United States Office of Drinking Center for Environmental
Environmental Protection Water Research Information
Agency Washington DC 20460 Cincinnati OH 45268
Technology Transfer
&EPA Workshops on
Assessment and
Management of
Drinking Water
Contamination
Revised March 1987
-------
&EPA
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
CENTER FOR ENVIRONMENTAL OFFICE OF DRINKING WATER
RESEARCH INFORMATION WASHINGTON, DC 20460
CINCINNATI, OHIO 45268
TECHNOLOGY TRANSFER
WORKSHOPS ON ASSESSMENT AND MANAGEMENT
OF DRINKING WATER CONTAMINATION
-------
WORKSHOP ON RISK ASSESSMENT AND MANAGEMENT OF DRINKING WATER CONTAMINATION
PART TABLE OF CONTENTS PAGES
Introduction
I. EPA'S OFFICE OF DRINKING WATER'S DEVELOPMENT OF STANDARDS
AND HEALTH ADVISORY PROGRAM
A. Glossary of Terms 1-10
B. Toxicological Approaches for Developing National
Drinking Water Standards S Health Advisories 11-18
C. EPA's Health Advisory Program 19-28
II. RISK ASSESSMENT
A. Safety Evaluation/General Principles of Toxicology 29-34
B. Acute and Chronic Toxicity Tests.......... 35-42
C. Use of Toxicity Data In Regulations 43-44
D. Principles of Absorption, Distribution, Excretion &
Metabolism of Chemicals ...45-50
E. Toxicology of Inorganics * 51-60
F. Toxicology of Pesticides 61-67
G. Toxicology of Solvents and Vapors... 68-71
H. Principles of Carcinogenicity 72-78
I. Principles of Risk Assessment 79-130
J. Assessing Risk/introduction to Case Study 131-180
K. Risk Assessment Case Study of Drinking Water
Contaminated by Vinyl Chloride 181-210
III. REGULATIONS AND ASSESSMENT OF RADIONUCLIDES IN DRINKING
WATER.. . 211-263
IV. RISK MANAGEMENT
A. Overview of Risk Management and Control Strategies.......265-279
B. Inorganics Treatment: Overview & Case Studies. ......280-310
C. Organics Treatment: Overview & Case Studies ......311-370
D. Case Study on Risk Management of Aldicarb, Trichloro-
ethylene and Vinyl Chloride in Drinking Water 371-391
E. Aldicarb Health Advisory .392-420
F. Trichloroethylene Health Advisory. 408-420
G. vinyl Chloride Health Advisory 421-435
V. RISK COMMUNICATION
Outline for Videotape..... 436-446
-------
WORKSHOP ON RISK ASSESSMENT AND MANAGEMENT OF DRINKING WATER CONTAMINATION
INTRODUCTION — STATEMENT OF PURPOSE
Every week the news media bombard us with reports of toxic wastes
threatening our environment, especially our drinking water supplies. The
topic of this seminar is how one identifies, assesses and manages the
occurrence of potentially toxic chemicals in drinking water. Obviously,
one cannot become an expert in the toxicology, chemistry and treatment
aspects in a two or three day seminar. Rather, the intent of this workshop
is to present a broad range of relevant information from the fields of
toxicology, chemistry and engineering to assist the workshop participants
in assessing and managing drinking water contamination problems.
This will be accomplished through a series of lectures on U.S. EPA
programs, toxicology, chemistry and treatment principles. There also will
be an opportunity for the workshop attendees to participate in group
exercises on particular risk assessment and management problems that center
around specific ODW Health Advisory chemicals. It is hoped that a broad
spectrum of academic and employment backgrounds among the participants will
make these exercises interesting and informative.
Finally, a videotape explaining how to handle media coverage and risk
communication will be presented. The emphasis here will be on the analysis
of actual new reels and how the water supply or health official might
handle media contacts during an emergency situation.
Because of the short time frame and the large quantity of information,
each attendee will be required to accomplish some reading on his or her own
time during the course of the seminar. It is essential that each person
arrives at the risk assessment and risk management group sessions well
prepared and ready to participate. A facilitator will be there to help
each group, but it is not our intention that this person will lecture. We
do expect each person to take part in the solutions of the problems.
We hope that by the closing of this workshop, each participant
will be able to better handle similar problems occurring in that partici-
pant's own Region, State or locality and that the procedures laid out in
this workshop will improve the quality of his or her performance on the
job.
-------
PART I
EPA's OFFICE OF DRINKING WATER'S DEVELOPMENT OF STANDARDS
AND
HEALTH ADVISORY PROGRAM
A. Glossary of Terms
B. Toxicological Approaches for Developing National Drinking Water
Standards and Health Advisories
C. EPA's Health Advisory Program
-------
A. GLOSSARY OF TERMS
Risk Assessment and Management
Absorbed dose. Hie amount of a chemical that enters the body of an
exposed organism.
Absorption. Hie uptake of water or dissolved chemicals by a cell or an
organism.
Absorption factor. Hie fraction of a chemical making contact with an
organism that is absorbed by the organism.
Acceptable daily intake (API). Estimate of the largest amount of
chemical to which a person can be exposed on a daily basis that is
not anticipated to result in adverse effects (usually expressed in
mg/kg/day). (Synonymous with RfD)
Active transport. An energy-expending mechanism by which a cell moves
a chemical across the cell membrane from a point of lower concen-
tration to a point of higher concentration, against the diffusion
gradient.
Acute. Occurring over a short period of time; used to describe brief
exposures and effects which appear promptly after exposure.
Additive Effect. Combined effect of two or more chemicals equal to the
sum of their individual effects.
Adsorption. The process by which chemicals are held on the surface of
a mineral or soil particle. Compare with absorption.
Ambient. Environmental or surrounding conditions.
Animal studies. Investigations using animals as surrogates for humans,
on the expectation that results in animals are pertinent to humans.
Antagonism. Interference or inhibition of the effect of one chemical
by the action of another chemical.
Assay. A test for a particular chemical or effect.
Bias. An inadequacy in experimental design that leads to results or
conclusions not representative of the population under study.
Bioaccumulation. Hie retention and concentration of a substance by an
organism.
Bioassay. Test which determines the effect of a chemical on a living
organism.
1
-------
Bioconcentration. The accumulation of a chemical in tissues of an
organism (such as fish) to levels that are greater than the level
in the medium (such as water) in which the organism resides (see
bioaccumulation).
Biodegradation« Decomposition of a substance into more elementary
compounds by the action of microorganisms such as bacteria.
Biotransformation. Conversion of a substance into other compounds by
organisms; includes biodegradation.
bw. Body weight.
CAG. Carcinogen Assessment Group.
Cancer. A disease characterized by the rapid and uncontrolled growth
of aberrent cells into malignant tumors.
Carcinogen. A chemical which causes or induces cancer.
CAS registration number. A number assigned by the Chemical Abstracts
Service to identify a chemical.
Central nervous system. Portion of the nervous system which consists
of the brain and spinal cord; CNS.
Chronic. Occurring over a long period of time, either continuously or
intermittently? used to describe ongoing exposures and effects
that develop only after a long exposure.
Chronic exposure. Long-term, low level exposure to a toxic chemical.
Clinical studies. Studies of humans suffering from symptoms induced by
chemical exposure.
Confounding factors. Variables other than chemical exposure level
which can affect the incidence or degree of a parameter being
measured.
Cost/benefit analysis. A quantitative evaluation of the costs which
would be incurred versus the overall benefits to society of a
proposed action such as the establishment of an acceptable dose of
a toxic chemical.
Cumulative exposure. The summation of exposures of an organism to a
chemical over a period of time.
Degradation. Chemical or biological breakdown of a complex compond
into simpler compounds.
Dermal exposure. Contact between a chemical and the skin.
2
-------
Diffusion. The movement of suspended or dissolved particles from a
more concentrated to a less concentrated region as a result of the
random movement of individual particles? the process tends to
distribute them uniformly throughout the available volume.
Dosage. The quantity of a chemical administered to an organism.
Dose. The actual quantity of a chemical to which an organism is exposed.
(See absorbed dose)
Dose-response. A quantitative relationship between the dose of a
chemical and an effect caused by the chemical.
Dose-response curve. A graphical presentation of the relationship
between degree of exposure to a chemical (dose) and observed
biological effect or response.
Dose-response evaluation. A component of risk assessment that describes
the quantitative relationship between the amount of exposure to a
substance and the extent of toxic injury or disease.
Dose-response relationship. The quantitative relationship between the
amount of exposure to a substance and the extent of toxic injury
produced.
DWEL. Drinking Water Equivalent Level — estimated exposure (in mg/L)
which is interpreted to be protetective for noncarcinogenic
endpoints of toxicity over a lifetime of exposure. DWEL was
developed for chemicals that have a significant carcinogenic
potential (Group B). Provides risk manager with evaluation on
non-cancer endpoints, but infers that carcinogenicity should be
considered the toxic effect of greatest concern.
Endangerment assessment. A site-specific risk assessment of the actual
or potential danger to human health or welfare and the environment
from the release of hazardous substances or waste. The endangerment
assessment document is prepared in support of enforcement actions
under CERCLA or RCRA.
Endpoint. A biological effect used as an index of the effect of a
chemical on an organism.
Epidemiologic study. Study of human populations to identify causes of
disease. Such studies often compare the health status of a group
of persons who have been exposed to a suspect agent with that of a
comparable non-exposed group.
Exposure. Contact with a chemical or physical agent.
Exposure assessment. The determination or estimation (qualitative or
quantitative) of the magnitude, frequency, duration, route, and
extent (number of people) of exposure to a chemical.
3
-------
Exposure coefficient. Term which combines information on the frequency,
mode, and magnitude of contact with contaminated medium to yield a
quantitative value of the amount of contaminated medium contacted
per day.
Exposure level, chemical. The amount (concentration) of a chemical at
the absorptive surfaces of an organism.
Exposure scenario. A set of conditions or assumptions about sources,
exposure pathways, concentrations of toxic chemicals and populations
(numbers, characteristics and habits) which aid the investigator in
evaluating and quantifying exposure in a given situation.
Extrapolation. Estimation of unknown values by extending or projecting
from known values.
Gavage. Type of exposure in which a substance is administered to an
animal through a stomach tube.
Gram. 1/454 of a pound.
Half-life. The length of time required for the mass, concentration, or
activity of a chemical or physical agent to be reduced by one-half.
Hazard evaluation. A component of risk assessment that involves
gathering and evaluating data on the types of health injury or
disease (e.g., cancer) that may be produced by a chemical and on
the conditions of exposure under which injury or disease is
produced.
Hematopoiesis. The production of blood and blood cells; hemopoiesis.
Hepatic. Pertaining to the liver.
Hepatoma. A malignant tumor occurring in the liver.
High-to-low-dose extrapolation. The process of prediction of low
exposure risks to rodents from the measured high exposure-high
risk data.
Histology. The study of the structure of cells and tissues; usually
involves microscopic examination of tissue slices.
Human equivalent dose. A dose which, when administered to humans,
produces an effect equal to that produced by a dose in animals.
Human exposure evaluation. A component of risk assessment that involves
describing the nature and size of the population exposed to a
substance and the magnitude and duration of their exposure. The
evaluation could concern past exposures, current exposures, or
anticipated exposures.
4
-------
Human health risk. The likelihood (or probability) that a given exposure
or aeries of exposures may have or will damage the health of indi-
viduals experiencing the exposures.
Incidence of tumors. Percentage of animals with tumors.
Ingestion. Type of exposure through the mouth.
Inhalation. Type of exposure through the lungs.
Integrated exposure assessment. A summation over time, in all media,
of the magnitude of exposure to a toxic chemical.
Interspecies extrapolation model. Model used to extrapolate from
results observed in laboratory animals to humans.
In vitro studies. Studies of chemical effects conducted in tissues,
cells or subcellular extracts from an organism (i.e., not in the
living organism).
In vivo studies. Studies of chemical effects conducted in intact living
organisms.
Irreversible effect. Effect characterized by the inability of the body
to partially or fully repair injury caused by a toxic agent.
Latency. Time from the first exposure to a chemical until the appearance
of a toxic effect.
LCgg* The concentration of a chemical in air or water which is expected
to cause death in 50 percent of test animals living in that air or
water.
LDij0» The dose of a chemical taken by mouth or absorbed by the skin
which is expected to cause death in 50 percent of the test animals
so treated.
Lesion. A pathological or traumatic discontinuity of tissue or loss of
function of a part.
Lethal. Deadly; fatal.
Lifetime exposure. Total amount of exposure to a substance that a
human would receive in a lifetime (usually assumed to be seventy
years).
Linearized multistage model. Derivation of the multistage model, where
the data are assumed to be linear at low doses.
LOAEL. Lowest-Observed-Adverse-Effect Level; the lowest dose in an
experiment which produced an observable adverse effect.
5
-------
Malignant. Very dangerous or virulent, causing or likely to cause
death.
Margin of safety (MPS). Maximum amount of exposure producing no
measurable effect in animals (or studied humans) divided by the
actual amount of human exposure in a population.
Mathematical model. Model used during risk assessment to perform
extrapolations.
Metabolism. The sum of the chemical reactions occurring within a cell
or a whole organism; includes the energy-releasing breakdown of
molecules (catabolism) and the synthesis of new molecules (anabolism).
Metabolite. Any product of metabolism, especially a transformed chemical.
Metastatic. Pertaining to the transfer of disease from one organ or
part to another not directly connected with it.
Microgram (ug). One-millionth of a gram (3.5 x 10~® oz. = 0.000000035 oz.).
Milligram (mg). One-thousandth of a gram (3.5 x 10-8 oz. = 0.000035 oz.).
Modeling. Use of mathematical equations to simulate and predict real
events and processes.
Monitoring. Measuring concentrations of substances in environmental
media or in human or other biological tissues.
Mortality. Death.
MPS. See Margin of safety.
MTD. Maximum tolerated dose, the dose that an animal species can
tolerate for a major portion of its lifetime without significant
impairment or toxic effect other than carcinogenicity.
Multistage model. Mathematical model based on the multistage theory of
the carcinogenic process, which yields risk estimates either equal
to or less than the one-hit model.
Mutagen. An agent that causes a permanent genetic change in a cell
other than that which occurs during normal genetic recombination.
Mutagenicity. The capacity of a chemical or physical agent to cause
permanent alteration of the genetic material within living cells.
Necrosis. Death of cells or tissue.
Neoplasm. An abnormal growth or tissue, as a tumor.
Neurotoxicity. Exerting a destructive or poisonous effect on nerve
tissue.
6
-------
NOAEL. No-Observed-Adverse-Effect Level; the highest dose in an
experiment which did not produce an observable adverse effect.
NOEL, No-Observed-Effect Levelj dose level at which no effects are
noted.
NTP. National Toxicology Program.
Oncology. Study of cancer.
One-hit model. Mathematical model based on the biological theory that
a single "hit" of some minimum critical amount of a carcinogen at
a cellular target — namely DNA — can initiate an irreversible series
of events, eventually leading to a tumor.
Oral. Of the mouth; through or by the mouth.
Pathogen. Any disease-causing agent, usually applied to living agents.
Pathology. The study of disease.
Permissible dose. The dose of a chemical that may be received by an
individual without the expectation of a significantly harmful
result.
Pharmacokinetics. The dynamic behavior of chemicals inside biological
systems; it includes the processes of uptake, distribution,
metabolism, and excretion.
Population at risk. A population subgroup that is more likely to be
exposed to a chemical, or is more sensitive to a chemical, than is
the general population.
Potency. Amount of material necessary to produce a given level of a
deleterious effect.
Potentiation. The effect of one chemical to increase the effect of
another chemical.
ppb. Parts per billion.
ppm. Parts per million.
Prevalence study. An epidemiological study which examines the
relationships between diseases and exposures as they exist in a
defined population at a particular point in time.
Prospective study. An epidemiological study which examines the
development of disease in a group of persons determined to be
presently free of the disease.
Qualitative. Descriptive of kind, type or direction, as opposed to
size, magnitude or degree.
7
-------
Quantitative. Descriptive of size, magnitude or degree.
Receptor. (1) In biochemistry: a specialized molecule in a cell that
binds a specific chemical with high specificity and high affinity;
(2) In exposure assessment: an organism that receives, may receive,
or has received environmental exposure to a chemical.
Renal. Pertaining to the kidney.
Reservoir. A tissue in an organism or a place in the environment where
a chemical accumulates, from which it may be released at a later
time.
Retrospective study. An epidemiological study which compares diseased
persons with non-diseased persons and works back in time to
determine exposures.
Reversible effect. An effect which is not permanent, especially adverse
effects which diminish when exposure to a toxic chemical is ceased.
RfD. Reference dose; the daily exposure level which, during an entire
lifetime of a human, appears to be without appreciable risk on the
basis of all facts known at the time. (Synonymous with ADI)
Rjsk. The potential for realization of unwanted adverse consequences
or events.
Rj.sk assessment. A qualitative or quantitative evaluation of the
environmental and/or health risk resulting from exposure to a
chemical or physical agent (pollutant); combines exposure assessment
results with toxicity assessment results to estimate risk.
Risk characterization. Final component of risk assessment that involves
integration of the data and analysis involved in hazard evaluation,
dose-response evaluation, and human exposure evaluation to determine
the likelihood that humans will experience any of the various
forms of toxicity associated with a substance.
Risk estimate. A description of the probability that organisms exposed
to a specified dose of chemical will develop an adverse response
(e.g., cancer).
Risk factor. Characteristic (e.g., race, sex, age, obesity) or variable
(e.g., smoking, occupational exposure level) associated with
increased probability of a toxic effect.
Risk management. Decisions about whether an assessed risk is sufficiently
high to present a public health concern and about the appropriate
means for control of a risk judged to be significant.
Risk specific dose. The dose associated with a specified risk level.
8
-------
Route of exposure. The avenue by which a chemical comes into contact
with an organism (e.g., inhalation, ingestion, dermal contact,
injection).
Safe. Condition of exposure under which there is a "practical certainty"
that no harm will result in exposed individuals.
Sink. A place in the environment where a compound or material collects
(see reservoir).
Sorption, a surface phenomenon which may be either absorption or
adsorption, or a combination of the twoj often used when the
specific mechanism is not known.
Stochastic. Based on the assumption that the actions of a chemical
substance results from probabilistic events.
Stratification. (1) The division of a population into subpopulations
for sampling purposes; (2) the separation of environmental media
into layers, as in lakes.
Subchronic. Of intermediate duration, usually used to describe studies
or levels of exposure between five and 90 days.
Synergism. An interaction of two or more chemicals that results in
an effect that is greater than the sum of their effects taken
independently.
Systemic. Relating to whole body, rather than its individual parts.
Systemic effects. Effects observed at sites distant from the entry
point of a chemical due to its absorption and distribution into
the body.
Teratogenesis. The induction of structural or functional development
abnormalities by exogenous factors acting during gestation;
interference with normal embryonic development.
Teratogenicity. The capacity of a physical or chemical agent to cause
non-hereditary congenital malformations (birth defects) in offspring.
Therapeutic index. The ratio of the dose required to produce toxic or
lethal effect to dose required to produce non-adverse or therapeutic
response.
Threshold. The lowest dose of a chemical at which a specified measurable
effect is observed and below which it is not observed.
Time-Weighted Average. The average value of a parameter (e.g., concen-
tration of a chemical in air) that varies over time.
Tissue. A group of similar cells.
9
-------
Toxicant. A harmful substance or agent that may injure an exposed
organism.
Toxicity. The quality or degree of being poisonous or harmful to plant,
animal or human life.
Toxicity assessment. Characterization of the toxicological properties
and effects of a chemical, including all aspects of its absorption,
metabolism, excretion and mechanism of action, with special emphasis
on establishment of dose-response characteristics.
Transformation. Acquisition by a cell of the property of uncontrolled
growth.
Tumor incidence. Fraction of animals having a tumor of a certain type.
Uncertainty factor. A number (equal to or greater than one) used to
divide NOAEL or LOAEL values derived from measurements in animals
or small groups of humans, in order to estimate a NOAEL value for
the whole human population.
Unit cancer risk. Estimate of the lifetime risk caused by each unit of
exposure in the low exposure region.
Upper bound estimate. Estimate not likely to be lower than the true risk.
Volatile. Readily vaporizable at a relatively low temperature.
10
-------
B. TOXICOLOGICAL APPROACHES FOR DEVELOPING
NATIONAL DRINKING WATER REGULATIONS AND HEALTH ADVISORIES
by Edward V. Ohanian, Ph.D.
Chief, Health Effects Branch
Office of Drinking Water (WH-550D)
Washington, D.C.
Safe Drinking Water Act Requirements
° PUBLISH PRIMARY DRINKING WATER REGULATIONS
- Specify contaminants which "in the judgment of the Administrator, may
have any adverse effect on the health of persons"
- Set for each contaminant either (a) MCL or (b) treatment technique
- Specify monitoring/reporting requirements and public notification
PRIMARY REGULATIONS
° Maximum Contaminant Level Goals (MCLGs)
- Health goal: non-enforceable
- Set at a level at which "no known or anticipated adverse effect on the
health of persons occur and which allows an adequate margin of safety"
- House Report no. 93-1185: set MCLGs for carcinogens at zero
0 Maximum Contaminant Levels (MCLs)
- Enforceable standards
- Set as close to MCLGs as feasible
SDWA AMENDMENTS — PRIMARY DRINKING WATER REGULATIONS
° RMCL becomes MCLG {MCL Goals)
° Distinction between Interim and Revised Regulation deleted
° Requires EPA to propose and promulgate MCLGs and MCLs simultaneously
0 NAS study deleted and replaced by requirement to consult with EPA Science
Advisory Board
° Requires EPA to set regulations requiring public water systems to monitor
for unregulated contaminants
° Requires EPA to prepare a Report to Congress on comparative health risks of
raw water contamination versus contamination by treatment chemicals (e.g.,
disinfection by-products)
8 prohibits use of lead pipes, solder and flux
11
-------
SDWA AMENDMENTS — PRIMARY DRINKING WATER REGULATIONS - cont'd
SDWA requires EPA to:
0 List 25 contaminants by January 1, 1988, for which MCLa would be set within
36 months
° Repeat every 3 years
° Establish Advisory Group to develop list
- Include NTP and various EPA program offices
- List must consider Section 101 CERCLA and registered pesticides
SDWA requires EPA to set regulations for 83 contaminants in two ANPRMs
0 9 MCLs in 12 months
0 40 MCLs in 24 months
0 34 MCLs in 36 months
MCLs REQUIRED UNDER SDWA AMENDMENTS
Volatile Organic Chemicals
Trichloroethylene
Te trachloroe thylene
Carbon tetrachloride
1,1,1-Trichloroethane
1,2-Dichloroethane
Total coliforms
Turbidity
Arsenic
Barium
Cadmium
Chromium
Lead
Vinyl chloride
Methylene chloride
Benzene
Chlorobenzene
Dichlorobenzene(s)
Microbiology and Turbidity
Trichlorobenzene(s)
1,1-Dichloroethylene
trans-1,2-Dichloroethylene
cis-1,2-Dichloroethylene
Mercury
Ni trate
Selenium
Silver
Fluoride
Giardia lamblia
Viruses
Inorganics
Aluminum
Antimony
Molybdenum
Asbestos
Sulfate
Standard plate count
Legionella
Copper
Vanadium
Sodium
Nickel
Zinc
Thallium
Beryllium
Cyanide
12
-------
MCLs REQUIRED UNDER SDWA AMENDMENTS (Continued)
Organics
Endrin
Lindane
Methoxychlor
Toxaphene
2,4-D
2,4,5-TP
Aldicarb
Chlordane
Dalapon
Diquat
Endotha11
Glyphosate
Carbofuran
Alachlor
Efcichlorohydrin
Toluene
Adipates
2,3,7,8-TCDD (Dioxin)
1,1,2-Trichloroethane
Vydate
Simazine
PAHs
PCBs
Atrazine
Phthalates
Acrylamide
Dibromochloropropane (DBCP)
1,2-Dichloropropane
Pentachlorophenol
Picloram
Dinoseb
Ethylene dibromide
Dibromomethane
Xylene
Hexachlorocyclopentadiene
Radionuclides
Radium 226 and 228
Beta particle and
photon radioactivity
Uranium
Gross alpha particle activity
Radon
ENVIRONMENTAL REGULATIONS
0 Risk Assessment
0 Risk Management
0 Risk Communication
REGULATORY DEVELOPMENT
Occurrence
+
Human Exposure
+
Health Effects
+
Risk Assessment
MCLG
Analytical Methods
+
Technology and Costs
+
Economic Impact
+
Regulatory Impact
MCL
13
-------
OBJECTIVES OP CRITERIA DOCUMENTS
0 Establish core information base on health effects of chemicals in drinking
water
° Compile and evaluate data for Maximum Contaminant Level Goals (MCLGs) and
provide health effects basis for Maximum Contaminant Levels (MCLs)
° Provide health effects basis for health advisory values
DATA REVIEW AND EVALUATION
Members of the office of Drinking Water's
Toxicology Review Panel (TRP)
Charles Abernathy, Ph.D.
Larry Anderson, Ph.D.
Kenneth Bailey, Ph.D., D.A.B.T.
Robert Cantilli, M.S.
Krishan Khanna, Ph.D.
Amal Mahfouz, Ph.D.
William Marcus, Ph.D., D.A.B.T.
Bruce Mintz, B.S.
James Murphy, Ph.D., D.A.B.T.
Edward Ohanian, Ph.D.
Jennifer Orme, M.S.
Yogendra patel, Ph.D.
CRITERIA DOCUMENT CONTENTS
I.
Summary
II.
Physical and Chemical Properties
III.
Toxicokinetics
IV.
Human Exposure
V.
Health Effects in Animals
VI.
Health Effects in Humans
VII.
Mechanism of Toxicity
VIII.
Quantification of Toxicological Effects (QTE)
IX.
References
CONTENT OF QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Noncarcinogenic Effects
- Selection of Key Studies
- Selection of Uncertainty Factors
- One-Day Health Advisory
- Ten-Day Health Advisory
- Longer-Term Health Advisory
- Lifetime Health Advisory; Drinking
Water Equivalent Level (DWEL)
0 Comparison with Existing
Guidelines and Standards
° Special Considerations
- High Risk Populations
- Interactions
- Beneficial Effects
- Other Factors
° Carcinogenic Effects (CAG Cancer
Risk'Estimates
1 4
-------
NOAEL = No-observed-adverse-effect level
LOAEL = Lowest-observed-adverse-effect level
MCLGS! NON-CARCINOGENS
0 Determine RfD (Reference Dose) in mg/kg/day
RfD = NOAEL or LOAEL in mg/kg/day
Uncertainty Factor
0 Determine DWEL (Drinking Water Equivalent Level) in mg/L assuming 100%
drinking water contribution
DWEL = (RfD) (70 kg person)
(2 L/day)
0 Determine MCLG in mg/L
MCLG = (DWEL) (% drinking water contribution)*
*10% inorganics/20% organics
NAS/ODW GUIDELINES FOR APPLYING UNCERTAINTY FACTORS
° An uncertainty factor of 10 is used when good acute or chronic human exposure
data are available and supported by acute or chronic toxicity data in other
species.
° An uncertainty factor of 100 is used when good acute or chronic toxicity data
identifying NOAEL are available for one or more species, but human data are
not available.
° An uncertainty factor of 1,000 is used when limited or incomplete acute or
chronic toxicity data in all species are available or when the acute or
chronic toxicity data identify a LOAEL (but not NOAEL) for one or more species,
but human data are not available.
° An intermediate uncertainty factor between 1 and 10 is used, according to
scientific judgment.
