        3-10
                        8-6
                        4-7
                        4-8,
                        4-9
                        7-18
                        7-23
                        5-5
                        5-8
                        2-6
                        7-1
                        7-16
                        7-14
                        4-4
                        7-17
                        7-18
                        4-1
                        6-1
                        6-8
                        6-8
                        4-11
                        8-5
                        4-4
intake assumptions	
laboratory animal studies.,

fas:::::::::::::::::::::::
legal requirements	
lethal concentration (LC)..
lethal dose (LD)	
limitations, toxicological.
LOAEL .................................
LOEL ...................................
mathematical models for extrapolation.
mechanisms, chemical toxicity .........
metabolism ............................
mutagenicity ........ . .................
neurotoxicity ............. ' ............
NOAEL .......... . ......................
NOEL ..................................
occurrence data, collection of ........
population analysis, exposure .........
protocols ... ..........................
renal toxicity ...... . .................
repair capacity .......................
reproductive toxicity .................
reserve capacity ......................
risk assessment ............. . .........
risk characterization .................
risk levels , non-threshold chemicals . .
species differences ...................
site history information checklist....
statistical analysis , example ......
statistical terms ..................
subchronic studies .................
surface area equivalence ...........
teratogenlcity
testing protocols
therapeutic index (TI)
                    (TC)
threshold	
toxic concentration
toxic dose (TD)	
toxicokinetic differences	
trichloroethylene (TCE)	
uncertainty factors	
uncertainty factors, selection of.
uncertainty, sources of	,
weight equivalence	
7-15
5-1
3-10
11-1
7-10
3-10
3-10
2-5,
3-5
3-1
4-7
6-8
2-1
4-5
4-11
4-11
3-1
4-7
7-1
7-13
5-2
4-12
2-5
4-12
2-5
8-1
8-4
3-5
4-5
7-2
6-4
6-3
5-4
6-2
3-10
4-12
5-2
3-10,
3-12
3-1
3-10
3-10
6-12
10-1
6-15
6-16
6-13
6-2
                              1-1
-------
-------