APPLICATION OF UNCERTAINTY FACTOR REQUIRING "BEST SCIENTIFIC JUDGEMENT"
0 Quality of toxicology data
0 Severity of effect
0 Duration/route of exposure
0 Beneficial effect(s)
15
-------
PREFERRED DATA FOR DWEL DEVELOPMENT
Duration of Exposure
- Chronic
- Subchronic
Route of Exposure
- Oral: drinking water,
gavage diet
- Inhalation
- Subcutaneous or intraperitoneal
Test Species
- Human
- Appropriate animal model
- Most sensitive species
0 Dose-Response Relationship
- NOAEL and LOAEL
- LOAEL
0 End-Point of Toxicity
- Biochemical/patho-
physiological changes
- Body/organ weight changes
- Mortality
I ARC* CLASSIFICATION OF CARCINOGENS
Group Evidence of Carcinogenicity
1 Suficient evidence of carcinogenicity to humans
2A Limited evidence of carcinogenicity to humans
2B insufficient evidence of carcinogenicity to humans and sufficient
evidence of carcinogenicity to animals
3 Available data cannot be classified as to its carcinogenicity to humans
* IARC - International Agency for Research on Cancer
B
EPA CLASSIFICATION OF CARCINOGENS
Group Evidence of Carcinogenicity
A Human carcinogen (sufficient evidence from epidemiological studies)
B Probable human carcinogen
1 At least limited evidence of carcinogenicity to humans
Usually a combination of sufficient evidence in animals and inadequate
data in humans
Possible human carcinogen (limited evidence of carcinogenicity in animals
in the absence of human data)
Not classified (inadequate animal evidence of carcinogenicity)
No evidence of carcinogenicity for humans (no evidence for carcinogenicity
in at least two adequate animal species or in both epidemiological and
animal studies)
D
E
16
-------
THREE-CATEGORY APPROACH FOR DEVELOPING MCLGs
Evidence of
Carcinogenicity
Strong
Equivocal
Inadequate
or lacking
Classification
EPA Group A or B
IARC Group 1, 2A or 2B
EPA Group C
IARC Group 3
EPA Group D or E
IARC Group 3
MCLG
0
(a) RfD approach with additional
safety factor, or
(b) 10~5 to 10""® cancer risk range
RfD approach
RISK ASSESSMENT CONCERNS
Science of Toxicology <-
FACT
1
carcinogenic in animals
-> Art of Toxicology
PREDICTION
carcinogenic in humans
17
-------
ODW REGULATORY HEALTH EFFECTS CRITERIA DOCUMENT (CD) DEVELOPMENT PROCESS
Ti me
(months)
0
12
24
36
Regulatory Process
Federal Register
Notice
ANPRM
Public Comment Period
Public Meeting
Public Workshop
FR Notice
MCLG/MCL
Proposal
Public Comment Period
Public Meeting (s)
FR Notice
CD Development Process
Chemical Identification
Rough Draft CD
ODW Review
L
Rough
External
Draft
Review CD
ODW/ECAO** Review
Expert Review (as needed)
External
Review
Draft
CD
ODW/ECAO** Review
External Peer Review
Agency Reivew
Technical Support
Final Draft CD
Document
Public Comments
ODW/ECAO** Review
Agency Review
Technical Support
Document
MCLG/ MCL
Promulgation
Final CD
* Not applied to CDs prepared by ECAO/OHEA
** CDs prepared by ECAO/OHEA
18
-------
c. EPA'S HEALTH ADVISORY PROGRAM
Health Effects Branch
Criteria and Standards Division
Office of Drinking Water
U.S. Environmental Protection Agency
The Office of Drinking Water's non-regulatory Health Advisory
Program provides information on health effects, analytical methodology
and treatment technology that will be useful in dealing with contamination
of drinking water. Health Advisories also describe concentrations of
contaminants in drinking water at which adverse effects would not be
anticipated to occur. A margin of safety is included to protect sensitive
members of the population.
Health Advisories are not legally enforceable Federal standards.
They are subject to change as new and better information becomes available.
The Advisories are offered as technical guidance to assist Federal, State
and local officials responsible for protection of the public health.
The Health Advisory numbers are developed from data describing non-
carcinogenic endpoints of toxicity. They do not incorporate quantitatively
any potential carcinogenic risk from such exposure. For those chemicals
that are known or probable human carcinogens according to the proposed
Agency classification scheme, non-zero One-day, Ten-day and Longer-term
Health Advisories may be derived, with attendant caveats. Health
Advisories for lifetime exposures may not be recommended. Projected
excess lifetime cancer risks are provided to give an estimate of the
concentrations of the contaminants at which a carcinogenic risk to humans
may be posed. These hypothetical estimates usually are presented as
upper 95% confidence limits derived from the linearized multistage model
considered to be unlikely to underestimate the probable true risk.
When an Office of Drinking Water draft Health Effects Criteria
Document is available, the Health Advisory is based upon information
presented in the Criteria Document. Hie Health Advisory and Criteria
Document formats are similar for easy reference. Individuals desiring
further information on the toxicological data base or rationale for
risk characterization of a specific chemical should consult the Criteria
Document for that chemical. Criteria Documents and Health Advisories
are available for review at each EPA Regional office of Drinking water
counterpart (e.g., Public Water Supply Branch or Drinking Water Branch),
or, for a fee, from the National Technical Information Service(NTIS),U.S.
department of Commerce, 5285 Port Royal Road, Springfield, VA. The
toll free number is (800) 336-4700; in the Washington DC area call
(703) 487-4650. *flie NTIS document access number for ordering all 52
Health Advisories is PB 86-118338/AS. For additional information on
the Health Advisory Program, please contact: Edward V. Ohanian, Ph.D.,
Chief, Health Effects Branch, Office of Drinking Water (WH-550D), U.S.
EPA, 401 M. St.,S.W., Washington, DC 20460? Tel: (202) 382-7571.
19
-------
ELEMENTS OF THE OFFICE OF DRINKING WATER'S HEALTH ADVISORY PROGRAM
0 Establish comprehensive Health Advisories Registry (Computer-based)
0 Prepare revised Health Advisories for about 50 contaminants
° Develop new Health Advisories for about 60 National Pesticide Survey(NPS) analytes
° Develop new Health Advisories for about 50 unregulated volatile synthetic
organic chemicals(SOCs) under Section 1445
° institute new preocedures to assure timely responses to emergency situations
and requests for information
° Establish cooperative program between EPA and the Department of the Army on
(Health Advisory development for) munitions chemicals in drinking water
0 Initiate information-sharing and toxicological support program between EPA
and States (FSTRAC)
0 Conduct 3-day Workshop for Users of Health Advisories and other water-related
numbers on Philosophy/Methodology/Application in Risk Assessment/Risk Management
Decision-making at all levels of government (PIP)
WHAT ARE HEALTH ADVISORIES?
° Health Advisories are not legally enforceable Federal standards. I?ley are
subject to change as new and better information becomes available.
0 Health Advisories describe concentrations of contaminants in drinking water
at which adverse noncarcinogenic effects would not be anticipated to occur
following 1-day, 10-day, longer-term or lifetime exposure
0 Health Advisories are developed from data describing noncarcinogenic end-points
to toxicity
° Health Advisories include carcinogenic potency factors and/or drinking water
concentrations estimated to represent excess lifetime cancer risks over the
range of 10-^ to 10"® for:
- All substances classified in Groups A and B
- Some substances classified in Group C
- No substances classified in Groups D and E
ODW HEALTH ADVISORY (HA) CONTENT
I. General Introduction
II. General information and Properties
0 Synonyms
° Uses
° Properties
° Sources of Exposure
0 Environmental Fate
20
-------
III. Pharmacokinetics
0 Absorption
0 Distribution
0 Biotransformation
° Excretion
IV. Health Effects
0 Humans
0 Animals
- Short-term Exposure
- Longer-term Exposure
° Developmental/Reproductive/Mutagenic/Carcinogenic Effects
V. Quantification of Toxicological Effects
0 One-day Health Advisory
0 Ten-day Health Advisory
0 Longer-term Health Advisory
° Lifetime Health Advisory
0 Evaluation of Carcinogenic Potential
VI. Other Criteria, Guidance and Standards
ASSUMPTIONS
Protected individual — One-day HA: 10 kg child
Ten-day HA: 10 kg child
Longer-term HA: 10 kg child and
70 kg adult
Lifetime HA: 70 kg adult
Cancer risk estimates: 70 kg adult
Volume of drinking water ingested/day
10 kg child: 1 liter
70 kg adult: 2 liters
Relative Source Contribution
In absence of chemical-specific data:
20% for organics
10% for inorganics
PREFERRED DATA FOR HA DEVELOPMENT
° Duration of Exposure: One-day HA: One to five (successive) daily doses
Ten-day HA: Seven to 14 (successive) daily doses
Longer-term HA: Subchronic (90 day) to one year
Lifetime HA: Chronic or subchronic (with an added
uncertainty factor)
° Route of Administration:
Oral: drinking water, gavage, diet, inhalation,
Subcutaneous or intraperitoneal (on a caseby-case
basis)
21
-------
0 Test Species:
Human
Appropriate animal model
Most sensitive species
HEALTH ADVISORY (HA) CALCULATION
Where:
NOAEL
LOAEL
BW
UF(s)
(NOAEL or LOAEL in mg/kg/day) (BW in kg)
(UP(s)) ( L/day)
mg/L
No Observed Adverse Effect Level
Lowest Observed Adverse Effect Level
Body Weight of Protected Individual (10 kg or 70 kg)
Uncertainty Factors
L/day » Daily Water Consumption (1 or 2 L/day)
DRINKING WATER EQUIVALENT LEVEL (DWEL)
° Definition:
Estimated exposure (in mg/L or ug/L) which is interpreted to be protective
for non-carcinogenic end-points of toxicity over a lifetime of exposure
° Application:
- Developed for chemicals which have significant carcinogenic potential
(Group B)
- Provides risk manager with evaluation on non-cancer end-points, but infers
that carcinogenicity should be considered the toxic effect of greatest concern
HEALTH ADVISORIES FOR Synthetic Organic Chemicals (SOCs), Volatile
Organic Chemicals(SOCs), inorganic Chemicals (IOCs) and MICROBIALS
Acrylamide
Alachlor
Aldicarb
Arsenic
Barium
Benzene
Cadmium
Carbofuran
Carbon Tetrachloride
Chlordane
Chlorobenzene
Chromium
Cyanide
2,4-D
DBCP
m/o-Dichlorobenzene
1,2-Dichloroethane
1,1-Dichlorqethylene
cis-1,2-Dichloroethylene
trans-1,2-Dichloroethylene
Dichloromethane
Di chloropropane
p-Dioxane
Dioxin
EDB
Endrin
Epichlorohydrin
Ethylbenzene
Ethylene Glycol
Heptachlor
Hexachlorobenzene
n-Hexane
Lead
Lindane
Mercury
Methoxychlor
Methyl Ethyl Ketone
Nickel
Nitrate/Nitrite
Oxamyl
PCBs
Pentachlorophenol
Styrene
Tetrachloroethylene
Toluene
Toxaphene
2,4,5-TP
1,1,1-Trichloroethane
Tri chloroe thylene
Vinyl Chloride
Xylenes
Legionella
22
-------
PESTICIDE MONITORING SURVEY
° joint ODW & OPP survey
0 ODW's Objectives - Occurrence of pesticides in drinking water
OPP's Objectives - Migration of pesticides from legal usage
0 Complex survey
- Sampling baaed upon pesticide usage and hydrogeology
- Sampling weighted towards areas of probable occurrence
- Approximately 1500 wells will be sampled
0 Estimated cost: $5 million
° Estimated Schedule:
FY85-86 - Identify chemicals and analytical methods
FY85-86 - Select hydrogeology scheme
FY86 - Finalize sampling technique
FY86 - Pilot sampling
FY87-89 - Full sampling
FY89-90 - Final report
TENTATIVE LIST OF ANALYTES FOR THE NATIONAL PESTICIDE SURVEY
Acifluorfen
Diazinon
Methomyl
Alachlor
Dicamba
Mthyl Parathion
Aldicarb
2,4-D
Metolachlor
Ametryn
1,2-Dichloropropane
Metribuzin
Ammonium Sulfamate
Dieldrin
Oxamyl
Atrazine
Dimethrin
Paraquat
Baygon
Dinoseb
PCP
Bentazon
Diphenamid
Picloram
Bromacil
Disulfoton
Prometone
Butylate
Diuron
Pronamide
Carbaryl
EDB
Propachlor
Carbofuran
ETU/EDBCs
Propazine
Carboxin
Endothall
Propham
Chloramben
Fenamiphos
Simazine
Chlordane
Fluometuron
Trifluralin
Chlorothalonil
Fonofos
2,4,5-T
Cyanazine
Glyphosate
2/ 4,5-TP
Cycloate
Hexazinone
Tebuthiuron
Dalapon
Maleic Hydrazide
Terbacil
DBCP
MCPA
Terbufos
DCPA/Dacthal
23
-------
TENTATIVE LIST OF HEALTH ADVISORIES FOR UNREGULATED VOCs UNDER SECTION 1445
HEALTH ADVISORIES ON MUNITIONS CHEMICALS -MEMORANDUM OF UNDERSTANDING BETWEEN
THE DEPARTMENT OF THE ARMY AND THE ENVIRONMENTAL PROTECTION AGENCY
RESPONSIBILITIES
Department of the Army
° Provide priority ranking of munitions compounds
° Provide central point of contact for coordination activities
° Disseminate agreement to affected Army subordinate commanders
° Provide relevant data from concerned Army activities
° Arrange visits by key EPA personnel to Army facilities
0 Provide support to EPA as resources permit
Environmental Protection Agency
° Authorize personnel to work with Army to develop data bases
0 Provide Health Advisories based on health effects* in a timely
manner when data are available
° Define significant data deficiencies or problem areas
° Provide recommendations for future data base development
0 Submit periodic progress reports
* Health Advisories do not address explosive, flammable, etc.
hazards of munitions.
Chloroform
Bromodichloromethane
Chlorodibromome thane
Bromoform
trans-1,2-Dichloroethylene
Chlorobenzene
m-Dichlorobenzene
Dichloromethane
cis-1,2-Dichloroethylene
o-Dichlorobenzene
1,2,4-Trichlorobenzene
Fluorotrichloromethane
Di chlo rod i fluorome thane
Di bromome thane
1,2-Dibromo-3-chloropropane
Toluene
p-Xylene
o-xylene
m-xylene
1,1 -Dichloroethane
1.2-Dichloropropane
1,1,2,2-Tetrachloroethane
Ethylbenzene
1.3-Dichloropropane
Styrene
Chloromethane
Bromomethane
Br omochloromethane
1,2,3-Trichloropropane
1.2.3-Trichlorobenzene
n-Propylbenzene
1,1,1,2-Tetrachloroethane
Chloroethane
1,1,2-Trichloroethane
Pentachloroethane
bis-2-Chloroisopropyl ether
sec-Dichloropropane
1.2.4-Trimethylbenzene
n-Butylbenzene
Naphthalene
Hexachlorobutadiene
o-Chlorotoluene
p-Chlorotoluene
1.3.5-Trimethylbenzene
p-Cymene
1,1-Dichloropropane
iso-Propylbenzene
tert-Butylbenzene
sec-Butylbenzene
Bromobenzene
24
-------
LIST OF CHEMICALS FOR WHICH TOXICITY PROFILES HAVE BEEN PREPARED FOR THE
DEPARTMENT OF THE ARMY
1-Nitronaphthalene
1-Methyl-2-nitrobenzene
3.4-Dinitrotoluene
3.5-Dinitrotoluene
2,5-Dinitrotoluene
2,6-Dinitrotoluene
1-Methyl-4-nitrobenzene
1-Chloro-4-nitrobenzene
1.2-Dichloro-4-nitrobenzene
2.3-Dinitrotoluene
FEDERAL-STATE TOXICOLOGICAL RISK ASSESSMENT COMMITTEE (FSTRAC)
Description:
Goals:
Activities:
Working Group composed of EPA and State experts in the areas of
risk assessment/management for drinking water contaminants
Cooperation, consistency and information exchange
Peer review, methodology articulation, survey coordination and
research
EPA PERFORMANCE IMPROVEMENT PROJECT (PIP) WORKSHOP ON ASSESSMENT AND MANAGEMENT OF
DRINKING WATER CONTAMINATION
° Principles of pharmacokinetics risk asessment and carcinogenicity
° Understanding ODW Health Advisories
° Toxicology of inorganics, solvents and pesticides
0 Drinking water treatment
° Treatment cost case study
0 Risk assessment case study
0 Risk communication
° Risk management case study
25
-------
ODW HEALTH ADVISORY (HA) DEVELOPMENT PROCESS
Time
(months)
0
>
Chemical Identification
¦N
'
Rough Draft HA
ODW Review *
1
Rough External Review
Draft HA
ODW Review*
Expert Review (as needed)
Editorial Review
*j
External Rev
iew / Draft HA
ODW Review
External Peer Review
(SAB/SAP Review)
Agency Review
1
Final Draft HA
Public Comments
ODW Review
Agency Review
12
FINAL HA
* CSD Toxicology Review Panel
26
-------
ODW PROCESSING OF EMERGENCY RESPONSE REQUESTS
Question
ODW
Approval
Director, Criteria &
Standards
ODW
• Notified
• Provides Input
Toxicotogicai
Review Panel
• Formulate
Proposed
Response
Other EPA Program Offices
• Current Regulations/Criteria
• Current Activities
• Planned Activities
HEB Staff Scientist
• Eval. OOVW Data/Files
• Response Leader
Chief, Health
Effects Br, ODW
• Receives Question
• Develops Plan
of Action
Contractor Staff
• Literature Search
• Eval. Literature Data
• Risk Assessment/Analyses
National Experts
• Current Rsch. Findings
• Opinions/Judgements
• Peer Review
-------
ODW EMERGENCY RESPONSE NETWORK
QUESTIONS ODW EVALUATIONS RESPONSES
By;
• Letter (normal)
CO
• Telephone (fast-response)
From:
• EPA Region
• Slate EPA/Health Dept.
• Local Government
• Water Treatment Fac.
• Others
HEB Staff Scientist
• Response Leader
• EPA Coordination
ODW
Health
Effects
Branch
Contractor
Support
• Contractor Staff
• National Experts
Formal:
Letter
InformaWnterim:
• Telephone Call
• Conference Call
-------
PART II
RISK ASSESSMENT
A. Safety Evaluation/General Principles of Toxicology
B. Acute and Chronic Toxicity Tests
C. Use of Toxicity Data in Regulations
D. Absorption, Distribution, Excretion and Metabolism
of Chemicals
E. Toxicology of Inorganics
F. Toxicology of Pesticides
G. Toxicology of Solvents and Vapors
H. Chemical Carcinogens
I. Principles of Risk Aysessement
J. Assessing Risk/Introduction to Case Study Exercise
K. Risk Assessment Case Study of Drinking Water Contaminated
by Vinyl Cloride
-------
A.
SAFETY EVALUATION
f\- GENERAL PRINCIPLES OF TOXICOLOGY
CURTIS D. KLAASSEN, PH.D.
I. GENERAL DEFINITIONS
A. Toxicology: The study of the adverse effects of chemicals on living
organisms.
B. Toxicologist: Trained to examine the nature of these adverse
effects and to assess the probability of their occurrence.
1. Descriptive
2. Mechanistic
3. Regulatory
II. SPECTRUM OF UNDESIRED EFFECTS
A. Side effects or undesirable
B. Adverse, deleterious, or toxic
1. Immediate versus delayed
2. Reversible versus irreversible
3. Local versus systemic
4. Idiosyncratic - genetically determined abnormal reactivity but
qualitatively similar
5. Allergic or sensitization reactions
III. CLASSIFICATION OF TOXIC AGENTS
A. Target organ
B. Source
C. Effects
D. Physical state
E. Labeling requirements
29
-------
F. Chemistry
G. Toxicity Rating
H. Mechanism of action
IV. CHEMICAL EXPOSURE
A. Acute: single
8. Subacute: less than 1 month
C. Subchronic: 1-3 months
D. Chronic: more than 3 months
V. DOSE-RESPONSE
90-
80-
70-
30-
10-
Ytttti—r
S to 20
TTrrm—i i 111ini—r~
SO 100 ZOO 400 800 2,000
Dose
hypersusceptible resistant
30
-------
VI. CONVERSION OF SIGMOID DOSE-RESPONSE CURVE TO
STRAIGHT LINE
so
80
70
S 60
§
5 so
5
* 4°
20
7.0
as
C 6.0
10 =
60 9
60 ^
40 3
30 S.
20 (/)
£¦ 5 .0
£ *.6 -
O 4.0
10 a
3.6
3.0
6 10 20 60 100 200 400 600
Dose (mg/kg)
31
-------
VII. POISON: Any Chemical Capable of Producing a Deleterious
Response in a Biologic System, Seriously Injuring Function or
Producing Death
"All Substances are Poisons; There is None which is Not a
Poison. The Right Dose Differentiates a Poison and a Remedy."
(Paracelsus 1493-1541)
VIII. CLASSIFICATION OF TOXICANTS
Probable Oral Lethal Dose for Humans
LD50 (mg/kg) Toxicity Rating
practically nontoxic
(above 15 g/kg)
Ethyl Alcohol
10,000
slightly toxic (5-15 g/kg)
Sodium chloride
4,000
moderately toxic (0.5-5 g/kg)
Phenobarbital
150
very toxic (50-500 mg/kg)
Parathion
7
extremely toxic (5-50 mg/kg)
Strychnine
Nicotine
d-tubocurarine
Tetradotoxin
TCDD
Botulinus toxin
2
1
0.05
0.01
0.001
0.00001
super toxic (less 5 mg/kg)
32
-------
IX. SLOPE OF THE DOSE-RESPONSE
7.0'
O. 5.0
O 4.0'
3.0
6 8 10 20 30 40 60
Dose (mg/kg)
X. USE OF DOSE-RESPONSE FOR EFFECTS OTHER THAN DEATH
A. Liver injury
B. Cancer
C. Etc.
7.0.
6.5
5.5'
60 &
50 as
40 S
5 0'
ED/ /TO
LD
® 40'
3.5
30'
TTTTTT
~i i iiiiii —
30 70 100
Dosaga (mg/kg)
300 700
33
-------
XI. THERAPEUTIC INDEX AND MARGIN OF SAFETY
LD50
A. Therapeutic index =
ED50
LD1
B. Margin of safety =
ED99
1. If use for 1 month = 10
2. If use for 6 months = 100
3. If food additive = 1000
XII. CHEMICAL INTERACTIONS
A. Additive: 2 + 3 = 5
.1
B. Synergistic: 2 + 3 = 20
C. Potentiation: 0 + 2 = 10
D. Antagonism: 4 + 6 = 8
4 + (-4) = 0
4 + 0 = 1
1. Functional
2. Chemical
3. Dispositional
4. Receptor
34
-------
B.
ACUTE AND CHRONIC TOXICITY TESTS
CURTIS D. KLAASSEN, PH.D.
I. TWO MAIN PRINCIPLES OF DESCRIPTIVE ANIMAL
TOXICITY TESTS
A. Effects produced by a compound in laboratory
animals, when properly qualified, are applicable
to man.
B. Exposure of experimental animals to toxic agents
in nigh doses is a necessary and valid method of
discovering possible hazards in man (for 0.01%
which is 20,000 people in 200 million, it requires
30,000 animals)
II. DESCRIPTIVE ANIMAL TOXICITY TESTS
A. Acute
1. Oral LD50 (gavage)
a. Often do a pilot range finding study first
(1) For small rodents inject 2 rats or 2 mice
each with 0.5, 5, 50, 500 and 5000 mg/kg
(2) For dogs, use one dog and increase dose 10
fold eacn day until death - then give that
dose to next dog
b. Typical protocol
(1) Often starve animals for 16 hrs before
administration
(2) Usually administer constant concentration for
various doses rather than a constant volume
(3) Observe the animals at 1, 2 and 4 hrs and
daily for 14 days
(4) Usually calculated as number of deaths at 14
days after administration
(5) Body weight of animals at 14 days
(6) Minimal or no histopathology or clinical
35
-------
chemistry except in the dog. Clinical
chemistry often performed oefore
administration and on days 2, 7 and 14
2. Acute dermal toxicity (LD50)
a. Typical protocol
(1) Albino rabbits
(2) Area of application free of hair and abraided
(3) If a solid, moistened with saline
(4) Kept in contact for 24 hrs
(5) Observe for 2 weeks
(6) If no toxicity at 2 g/kg, no further testing
necessary
3. Acute inhalation toxicity (LC50)
a. Typical protocol
(1) As above (under typical protocol for oral
LD50)
(2) 4 hr exposure
4. Primary eye irritation
a. Typical protocol
(1) Rabbits
(2) Place liquid or solid (not moistened) in eye
(0.1 ml of liquid or 100 mg of solid/
(3) Other eye serves as control
(4) In some animals flush eye, others don't
(5) Grade and score eye irritation at 1, 2, 3{ 4,
7 and every 3 days thereafter until toxicity
subsides
5. Primary skin irritation
a. Typical protocol
(1) Rabbit
36
-------
(2) Hair clipped
(3) 0.5 ml liquid or 0.5 g solid
(4) Covered by gauze and then plastic
(5) Chemical in contact with skin for 4 hrs
(6) Erythema and edema scored at 24 and 72 hrs
after application
6. Skin sensitization (Guinea pigs)
a. Draize
b. Freunds complete adjuvant test (FCAT)
c. Guinea pig maximization
d. Split adjuvant
e. Beuhler occlusive
f. Open epicutaneous
B. Subacute
1. To determine dose levels for subchronic study
2. Typical protocol
a. 14 days
b. In rodents, 4 doses, 10 animals per sex per dose,
for dogs, 3 doses, 3 dogs per sex per dose
c. Observe twice a day
d. Do clinical chemistry, histopathology, etc.
C. Subchronic
1. Typical protocol
a. 90 days (13 weeks)
b. At least 3 doses and controls
c. 2 species (15 rats of each sex per dose and 4
dogs of each sex per dose)
37
-------
d. Route of intended use or exposure (usually diet)
2. Typical observations
a. Mortality
b. Body weight changes
c. Diet comsumption
d. Urinalysis (color, specific gravity, pH, albumin,
sugar, leukocytes, erythrocytes, epithelial
ceils, casts, bacteria, crystals)
e. Hematology (RBC, WBC, platelets, differential)
f. Clinical chemistry (glucose, creatinine, BUN,
alkaline phosphatase, iron, total protein,
albumin, globulin)
g. Gross and microscopic examination (brain, heart,
iver, kidney, spleen, testes, thyroid, adrenal
and weigh the 8 aforementioned organs], aorta,
)one. bone marrow-smears, gall bladder,
esophagus, duodenum, jujunum, cecum, colon, lung,
lymph node, sciatic nerve, parathyroid,
pituitary, salivary gland, epididymis, prostate)
D. Chronic
1. Typical protocol
a. Duration depends on intended period of
exposure in man. May be only 6 months, if to
determine carcinogenic potential, then other
average lifetime of species. 60 Animals per sex
Ber dose often started to assure 30 rats survive,
otherwise similar to subchronic.
b. For dogs, often use 3 doses and 6 male and 6
female per dose. Typical duration is 12 months.
Clinical chemistry performed on dogs before and
at 1, 3, 6, 9 and 12 months after commencement of
chemical administration.
2. Typical observations
a< Similar to subchronic
38
-------
b. In does often do opthalmic examination every 6
months
E. Fertility and reproductive (Phase I)
1. Typical protocol
a. Two or three doses (which produce no maternal
toxicity)
b. Male given 60-80 days and female 14 days prior to
mating
c. 25 rats per dose
2. Typical observations
a. Percent pregnant
b. Number of stillborn and live offspring
c. Weight, growth, survival and general
condition during first 3 weeks of life.
F. Teratogenic (Phase II)
1. Typical protocol
a. Same doses as above
b. Rats (25 per dose) and rabbits (20 per dose)
c. Exposed on days 6-15
(1) Day 0 in rabbit is day of mating
(2) In rodents, day 0 is when vaginal plug or
sperm in vaginal smear
d. Fetuses removed by cesaerean section two or three
days before normal parturition
(1) Rat - day 20
(2) Rabbit - day 29
2. Typical observations
a. Number of implantations
b. Number of dead and living fetuses
39
-------
c. Fetuses weighed, measured and examined grossly
d. Histological and skeletal examination
G. Perinatal and Postnatal (Phase III)
1. Typical protocol
a. 15 days of gestation throughout delivery and
lactation
2. Typical observations
a. Similar to fertility study
H. Multigeneration reproduction study
1. Typical protocol
a. Rats
b. F0 generation given chemical from 40 days of age
until breeding at day 140. Fx thus exposed in
utero and all their life including breeding and
development of F, generation. F0 are exposed
about 160 days, rl about 270 days and r2 about 60
days.
c. 25 females
d. 3 dose levels and control
e. Gross necropsy and histopathology
(1) Fx: Ten males and 25 females from each dose
(2) F, and F2: Five randomly selected weanlings
of each sex of each dose and generation
I. Mutagenic
1. Cytogenic analysis of bone marrow
2. Dominant lethal
3. Salmonella reverse mutation (Ames)
J. Other tests
1. Toxicokinetics
2. Antidotes
40
-------
3. Wildlife
K. Typical costs of descriptive toxicity tests
Acute oral toxicity
2,000
Acute dermal toxicity
2,800
Acute inhalation toxicity
3,300
Acute dermal irritation
700
Acute eye irritation
450
Skin sensitization
Draize test 6,700
FCAT (Freunds Complete Adjuvant Test) 3,900
Guinea pig maximization test 5,500
Split adjuvant test 3,200
Buehfer test 3,500
Open epicutaneous test 3,200
Mauer optimization test 3,850
Repeated dose toxicity (oral gavage)
14-day exposure 10,200
28-day exposure 12,800
Genetic tox tests
Reverse mutation assay (S.typhimurium) 1,000
Mammalian bone marrow cytogenetics 13,000
(in vivo)
Micronucleus test 2,000
Dominant lethal in mice 8,500
Host mediated assay 4,400
Drosophila 12,500
41
-------
Subchronic mouse study (190 days)
45,000
Rat oncogenecity
450,000
Mouse oncogenicity
300,000
Reproduction
200,000
Teratology (2 species)
45,000
Acute toxicity in fish (LC50)
1,250
Daphnia reproduction study
1,400
Algae growth inhibition
1,450
42
-------
I. USE OF TOXICITY DATA IN REGULATIONS
A. If no carcinogenicity, teratogenicity, or mutagenicity use
uncertainty factor
NOEL
1. If prolonged ingestion studies in man
10
NOEL
2. If chronic studies in animals
100
NOEL
3. If only scanty results in animals
1000
B. Risk vs Safety
1. Risk: The probability that a substance will produce
harm under specifiea conditions
2. Safety: The probability that harm will not occur
under specified conditions
3. Estimated risks
a. 1/4000: Automobile accident
b. 1/2,000,000: Lightning
4. Acceptable risk
a. People in U.S. = 2.2 x 10s
b. Lifespan = 80 years
c. Acceptable risk = 30 tumors per years
= 1 in 100,000
= 0.00001 or 10-«
= 0.001%
5. VSD = Virtually safe dose
43
-------
6 Mathematics used in determining the dose that should give
dose that will produce that acceptable risk
97.5
6
5
4
2.5
3
2
0.2
0.004
0
0.00003
0.01 0
0.3
3
10
Dosage
44
-------
D.
ABSORPTION, DISTRIBUTION, EXCRETION & METABOLISM
CURTIS D. KLAASSEN, PH.D.
I. MECHANISMS BY WHICH TOXICANTS PASS BODY MEMBRANES
A. Passive Transport
1. Simple diffusion
a. Of lipid soluble compounds
b. Nonionized chemicals are more lipid soluble
2. Filtration: when water flows in bulk across a porous membrane,
any solute that is small enough to pass through the pores flows
with it.
II. ABSORPTION OF TOXICANTS
A. Gastrointestinal tract
1. Lipid soluble compounds (nonionized) more readily absorbed than
lipid insoluble compounds (water soluble, ionized)
2. Specialized transport systems - sugars, amino acids,
pyrimidines, calcium and sodium
3. Almost everything is absorbed at least to a small extent
4. Effect of digestive fluids on chemicals
a. Snake venom
b. Nitrate to nitrite in newborns
5. Age - newborn has poor intestinal barrier
6. First pass - chemical can be extracted and/or biotransformed by
intestine or liver before reaches systemic circulation
B. Lungs
1. Anatomically good for absorption
a. Large surface area (50-100 sq m)
b. Blood flow is high
c. Close to blood (10 um)
C. Skin
45
-------
1. Is a relatively good barrier (many cells thick)
2. Absorption through follicles is rapid
3. Absorption trans dermally is quantitatively more important
4. Absorption by passive diffusion
5. Abrasion increases absorption
III. DISTRIBUTION OF TOXICANTS
A. Distribution to various organs dependent on
1. Blood flow through the organ
2. Ease it crosses cell membranes
3. Affinity of various tissues for the toxicant
B. Site of concentration in body is not necessarily the target organ
of toxicity
C. Fat as a storage depot
D. Bone as a storage depot
E. Blood-brain barrier
F. Placenta barrier
IV. EXCRETION OF TOXICANTS
A. Route of excretion of toxicants
1. Urine
2. Bile
3. Air
4. Gastrointestinal tract
5. Cerebrospinal fluid
6. Milk
7. Saliva, sweat, tears, etc.
B. Mechanisms of excretion into urine
46
-------
1. Glomerular filtration
a. All toxicants with MW < 60,000
b. If not bound to plasma proteins
2. Passive tubular diffusion
a. If lipid soluble
3. Active secretion - carrier mediated
a. Two separate carriers
1) Organic acids - P-aminohippurate
2) Organic bases - N-methylnicotinamide
C. Biliary excretion
1. Mechanisms of excretion into bile
a. Diffusion
b. Carrier mediated transport
1) Organic acid
2) Organic base
3) Organic neutral
2. Enterohepatic circulation
D. Lung
1. Important for substances that exist in gas phase at body
temperature
2. Mechanisms of elimination - diffusion
E. Gastrointestinal tract
1. Sources of toxicants in feces
a. Not completely absorbed
b. Excreted into bile
c. From respiratory tract and swallowed
d. Excreted in saliva, pancreatic or gastric secretions
*
47
-------
F. Milk
1. Importance
a. Toxic material may be passed from mother to nursing child
b. Compounds may be passed from cows to humans
2. Diffusion is the mechanism of transfer
a. Ion trapping - pH is 6.5 - basic compounds may concentrate
b. Lipid - 3.5% - DDT. PCB, PBB
G. Sweat and saliva
H. Half life - time it takes for one half of the chemical to be
eliminated from the body
V. METABOLISM OR BIOTRANSFORMATION OF TOXICANTS
A. Purpose - make more water soluble
B. Result
1. Detoxification
2. Toxification
3. No change
C. Two phases of biotransformation
1. Phase I: oxidation, reduction, hydrolysis
2. Phase II: conjungation or synthesis
D. Location: mainly liver, but all tissues can
E. Qualitative
1. Phase I
a. Cytochrome P-450 monooxygenase
b. Example of the general tvpe of oxidation reactions catalyzed
by the cytochrome P-45u-containing monooxygenases
1) Aromatic hydroxylation
2) Aliphatic hydroxylation RC l-t^C 80HC
48
-------
3) N, O and S-dealkylation R -(/V, 0/-O
4) Epoxidation 1?-Ctf - CWK' r"» R-cS-ch-a'
4: /?
o
w
5) Desulfuration g R p-X —* ^»^a.P"XD
' * //
6) Sulfoxidation ^ R-3-Rj
7) N-hydroxylation RXfrt--c-o^5 —=? r-M>Hcc,H3
c. Non P-450
1) Amine oxidase - not P-450
2) Epoxide hydrolase (closely associated with P-450)
.0 , ,4>o ->
3) Esterases and amidases 0
crt3c-0CjHs ?ch3coH t c**a,*®l+
jOb^uj-JXaXi. 0Mhk. QJtiiL jAomA.
4) Alcohol and aldehyde dehydrogenase 0
Cf^C^oH -* NftD1"—¦* crt3cH -* cH3coH
auvJjJL&dhf*^ ojuXgJX'
cooH
Phase II - conjugation Joi*\
a. Glucuronic acid **
b. Glutathione S-transferase
1) Tripeptide (glycine, cysteine and glutamic acid)
2) Enzymatically take off by peptidases
(t) Glutamic acid
(2) Glycine
3) N-acetyl transferase
4) Then mercapturic acid
c. Sulfotransferase - sulfate
49
-------
d. Amino acid conjugates - glycine, glutamine, taurine
e. Methyl transferases
1) Does not increase water solubility
f. N-acetyl transferases
1) Decrease water solubility
2) Pharmacogenetics
VI. QUANTITATIVE - FACTORS THAT AFFECT RATE OF
BIOTRANSFORMATION
A. Species difference - quantitative and qualitative
B. Strain differences
C. Sex differences
D. Age
E. Enzyme induction
1- Type
a. Increase P-450, Phenobarb, DDT
b. Increase P-448, 3-MC, PCB, TCDD
VII. THE MATHEMATICAL QUANTITATION OF ABSORPTION
DISTRIBUTION AND EXCRETION IS REFERRED TO AS
1. Pharmacokinetics
2. Toxicokinetics
50
-------
TOXICOLOGY OF INORGANICS
CURTIS D. KLAASSEN, PH.D.
I. LEAD (0.020 MG/L)
A. Sources
1. Environment from tetraethyl lead in gasoline
2. Old paint - pica (craving for unnatural food)
3. Improperly lead-glazed earthenware - acid
4. Occupational - smelters, storage-battery factories
5. Moonshine
6. Automobile battery casings - fuel
7. Water distribution pipes and solder
B. Absorption, Distribution and Excretion
1. Absorption: 10% ingested absorbed
2. Initial distribution: kidneys and liver
3. Redistribution: 95% in bone (X-rays)
4. Does not readily enter CNS except in children
5. Excretion: laboratory animals in bile, humans in urine; since
lead is in erythrocytes it is filtered slowly
6. Excretion is limited
a. Normal intake 0.3 mg/day
b. Positive lead balance 0.6 mg/day - no toxicity in lifetime
c. 2.5 mg/day - 4 yrs to toxic burden
d. 3.5 mg/day - few months to toxicity
C. Acute Lead Poisoning
1. Rare
D. Chronic Lead Poisoning (plumbism)
1. Gastrointestinal effects
51
-------
a. More common among adults
b. Referred to as lead colic
c. Often the symptoms for which patient seeks relief
d. Calcium gluconate for relief of pain
2. Neuromuscular Effects
a. Referred to as lead palsy
b. Wrist-drop and foot-drop
3. Central Nervous System Effects
a. Termed lead encephalopathy
b. Most serious manifestation of lead toxicity
c. More common in children
d. 25% mortality - 40% of survivors have neurological sequelae
4. Hematologic Effects
a. Basophilic stippling (RNA in RBC's) - seen in only 60% of
cases among children and less in adults
b. Anemia
c. Heme synthesis: interference of heme synthesis resulting in
porphyria
5. Renal Effects
a. Kidney injury
b. Cancer in laboratory animals (B2)
E. Diagnosis of Lead Poisoning
1. Symptomology
2. History of exposure
3. Blood - lead concentration
a. 10-40 ug/100 g blood: normal
b. 40-60 ug/100 g blood: decrease ALA dehydrase and slight
increase in urinary ALA excretion
52
-------
c. 60-80 ug/100 g blood: mild symptoms
d. greater 80 ug/100 g: clear-cut symptoms
e. 120 ug/100 g: encephalopathy
4. X-rays of long bones
5. ALA and coproporphyrin concentrations in urine
F. Organic Lead Poisoning
1. CNS: insomnia, nightmares, irritability, anxiety
2. Car exhaust is organic
II. MERCURY (0.003 mg/L)
A. Chemical Forms and Sources of Mercury
1. Elemental mercury - mercury vapor
2. Mercury salts
a. Monovalent mercurous salts
ex) Mercurous chloride or calomel:
skin cream, antiseptic, diuretic, cathartic
b. Divalent mercuric salts
ex) Mercuric nitrate: felt-hat industry "madhatter"
3. Organomercurials
a. Fungicides
1) Huckleby family of Alamogordo, NM
2) Iraq. 1972
b. Fish
1) Minamata Bay, Japan
2) Tuna and Swordfish in USA
B. Absorption, Biotransformation, Distribution and Excretion
1. Elemental mercury
53
-------
a. Oraily - nontoxic
b. Lung - readily absorbed, oxidized by RBC to divalent
mercuric cation
c. Distribution: since Hg vapor crosses membranes more
readily, a significant amount enters brain before it is
oxidized.
2, Inorganic mercury salts
a. About 10% absorbed from G.I.
b. Concentration in RBC and plasma similar
c. Because ionized do not readily pass blood-brain barrier
or placenta
d. High concentration in kidneys
e. Half-life: 60 days
3. Organic mercurials
a. About 90% absorbed from G.L
b. More lipid soluble - more evenly distributed and enters
brain and passes placenta
c. 5-times higher cone in RBC than plasma
d. Half-life is 65 days
C. Acute Mercury Poisoning
i. Local effects
D. Chronic Mercury Poisoning
1. Central neural effects
a. Mercury vapor (elemental mercury): largely neuro-
psychiatric: depression irritability, shyness,
insomnia, emotional instability, forgettulness, confusion,
excessive perspiration, uncontrolled blushing (erethism) and
tremors
b. Methylmercury
1) Paresthesia (abnormal spontaneous sensation, ex.
tingling)
54
-------
2) Visual changes (constriction of visual field)
3) Hearing defects
4) Dysarthria (disturbance of articulation)
5) Ataxia
6) Fetus is extremely susceptible
d. Inorganic mercury: little known
2. Kidney: target organ of inorganic mercury toxicity
E. Diagnosis
1. Difficult: biochemical and functional aspects difficult to
quantitate
2. Hg in RBC and plasma (upper normal blood 0.01 - 0.03 ug/ml,
toxic symptoms at 0.2 ug/g)
3. He in urine (normal 25 ug/L: tremors at chlor-alkali plant at
5(H) ug/ml)
4. Hair: 300 X blood
ARSENIC (0.050 mg/L)
A. Exists in Elemental Form and in the Tri- and Pentavalent Oxidatio
States
B. Toxicity Rating:
RAs-X < As+B < As+3 < AsH3
C. Absorption, Distribution and Excretion
1. Variable absorption, soluble salts well absorbed and insoluble
salts are poorly absorbed
2. Distribution: liver and kidney, hair and nails
3. Methylated in body
4. Excretion
a. Excreted in urine
b. Half life about 2 days
55
-------
D. Biochemical Mechanism of Toxicity
1. As+S reacts with thiols (alpha-lipoic acid)
2. As+B uncouples oxidative phosphorylation
E. Toxicological Effects
1. Circulation: increase permeability
2. Gastrointestinal: "rice-water" stools
3. Kidney: glomerular capillaries
4. Skin: "milk and roses" complexion
5. CNS: peripheral neuritis, encephalopathy
6. Blood: decrease in RBC and other cells
7. Liver: fatty infiltration and necrosis
8. Metabolic effects: not a tonic
9. Carcinogenesis: skin and Lung (A)
F. Acute Arsenic Poisoning
1. Early Signs and Symptoms
a. Diarrhea
b. Skin pigmentation
c. Hyperkeratosis
d. Edema of lower eyelids, face and ankles
e. Garlic odor of breath
F. Etc.
2. Progression
a. Dermatitis and keratosis of palms soles - skin cancer
b. Enlarged liver
c. Renal injury
d., Peripheral neuritis (legs more than arms - contrast to
lead)
56
-------
e. Encephalopathy
f. Aplastic anemia
H. Arsine
1. Gas
2. Hemolysis
IV. CADMIUM (0.005 mg/L)
A. Occurrence and Uses
1. Associated with lead and zinc
2. Used as pigment
3. Corrosion, resistance - use in electroplating
4. Cadmium-nickel batteries
5. Coal and fossil fuels
6. Itai-itai (ouch-ouch disease
B. Absorption, Distribution and Excretion
1. 1-5% absorbed from G.I.
2. 10-40% absorbed from lung
3. Distributes to kidney and liver - metallothionein
4. Half-life: 10-30 yrs
5. Excretion: bile
C. Acute Cadmium Poisoning
1. Oral: G.I. effects
2. Inhalation: local irritation of respiratory tract
D. Chronic Cadmium Poisoning
1. Kidney
a. Most cadmium sensitive organ
b. Injury when 200 rig Cd/g
57
-------
c. Quantitate by B2-microglobulin
2. Lungs
a. After inhalation
b. Emphysema (loss of ventilatory capacity and increase in
lung volume)
3. Cardiovascular: hypertension
4. Bone
5. Testes - sensitive after acute, not after chronic
IV. IRON
A. Frequent in children
B. G.I. tract
C. Metabolic acidosis and cardiovascular collapse
VI. OTHER METALS
A. Aluminum
1. Low order of toxicity, aluminum hydroxide is antacid
2. Shaver's disease - by inhalation in industry - lung fibrosis
B. Antimony: toxicity similar to arsenic
C. Barium (1.5 mg/L)
1. Soluble salts (CI) - G.I. and cardiovascular
2. Insoluble salts (SOJ - G.I. scans
3. Convert with magnesium sulfate
D. Beryllium:
1. Granuloma
2. Carcinogen in animals
E. Chromium (0.12 mg/L)
58
-------
1. Necessary for glucose metabolism (trivalent)
2. Insoluble hexavalent cause lung cancer by inhalation
F. Cobalt
1. Essential element in vitamin B12
2. Polycythemia
3. Goiter
4. Cardiomyopathy - beer drinkers
G. Copper (1.3 mg/L)
1. Essential element
2. Wilson's disease
3. Therapy - penicillamine
H. Fluoride (4 mg/L)
1. Reduce dental caries at 0.7 - 1.2 mg/1 or ppm
2. Dental fluorosis (discoloration and/or pitting) in children
above 2 ppm
3. Brittle bones at higher concentrations
4. MCD = 4 ppm
SMCL = 2 pp,
J. Manganese
1. Managenese pneumonitis
2. CNS: Parkinson's disease
K. Nickel
1. Dermatitis (nickel itch)
2. Nickel carbonyl (Ni[CO]4) - pneumonitis leukocytosis,
temperature, delirium
3. Nickel subsulfide - carcinogen in man (nose)
L. Phosphorus
1. Used in matches, rat poisons, fireworks
59
-------
2. G.I. upset - vomitus may be phosphorescent
3. Liver injury - jaundice
4. Chronic - necrosis of bone "phosey jaw"
M. Selenium (0.045 mg/L)
1. Essential (glutathione peroxidase)
2. Excess in livestock - "blind staggers or alkali disease"
characterized by lack of vitality, Toss of hair, sterility,
atrophy of hooves, lameness and anemia
3. Excess in main - discolored or decayed teeth, skin eruptions,
G.I. distress, partial loss of hair and nails
4. Liver injury
N. Silver
1. Skin - argyria
O. Thallium
1. Used in rodenticides
2. Distributed like potassium
3. G.I. irritation - acute
4. Alopecia
P. Uranium
1. Kidney injury
Q. Zinc
1. Essential
2. Acute oral toxicity: vomiting, diarrhea, fever
3. Inhalation: metal fume fever - fever
60
-------
F.
PESTICIDES
I. CLASSIFICATION
A. Insecticides
B. Rodenticides
C. Fungicides
D. Herbicides
E. Fumigants
II. INSECTICIDES
A. Organochloride Insecticides
1. Chlorinated ethanes
1) high lipid solubility
a) stored in fat - 7 ppm
b) biomagnification - eggshell thinning
c) biotransformed - dechlorination - acid
d) slow elimination - 1%/day
2) wide margin of safety
3) Toxicology
a) CNS stimulation
b) induce P-450
c) hepatoma in laboratory animals
4) Dec. 31, 1972 banned in U.S.
H
b. Methoxychlor
v
61
-------
1) Much less persistence because biotransformed by 0-
demethylation
2. Chlorinated cyclodienes
a. Examples
1) Aldrin
2) Dieldrin & Endrin
3) Heptachlor
4) Chlordane
b. Toxicology
1) stimulate CNS
2) unlike DDT, have caused numerous fatalities
3) more readily absorbed across skin
4) lipid soluble, stored in fat, biodegraded slowly,
undergo biomagnification
5) greatest hazard of the insecticides to produce
cancer
6) n^^istration ^or agricultural crops suspended in
3. Other Chlorinated Hydrocarbons
a. Lindane (gamma isomer)
1) Toxicology £
a) CNS stimulation
b) induce P-450
c) less persistent than DDT
d) not carcinogenic
b. Toxaphene
1) most used insecticide in U.S.
62
-------
2) mixture of 175 chlorinated hydrocarbons
3) low persistence
4) recently been shown to be carcinogenic
c. Mirex & Kepone
1) extremely persistent
2) like other chlorinated insecticides
a) CNS stimulation
b) liver injury
c) induce P-450
d) carcinogenic
3) treatment - cholestyramine
B. Organophosphorus Insecticides
1. Have largely replaced chlorinated hydrocarbon insecticides
a. are not persistent in environment
b. extremely low potential to produce cancer
c. But - much higher acute toxicity in man
2. Are derivatives of phosphoric acid - most are sulfur analogues
and, have to be biotransformed to an oxygen analogue to be
3. Inhibit cholinesterase - accumulation of acetylcholine
a. Muscarinic - SLUD, sweating, bradycardia and hypotension
b. Nicotinic - involuntary twitching and scattered
fasciculations and eventually paralysis of the respiratory
muscles.
active.
parathion
paraxon
63
-------
c. CNS - confusion, ataxia, convulsions, etc.
4. Lab test - blood and plasma cholinesterase
5. Antidotes
a. Atropine
b. Pralidoxime (2-PAM)
6. Delayed neurotoxicity
a. TOCP (an adulterant of Jamaica ginger) ^
" . ^ *
b. Mipafox and leptophos \
C|}.
C. Carbamate Insecticides
1. examples are carbaryl and aldicarb
2. like organophosphates - inhibit acetylcholinesterase
3. direct inhibitors of acetylcholinesterase
4. carbamoylated enzyme is more readily reversible than the
phosphorylated enzyme.
5. antidotes - atropine, but not pralidoxime.
D. Botanical Insecticides
1. Pyrethrum (Chrysanthemum)
a. Rapid knock-down action for insects but combined with
piperonyl butoxide for increased duration.
b. Generally rated as safest insecticide
c. Allergic properties are marked
2. Rotenone
3. Nicotine - most toxic insecticide - convulsions
FUMIGANTS - CONTROL INSECTS, RODENTS AND SOIL
NEMATODES
A. Cyanide (also in silver polish, fruit seeds, laetrile)
1. Rapid acting
64
-------
2. Great affinity for iron in ferric (trivalent) state
a. cytochrome oxidase - inhibit cellular respiration
b. cells can't utilize oxygen
c. respiration stimulated
d. hypoxic convulsions
3. Therapy
a. form ferric iron in body by forming methemoglobin - give
sodium nitrite
b. thiosulfate to give sulfur to aid rhodanese to form
thiocyonate
c. oxygen
B. Methylbromide
1. Causes more deaths in California than organophosphates
2. CNS convulsions and pulmonary edema
C. Dibromochloropropane and ethylene dibromide
1. Produce CNS depression and pulmonary edema
2. Both produce malignant gastric squamous cell carcinoma
3. DBCP causes testicular injury
1. Clinical reports of poisoning are rare.
2. Not cumulative chemicals - actively excreted into urine, and
have Tl/2 of 24 hours in man.
3. Chloracne due to TCDD
HERBICIDES
A. Chloi
co&u
65
-------
a. most toxic manufactured chemical
b. induce P-448
c. teratogen, mutagen and carcinogen
B. Dipyridyl Compounds
i
2. Lung injury
C. Triazines
1. ex: Atrazine
2. low order of toxicity
3. aminotriazole
a. antithyroid
b. thyroid cancer
D. Amides
1. ex: Alachlor (Lasso), Propachlor (Ramrod), and Propanil
2. low acute toxicity
3. have caused severe irration of the skin
4. cancer
FUNGICIDES
A. Organic mercurial compounds
B. Dithiocarbamates
C. Hexachlorobenzene
1. increase P-450
2. produce porphyrea
D. Pentachlorophenol
1. uncouple oxidative phosphorylation like nitrophenol herbicides
2. fungicide in diapers has been fatal
66
-------
3. commercial samples are contaminated with polychlorinated
dibenzodioxins and dibenzofurans.
67
-------
G.
TOXICOLOGY OF SOLVENTS AND VAPORS
CURTIS D. KLAASSEN, PH.D.
I. GASOLINE AND KEROSENE
A. CNS depression — death from respiratory
failure
B. Sensitize myocardium to epinephrine —
ventricular fibrillation
C. Aspiration — chemical pneumonitis
II. HALOGENATED HYDROCARBONS
A. General characteristics
1. Excellent solvents
2. Low flammability
3. Depress CNS
B. Carbon tetrachloride
1. Use — hookworm, anesthetic, spot
remover, solvent
2. Toxic effects
a. CNS depression
b. Sensitize myocardium to catecholamine
c. Kidney injury
d. Liver injury
1) Mechanism
a) Biotransformed bv P-450 to trichloro-
methyl free radical
b) Attacks membrane lipids and
produces lipid peroxidation
2) Alcohol potentiation
68
-------
c.
a) Ethanol
b) Isopropanol
e. Carcinogenic
OTHER HALOGENATED HYDROCARBONS
CNS
Depression
Senzitize
Heart
Liver
Injury
Kidney
Injury
Cancer
Methanes
Carbon tetrachloride +
Chloroform +
Dichloromethane +
(methylene chloride)
Ethanes
1.1-Dichloroethane +
1.2-Dichloroethane +
1.1.1-Trichloroethane +
1.1.2-Trichloroethane +
1,1,2,2-Tetrachloroethane +
Hexachloroethane +
Ethylenes
Chloroethylene +
(vinyl chloride)
1.1-Dichloroethylene +
(vinylidine chloride)
1.2-Trans-dichloroethylene +
Trichloroethylene +
Tetrachloroethylene +
(perchloroethylene)
+
+
++++
+++
+-
+
+
+-
++
++
++
+++
++
+
+-
++
+++
++
+
+-
+-
+
+
+
+++
69
-------
A. Methanol
1. Used in canned fuels, some paints,
paint removers, antifreeze fluids
2. Distribution and biotransformation
like ethanol
3. Toxicology
a. CNS depression — but less inebriating
than etnanol
b. Acidosis — due to oxidation to formic acid
c. Blindness
B. Isopropanol
1. Use — rubbing alcohol, hand lotions,
deicing and antifreeze
2. Toxicity
a. CNS depression — longer lasting
(biotransformed slower)
b. Prominent gastritis
IV. GLYCOLS
A. Ethylene glycol (OHCH2CH2OH)
1. Toxicity
a. CNS depression
b. Kidney injury - oxalate
V. AROMATIC HYDROCARBON SOLVENTS
A. Benzene
1. Acute toxicity — CNS depression
2. Chronic toxicity
a. Bone marrow depression — aplastic
anemia
70
-------
b. Leukemia — humans but not in labora-
tory animals
c. Toxicity due to a metabolite
B. Toluene (C6H5CH8)
1. CNS depression
2. Relatively safe solvent
71
-------
H.
CHEMICAL CARCINOGENS
CURTIS D. KLAASSEN. PH.D.
I. DEFINITIONS
A. Cancer: A new growth (neoplasm) — an uncoordinated
growth of cells
1. Malignant
a. Invasive - infiltration into surrounding
tissue
b. Metastatic - gives rise to secondary discon-
tinuous tumor growth
c. Growth - rapid
2. Benign
a. Noninvasive and therefore compresses
surrounding tissue forming capsule
b. Nonmetastic, remains local
c. Slow and relatively limited growth
d. Close resemblance to cell of origin
II. HISTORICAL
A. Chimney sweeps had cancer of scrotum — late 18th
century
B. Dye workers — aromatic animes — cancer of urinary
bladder
III. TWO-STAGE CARCINOGENESIS (CO-CARCINOGENESIS)
A. Initiation: production of an irreversible cellular
damage
B. Promotion: process whereby a tumor is caused to
develop in which initiation has already occurred.
C. Complete carcinogen: does both initiation and
promotion
72
-------
IV. CLASSES OF CARCINOGENIC CHEMICALS
A. Genotoxic - binds to DNA
1. Direct acting or primary carcinogen
2. Procarcinogen or secondary carcinogen
3. Inorganic carcinogen
B. Epigenetic
1. Solid state carcinogen
2. Hormones
3. Immunosuppressor
4. Co-carcinogen
5. Promoter
V. DIRECT-ACTING, OR PRIMARY CARCINOGENS
A. Highly chemical reactive
B. Examples
1. Bis(Chloromethyl)ether — CICH2OCH2CI
2. Methyl iodide
3. Dimethyl sulfate
VI. PROCARCINOGENS OR SECONDARY CARCINOGENS
A. The ultimate carcinogen results from metabolic
activation (the final active forms are electron-
deficient or Electrophiles - these electrophiles
combine with electron-rich or Nucfeophfles in
nucleic acids to form covalent bonds)
Little is known of how this interaction ultimately
transforms the cell into a cancer cell. It may alter
gene expression and activate oncogenes.
B. Examples
1. Polycyclic or heterocyclic aromatic hydrocarbons
a. Benzo(a)pyrene, 3-methylcholanthrene,
7,12-dimetnylbenz(a)anttiracene
73
-------
b. Natural products in incomplete combustion
such as in soot, coal, tar, tobacco smoke,
petroleum and charcoal
2. Aromatic amines
a. Aniline cancers in dyestuff manufacture
b. 2-acetylaminofluorene (AAF)
c. 2-naphthylamine
d. 4-biphenylamine
e. 3-aminotriazole
f. Benzidine
g. Pyrolysis of protein-containing material
3. Azo dyes
a. 4-dimethylaminoazobenzene (butter yellow)
b. Amaranth — red dye #2
4. Nitrosamine and nitrosamides
a. Nitrosamine
b. Dimethylnitrosamine
c. Streptozotocin
5. Dioxane
6. Benzene - leukemia
7. Urethane
8. Carbon tetrachloride, chloroform, DDT,
Tris(2,3-dibromopropyl)-phosphate, vinyl
chloride (CH3=CHCI)
9. Microbiologic carcinogens
a. Mycotoxins
Aflatoxin (B2, G1( G2)
10. Plant carcinogens
74
-------
a. Tobacco - some carcinogens, some pyrolysis
products, promoter
b. Safrole
c. Senecio (se-ne-she o) (pyrolizidine)
alkaloids
VII. INORGANIC CARCINOGENS
A. Uranium
B. Polonium
C. Radium
D. Nickel
E. Titanium
F. Arsenic
VIII. SOLID STATE CARCINOGENS
A. Size and shape
B. Asbestos — mesotheliomas
IX. HORMONES
A. Estrogens
1. Estradiol - not genotoxic - promoter
2. Diethylstilbestrol
X. IMMUNOSUPPRESSIVE DRUGS
XI. CO-CARCINOGENS: AGENTS THAT INCREASE THE OVERALL
CARCINOGENIC PROCESS CAUSED BY A GENOTOXIC
CARCINOGEN WHEN ADMINISTERED WITH THE CARCINOGEN
A. Mechanisms of co-carcinogenesis
1. Altering biotransformation
2. Increasing cell growth
3. Increasing uptake of carcinogen
75
-------
4. Depletion of competing nucleophiles
5. Inhibit DNA repair
B. Examples
1. Croton oil (phorbol esters)
2. Tobacacco smoke (catechol)
XII. PROMOTERS; AGENTS THAT INCREASE THE TUMORIGENIC
RESPONSE TO A GENOTOXIC CARCINOGEN WHEN APPLIED
AFTER THE CARCINOGEN
A. Examples
1. Croton oil - phorbol esters, TPA (12-0-
tetradecanoylphorbol-13-acetate)
2. Bile acids
3. Phenobarbital, DDT, BHT
B. How to test for promoters
1. Two-state skin tumorigenesis: give carcinogen
(ex: 7,12-dimethylbenz(a)anthracene then
repeated administration of promoting agent
(often twice a week) over 2-5 months
2. Pitot and Farber liver methods: Do 2/3
hepatectomy, give genotixc chemical and
then promoter and Took for increase in
number of preneoplastic nodules
XIII. PHARMACOLOGICAL AND TOXICOLOGICAL IMPLICATIONS
A. Dose response
100
so
z
8 60
9
!9
0
C
40
1
20
0
0
1,2,5,6-Dlbenzanthracene
3,4-Benzpyrene
3-Methylcholanthrene
76
-------
B. Species and strain
1. Species - benzidene in man affects bladder:
in rat the liver
2. Age - younger more susceptible, DES transplacenta
XIV. DETECTION OF CHEMICAL CARCINOGENS
A. Structure of chemical
B. in vitro short term tests (genotoxic)
1. Bacterial mutagenesis (ex, Ames)
2. DNA repair
3. Mammalian mutagenesis
4. Sister chromatid exchange
5. Cell transformation
C. Limited in vivo bioassays
1. Skin tumor induction in mice
2. Pulmonary tumor induction in mice
(30-35 weeks)
3. Breast cancer induction in female
Sprague-Dawley rats
4. Altered foci induction in rodent liver
[Gamma-glutamyl transpeptidase, glucose-
6-phosphatase, adenosine triphosphatase,
resistance to iron accumulation, P-450.
flucuronosyltransferase) — 12 weeks, last
weeks plus iron
D. Chronic bioassay
XV. EPA PROPOSED CLASSIFICATION OF CARCINOGENS
A. Human carcinogen
B. Probable human carcinogen
Bl. Limited human data, sufficient animal
data
77
-------
B2. Sufficient animal data
C. Possible human carcinogen - limited animal data
D. Not classified - inadequate or no data
E. No evidence for carcinogenenicity in humans -
data in animals indicates the chemical is not
carcinogenic
78
-------
I. PRINCIPLES OP RISK ASSESSMENT
A Nontechnical Review
S7^
PRO^
WORKSHOP ON RISK ASSESSMENT
United States Environmental Protection Agency
-------
I.
Principles of Risk Assessment; A Nontechnical Review
CONTENTS
TOPIC PAGE
I. Introduction 80
II. Risk and Risk Assessment 81
Basic Concepts and Definitions 81
The Components of Risk Assessment 83
Dose . 84
III. Hazard Identification 92
Introduction 92
Toxicity Information form Animal Studies 92
The Use of Animal Toxicity Data 92
General Nature of Animal Toxicity Studies 9 3
Manifestations of Toxicity 95
Design and Conduct of Toxicity Tests 97
Designs of Tests for Carcinogenicity 99
Conduct and interpretation of Toxicity Tests 101
Categorization of Toxic Effects 102
Uncertainties in Evaluation of Animal Carcinogenicity
Test Results.. ........103
Short-term Tests for Carcinogens 104
Data from Human Studies 104
Hazard Identification: A Summary ..........107
IV. Dose-Response Evaluation 109
Introduction 109
Threshold Effects 109
Effects that May Not Exhibit Thresholds. 111
The Carcinogenic Process 111
Potency and High-to-Low Dose Extrapolation 112
Interspecies Extrapolation 115
Dose-Response Evaluation: A Summary 115
V. Human Exposure Evaluation. ........117
VI. Risk Characterization 119
Appendix - Toxic Effects on Organs or Other Target Systems 120
Introduction 121
Liver 121
Kidney ....122
Reproductive System ........123
Lungs. ..........125
Skin. 126
Central Nervous System. 1 26
Blood 128
Immune System ...129
Genetic Toxicology 129
-79-
-------
I. INTRODUCTION
This report provides general background information for
understanding the types of scientific data and methods currently
used to assess the human health risks of environmental chemicals.
Human health risk is the likelihood (or probability) that a given
chemical exposure or series of exposures may damage the health of
exposed individuals. Chemical risk assessment involves the anal-
ysis of exposures that have taken place in the past# the adverse
health effects of which may or may not have already occurred. It
also involves prediction of the likely consequences of exposures
that have not yet occurred. This document is by .no means a com-
plete survey of the complex subject of risk assessment, but it is
sufficiently comprehensive to assist conference participants in
dealing with the specific sets or data relevant to the case
study.
The report begins with a discussion of the four major compon-
ents of risk assessment and their interrelationships. This sec-
tion is followed by extensive discussion of these four major com-
ponents. Generally, each section focuses on the methods and
tests used to gather data, the principles used for data interpre-
tation, and the uncertainties in both the data and inferences
drawn from them. Throughout these discussions, key concepts
(e.g., exposure, dose, thresholds, and extrapolation) are defined
and extended descriptions provided.
Many of the principles discussed in this report are widely
accepted in the scientific community. Q£hers thresholds
for carcinogens, the utility of negative epidemiology data) are
controversial. In such cases we have attempted to describe the
various points of view and the reasons for them and have also
identified the viewpoint that seems to have been broadly adopted
by public health and regulatory officials.
Finally, the concepts and principles we describe here, al-
though broadly applicable, may not apply in specific cases. In
some instances, the data available on • specific chemical may
reveal aspects of its behavior in biological systems that suggest
a general principle (e.g., that data obtained in rodent studies
•re generally applicable to humans) may not hold. Zn such in-
stances, the usual approach is to modify the risk assessment
process to conform to the scientific finding.
80
-------
ZZ. RISK AND RZSK ASSESSMENT
BASIC CONCEPTS AND DEFINITIONS
Risk is the probability of injury, disease, or death under
specific circumstances. Zt nay be expressed in quantitative
terms, talcing values from sero (certainty that harm will not
occur) to one (certainty that it will). Xn many cases risk can
only be described qualitatively, as "high," "low," "trivial."
All human activities carry some degree of risk. Many risks
are known with a relatively high degree of accuracy, because we
have collected data on their historical occurrence. Table 1
lists the risks of some common activities.
Table 1
ANNUAL RISK Of DEATH FROM SELECTED COMMON HUMAN ACTIVITIES1
Number of Death*
in Repreeentative Lifetime
ISiL lS£i^£^iSLJSlS!^l£SL
Coal Mining
Aceident
Black lung diaeaae
180
1,135
1.30 x itr3
s x itr3
or 1/770
or 1/125
1/17
1/3
Motor Vehlele
46,000
2.2 X 10*4
or 1/4,500
1/65
Truck Driving
400
10-4
or 1/10,W0
1/222
Falls
16,339
7.7 x 1tr*
or 1/13,000
1/186
Horn Accident#
25,000
1.2 x 10-5
or 1/13,000
1/130
1 Selected from Hutt (1978) food. Drug,
Coemetle Law J.
33t558-309,
^Estimated baaed upon 70-yeer lifetime and 45-yeer work e^oeure.
The risks associated with many other activities, including
the exposure to various chemical substances, can not be readily
assessed and quantified. Although there are considerable histor-
ical data on the risks of some types of chemical exposures (e.g.,
the annual risk of death from intentional overdoses or accidental
exposures to drugs, pesticides, and Industrial chemicals), such
data are generally restricted to those situations in which a
¦ingle, very high exposure resulted in an immediately observable
form of Injury, thus leaving little doubt about causation.
Assessment of the risks of levels of chemical exposure that do
81
-------
II-2
not cause immediately observable forms o£ injury or disease (or
only minor forms such as transient eye or skin irritation) is far
more complex, irrespective of whether the exposure may have been
brief, extended but intermittent, or extended and continuous. It
is the latter type of risk assessment activity that is reviewed
in this report (although some review of acute poisoning is also
included).
As recently defined by the National Academy of Sciences, risk
assessment is the scientific activity of evaluating the toxic
properties of a chemical and the conditions of human exposure to
it in order both to ascertain the likelihood that exposed humans
will be adversely affected, and to characterize the nature of the
effects they may experience.*
The Academy distinguishes risk assessment from risk manage-
ment) the latter activity concerns decisions about whether an
assessed risk is sufficiently high to present a public health
concern and about the appropriate means for control of a risk
judged to be significant.
The term "safe,* in its common usage, means "without risk."
In technical terms,, however, this common usage is misleading
because science can not ascertain the conditions under which a
given chemical exposure is likely to be absolutely Without a risk
of any type. The latter condition—zero risk—is simply immea-
surable. Science can, however, describe the conditions under
which risks are so low that they would generally be considered to
be of no practical consequence to persons in a population. As a
technical matter, the safety of chemical substances—'Whether in
food, drinking water, air, or the workplace—has always been
defined as a condition of exposure under which there is a "prac-
tical certainty" that no harm will result in exposed individuals.
(As described later, these conditions usually incorporate large
safety factors, so that even more intense exposures than those
defined as safe may also carry extremely low risks). We note
that most "safe" exposure levels established in the way we have
described are probably risk-free, but science simply has no tools
to prove the existence of what is essentially a negative condi-
tion.
Another preliminary concept concerns classification of chemi-
cal substances as either "safe" or unsafe" (or as "toxic" and
"nontoxic"). This type of classification, while common (even
among scientists who should know better), is highly problematic
^Kisk Assessment in the Federal Governmentt Managing the Process
(Washington, D.C.t National Academy Press, 1963).
82
-------
II-3
and misleading. All substances, even those which we consume in
high amounts every day, can be made to produce a toxic response
under some conditions of exposure. Zn this sense, all substances
are toxic. The important question is not simply that of toxici-
ty, but rather that of risk—i.e., what is the probability that
the toxic properties of a chemical will be realised under actual
or anticipated conditions of human exposure? To answer the lat-
ter question requires far more extensive data and evaluation than
the characterization of toxicity.2
THE COMPONENTS OF RISK ASSESSMENT
There are four components to every (complete) risk assess-
ment:
A. Hazard Identification—Involves gathering and evaluating
data on the types of health injury or disease that may
be produced by a chemical and on the conditions of expo-
sure under which injury or disease is produced. It may
also involve characterisation of the behavior of a chem-
ical within the body and the interactions it undergoes
with organs, cellsr or even parts of cells. Data of the
latter types may be of value in answering the ultimate
question of, whether the forms of toxicity known to be
produced by a substance in one population proup or in
experimental settings are also likely to be produced in
humans. Hazard identification is not risk assessment;
we are simply determining whether it is scientifically
correct to infer that toxic effects observed in one
setting will occur in other settings
-------
II-4
different conditions of exposure. The risks of a sub-
stance can not be ascertained with any degree of confi-
dence unless dose-response relations are quantified,
even if the substance is known to be "toxic."
C. Human Exposure Evaluation—'Involves describing the
nature and size of the population exposed to a substance
and the magnitude and duration of their exposure. The
evaluation could concern past or current exposures, or
exposures anticipated in the future.
D. Risk Characterization—Generally involves the integra-
tion of the data and analysis of the first three compo-
nents to determine the likelihood that humans will
experience any of the various forms of toxicity associ-
ated with a substance. (In cases where exposure data
are not available, hypothetical riak can be character-
ized by the integration of hazard identification and
does-response evaluation data alone.)
The next four sections elaborate on each of these components
of risk assessment. However/ the concapt of "dose," which under-
lies all the discussions to follow of both •xperimental animals
and human populations, is reviewed first.
DOSE
Human exposures to substances in the environment may occur
because of their presence in air, water, or food. Other circum-
stances may provide the opportunity for exposure, such as direct
contact with a sample of the substance or contact with contami-
nated soil. Experiments for studying the toxicity of a substance
usually involve intentional administration to subjects through
the diet, air to be inhaled, or direct application to skin.
Experimental studies may include other routas of administration:
injection under the skin (subcutaneous), into tha blood (usually
intravenous), or into body cavities (intraperitoneal).
In both human and animal exposures, two types of measurement
must be distinguished*
1. Measurement of the amount of the substance in the
medium (air, diet, etc.) in which it is present or
adminiatared.
2. Measurement of the amount received by the subject,
whether human or animal.
84
-------
11-5
Zt is critically important to distinguish these two types of
measures. The second measure, which is usually expressed as a
dose, is the critical factor in assessing risk. The first mea-
sure, along with other information, usually is essential if the
dose is to be established. Zt stay be substituted or supple-
mented, however, in cases where environmental siodeling or biomon-
itoring data are available.
The difference between these two measures is best described
by example. Suppose a substance is present in drinking water to
be consumed by an individual. To determine the individual's dose
of this substance, it is first necessary to know the amount
present in a given volume of water. For many environmental sub-
stances, the amounts present fall in the milligram (mg, one-
thousandth of a gram ¦ 1/28571 ounce) or microgram (m9# one-
millionth of a gram « 1/28,571,429 ounce) range. The analyst
will usually report the number of mg or «g of the substance
present in one liter of water, i.e.# mg/1 or pg/1. These two
units are sometimes expressed as parts per Billion (ppm) or parts
par billion (ppb), respectively.3
Given the concentration of a substance in water (say in ppm),
it is possible to estimate the amount an individual will consume
by knowing the amount of Water he drinks. Time is another im-
portant factor in determining risk, so the amount of water con-
sumed per unit time is of interest. Zn most public health evalu-
ations, it is assumed that an individual consumes 2 liters of
water each day through all uses. Thus, if a substance is present
st 10 ppm in water, the average daily individual intake of the
substance is obtained as followst
10 mg/1iter x 2 liter/day ¦ 20 mg/day
For toxicity comparisons among different species, it is necessary
to take into account site differences, usually by dividing daily
intake by the weight of the individual. Thus, for a man of aver-
age weight (usually assumed to bt 70 kilograms (kg) or 1S4
pounds), the daily dose of our hypothttical substance is:
20 mg/day + 70 kg ¦ 0.29 mg/kg/day
liter of water weighs 1,000 g. One mg is thus one-millionth
the weight of a liter of water; and one p9 is one-billionth the
weight of a liter.
85
-------
II-6
For a person of lower weight (e.g., a female or child), the daily
dose at the same intake rate would be larger. For example, a 50
kg woman ingesting the hypothetical substance would receive a
dose of:
20 mg/day * 50 kg - 0.40 mg/kg/day
A child of 10 kg could receive a dose of 2.0 mg/kg/day, although
it must be remembered that such a child would drink less water
each day (say, 1 liter), so that the child's dose would be:
10 mg/liter x 1 liter/day r 10 kg * 1.0 mg/kg/day
Also, laboratory animals, usually rats or mice, receive a much
higher dose than humans at the same daily intake rate because of
their much smaller body weights (of course, rats and mice do not
drink 2 liters of water each day!).
These sample calculations point out the difference between
measurement of environmental concentrations and dose, at least
for drinking water. The relationships between measured environ-
mental concentrations and dose are more complex for air and other
media. Table 2 lists the data necessary to obtain dose from data
on the concentration of a substance in water. Each medium of
exposure must be treated separately and some calculations are
more complex than in the dose per liter of water example.
86
-------
II-7
Tabla 2
DATA AND ASSUMPTIONS NECESSARY TO ESTIMATE
HIM AN DOSE OP A HATCH CONTAMINANT HUM MONLEDGE OF ITS CONCENTRATION
Total Ooaa ia Equal to the Sua of (baaa Proa Five toutea
1. Olrect Ingaation Through Drinldng
Aaount of nt»r eonauaad each day (generally eaotaed to be 2 litera for
adulta and 1 titer for 10 kg child).
Fraction of eontaainant abaorbad through nail of geetrointeetinel tract.
Average huaan body waight.
2. Inhalation of Contaainanta
Air concentrations resulting froa ehoworing, lathing, and othar uaaa of
aatar.
Variation in air eoncantration over tiaa.
Aaount of eontaainatad air braathad during thoaa aetivitiaa that Bay laad
to volatilisation.
Fraction of inhalod eontaainant abaorbad through lunga.
Avaraga huaan body aaight.
3. Skin Afaaorption froa Mater
Period of tiaa opent vaahing and bathing.
Fraction of eehtaalnant abaorbad throu$\ tho akin during waahing and
bathing.
Avaraga hiaan body weight.
4. Ingaation of Contoainatad Food
Concantrations of eontaainant in adlbla portions of various plants and
aniaala axpoaad to eontaainatad groundwtar.
Mount of eontaainatad food ingeeted aaeh day.
Fraction of eontaainant abaorbad through wall of gaatrointoatinal traet.
Avaraga huMrt body weight.
I, Sdn Absorption for eontaainatad toll
Coneantrationa of eontaainant in aoll axpoaad to eontaainatad
groundwater.
Mount of daily akin contact with aoll.
Mount of aoil ingaatad par day (by children).
Absorption rates.
Avaraga hoan body weight.
87
-------
II-8
It is important always to consider that a human may be
simultaneously exposed to the same substance through several
media. That is, a dose may be received through more than one
route of exposure (inhalation, ingestion, dermal contact). The
"total dose" received by an individual is the sum of doses re-
ceived by each individual route (see the example in Table 2).
Zn some cases, it may not be appropriate to add doses in
this fashion. In these cases, the toxic effects of a substance
may depend on the route of exposure. For example, inhaled chrom-
ium is carcinogenic to the lung, but it appears that ingested
chromium is not. In most cases, however, as long as a substance
acts at an internal body site (i.e., acts avstemicallv rather
than only at the point of initial contact), it is usually con-
sidered appropriate to add doses received from several routes.
Two additional factors concerning dose require special atten-
tion. The first is the concept of absorption (or absorbed dose).
The second concerns inferences to be drawn from toxicities ob-
served under one route of exposure for purposes of predicting the
likelihood of toxicity under other routes.
Absorption
When a substance is ingested in the diet or in drinking
water, it enters the gastrointestinal tract. When it is present
in air (as a gas, aerosol, particle, dust, fume, etc.) it enters
the upper airways and lungs. A substance may also come into
contact with the skin and other body surfaces as a liquid or
solid. Some substances may cause toxic injury at the point of
initial contact (skin, gastrointestinal tract, upper airways,
lungs, eyes). Indeed, at high concentrations, most substances
will cause at laast irritation at these points of contact. But
for many substances, toxicity occurs after they pass through
certain barriers (e.g., the wall of the gastrointestinal tract or
the skin itself), enter blood or lymph, and gain access to the
various organs or systems of the body. Figure 1 is a diagram of
some of the important routes of absorption. This figure also
shows that chemicals may be distributed in the body in various
ways and then axcreted. (However, tome chemical types—usually
substances with high solubility in fat, such as DDT—are stored
for long periods of time, usually in fat.)
88
-------
II-9
'Figure 1
KEY ROUTES OF CHEMICAL ABSORPTION, DISTRIBUTION, AND EXCRETION
Boma chamicali undargo ehamieal changi (mnabeliim) wtthin tha catli of tha body brfora txcrttion.
Toxicity may ba produced by tha ehamieal as introducad, or by ona or mora metabolites.
Ingestion
Gartrointattina!
Tract
Inhalation
Lu
ng
Darmal
Contact
Absorption-
Lh
rer
B
la
Blood and Lymph
Extracellular '
Fluids
Fat
Kidneys
Lung
2
Bladder
Secretion
Glands
Organs of
the Body
Soft Twues
or Bonas
Urlna
Expired
Air
Secretions
CXCRETION
89
-------
11-10
Substances vary widely in extent of absorption. The frac-
tion of a dose that passes through the wall of the gastrointes-
tinal tract may be very small (e.g., 1 to 10% for some metals) to
substantial (close to 1001 for certain types of organic mole-
cules). Absorption rates also depend upon the medium in which a
chemical is present (e.g., a substance present in water might be
absorbed differently from the same substance present in a fatty
diet). These rates also vary among animal species and among
individuals within a species.
Ideally, estimating systemic dose should include considera-
tion of absorption rates. Unfortunately, data on absorption are
limited for most substances, especially in humans. As a result,
absorption is not always included in dose estimation (i.e., by
default, it is frequently considered to be complete). Sometimes
crude adjustments are made based on some general principles con-
cerning expected rates based on the molecular characteristics of
a substance.
Interspecies Differences in Exposure Route
As described later, a critical feature of risk characteriza-
tion is a comparison of doses that are toxic in experimental
animals and the doses received by exposed humans. If humans are
exposed by the same route as the experimental animals, it is
frequently assumed (ih the absence of data) that the extent of
absorption in animAls and humans is approximately the same; under
such an assumption, it is unnecessary to estimate the absorbed
dose by taking absorption rate into account. However, humans are
often exposed by a different route than that used to obtain tox-
icity data in experimental animals. If the observed toxic effect
is a systemic one, it may be appropriate to infer the possibility
of human toxicity even under the different exposure route. Be-
fore doing so, however, it is critical to consider the relative
degrees of absorption by different exposure routes. Tor example,
if a substance is administered orally to a test animal but human
exposure is usually by inhalation, knowledge of the percentage
absorbed orally by the animal and by inhalation in humans is
necessary to properly compare human and animal doses. These
calculations and underlying assumptions are too complex for dis-
cussion here, but they should be kept in mind when risks are
being described.
In the following discussion of the components of risk assess-
ment, we shall use the term dose only as described. Many risk
assessors use the terms exposure and dose synonomously. In this
document, however, the term exposure describes contact with a
90
-------
11-11
substance (e.g., we say that animals are exposed to air contain-
ing 10 mg/m^, of a compound), as well as the size of the dose,
the duration of exposure, and the nature and size of the exposed
population. In our usage, exposure is a broader term than dose.
Although our usages of those terms are technically correct, it
should be recognized that some assessors use the term exposure to
mean dose (although the reverse is not true).
91
-------
ZZZ. HAZARD IDENTIFICATION
INTRODUCTION
Information on the toxic properties of chemical substances is
obtained from animal studies, controlled epidemiological investi-
gations of exposed human populations, and clinical studies or
case reports of exposed humans. Other information bearing on
toxicity derives from experimental studies in systems other than
whole animals (e.g., in isolated organs, cells, subcellular com-
ponents) and from analysis of the molecular structures of the
substances of interest. These last two sources of information
are generally considered less certain indicators of toxic poten-
tial, and accordingly, they receive limited treatment here.
Similarly, clinical studies or case reports, while sometimes
very important (e.g., the earliest signs that benzene was a human
leukemogen came from a series of case reports), seldom provide
the central body of information for risk assessment. For this
reason, and because they usually present no unusual problems of
interpretation, they are not further reviewed here. Rather, our
attention is devoted to the two principal sources of toxicity
data: animal tests; and epidemiology studies. These two types of
investigation are not only principal sources of data, but also
present interpretative difficulties, some rather subtle, some
highly controversial.
TOXICITY INFORMATION FROM ANIMAL STUDIES'
The Pse of Animal Toxicity Data
Animal toxicity studies are conducted based primarily on the
longstanding assumption that effects in humans can be inferred
from effects in animals. Zn fact, this assumption has been shown
to be generally correct* Thus, all the chemicals that have been
demonstrated to be carcinogenic in humans, with the possible
exception of arsenic, are carcinogenic in some although not all,
experimental animal species. Zn addition, the acutely toxic
doaes of many chemicals are similar in humans and a variety of
experimental animals. This principle of extrapolation of animal
data to humans has been widely accepted in the scientific and
regulatory communities. The foundation of our ability to infer
effects in humans from effects in animals has been attributed to
the evolutionary relationships and the phylogenetic continuity of
animal species including man. Thus, at least among mammals, the
bfcsic anatomical, physiological, and biochemical parameters are
similar across species.
92
-------
III-2
However, although the general principle of inferring effects in
humans from effects in experimental animals is well founded,
there have been a number of exceptions. Many of these exceptions
relate to differences in the way various species handle a chemi-
cal to which they are exposed and to differences in metabolism,
distribution and pharmacokinetics of the chemical. Because of
these potential differences, it is essential to evaluate all
interspecies differences carefully in inferring human toxicity
from animal toxicologic study results.
In the particular case of evaluation of long-term animal
studies conducted primarily to assess the carcinogenic potential
of a compound, certain general observations increase the overall
strength of the evidence that the compound is carcinogenic. With
en increase in the number of tissue sites affected by the agent,
there is an increase in the strength of the evidence. Similarly,
en increase in the number of animal species, strains, and sexes
showing a carcinogenic response will increase the strength of the
evidence of carcinogenicity. Other aspects of importance are the
occurrence of clear-cut dose-response relationships in the data
evaluated; the achievement of a high level of statistical signif-
icance of the increase of tumor incidence in treated versus con-
trol animals; dose-related shortening of the time-to-tumor occur-
rence or time-to-death with tumor; and a dose-related increase in
the proportion of tumors that are malignant. The following sec-
tions describe the general nature of animal toxicity studies,
including major areas of importance in their design, conduct, and
interpretation. Particular consideration will be given to the
uncertainties involved in the evaluation of their results.
General Nature of Animal Toxicity Studies
Toxicity studies are conducted to identify the nature of
health damage produced by a substance4 and the range of doses
over which damage is produced. The usual starting point for such
investigations is a study of the acute (single-dose) toxicity of
a chemical in experimental animals. Acute toxicity studies are
necessary to calculate doses that will not be lethal to animals
used in toxicity studies of longer durations. Moreover, such
4We use the term eubstance to ***** J EX£ture*ofCehemicals.
chemical containing impurities, or titv and composition of
Xt is cleerly important to know the identity toxicity
a tested substance before fIJel that might have a some-
of other samples of the same substance that mign*
what different composition.
93
-------
III-3
Studies will give one estimate of the compound's comparative
toxicity and may indicate the target organ system for chronic
toxicity (e.g., kidney, lung, or heart). Toxicologists examine
the lethal properties of a substance and estimate its LD50
(lethal dose, on average, for 50% of an exposed population). In
a group of chemicals, those exhibiting lower LD5QS are more
acutely toxic than those with higher values. A group of well-
known substances and their LD50 values are listed in Table 3.
labia 3
APPROXIMATE ORAL lD50a IN RATS FOR A
CROUP Or HELL-KNOWN CHEMICALS '
Chwucel
LO«n(ao/ka)
Sucroaa (table ougar)
29,700
Ethyl alcohol
14,000
Sodium chloride (common aalt)
3,000
Vitamin A
2,000
Vanillin
1,580
Aapirin
1,000
Chloroform
800
Coppar aulfate
300
Caffeine
192
Phanobarbltali sodium aalt
162
DOT
113
Sodiui nitrite
15
Nicotine
53
Aflatonin B1
7
SodlvN cyanide
<.4
Stryohnlrie
2.5
*5olectad from NIOSH, Reolatry of Toxic Effocta of Chemical
Subatancea. 1»7f. Reeulte reported al»e«*ore ««y diffar.
*£onpoundaart Hated in ardor of increaaing toxicity—i.t.,
aucrooo la the laaat toxic and atrychnlna la tha aeat toxic.
94
-------
111 -4
LD50 studies reveal one of the basic principles of toxi-
cology: not all Individuals exposed to the same dose of a sub-
stance will respond in the same way. Thus, at a dose of a sub-
stance that leads to the death of scSme experimental animals,
other animals dosed in the same way will get sick but will re-
cover, and still others will not appear to be affected at all.
We shall return to this point after a fuller discussion of other
forms of toxicity.
Bach of the many different types of toxicology studies has a
different purpose. Animals may be exposed repeatedly or contin-
uously for several weeks or months (subchronic toxicity studies)
or for close to their full lifetimes (chronic toxicity studies)
to learn how the period of exposure affects toxic response. Zn
general, the reasons to conduct toxicity studies can be summar-
ised as follows:
• Identify the specific organs or systems of the body
that may be damaged by a substance.
e Identify specific abnormalities or diseases that a
substance may produce, such as cancer, birth defects,
nervous disorders, or behavioral problems.
e Establish the conditions of exposure and dose that give
rise to specific forms of damage or disease.
e Identify tHe specific nature and course of the injury
or disease produced by a substance.
• Identify the biological processes that underlie the
production of observable damage or disease.
The laboratory methods needed to accomplish many of these
goals have been in use for many years, although some methods are
•till being developed. Before describing some of the tests, it
is useful to say more about the various manifestations of toxi-
city.
Manifestations of Toxicity
Toxic responses, regardless of the organ or system in which
they occur, can be of several types. For some, the severity of
the injury increases as the dose increases. Thus, for example,
some chemicals affect the liver. At high doses they may kill
liver cells, perhaps so many as to destroy the liver and thus
cause the deaths of some or all experimental subjects. As the
dose is lowered, fewer cells may be killed, but they may exhibit
other forms of damage, causing imperfections in their function-
ing. At lower doses still, no cell deaths may occur and there
95
-------
III-5
may be only slight alterations in cell function or structure.
Finally, a dose may be achieved at which no effect is observed,
or at which there are only biochemical alterations that have no
known adverse effects on the health of the animal (although some
toxicologists consider any such alteration, even if its long-term
consequences are unknown, to be "adverse," there is no clear
consensus on this issue.) One of the goals of toxicity studies
is to determine the "no observed effect level" (NOEL), which is
the dose at which no effect it teen; the role of the NOEL in risk
assessment is discussed later.
In other cases, the severity of an effect may not increase
with dose, but the incidence of the effect will increase with
increasing dose. In such cases, the number of animals experienc-
ing an adverse effect at a given dose is less than the total
number, and, as the dose increases, the fraction experiencing
adverse effects (i.e., the incidence of disease or injury) in-
creases} at sufficiently high dose, all experimental subjects
will experience the effect. The latter responses are properly
characterized as probabilistic. Increasing the dose increases
the probability (i.e., risk) that the •abnormality will develop in
an exposed population. Often with toxic effects, including can-
cer, both the severity and the incidence increase as the level of
exposure is raised. The increase in severity is a result of
increased damage at higher doses, while the increase in incidence
is a result of differences in individual sensitivity. In addi-
tion, the site at which a substance acts (e.g., liver, kidney)
may change as the dose changes.
Generally, as the duration of exposure increases, both the
NOEL and the doses at which effects appear decrease; in some
eases, new effects not apparent upon exposures of short duration
become manifest.
Toxic responses also vary in degree of reversibility. In
some cases, an effect will disappear almost immediately following
cessation of exposure. At the other extreme, some exposures will
result in a permanent injury—for example, a severe birth defect
resulting from a substance that irreversibly damages a fetus at a
critical moment of its development. Most toxic responses fall
somewhere between these extremes. In many experiments, however,
the degree of reversibility cannot be ascertained by the investi-
gator.
Seriousness is another characteristic of a toxic response.
Certain types of toxic damage ere clearly adverse and are a def-
inite threat to health. However, other types of effects observed
during toxicity studies are not clearly of health significance.
For example, at a given dose a chemical may produce a slight
96
-------
III-6
increase in red blood cell count. If no other effects are ob-
served at this dose, it will not be at all clear that a true
adverse response has occurred. Determining whether such slight
changes are significant to health is one of the critical issues
in assessing safety that has not been fully clarified.
Design and Conduct of Toxicity Tests
Toxicity experiments vary widely in design and conduct.
Although there are relatively well standardized tests for various
types of toxicity (e.g.* National Cancer Institute carcinogen-
icity bioassays) developed by regulatory and public agencies in
connection with the premarket testing requirements imposed on
certain classes of chemicals, large numbers of other tests and
research-oriented investigations are conducted using specialized
study designs (e.g., carcinogenicity assays in fish). In this
•action, we present a few of the critical considerations that
enter into the design of toxicity experiments. However, there
are numerous variations on the general themes we describe.
Selection of Animal Species
Rodents, usually rats or mice, are the most commonly used
laboratory animals for toxicity testing. Other rodents (e.g.,
hamsters and guinea pigs) are sometimes used, and many experi-
ments are conducted using rabbits, dogs, and such nonhuman pri-
mates as monkeys or baboons. For example, although nonhuman
primates may be chosen for some reproductive studies because
their reproductive systems are similar to that of humans, rabbits
are often used for testing dermal toxicity because their shaved
skin is more sensitive.
Rats and mice are the most common choice because they are
inexpensive and can be handled relatively easily. Furthermore,
such factors as genetic background and disease susceptibility are
well established for these species. The full lifespans of these
smaller rodents are complete in two to three years, so that the
effects of lifetime exposure to a substance can be measured rela-
tively quickly (as compared to the much longer-lived dog or
monkey).
Dose and Duration
An LD50 using high doses of the eubstance is frequently the
first toxicity experiment performed. After completing these
experiments, investigators study the effects of lower doses
97
-------
III-7
administered over longer periods. The purpose is to find the
range of doses over which adverse effects occur and to identify
the NOEL for these effects (although the latter ia ot always
nought or achieved). A toxicity experiment is of limited value
unless a dose of sufficient r&gnitude to cause some type of
idverse effect within the duration of the experiment is achieved.
3f no effects are teen at all doses adminiftered, the toxic
properties of the substances fill not have been characterized!
and the investigator will usually repeat the experiment at higher
doses or will extend its duration.5
Studies are frequently characterized according to the dura-
tion of exposure. Acute toxicity studies involve a single dose,
or exposures of very short deration (e.g., 8 hours of inhala-
tion). Chronic studies invol/e exposures for near the full life-
times of the experimental aninals. Experiments of 'arying dura-
tion between these extremes are referred to as subci ronic stud-
ies.
Number of Dose Levels
Although it is desirable that many different dose levels be
used to develop a well characterized dose-response relationsh iP/
practical considerations usually limit the number to two or
three, especially in chronic studies. Experiments involving a
single dose are frequently reported and leave great uncertainty
about the full range of doses over which effects are expected.
Controls
No toxicity experiment is interpretable if control animals
are omitted. Control animals must be of the same species,
¦train, sex, age, and state of health as the treated animals, and
must be held under identical conditions throughout the experi-
ment. (Indeed, allocation of animals to control and treatment
groups should be performed on a completely random basis.) Of
course, the control animals are not exposed to the substance
under test.
5Some substances with extremely low toxicity must be administered
at extremely high levels to produce effects? in many cases, such
high levels will cause dietary maladjustments leading to an
sdverse nutritional effect that confounds interpretation. As a
practical matter, the highest level of a compound fed to an
animal in toxicity studies is 5% of the diet, even if no toxic
effect is seen at this level.
98
-------
III-8
Route of Exposure
Animals are usually exposed by a route that is as close as
possible to that through which humans will be exposed, because
the purpose of most such tests is to produce the data upon which
human safety decisions will be based. In tome cases, however,
the investigator may have to use other routes or conditions of
dosing to achieve the desired experimental dose. For example,
some chemicals are administered by stomach tube (gavage) because
they are too volatile or unpalatable to be placed in the animals'
diets at the high levels needed for toxicity studies.
Specialised Designs
Generally, the toxicologist exposes test animals and simply
records whatever effects happen to occur under the conditions of
the experiment. If, however, it is decided that certain highly
specific hypotheses about a substance are to be tested (e.g.,
does the substance cause birth defects or does it affect the
immune system?), certain specialised designs must be used. Thus,
for example, the hypothesis that a chemical is teratogenic
(causes birth defects) can be tested only if pregnant females are
exposed at certain critical times during pregnancy.
One of the most complex of the specialised tests is the
carcinogenesis bioassav. These experiments are used to test the
hypothesis of carcinogenicity—that is, the capacity of a sub-
stance to produce tumors. Because of the importance of the car-
cinogenesis bioassay, a full section is devoted to it. Me shall
then discuss, in turn, controversial issues in the design of
animal tests and interpretation of test results.
Pasicn of Tests for Carcinogenicity
Zn a National Cancer Institute (NCI) carcinogenicity bioas-
say, the test substance is administered over most of the adult
life of the animal, and the animal is observed for formation of
tumors. The general principles of test dssign previously dis-
cussed apply to carcinogenicity testing, but one critical design
issue that has been highly controversial requires sxtensive dis-
cussion. The issue is the concept of maximum tolerated dose
(M7D), which is dafinad as the maximum dose that an animal spe-
cies can tolerate for a major portion of its lifetime without
significant impairment of growth or observable toxic effect other
than carcinogenicity. Cancer can take most of a lifetime to
develop, and it is thus widely agreed that studies should be
designed so that the animals survive in relatively good health
for a normal lifetime. It is not so widely agreed, however, that
99
-------
III-9
the MTD, as currently used, is the best way to achieve this
objective. The MTD and half the MTD are the usual doses used in
the NCI carcinogenicity bioassay.
The main reason cited for using the MTD as the highest dose
in the bioassay is that experimental studies ere conducted on a
small scale, making them "statistically insensitive," and that
very high doses overcome this problem. For practical reasons,
experimental studies are carried out with relatively small groups
of animals. Typically, 50 or 60 animals of each species and sex
will be used at each dose level, including the control group. At
the end of such an experiment, the incidence of cancer as a func-
tion of dose (including control animal incidence) is tabulated by
the examining pathologists. Statisticians then analyze the data
to determine whether any observed differences in tumor incidence
(fraction of animals having a tumor of a certain type) are due to
random variations in tumor incidence or to treatment with the
substance.
In an experiment of about this site, assuming none of the
control animals develop tumors, the lowest incidence of cancer
that is detectable with statistical reliability is in the range
of 51, or 3 animals with tumors in a test group of 60 animals.
If control animals develop tumors (as they frequently do), the
lowest range of cancer incidence detectability is even higher. A
cancer incidence of 51 is very high, yet ordinary experimental
studies are not capable of detecting lower rates and most are
even less sensitive.
MTD advocates argue that inclusion of high doses will com-
pensate for the weak detection power of these experiments. jBy
using the MTD, the toxicologiit hopes to elicit any important
toxic effects of a substance and ensure that even weak carcin-
ogenic effects of the chemical will be detected by the study.
MTD critics do not reject the notion that animal experiments may
be statistically insensitive, but rather are concerned about the
biological implications of such high doses.
Concerns about use of MTDs can be summarised! (1) the
underlying biological mechanisms that lead to the production of
cancer may change as the dose of the carcinogen changes; (2) cur-
rent methods for estimating en MTD for use in an experiment do
not usually take these mechanisms into account> (3) the biologi-
cal mechanisms at work under conditions of actual human exposure
may be quite different from those at fork at or near the MTD; and
(4> therefore, observations at or near an MTD (as determined by
current methods) may not be qualitatively relevant to conditions
of actual human exposure.
100
-------
XII-10
Many agree that greater attention should be paid to develop-
ing data on the underlying mechanisms of carcinogenicity and
their relation to dose. Also, a range of doses should be includ-
ed in carcinogenicity testing to assess whether physiological
mechanisms that would normally detoxify the chemical are over-
whelmed at an MTD. These biological considerations have consid-
erable merit, but they are frequently disregarded in designing
studies and interpreting data. Although there are occasional
attempts to develop a more biologically relevant definition of
MTD, most current tests (e.g., those carried out by the National
Toxicology Program) use a definition of MTD that does not take
biological mechanisms into account.
This state of affairs is not likely to change. Those who
promote the use of MTD, as currently defined, frequently argue
that if the highest dose used waa not the MTD, failure to observe
a carcinogenic effect in a given experiment does not permit the
conclusion that the tested substance is not carcinogenic. A
similar argument is made if the survival of the test animals did
not approximate their full lifetimes.
Conduct and Interpretation of Toxicity Tests
Many factors must be considered in the conduct of toxicity
tests to ensure their success and the utility of their results.
Zn evaluating the results of such tests, certain questions must
be asked about the design and conduct of a test to ensure criti-
cal appraisal. The major questions include the following:
1. Has the experimental design adequate to test the hypo-
thesis under examination?
2. Was the general conduct of the test in compliance with
standards of good laboratory practice?
3. Mas the dose of test compound correctly determined by
chemical analysis?
4. Mas the test compound adequately characterised with
regard to the nature and extent of impurities?
5. Did the animals actually receive the test compound?
6. Mere animals that died during the test adequately exam-
ined?
7. Bow carefully were test animals observed during the
conduct of the test?
101
-------
111-11
8. What tests were performed on the animals (e.g., blood
tests, clinical chemistry tests) and were they ade-
quately performed?
9. If the animals were examined histopathologically (i.e.,
detailed pathological examination based on sections
taken from individual tissues), was the examination
performed by a qualified pathologist?
10. Was the extent of animal and animal tissue examination
adequate?
11. Were the various sets of clinical and pathology data
properly tabulated?
12. Were the statistical tests used appropriate and were
they adequately performed?
13. Was the report of the test sufficiently detailed so
that these questions can be answered?
A proper evaluation would ensure that these and other types
of questions were examined and would include a list of qualifica-
tions on test result* in areas where answers were missing or
unsatisfactory.
Categorisation of Toxic Effects
Toxicity tests nay reveal that a substance produces a wide
variety of adverse effects on different organs or systems of the
body or that the range of effects is narrow. Same effects may
occur only at the higher doses used, and only the most sensitive
indicators of a substance's toxicity may be manifest at the lower
doses.
The toxic characteristics of a substance are usually catego-
rixed according to the organ* or systems they affect (e.g., liv-
er, kidney, nervous system) or the diseases they cause (e.g.,
cancer, birth defects). The siost commonly used categorisations
of toxicity are briefly described in Appendix Z.
Although there are uncertainties associated with most evalu-
ations of anisial toxicity data, there are some special problems
associated with interpretation of carcinogenicity data. Because
these problems are the source of much controversy, we afford them
special attention in the next section.
102
-------
111-12
Uncertainties in Evaluation
of Animal Carcinogenicity
frest Result*
One area of uncertainty and controversy concerns the occur-
rence of certain types of tumors in control animals. Zn most
animal experiments, control animals will also develop tumors, and
interpretation of such experiments depends on comparing the inci-
dence of tumors in control animals with that observed in treated
animals, Zn some instances, this is not as straightforward as it
may seem. For example, the lifetime incidence of lung tumors in
a certain strain of male mice, untreated with any substance, may
vary from a low of about 2% to a high of about 40*; the average
rate is about 14«. Suppose that, in a particular experiment,
male mice treated with a substance exhibited a 351 incidence of
lung tumors, and control animals exhibited an incidence of 8%.
Statistical analysis of such data would show that the treated
animals experienced a statistically aignificant increase in tumor
incidence, and the substance producing this effect might be la-
beled a lung carcinogen.
Further analysis of the incidence data suggests that such a
statistical analysis may be misleading. The 351 incidence ob-
served in treated animals is within the range of tumor incidence
that is normally experienced by male mice, although the particu-
lar group of male mice used as controls in this experiment exhib-
ited an incidence in the low end of the normal range. Under such
circumstances, use of the simple statistical test of significance
might be misleading and result in the erroneous labeling of a
substance as a carcinogen.
Another major area of uncertainty arises in the interpreta-
tion of experimental observations of benign tumors. Some types
of tumors are clearly malignant} that is, they are groups of
cells that grow in uncontrolled ways, Invade other tissues, and
are frequently fatal. There is usually no significant contro-
versy about such tumors, and pathologists generally agree that
their presence is a clear sign that a carcinogenic process has
occurred. Other tumors are benign at the time they are observed
by pathologists, and it is not always clear they should be con-
sidered indicators of a carcinogenic process. Some tumors will
remain benign for ths lifetime of tbe animal, but in some cases
they have been observed to progress to malignancy. Generally,
the numbers of animals with benign tumors that are thought to be
part of the carcinogenic process are combined with those having
malignancies to establish the totsl tumor incidence. Many path-
ologists disagree with such combining, and there appears to be no
end to tbe controversy in this area. The issue has been espe-
cially controversial in connection with tumors found in rodent
livers.
103
-------
.111-13
Short-Term Tests for Carcinogens
The lifetime animal study is the primary method used for
detecting the carcinogenic properties of a substance. In recent
years, other experimental techniques have become available and,
although none is yet considered definitive* they may provide
important information.
Short-term tests for carcinogenicity measure effects that
empirically or theoretically appear to be correlated with carcin-
ogenic activity. These tests include assays for gene mutations
in bacteria, yeast, fungi# insects, and mammalian cells; mamma-
lian cell transformation assays; assays for DNA damage and re-
pair; and in vitro (outside the animal—e.g., bacterial cells as
in the Ames mutagenicity assay) and in vivo (within the animal)
assays for chromosomal mutations in animals' cells. In addition
to these rapid (test-tube) tests, several tests of intermediate
duration involving whole animals have been used. These include
the induction of skin and lung tumors in mice, breast cancer in
female certain species of rats, and anatomical changes in the
livers of rodents.
Other tests are used to determine whether a substance will
interact with the.genetic apparatus of the cell, as some well-
known carcinogens apparently do. However, not all substances
that interact with DNA have been found to be carcinogenic in
animal systems. Furthermore, not all animal carcinogens interact
directly with genetic material.
These short-term tests are playing increasingly important
roles in helping to identify suspected carcinogens. They provide
useful information in a relatively short' period, and may become
critical screening tools, particularly for selecting chemicals
for long-term animal tests. They may also assist in understand-
ing the biological processes underlying the production of tumors.
They have not been definitively correlated with results in animal
models, however, and regulatory agencies and other public health
institutions do not consider positive or negative results in
these systems as definitive indicators of carcinogenicity or the
lack thereof, but only as ancillary evidence.
DATA FROM BUMAM STUDIES
Information on adverse health effects in human populations
is obtained from four sources* (1) summaries of self-reported
symptoms in exposed persons; (2) case reports prepared by medical
personnel; (3) correlational studies (in which differences in
104
-------
111 -14
disease rates in human populations are associated with differ-
ences in environmental conditions); and (4) epidemiological stud-
ies. The first three types of study can be characterized as
descriptive epidemiology and are often useful in drawing atten-
tion to previously unsuspected problems. Although they cannot
identify a cause-and-effeet relationship, they have value in
generating hypotheses that can be further tested. Epidemiologic
studies involve comparing the health status of a group of persons
who have been exposed to a suspected agent with that of a compar-
able nonexposed group.
Most epidemiology studies are either case-control studies or
cohort studies. Zn case-control studies, a group of individuals
With a specific disease is identifi«l and an attempt is made to
ascertain commonalities in exposures they may have experienced in
the past. The carcinogenic properties of DBS were discovered
through such studies. Zn cohort studies, the health status of
individuals known to have had a common exposure is examined to
determine whether any specific condition or cause of death is
revealed to be excessive, compared to an appropriately matched
control population. Bensene leukemogenesis was established with
studies of these types. Generally, epidemiologists have turned
to occupational settings or to patients treated with certain
drugs to conduct their studies.
When epidemiological investigations yield convincing re-
sults, they are enormously beneficial because they provide infor-
mation about humans 6nder actual conditions of exposure to a
•pacific agent. Therefore, results from well-designed, properly
controlled studies are usually given more weight than results
from animal studies in the evaluation of the total database.
Although no study can provide complete assurance that no risk
exists, negative data from epidemiological studies of sufficient
site can be used to establish the level of risk that exposure to
an agent almost assuredly will not exceed.
Although epidemiology studies are powerful when clearcut
diffarences exist, several points must be considered when their
results are interpretedi
• Appropriately matched control groups are difficult to
identify, because the fsctors that lead to the exposure
of the study group (e.g., occupation or residence) are
often associated with other factors that affect health
status (e.g., lifestyle and socioeconomic status).
• Zt is difficult to control for related risk factors
(e.g., cigarette emoking) that have strong effects
on health.
105
-------
111-15
• Pew types of health effects (other than death) are
recorded systematically in human populations (and even
the information on cause of death is of limited relia-
bility). For example, infertility, miscarriages, and
mental illnesses are not as a rule systematically re-
corded by public health agencies.
• Accurate data on the degree of exposure to potentially
hazardous substances are rarely available, especially
when exposures have taken place in the past. Estab-
lishing dose-response relations is thus frequently
impossible.
e For investigation of diseases that take many years
to develop, such as cancer, it is necessary to wait
many years to ascertain the absence of an effect.
Of course, exposure to suspect agents could continue
during these extended periods of time and thereby
further increase risk.
e The statistical detection power of epidemiological
studies is limited, unless very large populations are
studied.
For these reasons, epidemiological studies are subject to
sometimes extreme uncertainties. It is usually necessary to have
independent confirmatory evidence, such as a concordant result in
a second epidemiological study, or supporting data from experi-
mental studies in animals. Because of the limitations of epi-
demiology, negative findings must also be interpreted with cau-
*Xt is important to recognise the limitations of negative epide-
mioldgical findings. A simple example reveals why this is so.
Suppos* a drug that causes cancer in one out of every 100 people
exposed to 10 units is released for use (no one is aware of the
risks). Moreover, the average time required for cancer to
develop from 10 units' exposure is 30 years (not uncommon for a
carcinogen). After the drug has been in use for IS years, an
epidemiologist decides to study its effects, lie locates the
death certificates of 20 people who took the drug, but finds
little information on their dosage. Some took the drug when it
was first released, others not for several years after its
release. The health records, which are incomplete, reveal no
excess^cancer in the 20 people when compared to an appropriate
control group. Zs it correct to conclude that the drug is not
carcinogenic?
106
-------
111-16
HAZARD IDENTIFICATIONg A SUMMARY
For tone substances the Available database may include sub-
stantial information on effects in humans and experimental
animals, and may also include information on the biological mech-
anisms underlying the production of one or more forms of toxi-
city. In other cases, the database may be highly limited and may
include only a few studies in experimental animals.
In some cases, all the available data may point clearly in a
single direction, leaving little ambiguity about the nature of
toxicity associated with a given compound; in others, the data
may include apparently conflicting sets of experimental or epide-
miological findings. It is not unusual for a well-studied com-
pound to have conflicting results from toxicity tests. If the
tests are performed properly, positive tests results usually
outweigh negative test results. Confusion may be compounded by
the observation that the type, severity, or site of toxicity may
vary with the species of animal exposed. Although it is gen-
erally accepted that results in animals are and have been useful
in predicting effects in humans, such notable exceptions as
thalidomide have occurred. This complex issue, briefly mentioned
here, must be considered for each compound examined.
The foregoing discussion of hazard evaluation was derived
'or exposures to a single toxic agent. Humans are rarely exposed
to only one substance': commercial chemicals contain impurities,
chemicals are used in combinations, and lifestyle choices (e.g.,
•noking, drinking) may increase exposure to mixtures of chemi-
cals. When humans are exposed to two or more chemicals, several
results may occur. The compounds may act independently; that is,
exposure to the additional chemical(s) has no observable effect
on the toxic properties of the substance. Toxic effects of chem-
icals may be additive; that is, if chemical A produces 1 unit of
disease and chemical B produces 2 units of disease, then exposure
to chemicals A and B produces 3 units of disease. Exposure to
combinations of chemicals may produce a greater than additive
(synergistic) effect; that is, exposure to chemicals A and B
produces more than 3 units of disease. Finally, chemicals may
reduce the degree of toxicity of each other (antagonism); that
it, exposure to chemicals A and B produces less than 3 units of
disease. Hazard evaluation of mixtures of chemicals is complex
*nd not standardised.
A proper hazard evaluation should include a critical review
of each pertinent data set and of the total database bearing on
toxicity. It should also include an evaluation of the inferences
107
-------
111-17
about toxicity in human populations who might be exposed. At
this stage of risk assessment, however, there is no attempt to
project human risk. For the latter, at least two additional sets
of analyses must be conducted.
108
-------
IV. DOSE-RESPONSE EVALUATION
INTRODUCTION
The next step in risk assessment is to estimate the dose-
response relationships for the various forms of toxicity exhib-
ited by the substance under review. Even where good epidemiolo-
gical studies have been conducted, there are rarely reliable
quantitative data on exposure. Bence, in most cases dose-
response relationships must be estimated from studies in animals
which immediately raises three serious problems: (1) animals are
usually exposed at high doses, and effects at low doses must be
predicted, using theories about the form of the dose-response
relationship; (2) animals and humans often differ in suspectibil-
ity, if only because of differences in size and metabolism; and
(3) the human population is very heterogeneous, so that some
individuals are likely to be more susceptible than average.
Toxicologists conventionally make two general assumptions
about the form of dose-response relationships at low doses. For
•ffects that involve alteration of genetic material (including
the initiation of cancer), there are theoretical reasons to be-
lieve that effects m^y take place at very low dose levels; sever-
al specific mathematical models of dose-reponse relationships
nave been proposed. For most other biological effects, it is
usually assumed that "threshold" levels exist, fiowever, it is
vary difficult to use such measures to predict "safe" levels in
humans. Even if it is assumed that humans and animals are, on
the average, similar in intrinsic susceptibility, humans are
expected to have more variable responses to toxic agents. We
discuss these and other issues at length in the following subsec-
tions .
-THRESHOLD effects
It is widely accepted on theoretical grounds, if not defini-
tively proved empirically, that most biological effects of chemi-
cal substances occur only after a threshold dose is achieved. In
tne experimental systems described here, the threshold dose is
approximated by the no-observable-effect level or NOEL.
It has also been widely accepted, at least in the process of
*^£ting public health standards, that the human population is
likely to have much more variable responses to toxic agents.than
•re the small groups of well-controlled, genetically homogeneous
109
-------
IV- 2
Animals ordinarily used in experiments. Moreover, the NOEL is
itself subject to some uncertainty (e.g., how can it be known
that the most serious effects of a substance have been identi-
fied?).. For these reasons, standard-setting and public health
agencies protect populations from substances displaying threshold
effects by dividing experimental NOELs by large "safety factors."
The magnitude of safety factors varies according to the nature
and quality of the data from which the NOEL is derived; the seri-
ousness of the toxic effects; the type of protection being sought
(e.g.r are we protecting against acute, subchronic, or chronic
exposures?); and the nature of the population to be protected
(e.g., the general population, or populations—such as workers—
expected to exhibit a narrower range of susceptibilities). Safe-
ty factors of 10; 100; 1*000; and 10,000 have been used in vari-
ous circumstances.
NOELs are used to calculate the Acceptable Daily Intake
(ADD for humans (which goes by other names in some circum-
stances) for chemical exposures. The ADI is derived by dividing
the experimental NOEL, in mg/kg/day, for the toxic effect appear-
ing at lowest dose, by one of the safety factors listed above.
The ADI (or its equivalent) is thus expressed in mg/kg/day. For
example, a substance with a NOEL from a chronic toxicity study of
100 mg/kg/day may be assigned an ADI of 1 mg/kg/day, for chronic
human exposure. The concentration of the substance—be it pesti-
cide, food additive, or drinking water contaminant—permitted in
various media must'be determined by taking into account the vari-
ous uses to which the material has been or will be put, the pos-
sible routes of exposure, and the degree of human contact. The
permitted concentrations, sometimes called tolerances or crite-
ria, are assigned to ensure the ADI is not exceeded.
This approach has been used for several decades by such
federal regulatory agencies as FDA and EFA, as well as by such
international bodies as the World Health Organization and by
various committees of the National Academy of Sciences.
Although there may be some biological justification for
assuming the need for safety factors to protect the more sensi-
tive members of the human population, there is very little scien-
tific support for the specific safety factors used. They are
arbitrarily chosen to compensate for uncertainty and, in fact,
could be seen as policy rather than scientific choices.
There is no way to determine that exposures at ADIs esti-
mated in this fashion are without risk. The ADI represents an
acceptable, low level of risk but not a guarantee of safety.
Conversely, there may be a range of exposures well above the ADI,
perhaps including the experimental NOEL itself, that bears no
110
-------
IV-3
risk to humans. The *NOEL-safety factor" approach includes no
attempt to ascertain how risk changes below the range ot experi-
mentally-observed dose-response relations.
The assessment of low dose •risks" from threshold agents are
discussed in Section VI on Risk Characterisation.
effects that may not exhibit thresholds
At present, only agents displaying carcinogenic properties
&re treated as if they do not display thresholds (although a few
scientists suggest that some teratogens and mutagens may behave
similarly). In somewhat more technical terms, the dose-response
curve for carcinogens in the human population achieves zero risk
only at sero dose; as the dose Increases above sero, the risk
immediately becomes finite and thereafter increases as a function
of dose. Risk is the probability of cancer, and at very low
dotes the risk can be extremely small (this will vary according
to the potency of the carcinogen). In this respect, carcinogens
are not much different from agents for which ADIs are established
(i.e., the most that can be said about an ADI is that it repre-
sents a very low risk, not that it represents the condition of
absolute safety).
The Carcinogenic Process
If a particular type of damage occurs to the genetic mate-
rial (DNA) of even a single cell, that c«l11 may undergo a series
of changes that eventually result in.the production of a tumor;
however, the time required for all the necessary transitions that
culminate in cancer may be a substantial portion of an animal's
or human's lifetime. Carcinogens may also affect any number of
the transitions from one stage of cancer development to the next.
Some carcinogens appear capable only of initiating the process
(these are termed "initiators"). Still others act only at later
stages, the natures of which are not well known (so-called promo-
tors may act at one or more of these later stages). And some
carcinogens may act at several stages. Some scientists postulate
that an arbitrarily small amount of a carcinogen, even a single
molecule, could affect the transition of normal cells to eancer-
°us cells at one or more of the various stages, and that a great-
er amount of the carcinogen merely increases the probability that
* given transition would occur. Dnder these circumstances there
*• little likelihood of an absolute threshold below which there
*» no effect on the process (even though the affect may be ex-
ceedingly small).
111
-------
IV-4
This description of the carcinogenic process is still under
extensive scientific scrutiny and is by no means established.
However, it is by far the dominant model and it has substantial
support. This multistage model has influenced the development of
some of the models used for dose-response evaluation. Before
discussing these models further# it is useful to review the ex-
perimental dose-response information obtained from bioassays and
to discuss why models of the dose-response relation are needed.
Potency and Hiqh-to-Low Dose Extrapolation
The following example, drawn from Rodricks and TaylorP
illustrates the need for high-to-low dose extrapolation. Assume
that a substance has been tested in mice and rats of both sexes
and been found to produce liver cancer in male rats. A typical
summary of the data from such an experiment might be as follows:
Lifetime Incidence Lifetime
Lifetime Daily of Liver Cancer Probability of
Dose in Rats Liver Cancer
0 mg/kg/day 0/50 0.0
125 mg/kg/day 0/50 0.0
250 mg/kg/day 10/50 0.20
500 mg/kg/day 25/50 0.50
1000 mg/kg/day 40/50 0.80
The incidence of liver cancer is expressed as a fraction,
and is the number of animals found to have liver tumors divided
by the total number of animals at risk. The probability (P) of
cancer is simply the fraction expressed as a decimal (e.g., 25/50
- 0.50).
Although there is "no-effect" at 125 mg/kg/day, the response
is nevertheless compatible with a risk of about 0.05 (5%) because
of the statistical uncertainties associated with the small num-
bers of animals used.
This experiment reveals that if humans and rats are about
equally susceptible to the agent, an exposure of 250 mg/kg/day in
humans will increase their lifetime risk by 20tj if 1,000 people
were to be exposed to this substance at this dose for a lifetime,
then 200 of these people will be expected to contract cancer from
this substance. This is an extremely high risk and obviously one
^"Application of Risk Assessment to Pood Safety Decision-Making,"
Regulatory Toxicology t Pharmacology (1983), 3*275-307.
112
-------
•IV-5
that no one would sanction. However, it is near the low end of
the range of risks that can be detected in animal experiments.
To continue with the illustration, assume that it is possi-
ble to estimate the daily dose of the chemical in the human popu-
lation. For the present example, assume that the exposed human
population receives a dose of 1.0 mg/kg/day. It thus becomes of
interest to know the risk to male rats at 1.0 mg/kg/day.
There is a great difference between the doses used experi-
mentally and the dose of interest. The risks that would likely
exist at a dose of 1.0 mg/kg/day are quite small and to determine
whether they exist at all would require enormous numbers of ani-
mals (perhaps hundreds of thousands). It is thus necessary under
these circumstances to rely on means other than experimentation
to estimate potential risk.
Scientists have developed several mathematical models to
estimate low dose risks from high dose risks. Such models de-
scribe the expected quantitative relationship between risk (P)
and dose (d), and are used to estimate a value for P (the risk)
at the dose of interest (in our example, the dose of 1.0 mg/kg/
day). The accuracy of the projected P at the dose of interest,
d, is a function of how accurately the mathematical model de-
scribes the true, but, immeasurable, relationship between dose and
risk at the low dose levels.
These mathematical models are too complex for detailed expo-
sition in this document. Various models may lead to very differ-
ent estimations of risk. None is chemical-specific; that is,
each is based on general theories of carcinogenesis rather than
on data for a specific chemical. None can be proved or disproved
by current scientific data, although future results of research
may increase our understanding of carcinogenesis and help in
refining these models. Regulatory agencies currently use one-
hit, multistage, and probit models, although regulatory decisions
axe usually based on results of the one-hit or multistage models.
They also use multihit, Weibull, and logit models for riek
assessment.
If these models are applied to the data recorded earlier for
the hypothetical chemical, the following estimates of lifetime
risk for male rats8 at the dose of 1.0 mg/kg/day are derived:
1*11 risks are for a full lifetime of daily exposure. The life-
time is the unit of risk measurement because the experimental
data reflect the risk experienced by animals over their full
lifetimes. The values shown are upper confidence limits on risk
(data drawn from Rodrieks and Taylor, 1983).
113
-------
IV-6
Model Applied
Lifetime Risk at 1.0 mg/kg/day
Multihit
Weibull
Probit
One-hit
Multistage
1.7 x 10"® (one in 59 million)
1,9 x 10""*0(one in 5.2 billion)
6.0 x 10-5 (0ne *n 17,000)
6.0 x 10-6
-------
IV-7
widely used we shall not discuss then. None of the models, as
currently used, incorporates a threshold dose for an exposed
population.
Interspecies Extrapolation
Tor the majority of agents, dose-response evaluation primar-
ily involves the analysis of tests that were performed on labor-
atory animals, because useful human data are generally not avail-
able. In extrapolating the results of these animal tests to
humans, the doses administered to animals must be adjusted to
account for differences in size and metabolic rates. Differences
in metabolism may influence the validity of extrapolating from
animals to man if, for example, the actual material producing the
carcinogenic effect is a metabolite of the tested chemical, and
the animal species tested and humans differ significantly in
their metabolism of the material.
Several methods have been developed to adjust the doses used
in animal tests to allow for differences in site and metabolism.
They assume that human and animal risks are equivalent when doses
are measured in:
o Milligrams per kilogram body weight per day
o Milligrams per square meter of body surface area per
day
o Parts per million in the air, water, or diet
o Milligrams per kilogram per lifetime.
Currently, a scientific basis for using one extrapolation method
over another has not been established.
POSE-RESPONSE EVALUATION t A SUMMARY
Por substances that do not display carcinogenic properties,
or for the noncareinogenic effects of carcinogens# dose-response
evaluation consists of describing observed dose-response rela-
tions and identifying experimental NOELs. NOEL* can be used to
establish ADls, or can be used for the type of risk character-
isation described in Section VI.
Por carcinogens, various models are applied to project the
dose-response curve from the range of observed dose-responses to
115
-------
IV-8
th« range of expected human doses. After the known or expected
human dose is estimated (Section V) carcinogenic risk can be
characterized (Section VI). Although the models in use yield a
range of dose-response relations, it is highly likely that the
projections of the more protective models vill not underestimate
risk, at least to experimental animals, and they may strongly
overestimate it. None of the models includes a threshold. In a
few cases, dose-response data are available from human epidemi-
ology studies and may be used in lieu of animal data for low dose
extrapolation.
It appears that certain classes of carcinogens do not possess
the capacity to damage DNA (they are not genotoxic); in our ear-
lier discussion of the carcinogenic process, such substances
would affect only late stages in the process. Some scientists
maintain that such (nongenotoxic) carcinogens must operate under
threshold mechanisms. Many of the reasons for such a hypothesis
are sound, but no general consensus has yet emerged on this mat-
ter. It is nevertheless possible that some classes of carcino-
gens could be treated in the same way noncarcinogens are treated
for purposes of establishing ADIs.
116
-------
V. HUMAN EXPOSURE EVALUATION
Assessment of human exposure involves estimation of the num-
ber of people exposed and the magnitude, duration, and timing of
their exposure. In some eases, it is fairly straightforward to
measure human exposure directly, either by measuring levels of
the hazardous agents in the ambient environment or by using per-
sonal monitors. In most cases, however, detailed knowledge is
required of the factors that control human exposure, including
-those factors which determine the behavior of the agent after its
release into the environment. The following types of information
are required for this type of exposure assessments
e Information on the factors controlling the production
of the hazardous agent and its release into the envi-
ronment.
e Information on the quantities of the agent that are
released, and the location and timing of release.
e Information on the factors controlling the fate of the
agent in the environment after release, including fac-
tors controlling its movement, persistence, and degrad-
ation. (The degradation products may be more or less
toxic than the original agent.)
e Information on factors controlling human contact with
the agent, including the sise and distribution of vul-
nerable human populations, and activities that facili-
tate or prevent contact.
e Information on human intakes.
The amount of information of these types that it available
varies greatly from case to case and is difficult to discuss in
general terms. For tome agents, there is fairly detailed infor-
mation on the sources of release into the environment and on the
factors controlling the quantities released. However, for many
agents there is very limited knowledge of the factors controlling
dispersion and fate after release. Measurements of transport and
degradation in the complex natural environment are often diffi-
cult to conduct, so it is more conmon to rely on mathematical
models of the key physical and chemical processes, supplemented
with experimental studies conducted under simplified conditions.
Such models have been developed in considerable detail for radio-
isotopes, but have not yet been developed in comparable detail
for other physical and chemical agents.
117
-------
V-2
In comparison with toxicology and epidemiology, the science
of exposure assessment is still at a very early stage of develop-
ment. Except in fortunate circumstances, in which the behavior
of an agent in the environment is unusually simple, uncertainties
arising in exposure assessments are often at least as large as
those arising in assessments of inherent toxicity.
Once these various factors are known human data can be esti-
mated, as described earlier. The dose, its duration and timing,
and the nature and size of the population receiving it are the
critical measures of exposure for risk characterization.
118
-------
VI. RISK CHARACTERIZATION
The final step in risk assessment involves bringing together
the information and analysis of the first three steps. Risk is
generally characterized as follows:
1. For noncarcinogens, and for the noncarcinogenic effects
of carcinogens, the margin-of-safety (MOS) is estimated
by dividing the experimental NOEL by the estimated
daily human dose.
2. For carcinogens, risk is estimated at the human dose by
multiplying the actual human dose by the risk per unit
of dose projected from the dose-response modelling. A
range of risks might be produced, using different mod-
els and assumptions about dose-response curves and the
relative susceptibilities of humans and animals.
Although this step can be far more complex than is indicated
here, especially if problems of timing and duration of exposure
are introduced (as they no doubt need to be in the present case),
the MOS and the carcinogenic risk are the ultimate measures of
the likelihood of human injury or disease from a given exposure
or range of exposures.
The ADIs described earlier are not measures of risk; they
are derived by imposing a specified safety factor (or, in the
above language, a specified MOS). Our purpose here is not to
specify an ADI, but to ascertain risk. There is no means availa-
ble to accomplish this for noncarcinogens. The HOS is used as a
surrogate for risk: as the MOS becomes larger, the risk becomes
smaller. At some point, most scientists agree that the MOS is so
large that human health is almost certainly not jeopardised. The
magnitude of the MOS needed to achieve this condition will vary
anong different substances, but its selection would be based on
factors similar to those used to select safety factors to estab-
lish ADIs.
119
-------
Appendix
TOXIC EFFECTS ON ORGANS AND OTBER TARGET SYSTEMS
120
-------
Appendix
INTRODUCTION
To understand the potential toxic effects of chemicals, it is
useful to understand the toxic effects (i.e., measurable effects)
on endpoints that are commonly observed in animals, including
humans. While the following discussion is presented by organ or
system, chemicals frequently affect more than one organ and can
produce a variety of endpoints. Concentration of the chemical,
duration of exposure, and route of exposure are three of the
factors that can influence the potential toxic effect.
LIVER
A major function of the liver is metabolism—i .e., the bio-
chemical conversion of one substance into another for purposes of
nutrition, storage, detoxification, or excretion. The liver has
aultiple mechanisms for each of these processes, and interference
with any of the processes can lead to a toxic effect. Chemicals
that damage the liver are termed "hepatotoxic." Toxic endpoints
of the liver can include lipid (e.g., fat) accumulation, jaun-
dice, cell death (necrosis), cirrhosis, and cancer. In addition,
chemicals that increase the level of metabolic enzymes, i.e.,
enzyme inducers, can dramatically affect the toxicity of other
compounds.
The accumulation of lipids, primarily triglycerides, is re-
lated to the liver's conversion of sugars and carbohydrates into
fat for storage (or vice versa for energy production during star-
vation). Chemicals that increase the rate of triglyceride syn-
thesis, decrease the rate of triglyceride excretion, or both can
lead to an accumulation of lipids in the liver and a concomitant
decrease of triglycerides in the blood. While the effects of
lipid accumulation in the liver are not known, a fatty liver is
generally regarded as an indication of an injury to the organ.
Jaundice is a frequent endpoint when the excretory functions
of the liver are impaired} the yellow east of the skin is caused
by the retention in the blood of the yellow bile pigments that
would normally be excreted. Since blood that has absorbed com-
pounds from the gastrointestinal tract passes through the liver
before the rest of the body, the liver is a major site for the
removal of nutrients and toxicants. Elimination of the absorbed
toxicants can occur in the feces via the bile. In addition to
1 21
-------
A-2
bile acting as a mechanism of excretion, bile salts aid in the
absorption of nutrients that are not water soluble. Thus, im-
pairing liver function can affect absorption of compounds. Fi-
nally , the liver is also a site of the destruction of aged red
blood cells. Jaundice is an indicator of liver malfunction.
Necrosis, or cell death, can occur from multiple causes.
There are many mechanisms by which toxicants can directly or
indirectly inhibit required cell functions. The liver has a
limited ability to regenerate destroyed cells. Chronic destruc-
tion of cells, however, may lead to cirrhosis of the liver in
which the normal liver cells (hepatocytes) are replaced by al-
tered cells and connective tissue such as collagen.
A wide variety of chemicals have been shown to cause liver
cancers in laboratory animals. Exposure to vinyl chloride has
been associated with liver cancers in humans. The theories and
uncertainties of carcinogenesis are discussed in the main text.
As a major site of metabolism and and detoxification, the
liver contains enzyme systems that biochemically alter compounds.
Many of these processes facilitate excretion by making the com-
pound more polar, i.e., highly charged (e.g., cytochrome F-450
systems) or attaching polar groups to the compound (e.g., gluta-
thione, glycuronyl, or eulfo-transferases). The speed at which
this occurs depends on the amount of enzyme present; the amount
of enzyme can be increased by exposure to certain chemicals
called inducers. Zf 'a nonmetabolised compound is toxic, exposure
to an Inducer may decrease the toxic effect by increasing the
rate at which the compound is metabolized. Zf the compound needs
to be metabolised to be toxic, however, exposure to an inducer
may increase the toxic effect by increasing the rate of its meta-
bolism.
KIPMEY
As an organ whose major function is the elimination of toxi-
cants and other waste products, the kidney can be considered
a complex, elaborate filter. The kidney concentrates wastes for
elimination and retains nutrients and water that are useful to
the body. The kidney can metabolise and detoxify son* of the
same compounds as the liver, although the tate of metabolism is
usually slower. Compounds that injure the kidney are called
renal toxicants. Some renal toxicants may cause cell death
(necrosis) or cancer. Zn addition, the kidney produces chemicals
necessary for homeostasis (maintenance of the body's balance of
functions) and respond* to the sympathetic nervous system. To
efficiently remove the body's waste, the kidneys must process
122
-------
large volumes of blood. Thus, the first level of susceptibility
of the kidney is that which changes the flow of fluids. This '
change can be mechanical—e.g., kidney stones or puncturing
vesicles—or chemicals that dilate or constrict the passages.
The complexity of the kidney's filtering function makes it
susceptible to a number of toxicants. Although some of the fil-
tering requires no energy or special enzymes since the flow is
from high to low concentrations, much of the selection is to a
higher concentration than in the blood and is performed by en-
zymes that may be affected by chemicals. Excessive elimination
Of water, salts, or other nutrients can be as harmful as failure
to eliminate wastes. Furthermore, because the kidneys concen-
trate some toxicants, the effective dose of toxicants to the
kidneys may be higher than that for the rest of the body. Toxi-
cants that cause necrosis can also impair renal function. Fail-
ure of the kidneys to filter properly is frequently detected by
an increase in wastes in the blood or an increase in nutrients in
the urine.
The ability of•the kidney to metabolise compounds has not
been studied as extensively as has metabolism in the liver. The
presence of inducible metabolic enzyme systems is known. Other
specific metabolic functions occur in the kidney. Finally, be-
cause the kidney produces compounds that are necessary for other
body functions, damage to the kidney may affect other organ sys-
tems.
REPRODUCTIVE SYSTEM
Reproductive toxicology involves at least three organisms
(both male and female parents and their offspring) and consists
of many steps and stages. Toxic effects to the reproductive
system can be classified into three general endpointst impaired
ability to conceive, failure of the conceptus to survive, and
production of abnormal offspring.
Problems with conception usually result from impaired produc-
tion of the sperm ©r egg. The formation of sperm (spermatogene-
sis) is continuous in the male and requires a series of steps.
Chemicals that interfere with these steps may prevent sperm pro-
duction and cause sterility, reduce sperm production, or result
in abnormal sperm that have reduced capacity to fertilise. Al-
though in mammals all eggs are formed before birth, their final
maturation occurs in cycles after puberty. Chemicals, e.g.,
contraceptives, can impede this process. Mature sperm and egg#
as well as proper biochemical and physiological conditions within
the body, are required for fertilisation.
123
-------
A-4
Viability of the conceptus depends on a series of steps, in-
cluding implantation and development of the amniotic sac and
placenta. Death of the conceptus, whether at the early embryonic
stage or later fetal stage/ can be caused by a variety of factors
including chemicals. Such chemicals are labeled "embryotoxic"
and "fetotoxic," respectively.
Chemicals that cause defects in development and result in
abnormal offspring are called ¦teratogens." Defects range from
abnormal skeletal or muscle structure and mental retardation, to
metabolic malfunctions, to subtle malfunctions that may not be
noticed during a normal life.
Functionally, for the developing mammal to be exposed, the
chemical must pass through two barriers* the mother and the
placenta. If a given dose of a compound is sufficiently toxic to
kill the aiother, resultant toxic effects on the offspring will
not be observed. Although this statement may seem trivial, its
converse is an important principle in teratogenesis. The more
dangerous teratogens are those which affect the developing organ-
ism at concentrations that are significantly lower than those
that affect the adult mother.
Although the placenta was once thought to be a rather strong
barrier, many chemicals have been found to cross to the con-
ceptus. Depending on the compound, the final concentration may
be higher in the mother, higher in the conceptus, or equal in
mother and conceptus. Moreover, the placenta is not inert but is
capable of metabolising some chemicals into either more or less
toxic substances. Metabolism may also affect the flow of com-
pound across the placenta.
Timing has two critical aspects in teratogenesis: timing of
the dose during development and parallel timing of developing
systems. Time of exposure to the potential teratogen may not
only determine which developing system is affected but also
whether the compound will have any effect at all. For each de-
veloping system there is a critical period, usually between three
and twelve weeks in the human, during which the system is parti-
cularly sensitive to chemically induced abnormal development.
Although terata may form after this period, the abnormalities are
usually less sever*•
The second aspect of timing Involves the relative rate of
development of each of the organ systems. To produce a well-
formed offspring, development must be well orchestrated. As with
a symphony, the pace must be parallel in all sections. Nerves
cannot attach to muscles that are not present» cleft palate in
laboratory animals is frequently caused by events occurring out
1 24
-------
of sequence. If all the developing systems were equally re-
tarded, the result might be an immature, but not malformed fetus.
LUNGS
The major function of the lungs is to exchange oxygen and
carbon dioxide between blood and air. This same mechanism can
facilitate entry and exit of other compounds from the body. In
addition, the lungs have the ability to alter some chemicals
metabolically. Damage to the lung can range from irritation and
constriction, to cell death (necrosis), edema, or fibrosis, to
cancer.
The air not only contains a variety of gases but also small
suspended particulates and liquid aerosols. The fate and, there-
fore r potential to cause damage, for each physical state depends
on the sise and composition of the inhaled substance. An analogy
is often drawn between the airways of the respiratory passages
and the structure of a tree, in both, the starting point has a
large diameter and branches into more numerous but increasingly
•mailer appendages. Given the sise of the passage and the fact
that large particles fall out of suspension faster, larger in-
baled particulates and droplets will generally deposit in the
upper respiratory tract. Deposition is also affected by the
breathing pattern--fbr example, how fast and how deep.
The lung contains other mechanisms for handling inhaled sub-
stances including secretions, the mucociliary escalator, and
macrophages. Secretions, including mucus, can facilitate trans-
port of compounds across the lungs, between the air and blood.
The mucociliary escalator consists of mucus and hairlike projec-
tions in the upper respiratory passages. The latter move so that
particles that have been deposited are transported up the passage
until they can be swallowed. Substances that either affect the
mucus or inhibit the cilia movement can impair this process.
Macrophages are a type of mobile cell that can engulf particles.
Lungs facilitate exchange in both directions between air and
blood} thus, they can be equally efficient in absorption or ex-
cretion from th« body. Whether a given substance is concentrated
in the blood or in the lung air or is at equal concentrations on
both sides depends on several factors, including its solubility
in water and ability to be bound to proteins in the blood. Fur-
thermore# lungs are able to metabolise some chemicals. These
changes may alter the chemical properties and, therefore, the
transport of the chemical.
125
-------
A-6
Chemicals that irritate the lung can lead to discomfort.
Although the effects of exposure to irritants are usually revers-
ible, chronic exposure may lead to permanent cell damage. The
normal, necessary exchange of gases across the lung can be im-
paired by compounds that constrict the respiratory passages,
affect secretions or other normal functions, or physically remain
in the lung. Substances that cause necrosis, edema (excessive
fluid retention), or fibrosis (a change in cell type and composi-
tion) will impair lung function. Exposure to some substances,
such as cigarette smoke, asbestos, and arsenic, can lead to im-
paired lung function and cancer.
SKIN
Skin is a barrier between the internal organism and the ex-
ternal environment. It prevents loss of body fluids, regulates
body temperature, and prevents entry of many substances. Bow-
ever, the skin is a route of entry for tome toxicants. Dermal
toxicants csn cause irritation, sensitication, pigmentation
changes, chloracne, ulcerations, and cancer.
The skin can also be a major route of entry for other sub-
stances—for example, some pesticides and solvents. Moreover,
abrasions or cuts on the skin can compromise the barrier. Com-
pounds that are absorbed through the skin may affect other
systems—for example, organophosphate pesticides that affect the
nervous system. Similarly, compounds that enter by other routes
nay affect the skin—for example, the oral ingestion of arsenic
causes dermal changes*
Irritation, rashes, and itching are common toxic reactions to
dermal exposures. Chemical sensitizers may cause an allergic
reaction that becomes more severe with continued exposure to
light. Folliculitis (damage to the hair follicles) and acne are
other common skin disorders. Chloracne is a particular form of
acne that is often caused by exposure to chlorinated hydrocar-
bons. Compounds can change skin pigmentation. Skin keratoses
(hardening or scaling) or ulcers are additional toxic responses.
Skin cancer may be caused by dermal contact with some agents or
systemic administration of others.
CENTRAL NERVOUS SYSTEM
The attjor function of the central nervous system (CKS) is
communication. Control of reflexes, movement, sensory informa-
tion, autonomic functions (e.g.* breathing), and intelligence are
126
-------
A-7
controlled by the CNS. These functions can be impaired by toxi-
cants. Damage to the nervous system can occur in the brain or
other nerve cell bodies, to nerve processes that extend through
the body, to the myelin sheaths that cover these processes, and
at the nerve-nerve or nerve-muscle junctions. Damage to nerve
cell functions are often called "neuropathies.*
As in other cells, damage to the cell body of a neuron (nerve
cell) can result in impaired function or death. The br&in is
partially protected by the blood-brain barrier. Like other phy-
siological barriers, this one has proven more permeable than
originally thought, although it does block or reduce the passage
of some substances to the brain. Zn contrast, certain substan-
ces, such as organic mercury, have been shown to concentrate in
the CNS.
Axons are long processes that conduct impulses from the nerve
cell body; they can span much of the length of an animal. Sever-
ing the axon can destroy transmission of signals along the nerve.
Because electrical signals are transmitted by charged elements
(ions), chemicals that change the permeability of the cell mem-
brane to ions can also impair transmission of the signal.
Myelin is the insulating cover of axons. Special cells,
called Schwann cells, form myelin by wrapping themselves in many
layers around the axons. Chemicals can either destroy the myelin
or decrease its amount, both of which decrease the insulation and
impair signal transmission. Furthermore, demyelination of nerves
can cause a degeneration of the axon. These effects take time to
occur, even if damage is caused by a single exposure. Thus, the
effect may be delayed and not immediately associated with the
exposure.
Transmission of signals between nerves or from a nerve to a
muscle occurs across a space or junction. Chemical compounds
that are stored in vesicles at the nerve endings carry the signal
across the junctions. Exposure to chemicals may accelerate or
inhibit release of these vesicles, mimic the compounds that are
rsleased from the vesicles, or block the receptors that react to
release of the compounds. Any of these responses will distort
the signal.
Subjective or behavior neurological toxicology may be the
most difficult toxicological effects to assess. While generally
accepted that exposure to eome chemicals can cause headaches,
fatigue, or irritability, it is difficult to determine whether
such symptoms are caused by chemical exposure, lack of sleep,
depression, or other factors. Although these symptoms may be
mild and difficult to assess, they are frequently an early warn-
ing of exposure to a toxicant.
127
-------
A-8
Behavioral changes are often caused by damage to the nervous
system. In laboratory animals, such damage may be as precise and
fatal as failure of pups to nurse. Mental retardation and learn-
ing disabilities are other measurable behavioral changes. Chemi-
cal alteration of behavior is the basis for psychological drug
therapy. Thus, although they are difficult to assess, behavioral
changes should not be ignored.
BLOOD
Transport of oxygen, carbon dioxide, and other materials is
the major function of blood. The hematopoietic system, which
includes organs and tissues that produce, transport, and filter
blood, interacts with the cells of all other systems. Toxicity
can occur to developing blood cells, existing cells, or the hema-
topoietic organs.
Zn the human being and other mammals, blood cells are formed
in bone marrow} the three major types of blood 6ells are formed
by branches from a common precursor cell. Red blood cells con-
tain hemoglobin and transport oxygen and carbon dioxide.White
blood cells function as part of the immune system. Platelets are
necessary tor blood clotting. Chemicals toxic to bone marrow can
affect blood formation. Depending on the stage and cell affect-
ed, any or all of the major blood cells may be decreased in num-
ber. Abnormal increases in production of certain blood cells are
also possible, as in leukemia (excess white cells).
Blood plasma contains a number of proteins, ions, and other
compounds. Changes in the chemical composition of blood may
indicate a toxic response. Furthermore, some chemicals bind to
plasma proteins. Changes in plasma protein composition could
effect the effective concentration of a toxicant.
The normal function of the hemoglobin in circulating red
blood cells is critical to the transport of oxygen to and carbon
dioxide from all cells in the body. Reduced oxygen supply can be
very detrimental; the effects resulting from oxygen deprivation
vary with the site of action. Chemicals can affect hemoglobin by
chemically oxidising the heme group (causing methemoglobin) or by
denaturing the hemoglobin (which stay lead to the formation of
¦eins bodies).
Two other hematopoietic organs that may be affected are the
spleen and heart. The former removes old or damaged red blood
cells from circulation. The rate and efficiency of the heart's
pumping action can be altered by many causes. Chemicals that
1 28
-------
A-9
constrict or dilate the blood vesicles can also affect circu-
latory function.
IKMPNE SYSTEM
Recognition and protection against foreign substances in the
body is handled by the immune system. Rapid advances are being
made in immunology research; therefore, current knowledge may
soon be obsolete. Three types of cells (macrophages, B lympho-
cytes, and T lymphocytes) are part of the body's immune response.
These cells interact at the peripheral lymphoid organs (lymph
nodes, spleen, and tonsils). Exposure to chemicals may activate
or supress the immune system.
The cells involved in the immune system are formed in bone
marrow; hence, chemicals that affect bone marrow may impair im-
munt function. One type of cell engulfs foreign matter, especi-
ally bacterial and viruses, by phagocytosis. Another type pro-
duces the five classes of antibodies. A third type produces
Polypeptides, such as interferon, that are important for tome
immune responses; this type of cell is also involved in cell-
mediated immunity, such as contact dermatitis, and may partially
regulate the function of antibody-producing cells.
Chemicals may stimulate immune responses by several mecha-
nisms including acting as allergens or by stimulating production
of interferon. Chemicals may also suppress immune response; im-
munosuppressants result in an increased susceptibility to infec-
tion and may result in an increased susceptibility to some forms
of cancer.
GENETIC TOXICOLOGY
The integrity of genetic material (DMA) in all cells is crit-
ical to cell function and may be affected by some toxic agents.
Damage may take several formss Alteration la the chemical compo-
sition of DNA, change in the physical structure of DNA, or addi-
tion or deletion of chromosomes. Effects of genetic toxicity can
range from no observable effect to cancer. Genetic toxicity has
become a popular endpoint for toxicity testing because test re-
sults can be obtained relatively rapidly and inexpensively.
Genetic damage can occur by many mechanismsy the results are
generally classified in three groups * mutations, clastogenic
events, and aneuploidy. Mutagens are substances that change the
129
-------
A-10
chemical structure o£ DNA. Since DNA is "read" to provide infor-
mation necessary for cell function and proliferation, mutations
may cause a misreading, leading to cell damage. Clastogens cause
a break in one or more strands of DNA and a physical rearrange-
ment of its parts. Depending on where the break occurs, clasto-
gens may affect cell proliferation or the production of cell
proteins. Aneuploidy is an addition or deletion of the number of
chromosomes; a commonly known aneuploidy is Down's syndrome
(Mongolism) in which there is an extra chromosome. Aneuploidy is
often caused by chemicals that affect cell division.
Genetic toxicology is often considered with carcinogenicity
since many carcinogens are mutagens and testing for mutagenicity
is easier than testing for carcinogenicity. Genetic toxicants,
however, can have many effects. Much of the DNA in cells is
quiescent. Since skin cells do not produce hemoglobin, there
will be little damage if instructions for producing hemoglobin
are damaged in a skin cell. Such events are called silent muta-
tions. Genetic damage can alter cell proteins and, therefore,
normal functioning of cells. Improper cell function may lead to
cell death or cancer. Finally, if the damage is in the reproduc-
tive system, genetic toxicants can cause reproductive failure or
abnormal offspring.
A variety of genetic toxicology tests have been developed in
recent years. Many are performed in vitro (outside the whole
animal—e.g., the Am?s mutagenicity assay) and use cells grown in
liquids; some are performed in vivo (within the animal). These
tests are often referred to as short-term testing and require
less time, and therefore, less money. Typically, short-term
tests take days to months as contrasted with several years re-
quired for carcinogenicity testing.
130
-------
J. ASSESSING RISK
INTRODUCTION TO PRINCIPLES USED IN RISK ASSESSMENT CASE STUDY
Prepared by C. Richard Cothern
Health Effects Branch
Criteria and Standards Division
EPA Office of Drinking Water
Washington, DC 20460
131
-------
RISK
• SUBJECTIVE
• NOT A RISK FREE WORLD
• UNCERTAINTY AND COMPLEXITY
• PROBABILISTIC
• BENCHMARKS
• PRODUCT OF PROBABILITY
AND CONSEQUENCE
132
-------
RISK ESTIMATION
• RANGE-WANT TO NARROW
• NOT NEW
• QC
• INSURANCE
• MEDICAL COUNSELING
• NEW PROBLEMS
• RARE EVENTS
• PERCEPTION OF VALUE
• LARGE UNCERTAINTIES
-------
WHAT ARE THE
COMPONENTS OF
RISK ASSESSMENT?
Hazard Identification
Dose-Response Evaluation
Human Exposure Evaluation
Risk Characterization
134
-------
RISK ASSESSMENT
Dose-Response
Assessment
Hazard
Identification
Risk
Characterization
Exposure
Assessment
135
-------
HAZARD IDENTIFICATION
• Review and analyze toxicity data
• Weigh the evidence that a
substance causes various toxic
effects
• Evaluate whether toxic effects in
one setting win occur in other
settings
136
-------
RISK ASSESSMENT ISSUES
Hazard Use of animal data
Identification
Negative epidemio-
logical studtes
-------
SOURCES OF TOXICITY DATA
Human Studtes Animal Studes
Case reports
Epidemiologic stucfies
Geographical
Temporal
Test Tube Studtes
• Microbiological
• Mammalan
General toxicity studies
• Acute
• Chronic
Specialized toxicity studies
• Teratology
• Mutagenicity
-------
U>
\o
FORMS OF
HUMAN EXPOSURE
Inhalation
Ingestion
Skin Contact
-------
HUMAN EXPOSURE
EVALUATION
• How may people be exposed?
• Through which routes?
• Who is exposed?
• What is the magnitude, duration,
and timing of the exposure?
-------
RISK ASSESSMENT ISSUES
Hazard Use of animal data
Identification
Negative epidemio-
logical studtes
Dose-Response Extrapolating from high
Evaluation dose to low dose
Extrapolating from
animals to humans
-------
Hazard
Identification Data
*
to
Dose-Response
Evaluation Data
Human Exposure
Evaluation Data
Risk
Characterization
Level of
Potential
Risk to
Humans
-------
DOSE-RESPONSE EVALUATION
Performed to estimate the incidence
of the adverse effect as a function
of the magnitude of human exposure
to a substance
Dose
-------
DOSE-RESPONSE CURVE
R
e
s
P
o
n
s
e
0
- /»
i
/
Observable
Range
Range of
Inference
Dose
-------
ESTIMATED NUMBER OF GROUNDWATER SYSTEMS IN EACH SIZE CATEGORY
WITH TRICHLOROETHYLENE IN THE INDICATED CONCENTRATION RANGES
(MICROGRAMS/LITER)
Estimated Number of Systems with Concentrations (micrograms/liter) of:
System Size No. of
(population Systems >10- >20- >30- >40- >50- >60- >70- >80- >90-
served) In U.S. <0.5a 0.5-5 >5-10 20 30 40 50 60 70 80 90 100 >100
25-100
19125
18506
465
26
52
0
26
0
26
0
0
0
0
26
101-500
15674
15166
381
21
42
0
21
0
21
0
0
0
0
21
501-1,000
4877
4719
118
7
13
0
7
0
7
0
0
0
0
7
1,001-2,500
4400
4257
107
6
12
0
6
0
6
0
0
0
0
6
2,501-3,300
891
862
22
1
2
0
1
0
1
0
0
0
0
1
3,301-5,000
1065
1031
26
1
3
0
1
0
1
0
0
0
0
1
5,001-10,000
1168
1130
28
2
3
0
2
0
2
0
0
0
0
2
10,001-25,000
835
775
34
11
4
0
0
8
0
0
4
0
0
0
25,001-50,000
290
269
12
4
1
0
0
3
0
0
1
0
0
0
50,001-75,000
64
59
3
1
0
0
0
1
0
0
0
0
0
0
75,001-100,000
14
13
1
0
0
0
0
0
0
0
0
0
0
0
>100,000
55
41
14
0
0
0
0
0
0
0
0
0
0
0
TOTAL
48458
46828
1211
80
132
0
64
12
64
0
5
0
0
64
-------
TRICHLOROETHYLENE
Hepatocellular Carcinomas in Male Mice
Animal Human
dose Equivalent Animals
(mg/kg/day) (mg/kg/day) Affected/Total
0 0 1/20
1530 56.3 26/50
2700 112.6 31/48
5 days/wk - multiply by 5/7
1 1/2 yr experiment - multiply by 1.5/2
bodysize - multiply by (0.033/70) '3
-------
•-4
MODEL
PROBABILITY Pid) OF
A RESPONSE AT DOSE d
LOW-DOSE BEHAVIOR
UNEAR
SUB
UNEAR
SUPRA
UNEAR
PROBfT
(2n)'W [<*$***
J exp (-u*/2)du (p > o)
-CO
—
P>0
—
LOGIT
[l + exp (- a — p log dj| ~1 (p>o)
P=1
P>1
P<1
WE1BULL
1-exp (- Xdm) ( X,m >o)
m=1
m>1
m<1
ONE-HIT
1—exp (- Xd) d>o
A>o
—
—
MULTI-STAGE
1—exp (-I* P jrf) ( p!>o)
i=1
"CD
V
o
Pi -o
—
MULTI-HIT
Pd
f (uk_1 e"41) du
o J f(k)
k=1
k>1
k<1
-------
TRICHLOROETHYLENE
(Ingestion}
<
>
z
O
m
M
z
z
> r-
=r2 m
o?S?
T) -n m
r®a
c2«
0> >0
OfZ
(*» 3D m
2 OX
2 c 3
> H O
t-mtn
-wm
8>
c
2
D
Z
o
m
(A
H
0
z
1
LOGIT
MULTISTAGE
PROBIT
0.001
10,000 100.000 1,000,000 10.000,000
CONCENTRATION IN DRINKING WATER (mierograms/liter)
-------
TRICHLOROETHYLENE
Drinking
Water
Number
Lifetime
Lifetime
Concentration
of People
Individual
Population
(H./L)
Served
Risk Range
Risk
0.25
1.9*10®
<10*10
6x10 "4
<1-
100,000
2.75
2.3x10 7
<10"10
1x10 "3
<1-
20,000
7.5
4.3x10 s
<10"10
2x10 "3
<1-
800
15
2.1x10 s
<10-10
6x10 "3
<1 -
1,200
35
7.4x10 s
7x10 "8
1x10 "2
<1-
7,000
45
2.6x10 s
3x10 "7
1x10 *2
<1-
3,000
55
4.2x10 4
4x10 "7
1x10 "2
<1-
400
75
1.3x10 5
6x10 "7
2x10 "2
<1 -
2,000
100
4.2x10 4
1x10"®
2x10 "2
<1 -
800
1 -
100,000
-------
CONTAMINANT
Cigarette Smoke
Active
Passive
Radon
Soil
Water
Radium-226
Uranium-Nat
Strontium -90
1,2 Dichloropropane
Aiachlor
Asbestos
Chloroform
T richloroe thy lene
ANNUAL
POPULATION
RISK RANGE
100,000
2,000-5,000
5,000-20,000
50-2,000
3-60
1-10
1-2
<10"8- 100
<10*8 -1
5x10 "4 -1
<10 *4 -10
<10 "5 -1,000
-------
MFO
Stim.
Z
Fatty
Change
Decreased
BSP
Clearance
Mortality
DOSE RATE (mg/kg)
-------
<
>
z
o
m
3
5
z
z
> r-
5 5 5
>51
en
¦Mi
o°"
Z%z
?f3
C^U
M >0
OrZ
fliam
2 ox
153
CKm
>°
8
c
I
z
o
z
o
PI
M
0
z
1
VINYL CHLORIDE
WEiBULL
MULTISTAGE
LOGIT
PR08IT
0.001 0.01
10.000 100,000 1,000,000 10,000.000
CONCENTRATION IN DRINKING WATER (micrograms/littr)
-------
VINYL CHLORIDE
CONCENTRATION IN DRINKING WATER (imcropams/litar)
-------
Threshold
en
No Effect Organ Damage
Non-Threshold
Cancer
-------
RISK CHARACTERIZATION
327 per 1,000,000 exposed people wB die
from fifetime exposure to Chemical A.
in
ui
-------
RISK CHARACTERIZATION
327 per 1,000,000 exposed people wl de
from Wetime exposure to Chemical A.
Chemical A is carcinogenic in rats and mice.
Application of low-dose extrapolation
models and human exposure estimates
suggests that the range of risks in humans
is 100-1,000 deaths per 1,000,000 persons
exposed.
-------
RISK CHARACTERIZATION
327 per 1,000,000 exposed people wl cfle
from Rfetime exposure to Chemical A.
Chemical A is carcinogenic in rats and mice.
Applcation of low-dose extrapolation
models and human exposure estimates
suggests that the range of risks In humans
is 100-1,000 deaths per 1,000,000 persons
exposed.
Chemical A is carcinogenic in rats and mice
and it is prudent pubic health policy to
assume it is also carcinogenic in humans.
-------
cn
oo
DATA
LIMITATION
SCIENCE POLICY
OPTIONS
COMMENTS
ANIMAL
• ASSUME THAT
• ZYMBAL
ENDPOINTS
THERE IS CANCER
GLAND
MAY NOT
IN ANIMALS, WILL
BE FOUND
HAVE CANCER
• LIVER
IN HUMANS
FOR SOME
HUMAN ENDPOINTS
• MULTITUDE
OF
• ASSUME WILL
ENDPOINTS -
NOT OCCUR
e.g., LEAD
IN HUMANS
• ASSUME SAME
ENDPOINTS
-------
Ol
u>
DATA
LIMITATION
SCIENCE POLICY
OPTIONS
COMMENTS
SYNERGISM
• ASSUME THAT
• ASBESTOS,
AND
NEITHER EXISTS
RADON AND
ANTAGONISM
AND THAT
CIGARETTE
EFFECTS ADD
SMOKE
LINEARLY
• FEW MORE
• USE A SAFETY
THAN 10.
FACTOR
MOST 2
OR LESS
• COST OF
TESTING
-------
COMPARATIVE RISKS
OF DEATH
Number of Lifetime
Deaths/Year Risks
Motor vehicle 46,000 1 /65
accidents
Home 25,000 1/130
accidents
Lung cancer 80,000 1/12
deaths in
smokers
-------
ACTIVITIES THAT
INCREASE CHANCE
OF DEATH BY ONE
IN A MILLION YEARLY
CAUSE OF DEATH
SMOKING 1.4 CIGARETTES
CANCER. HEART DISEASE
SPENDING 1 HR. IN A COAL MINE
BLACK LUNG DISEASE
SPENDING 3 HRS. IN A COAL MINE
ACCIDENT
TRAVELING 10 MILES BY BICYCLE
ACCIDENT
TRAVELING 300 MILES BY CAR
ACCIDENT
FLYING 1000 MILES BY JET
ACCIDENT
FLYING 6000 MILES BY JET
CANCER FROM COSMIC RADIATION
LIVING 2 MONTHS IN DENVER
CANCER FROM COSMIC RADIATION
LIVING 2 MONTHS IN AVERAGE
STONE OR BRICK BUILDING
CANCER FROM NATURAL RADIO-
ACTIVITY
ONE CHEST X-RAY TAKEN IN A
GOOD HOSPITAL
CANCER FROM RADIATION
LIVING 2 MONTHS WITH A
CIGARETTE SMOKER
CANCER. HEART DISEASE
DRINKING 30 12-OUNCE CANS
OF DIET SODA
CANCER FROM SACCHARIN
LIVING FIVE YEARS AT SITE
BOUNDARY OF A TYPICAL
NUCLEAR POWER PLANT
IN THE OPEN
CANCER FROM RADIATION
DRINKING 1000 24-OZ SOFT
DRINKS FROM RECENTLY
BANNED PLASTIC BOTTLES
CANCER FROM ACRYLONITRILE
MONOMER
EATING 100 CHARCOAL
BROILED STEAKS
CANCER FROM BENZOPYRENE
SOURCE: "ANALYZING THE DAILY RISKS OF LIFE/' BY RICHARD WILSON,
TECHNOLOQY REVIEW. FEBRUARY 1979. BECAUSE OF THE NATURE OF THE
DATA ON WHICH THEY ARE BASED, SOME OF THESE EXAMPLES ARE SUBJECT
TO CONSIDERABLE UNCERTAINTY. IN A FEW CASES INVOLVING PROBABLY
AS MUCH AS SEVERAL FACTORS OF 10.
161
-------
CONTAMINANT
ESTIMATED NUMBER OF DEATHS IN A LIFE-
TIME IN THE U.S. DUE TO CONCENTRATIONS
IN THE DRINKING WATER
RADIUM
500 - 1000
URANIUM
500 - 1000
RADON
6000-100.000
CHLOROFORM
50,000 - 200,000
CARBON TETRACHLORIDE
100 - 300
TRICHLOROETHYLENE
o
to
i
o
TETRACHLOROETHYLENE
20 - 100
BENZENE
JO - 200
VINYL CHLORIDE
0-200
162
-------
General Problems in Communicating Risk Assessment Information
to Regulatory Decisionmakers and Some Possible Solutions.
o\
U»
COMMUNICATION PROBLEM
POTENTIAL SOLUTION
• LANGUAGE
• COMPLEX NATURE OF RISK
ASSESSMENT INFORMATION
• LACK OF UNDERSTANDING
OF CONCEPTS SUCH AS
UNCERTAINTY AND PROBABILITY
• USE WORDS WITH POSITIVE CONNOTATION
• MORE CLARITY AND REALITY IN SCIENTIFIC
AND TECHNICAL INFORMATION PRESENTED
(e.g., USE UNCERTAINTY)
• EDUCATION
- SCHOOLS
- NEWS MEDIA
- USE EVERYDAY EXAMPLES
-------
100.000
at
*
m
r*
3
a
a
c
3
or
01
«"»
7
"O
«<
10,000
x All accidents
Motor vehicle accidents %r M ^
AH cancer
~
Heart disease §
Stroke
Stomach cancer
1.000 —
Homicide
Pregnancy
Diabetes
Botulism
Smallpox vaccination
LZ_ 1
100
1,000
10.000 100,000 1,000,000
Actual number of deaths per year
-------
RISK ASSESSMENT
Hazard
Identification
-------
RISK ASSESSMENT
RISK
MANAGEMENT
-------
NON
o\
ni
Risk
Characterization
Control
Options
Non-Risk
Analyses
RISK ANALYSES
economics
pofitics
statutory and
legal considerations
social factors
-------
0
-1-
00
s
a
o
-n
*n
m
2
m
Tk
M
X
3
r-
-2-
-3H
-5-
-6-
-7-
— "J"
¦ ¦¦ 7"
R. = JUS.
L ip
¦ REGULATED OR REGULATION UNDER STUDY
A DECISION NOT TO REGULATE
O FATAL ACCIDENTS
T
"i 1 r
4 5 6
LOG OF POPULATION (P)
T
7
T
8
-------
ACTION
INDIVIDUAL LIFETIME
RISK ROLE
LIFETIME POPULATION
RISK IF ENTIRE
U.& IS EXPOSED
KT4
-20,000
DECISION
.KT6.
•200
DEMINIMUS
RADON
t
CHLOROFORM,
CARBONTETRACHLORIDE,
AND MANY ORGAN ICS
AND INORGANICS
R/CDIUM URANIUM
I
I
OTHER
ORGANICS
AND
INORGANICS
-------
Activities or Types of Exposure that Will Reduce
One's Life Expectancy by Eight Minutes
Due to the Increased Likelihood of Having Cancer
•
Smoking 1.4 cigarettes
•
Living two months with a cigarette smoker
•
One x-ray (in a good hospital)
•
Eating 100 charcoal-broiled steaks
•
Eating 40 tablespoons of peanut butter
•
Drinking 30 12-oz soft drinks from recently
banned plastic bottles
•
Living 20 years near a polyvinyl chloride plant
•
Living 15 years within 30 mi of a nuclear power plant
(From Wilson,
R., "A Rational Approach to Reducing Cancer Risk". New York Times, July 7, 1978)
-------
Common Daily Probabilistic Choices
Category
Probability
Weatherman
(forecast probabilities
10% ... . 80%
Bus or Train Being Late
5 minutes
50%
10 minutes
40%
20 minutes
5%
30 minutes
1%
Airplane
Takeoff or Arrival Being Late
50%
Medical Probabilities
Inheritable traits
25%
(color blindness,
Huntington's Chorea,
diabetes)
Heart trouble
40%
Breast cancer
20%
Lung cancer
Smoker (3 packs a day)
60%
Non-smoker
5%
Alarm Clock Failure
1/365
Car Failing to Start
1/365
Gambling
Poker
1/52
Roulette
1/38
Dice
1/6 A
Lotteries (winning jackpot)
1 x 10®
171
-------
RISK FACTORS
VOLITION
VOLUNTARY
-
INVOLUNTARY
SEVERITY
ORDINARY
-
CATASTROPHIC
ORIGIN
NATURAL
-
MAN-MADE
EFFECT MANIFESTATION
IMMEDIATE
-
DELAYED
EXPOSURE PATTERN
CONTINUOUS
—
OCCASIONAL
CONTROLLABILITY
CONTROLLABLE
-
UNCONTROLLABLE
FAMILIARITY
OLD
-
NEW
BENEFIT
CLEAR
-
UNCLEAR
NECESSITY
NECESSARY
-
LUXURY
172
-------
COMPARISON OF RCF VALUES
RCF
VALUE
LATAIft
RASMUSSEN
ROWE
STARR
KINCHIN
OTWAY&
COHEN
¦aturalauummde
a
ia
ORDMARY/CATASTROPMC
31
sa
VOLIMTARY/M VOLUNTARY
IN
in
1 - IMC
DELAYED/IMMEDIATE
11
2M/YR
31
CONTROLLABLE/UNCONTROLLABLE
5-1»
1M
OLO/NEW
11
NECESSARY/LUXURY
1
RE6ULAR/DCCASHJNAL
1
-------
UNCERTAINTY/ TOXICOLOGY
MANY ORDERS OF MAGNITUDE:
• BIOASSAY EXTRAPOLATION
• DOSE LEVEL DISTRIBUTION
• CURABLE CANCER
• SURROUNDINGS
• ANIMAL VARIABILITY
• INTERSPECIES COMPARISON
• COMPOUND PURITY
• GLPs
• SYNERGISM/ANTAGONISM
174
-------
UNCERTAINTY/ TOXICOLOGY
(Con't)
UTTLE CHANGE UP TO
ONE ORDER OF MAGNITUDE:
• SELECTION OF DOSE LEVELS
• PRE-CURSERS
• DIET
• TIME-TO-TUMOR
• ADD BENIGN TUMORS
• DISEASE INTERFERENCE
• STATISTICAL NOISE
• NO CORRESPONDING HUMAN TUMOR
• BODY WEIGHT vs SURFACE
• UPPER 95% LIMIT
• HOUSEKEEPING
175
-------
UNCERTAINTY/ TOXICOLOGY
(Con't)
ALL OR NOTHING:
• ENDPOINT
• DOSE LEVELS
• PERSONNEL
• SPECIES
• STRAIN
• AGE
• SEX
• STATISTICS
• HISTORY
• p LEVEL
176
-------
Sources of Uncertainty for Occurrence, Population
Concentration and Exposure Estimates Used in the Assessment
of Volatile Organic Chemicals in Drinking Water
Impact on estimate oft:
Population
Factors
Occurrence Concentration
Risk
Generation of monitoring data
Proportion of population sampled 5% (U)
Representativeness of systems selected
Geographic distribution* system
sice and source of water 10% (E)
Sampling methods
Site of sample collection
Time of sample collection
Method of sample collection
Container type
Stability during storage
Sample analysis
% recovery from sample
Compound identification
Accuracy of quantitative
determination
Assumptions during data analysis
Lower limits of quantification
Oral exposure rates
Intake rate of water
Pollutant level in concumed
water(hot vs cold)
% absorption for oral Intake
Respiratory exposure rates
Dermal exposure
20%
20%
10%
10%
100%
10%
10%
(E)
-------
Vinyl Chloride-Population Risk Estimates
For Current Levels of Drinking Water Exposure
(Maltoni-Old)
Mean Drinking Hater
Concentration
(Micrograms/Liter)
Number of People
Being Served
Total Lifetime Individual Risk
For the Mean Concentration*
Papulation
Risk
Low
High
(Probit)
(Weibull)
0.25
2.1 x 108
2 x 10-9
2.1 x 10-4
<1 - 50,000
2.75
1.3 x 106
3 x 10-7
1.1 x 10-3
<1 - 1430
7.5
4.7 x 10*
1 x 10-6
2.2 x 10-3
<1 - 1030
65
1.2 x 10*
9 x 10-6
3.5 x 10-3
<1 - 420
Ibtalt 1 - 50,000
Vinyl Chloride (Maltoni)-Risk Reduction Analysis
For Limiting Drinking Water Concentration
Maximum Allowable
Drinking Water
Concentrations
(Nicrograms/Li ter)
65
7.5
2.75
Approximate Individual
Risk Rate for Maxinun
Concentration
6 x 10-6 - e x 10-3
3 X 10-7 - 2 x 10-3
1 x 10-7 - 1 x 10-3
Cumulative Cases
Averted*
<1 - 420
<1 - 1450
<1 - 2880
t Rounded to one significant figure
* The total individual risk was determined by assuming that the risk due to
inhalation is equal to that due to ingestion
* Number of cases averted for concentrations shown in first column
178
-------
LEGEND
O COLORADO PLATEAU URANIUM MINERS ~ SWEDISH METAL MINERS
A CZECHOSL0VAKIAN URANIUM MINERS O NEWFOUNDLAND FLUOSPAR MINERS
SOLID MARKS ARE DATA - OPEN ONES IDENTIFY CURVES
MULTISTAGE
ir2
PRO BIT
WEIBULL
I
UNSCEAR 1t77
X BEIR Kl
W3
2 W®
Mr*
nr7
OjBI
-J* V
""" ~ ~ ^
CUMULATIVE WLM
-------
ADVANTAGES AND
UNCERTAINTIES
OF ANIMAL
DATA
-------
K.
CASE STUDY ON RISK ASSESSMENT OF
VINYL CHLORIDE
Introduction
P.
182
I.
Background Information on Vinyl Chloride
P.
185
II.
Hazard Evaluation
P.
186
III.
Dose-Response Evaluation
P«
191
IV.
Human Exposure Evaluation
P.
197
V.
Risk Characterization
P*
201
Appendix
P.
204
181
-------
Introduction to Risk Assessment Case Study
on Vinyl Chloride Contamination of Drinking Water
New information on the toxic properties of a widely used chemical,
vinyl chloride (VC), has just been published in a major scientific journal.
The uses of VC place it under the jurisdiction of EPA, and a senior agency
policymaker must decide whether the new information justifies regulatory
action. As a first step the policymaker must determine whether and to
what extent current uses of VC endanger the public health. Che senior
policymaker thus assembled a group of top agency scientists from various
disciplines — epidemiology, toxicology, biochemistry, pathology,
statistics, chemistry — and posed the following questions:
1. What types of health hazards might be associated with VC, and
how well are these known?
2. What is the magnitude of human exposure to VC, and how is the
exposure distributed in various population groups?
3. What is the nature and magnitude of human risk associated with
the various sources of exposure?
The group of scientists collected data to conduct a risk assessment.
In particular, they developed information to estimate the likelihood that
VC will exhibit one or more of its hazardous properties under actual
conditions of human exposure. At this stage the senior policymaker is
only concerned with understanding the risks of VC and the ways in which
that risk can be characterized. The senior policymaker is not presently
concerned with what has been referred to as risk management, or the issue
of how to regulate VC if a risk has been identified. Hence, the senior
policymaker is not considering the commercial importance of VC and the
possible regulatory consequences of reporting a significant health risk.
The senior policymaker believes strongly that it would not be satis-
factory to conclude that no risk assessment could be performed, or that
"more research" had to be conducted before any conclusions could be
reached. Rather, the senior policymaker felt it was essential that as
definitive a statement as was currently possible be made about the health
risk of VC, and that the uncertainties in the assessment be identified.
The senior policymaker knew it would have to be decided how to handle the
scientific uncertainties in the risk management decision, but for now the
need was to understand and characterize the current scientific knowledge
of the risks of VC.
182
-------
YOUR ROLE
For this exercise, you will play the role of the senior policymaker.
Your objective is to ensure that you thoroughly understand the possible
health risks associated with various uses of VC and that you can convey
your understanding to other people. You are not yet concerned with the
ultimate regulatory question of whether and to what extent these uses
should be controlled or eliminated; you are concerned with the risk assess-
ment, not risk management.
You will receive various sets of data and analysis from the team of
scientists you have assigned to the problem. You will conduct an analysis
of the information and its implications for risk. You will review and
evaluate the contents of the document. You will be asked to formulate
some conclusions based on the data and analysis.
Your review and evaluation will take place within a small working
group. After the various issues are aired and discussed, the working
group (which collectively represents the senior policymaker) should reach
a consensus on how best to characterize the data and the risk. If a
consensus cannot be reached, the alternative views should be expressed.
The conclusions of each working group will then be compared and contrasted.
Again, at this stage you are concerned only with risk assessment,
not with risk management.
NATURE OF THE DATA AND ANALYSIS TO BE REVIEWED
The report contains a discussion of the nature and uses of VC, and
the known extent of human exposure to it. ttie toxicological data on VC
will be presented in summary form. You will be asked to examine several
issues relating to the data and reach conclusions regarding them, ttiis
section constitutes the Hazard Evaluation.
The relationship between exposure to VC and the risk of adverse
health effects (Dose-Response Evaluation) is the next subject. There may
be several scientifically plausible options for describing this relationship
in the region of human exposure, and you will be asked to judge the
relative merits of these various options, ttiat is, you will be asked to
choose among them, or formulate a better one.
The third section will contain a summary of data on the Exposure of
various population groups to VC. Again, several issues arise concerning
the interpretation and use of this information, and it will be necessary
for the senior policymaker to formulate appropriate conclusions.
In the final step (Risk Characterization) you will be asked to present
your conclusions regarding the human health risks posed by VC and the
uncertainties in your knowledge*
183
-------
At each of the four major steps of this exercise, issues and data
will be presented, and alternative conclusions will be listed. After
discussion, you may select the conclusion that seems most appropriate; if
none seems appropriate, you should offer your own.
RESOURCE MATERIAL
The document entitled Principles of Risk Assessment: A Non-Technical
Review (Sec.II.I, pp. 79-130) provides background material needed to
assist your evaluation. You also will be exposed to some key principles
and additional background material at the two lectures to be presented
before the group sessions.
In addition, each of the following sections contains a discussion of
the key principles directly relevant to the specific issues under
consideration.
184
-------
1-1
I. BACKGROUND INFORMATION ON VINYL CHLORIDE
USES OF VINYL CHLORIDE
° RAW MATERIALS
in plastics, rubber, paper, glass and
automotive industries.
0 MANUFACTURE OF -
electric wire, insulation and cables,
piping, industrial and household
equipment, medical supplies, food
packaging and building supplies.
CHEMICAL & PHYSICAL PROPERTIES OF VINYL CHLORIDE
Structure
° Physical state -
• Stability
° Solubility in
Water
H-C-C-Cl
I I
H H
Gas
Degrades rapidly in the environment
1.1 g/L at 28°C
PRODUCTION IN U.S.A.
1983 — 7 billion pounds
HUMAN EXPOSURE
° General Population -
Humans could be exposed to vinyl chloride in
drinking water, food and air. Some people
could be exposed also through occupational
and consumer usage.
0 Worker Populations - Workers are exposed during manufacture.
185
-------
II-1
II. HAZARD EVALUATION
SOME PRINCIPLES FOR HAZARD EVALUATION
0 Hie purpose of hazard evaluation is to identify the types of
adverse health effects that may be associated with exposure to VC,
and to characterize the quality and strength of evidence supporting
this identification.
0 Hie specific hazard of concern in this review is cancer.
0 Epidemiological studies in exposed human populations generally are
considered to be the best source of information for hazard identi-
fication. Unfortunately, they are not available for most substances.
Moreover, establishing firm causal links between exposure and
human disease is very difficult.
0 Studies in experimental animals also provide useful information
for hazard identification. Such studies can be controlled, and
thus can more easily establish causality. Results from such
studies suffer from the obvious limitation that experimental
animals are not the species of ultimate interest.
0 With one possible exception (arsenic), all known human carcinogens
also are carcinogenic in one or more experimental animal species.
Many animal carcinogens have not been established as human
carcinogens, in most cases because of the lack of adequate
epidemiological data.
° There are biological reasons to believe that responses in
experimental animals could be mimicked by responses in humans, a
proposition supported by considerable empirical data. However,
other data show that species differ in response to the same agent.
0 It is known that the specific site(s) of tumor formation in humans
may be different from that observed in experimental animals.
° Data obtained by administering a substance by the same route of
exposure that is experienced by humans are considered more
predictive than data obtained by a different route. But if tumors
form at internal body sites, the route of exposure may not be
important.
0 In general, a varied response in experimental animals — tumor
formation in several species, both sexes, at several different
exposure levels with increasing response *t increasing exposure,
and at multiple body sites — provides more convincing evidence
of potential human carcinogenicity than does a response that is
limited to a single species or sex, or to a single common site of
tuipor formation.
186
-------
II-2
A number of studies have been conducted in rats, mice and rabbits
which show that vinyl chloride is carcinogenic in these species. Statis-
tically significant increases in the numbers of tumors at a variety of
sites have been reported following both inhalation and oral exposure.
During the risk assessment case study, we are focusing upon the
results of just one of those studies. Hie reasons for this decision should
become clear as you become more acquainted with the data.
THE PERON, BT AL. STUDY
In 1981, an article by Feron, et al. entitled "Lifetime Oral Toxicity
Study of Vinyl Chloride in Rats" appeared in a respected scientific
journal (Pood and Cosmetic Toxicology). This paper presented data on the
effects in rats of lifetime oral exposure to vinyl chloride, ihe design of
the experiments and the major findings are presented in Tables I and II.
TABLE I
Design of the Feron, et al. Study
Species & Route Grpa.Receiving
# of
Animals
A»t VC Reed
Duration
of Exp.
(weeks)
Hale
Female
Rat, Dietary
Control
60
60
0
104
Low Dose
60
60
1.7
104
Mid Dose
60
60
5.0
104
High Dose
60
60
14.1
104
Rat, Gavage
-
60
60
300.0
104
The units of "amount received" are milligrams of vinyl chloride (VC)
per kilogram of the animal's body weight.
j Gavage is the administration of a substance by means of a stomach
tube.
187
-------
II-3
TABLE II
Significant Findings from the Feron, et al. Study
Following are the groups in which a statistically significant excess of
tumors was found, complete assessment of tumor formation was made in
each sex.
Tumor Incidence (number
of animals with tumors)
Study Group Sex
Rat, Dietary Male
Rat, Dietary Female
Rat, Gavage Male
Rat, Gavage Female
Tumors Founda
Liver
a. neoplastic nodule
b. hepatocellular
carcinoma
c. angiosarcoma
Lung
a. angiosarcoma
Liver
a. neoplastic nodule
b. hepatocellular
carcinoma
c. angiosarcoma
Lung
a. angiosarcoma
Liver
a. neoplastic nodule
b. hepatocellular carcinoma
c. angiosarcoma
Liver
a. neoplastic nodule
b. hepatocellular carcinoma
c. angiosarcoma
Low-
Mid-
High-
Control
Dose
Dose
Dose
0
1
7
24°
0
1
2
9C
0
0
6°
27c
0
0
4C
19c
2
26c
39°
44c
0
4
19c
29c
0
0
2
9c
0
0
1
5C
Dose*
3
1
27
2
0
29
a Tumors are described both in terms of target organ and tumor type within
the target organ. There are three tumor types distinguished in liver.
b There was no matched control group with the treated group given VC by
gavage. Thus, statistical comparison could not be done.
c A statistically significant excess of tumors relative to untreated
control animals. This means that the difference in tumor incidence
between the treated and control animals is not likely due to chance.
Because the only difference between the control and treated animals was
the presence of VC, it is thus likely that the excess tumor incidence
is due to this compound. Tumors were found at other sites in both
control and treated animals, but no others occurred in statistically
significant excess.
188
-------
II-4
REMARKS ON THE FERON, ET AL. STUDY
1. As far as can be determined from the published Peron, et al. article,
this study was carefully conducted and there is no reason to doubt
the accuracy of the reported data.
2. VC increased the incidence of rislc of tumors (number of animals with
tumors) in all groups of animals given VC in the diet, although the
increase in low-dose males was not statistically significant.
3. Rats treated with VC by gavage developed the same tumor types in
liver as those treated with VC in the diet, but lung angiosarcomas
were not apparent with gavage exposure.
4. Rats developed liver tumors following both dietary and gavage
exposures. Lung tumors were produced only by dietary exposure.
5. Following dietary exposure to VC, females showed more neoplastic
nodules and hepatocellular carcinomas, whereas males showed more
angiosarcomas in liver and lung.
6. Neoplastic nodules and hepatocellular carcinomas were proportionally
greater than liver angiosarcomas with dietary exposure to VC, whereas
the opposite was evident with gavage exposure to VC.
7. Liver and lung tumors observed in treated animals are rarely formed
in untreated (control) rats of the strain (Wistar) used by Feron,
et al. This is particularly important in the interpretation of
liver tumor data in rats treated with VC by gavage as a treatment-
related effect.
8. Neoplastic nodules are considered to be a progression towards hepato-
cellular carcinomas and are, therefore, included in the tumor incidence
table, ttiese tumor types are of different cellular origin, and are
thus considered distinct tumor types from liver angiosarcomas.
9. identification of tumor types in each animal individually was not
given. Therefore, for the purpose of quantitative risk assessment,
animals with hepatocellular carcinoma also are assumed to have
neoplastic nodules. Therefore, only neoplastic nodules and angio-
sarcomas are added together to derive total liver tumors.
ISSUES TO BE CONSIDERED BY THE SENIOR POLICYMAKER
1. How do these data conform (or not conform) to the principles laid
out on page II-1 ~ particularly the last one?
2. In view of these principles, is there any reason to conclude that VC
is not carcinogenic in rats of both sexes (by dietary and gavage
exposures)?
189
-------
II-5
3. Is there any reason to believe that humans would not be at risk of
developing these various tumors, assuming they were exposed to VC?
4. Is there any way to determine, from the data given, whether responses
in humans are likely to be similar to those of rats? Males or females?
5. Should the liver tumors be considered relevant to humans?
6. Should the data obtained by gavage treatment be considered relevant
to human exposure?
CONCLUSIONS REGARDING VC CARCINOGENICITY
Which of the following conclusions best characterize the
evidence you have seen?
1. VC is a human carcinogen.
2. VC is a probable human carcinogen.
3. VC is a carcinogen at several sites in rats of both sexes, by
both dietary and oral routes of administration. VC is thus a
human carcinogen and is expected to increase the incidence of
lung and liver tumors in the exposed human population.
4. VC is a carcinogen at several sites in rats of both sexes.
VC is thus a probable human carcinogen, although only humans
exposed orally are likely to be at risk. Data obtained when
VC was administered by stomach tube are not relevant to any
route of human exposure, lhus, exposure through other routes
has no identifiable risk for humans.
5. Although VC is carcinogenic in rats, no data suggest that it
is carcinogenic in humans. The animal data provide only weak
evidence that VC may be a human carcinogen.
6. Because of the extreme conditions under which tumors were
produced in these animal experiments, there is no reason to
believe VC is a possible human carcinogen.
7. Other (formulate your own conclusion).
190
-------
III-1
III. DOSE-RESPONSE EVALUATION
THE GENERAL PROBLEM AND PRINCIPLES GUIDING APPROACHES TO ITS SOLUTION
Because of the relative complexity of dose-response evaluation, the
following discussion is substituted for a statement of key principles.
Recall that animal data showing that a chemical is carcinogenic
usually are obtained in the high exposure region of the dose-response
curve. Thus, animal exposures were in the 1.7 to 300 mg/kg/day ranges
(Table I). Human exposure is in the range of 0.03 to 2.0 ug/kg/day over
a range of potential drinking water concentration levels (Table VI).
What can be said about risks in the range of human exposure?
At least three general approaches to this problem have been proposed
by various experts.
Approach 1
Based on general theories of how carcinogens act to produce cancer
(largely derived from experimental studies and epidemiological data), all
finite exposure levels will produce a finite risk. The magnitude of the
risk will decline as the magnitude of exposure declines (this is even
clear in the animal data).1
If the quantitative relationship between exposure and risk were
known for all exposures, risk to rodents exposed at very low levels could
be predicted from the measured exposure-risk data. Risks to humans could
be predicted at these very low levels if the relationship between rodent
and human susceptibilities were known. Although these relationships
cannot be known with accuracy, a plausible upper limit on human risk can
be predicted with sufficient accuracy to be used as a guide to making
risk decisions. Actual human risk is not likely to exceed the upper
limit (although it may), and it may be less.
Approach 2
The quantitative relationships between high exposure and low exposure
risks in rodents and between rodent and human risk are not known with
sufficient reliability to be used in risk assessment* Moreover, there is
no reliable theory on which it can be concluded with assurance that low-
level human exposure (i.e., exposure below the range producing detectable
risks) poses any risk at all. As with other toxic effects, carcinogenicity
will not be initiated within an individual until a minimum threshold of
1 These two sentences are the proper formulation of the "no-threshold"
concept. Die "no-threshold" concept does not mean that all finite
exposures will cause cancer; instead, it means that all finite exposures
will increase the probability that cancer will occur.
191
-------
III-2
exposure is exceeded. In such circumstances, the only reasonable course
1b to report the magnitude of the margin of safety (MOS) by which humans
are protected. MOS is the maximum amount of exposure producing no
measurable tumorigenic response in animals divided by the actual amount
of human exposure. MOS gives the risk manager adequate information on
which to decide whether exposures must be reduced or eliminated to provide
human protection, A relatively large MOS is desirable because it is
likely that the threshold for the entire human population is substantially
lower than that observed in small groups of experimental animals.
Approach 3
Although there is adequate theory and some evidence to permit the
conclusion that humans are at finite risk at all finite exposure levels,
there is insufficient knowledge to allow prediction of the risk in
quantitative terms. Hie risk assessor should simply attempt to describe
risks qualitatively, perhaps coupling this description with some information
on the potency of the compound and the magnitude of human exposure. This
type of presentation is adequate for the risk manager, who should not be
concerned with the quantitative magnitude of risk in any case.
Bach of these views, and perhaps others as well, has some merit, it
would seem that the first approach, if correct, would provide the most
useful approach for decision making. Indeed, it is the approach now used
by EPA and other agencies as well. EPA and the other agencies emphasize
that the predicted numerical risks are not known to be accurate, but,
because of the nature of the models used to predict them, they are likely
to be upper bound estimates of human risk. An upper bound estimate is
one that is not likely to be lower than the true risk.
For this exercise we shall estimate low exposure risks using the
model currently used by EPA. A model is a mathematical formula that
describes the relationships between various measures. Two models are
needed to predict low exposure risk:
0 A high-to-low exposure extrapolation model is needed to predict
low exposure risks to rodents from the measured high exposure-
high risk data (Table II). EPA currently uses a so-called
linearized multistage model for this purpose. This model is
based on general (not chemical-specific), widely held theories
of the biological processes underlying carcinogenesis. Application
of the model to the rodent exposure risk data produces an estimate
of the lifetime risk for each unit of exposure in the low exposure
region. This is called the unit cancer risk, lhe "linearized"
model is used to ensure that the unit cancer risk is an upper
bound on risk.
192
-------
III-3
0 An interspecies extrapolation model is used to extrapolate from
rodent unit risks to human unit risks. There are empirical data
and theory to support EPA's current use of the assumption that
rodents and humans are at equal risk at the same exposure measured
in milligrams of carcinogen per square metdr of body surface area
per day.
EPA's selection of these models is based on the agency's view that
they are the best supported for purposes of deriving an upper bound
estimate of risk. Alternative models are available for both these forms
of extrapolation and cannot be ruled out. In most cases, but not always,
use of plausible alternative models will yield lower estimates of risk
than those predicted by the two described here* Differences can sometimes
be very large, but in most cases differences are relatively small,
especially when the models are limited to those which are linear at low
exposure.
Further discussions of various models and their plausibility can be
found in the resource material.
APPROACH TAKEN FOR THIS EXERCISE
In this exercise we reveal the upper bound of unit cancer risks
predicted for VC using the models currently preferred by EPA. The effect
of using alternative, plausible models is also described.
Estimates of Upper Bound, Lifetime Unit
Cancer Risks Using Current EPA Models
Application of the EPA models for high-to-low dose and interspecies
extrapolation to the measured animal cancer data of Table II yields the
results shown in Table III.
Estimates of Lifetime Unit Cancer
Risks Using Other Models
Application of other models for hlgh-to-low dose extrapolation
usually yields unit risks equal to or slightly lower than those in Table III,
as long as the other models incorporate the concept that risk increases in
direct proportion to exposure in the low exposure region (linear models).
Adoption of certain nonlinear models for high-to-low dose extrapolation
predicts risk about 1,000 to 10,000 times lower than those predicted by
use of the EPA model. Ttie nonlinear models are not widely recommended.
193
-------
III-4
TABLE III
Upper Bounds on Lifetime Unit cancer Risks Predicted from
Application of EPA's Preferred Model to Tumor Data, Table II
Route of
Species, Sex Exposure
Unit
Cancer
Tumor Site Risk1
Rat, Female
Rat, Female
Rat, Female
Rat, Male
Rat, Male
Rat, Male
Diet
Diet
Diet
Diet
Diet
Diet
Lung
Liver
Lung
Liver
All tumors
All tumors
0.058
1.9
2.3
0.11
0.3
0.29
^Risk for an average dally lifetime exposure of 1 unit
Units are same as those used earlier for describing the
animal exposure (Table I) and the human exposure (Table V)
(mg/kg bw/day). Risk is obtained from unit risk by multiply^
ing the latter by the actual number of units of human
exposure;the higher the unit risk, the higher the risk.
Dose-Response Evaluation not
Involving Formal Extrapolation
For those who believe formal extrapolation beyond the measurable
dose-response data should not be performed, it is important to identify
the exposures at which VC produces tumors and those at which no tumor
excess is found (the "no observed effect level" or NOEL)* Table IV
identifies NOELs from data in Table II.
194
-------
III-5
TABLE IV
No-Observed Effect Levels (NOELs)
for Chronic Exposure to vc
Study Group
Sex
Tumor
NOEL1
Rat, dietary
Rat, dietary
Rat, dietary
Rat, dietary
Rat, gavage
Rat, gavage
Male
Female
Male
Female
Male
Female
Liver
Liver
Lung
Lung
Liver
Liver
1.7
None found
1.7
5.0
None found
None found
1 Units are expressed as mg/kg bw/day. "None found" means
that a measurable excess of tumors was found at all
levels of exposure used in the experiment.
ISSUES TO BE CONSIDERED BY THE SENIOR POLICYMAKER
1. Which of the three possible approaches should be taken? Explicit
estimate of risk? Quantitative estimate of MOS? Qualitative
descriptions only? Should other approaches be considered?
2. If explicit estimates of unit risks are made, should only EPA's
currently preferred models be used? Should the results of applying
other models also be displayed?
3. Which Bpecies/sex/tumor site data from Table III should be used for
unit risk assessment? All, shown individually as in Table III? Only
the data set yielding the highest unit risk? A sum of all? Other?
4. How should the uncertainties in use of models be described?
5. Are the observed NOELs true "no-effect" levels? Could they simply
reflect the fact that in experiments with relatively small numbers
of animals, the failure to observe a statistically significant
increase of tumors is an artifact of the experimental design, and
not a true absence of biological effect? How should this uncertainty,
if it is real, be taken into account?
195
-------
III-6
ALTERNATIVE CONCLUSIONS REGARDING DOSE-RESPONSE EVALUATION
1. The unit cancer risks listed in Table III are true upper
bound estimates, The true unit risk is not likely to
exceed those determined, may be lower, and could be zero.
2. The same as the first conclusion, but add: The use of
alternative, plausible models yields unit risks about 10 to
100 times lower than those from Table III.
3. Unit risks should be reported for all plausible models, and
the full range of estimates should be reported without bias.
4. There is no justification for calculating and reporting unit
risks. What is critical for understanding the public health
importance of low level exposure to VC is the margin of safety
(MOS). Estimation of the MOS is based on the NOELs for its
carcinogenic effects; these figures are reported in Table IV.
5. Neither unit cancer risks nor NOELs are reliable indicators of
human risk, and neither should be considered for risk assess-
ment. Dose-response relations for the human population are
not known for VC; risk should be described in qualitative
terms only.
6. Other (formulate your own conclusion).
196
-------
IV-1
IV. HUMAN EXPOSURE EVALUATION
SOME PRINCIPLES FOR EXPOSURE EVALUATION
0 The purpose of the exposure evaluation is to identify the magnitude
of human exposure to VC, the frequency and duration of that exposure
and the routes by which humans are exposed, The number of exposed
people also must be identified, along with other characteristics
of the exposed population (e.g. age and sex).
0 Exposure may be based upon measurement of the amount of VC in
various media (air, water, food) and knowledge of the amount of
human intake of these media per unit of time (usually per day)
under different conditions of activity.
0 Some individuals may be exposed by contact with several media.
It is important to consider total intake from all media in
such situations.
0 Because only a limited number of samples of various media can be
taken for measurement, the representativeness of measured values
of environmental contaminants are always uncertain. If a sampling
is planned adequately, the degree to which data for a given medium
are representative of that medium usually can be known.
0 Sometimes air levels of pollutants can be estimated by the use of
mathematical models. Although some of these models are known to
be predictive in many cases, they are not thought to be so in
other cases.
0 Standard average values and ranges for human intake of various
media are available and generally are used unless data for
specific agents indicate such values are inappropriate.
AVAILABLE INFORMATION ON VINYL CHLORIDE
Die following information has been summarized from the Human
Exposure section of the office of Drinking Water Criteria Document on
Vinyl Chloride. Use this information in formulating your risk assessment
decision.
Humans may be exposed to vinyl chloride in drinking water, air and food.
Tfii8 analysis is confined to these three media since they are considered
to be general sources common to all individuals. Some individuals may be
exposed to VC from sources other than those cited here, notably in
occupational settings and from the use of consumer products containing
vinyl chloride.
Unfortunately, data and methods to estimate exposure of identificable
population subgroups from all sources simultaneously have not yet been developed.
To the extent possible, estimates are provided of the number of individuals
exposed to each medium at various VC concentrations. The 70 kg adult
male is used for estimating intake*
197
-------
IV-2
Water
Cumulative estimates of the U.S. populations exposed to various VC
levels in drinking water from public drinking water systems are presented
in Table V. Of the approximately 1.3 million people exposed to levels
ranging from 1 to 5 ug/L, 0.9 million (65%) obtain water from surface
supplies. All exposure to VC in drinking water at levels above 5 ug/L is
expected to be from groundwater sources.
No data were obtained on regional variations in the concentration of
VC in drinking water. The highest concentrations are expected to be near
sites of polyvinyl chloride production.
Table V also shows daily intake levels of VC in drinking water estimated
at various exposure levels. The data in the table suggest that the majority
of the persons using public water supplies would be exposed to intake
levels below 0.028 ug/kg bw/day.
Table V
Estimated Drinking Water intake of vinyl Chloride
Persons using supplies
exposed at indicated levels
Exposure level % of total
(ug/L)
Population
population
Intake (ug/kg/day)
_> 1
1,922, 000
0.9%
j> 0.028
> 5
591,000
0.3%
> 0.14
> 10
118,000
0.1%
> 0.29
> 50
118,000
0.1%
> 1.4
> 70
0 0 >2.0
Assumptions: 70 kg adult male, 2 liters of water per day
Diet
No data were obtained on levels of VC found in foods in the United States.
Therefore, no estimates of the daily intake of VC from the U.S. diet could
be made.
198
-------
IV-3
Air
Exposure to vinyl chloride in the atmosphere varies from one location
to another. The highest level of VC reported in the atmosphere was 2100
ug/m3. High levels (> 15 ug/m3) have been detected in other areas.
Normal levels, however, are somewhat lower. Brodzinsky and Singh (1982)
calculated a median air level of 0.0 ng/m3 (0.0 ug/m3) in each of three
types of areas: rural/remote, urban/suburban and source-dominated.
The monitoring data are not sufficient to determine regional variations
in the exposure levels.
Table VI describes the daily respiratory intake of VC from air as
estimated using the assumptions presented and ther maximum and minimum
ambient levels reported above. Intake calculated using the maximum VC
level reported is 690 ug/kg/dayj few, in any, persons are believed to be
exposed to that level. Estimated daily intake under other circumstances
is estimated to be 0 ug/kg/day.
Table VI
Estimated Respiratory Intake of Vinyl Chloride
Exposure (ug/m3)
Intake (ug/kg/day)
Rural/remote (0.0)
0
Urban/suburban (0.0)
0
Source dominated (0.0)
0
Maximum (2100)
690
Assumptions: 70 kg adult male; 23 m3 of air inhaled/day (ICRP, 1975)
199
-------
IV-4
ISSUES TO BE CONSIDERED BY THE POLICYMAKER
0 Is there any reason to believe that animal data obtained from
continuous lifetime exposure should not be used to characterize the
risk to people exposed intermittently?
CONCLUSIONS REGARDING HUMAN EXPOSURE TO VINYL CHLORIDE
1. Although the estimates for air and water are based upon different
data and different assumptions, these data are adequate for
assessing vinyl chloride risks* Ihe risk manager should be made
aware of the uncertainties in each of the data sets.
2. in addition to Conclusion #1, it should be noted that all the
exposures should be added because some people will be exposed to
all sources of vinyl chloride.
3. None of the exposure estimates is adequate for use in risk
assessment. Hie risk assessment should describe exposure in
qualitative terms only. Such a qualitative description is
appropriate and adequate for characterizing risk, which also can
be done in qualititative terms only.
4. other (formulate your own conclusion).
200
-------
V-1
V. RISK CHARACTERIZATION
PURPOSE
In the last step of risk assessment, the information collected and
analyzed in the first three steps is> integrated to characterize the risks
to humans. In line with the alternative approaches for describing dose-
response relations, at least three approaches can be taken to this step.
1. Provide an explicit numerical estimate of risk for each population
group by multiplying the unit risk times the number of units of
exposure experienced by each group:
(unit cancer risk) x (units of exposure) * risk
In this equation, risk is unitless — it is a probability.
Equation:
Unit risk x Ingestion volume x Body weight x Conversion of mg to ug x Unit(s) of exposure
2* Provide an estimate of the MOS for each group by dividing the NOEL
by the exposure experienced by that group.
3. Describe risks qualitatively for each of the population groups.
Risk characterization also might include some combination of all
three approaches, along with a description of their relative merits.
It also is essential that the statistical and biological uncertainties
in estimating the extent of health effects be described in this step.
Attached you will find Appendix 1: Unit Risk Assessment for Vinyl
Chloride. This document describes the use of Feron, et al. data for the
estimation of a unit risk for oral exposure to vinyl chloride.
In Table VII, the risks for each population group using data from
Table V are reported. These risks are based
-------
V-2
TABLE VII
Risks
in Each Population Group for Risk Characterization
Upper Bound
Size of
on Number of
Source
Risk
Population Group
Cancer Cases over
Lifetime
Drinking
Water alone at:
0 ug/L
0
220 million +
0
1 ug/L
7 x 10~5
1.9 million +
133
5 ug/L
3 x 10~4
591,000
177
10 ug/L
7x10~4
118,000
83
50 ug/L
3 x 10"3
118,000
354
70 ug/L
5 x 10"3
0
0
ISSUES TO BE CONSIDERED BY THE SENIOR POLICYMAKER
1. Are the results reported in Table VII an adequate characterization of
VC risks? What else should be added?
2. Should risks derived from all the unit risks reported in the Appendix
and unit risks obtained using alternative models also be reported?
3. The risks and number of cases reported in Table VII depend on the
assumption that the number of people exposed and their level of
exposure will remain constant over a lifetime. Is this a plausible
assumption? Can alternative assumptions be used?
4. Is it important to distinguish routes of exposure? Should unit
risks obtained from the inhalation data be used only for population
groups exposed by inhalation? Should gavage data be used at all?
5. Is it important to know whether a finite risk exists at all exposure
levels, or whether a threshold exists?
6. Is it appropriate to estimate the number of cancer cases expected by
multiplying risk times population size (last column of Table VII)?
What is more important — risk to an individual, or risk to a
population?
7. What are the biological and statistical uncertainties in estimating
the number of expected cancer cases? How should they be estimated
and described?
202
-------
V-3
ALTERNATIVE CONCLUSIONS
1. Upper bound risks to humans exposed to VC are those reported
in Table VII. Although risks obtained from the use of other
models may be lower, the risks could be as high as those
reported in Table VII.
2. The risks shown in Table VII, as well as those obtained from
use of all other plausible models and all of the various tumor
site data, should be reported, and all estimates should be
given equal weight. Such a presentation affords the decision
maker a view of the uncertainty in the estimated risks.
3. Upper bound estimates of lifetime risks to humans are those
reported in Table VII. Use of all other animal data sets and
alternative, plausible risk models would result in prediction
of lower risks, perhaps up to 100 times lower. ttiese risks
are conditional on the assumption the VC is a probable human
carcinogen, based solely on observations of carcinogenicity
in several species of experimental animals, uncertainties in
exposure and population estimates are those described in the
Exposure Assessment section.
4. VC is a probable human carcinogen, based on observations of
carcinogenicity in more than one animal species. Exposures
needed to produce animal carcinogenicity are many thousands
of times higher than those to which humans are exposed. The
margins of safety by which humans are protected are shown in
Table VII. Because a NOEL has not been identified for all
the various carcinogenic endpoints, a greater than usual MOS
should be employed to protect human beings.
5. VC is a probable human carcinogen, based on observations
of carcinogenicity in more than one species of animals.
Humans may be exposed through air, water and during employment.
In general, small numbers of people may be exposed continuously
to very low levels of VC, and a few groups are exposed inter-
mittently. Die individual risk in the general population
is probably low to moderate, but this translates to a relatively
large number of cancer cases because of the large population
size, etc.
6. Other? Some combination of the others?
203
-------
APPENDIX 1
UNIT RISK ASSESSMENT FOP VINYL CHLORIDE
The data used Co estimate a unit risk for oral exposure to vinyl chloride
are based on the Feron et al. (1981) study. The statistically significant
increases reported for liver and lung tumors were considered biologically
significant. For the liver tumors, neoplastic nodules vere considered a
progression toward hepatocellular carcinomas, and these are included in the
analysis in Tables 1 and 2. Extrapolations using the linearized multistage
-2
model show values of q1| for the individual tumors ranging from 8.8 x 10 to
1.3 x 10** for the males and from 5.8x10 to 1.3 for the females. The
value of q* based on males was 3.0 x 10 * for liver tumors and 2.9 x 10 *
based on all tumors combined.' For the females the value of q^ based on liver
tumors was 1.9 and for all tumors combined was 2.3. All units of of are per
mg/kg/day.
Before proceeding with the unit risk estimates an explanation of the
total tumor counts in Table* 1 and 2 Is necessary. For the liver all animals
with hepatocellular carcinomas vere assumed to also have the neoplastic
nodules. Thus, only the neoplastic nodules and liver angiosarcomas were added
to derive the total liver tumors. Otherwise, the total* vould have exceeded
the number of animals examined. Also, in adding the lung and liver tumor*,
the total* vere not allowed to exceed one le** than the number examined. The
204
-------
Table 1 Type end Incidence of Statistically Significant Treatment-Releated
Changes In the Liver and Lung of Male Vl6tar Rats Exposed to VCM In
the Diet. Values of q* and Concentration fro* Multistage
Extrapolation Model Included
Treatment group 9SZ laver-llalt concentration
(¦g/kg/day) q*a associated with risk (ug/L)
1.7 5.0 14.1 Cmg/kg/day)"1 10~4 10~5 10"6
Ruaber of rats exaalned0 55 58 56 59
Liver
Neoplastic nodules
0
1
7
23
2.1
X
10"'
16.7
1.7
0.2
Hepatocellular carcinoses
0
1
2
8
8.8
X
ID"2
39.8
4.0
0.4
Anglosarcoaas
0
0
6
27
1.3
X
10"1
27.0
2.7
0.3
Total liver tuaors^
* . ,n „
0
2
13
50
3.0
X
io-'
11.7
1.2
0.1
Anglosarcoaas
0
0
4
19
1.1
X
10"'
31.8
3.2
0.3
Total anlaal with tuaors'
0
2
17
58
2.9
X
10"'
12.1
1.2
0.1
flluaan equivalent q* « q* (a) (W,/W ) In (ag/kg/day)
cConcentratlon in ug/L - (-35,00u/q^) In(l-R).
jFound dead or killed In extremis or terminally.
Sua of neoplastic nodules and liver anglosarcoaas.
Total aust be at least less than total exaalned.
-------
Table 2 Type and Incidence of Statistically Significant Treatment-Related Changes
in the Liver and Lung of Female Wlstar Rats Exposed to VCM In the Diet. Values
of q| and Concentration from Multistage Extrapolation Model Included
Treatment group
(mg/kg/day)
1.7 5.0 14.1
<
(mg/kg/day)
95X lower-limit concentrating
associated with risk (ug/L)
-I ,„-4 .--5 ,_-6
10
10
10
Number of rats examined
Liver
Neoplastic nodules
Hepatocellular carcinomas
Angiosarcomas
Total liver tumors'*
Lung
Angiosarcomas
Total animal with tumors6
57
58
59
57
2
26
39
44
1.3
2.7
0.3
0.03
0
4
19
29
5.0 x 10"1
70.0
0.7
0.07
0
0
2
9
8.8 x 10~2
39.8
4.0
0.4
2
26
41
53
1.9
1.8
0.2
0.02
0
0
1
5
5.8 x I0~2
60.3
6.0
0.6
2
26
42
56
2.3
1.5
0.2
0.02
ffluman equivalent q* • q* (a) (W./W V'3 in (mg/kg/day)-1.
^^Concentration in ug/L • (-35,000/q^)ln(l-R).
dFound dead or killed in extremis or terminally.
Sum of neoplastic nodules and liver angiosarcomas.
Total must be at least less than total examined.
-------
result of this latter restriction was to raise the value of q* slightly due to
increased variance. In fitting the response data in Tables 1 and 2 with the
human equivalent dosages, the human equivalent dosages vere derived by
1/3
dividing the corresponding animal dosages by • The human weight
(W^) was assumed to be 70 kg; the male rats vere estimated to weight 350 g and
the female rats were estimated to weigh 200 g (Figure 1). Thus, the corres-
ponding human equivalent dosages were 0, 0.29, 0.85, and 2.41 mg/kg/day based
on the male rats, and 0, 0.24, 0.71 and 2 mg/kg/day based on the female rats.
When the response and human equivalent dose data vere fit to the
linearized multistage model, the 95Z upper limit on the largest linear term
(Table 2) was:
q* » 2.3 (mg/kg/day)"1
To derive an estimate of the 95X lover level of concentration, d,
corresponding to a 952 upper level of risk, R, the following equation Is used:
R .
vhere d Is the lover limit on dose In mg/kg/day. To solve for d In ug/L, va
use the transformation
1 mg/kg/day x (70 kg/2 I) x 1,000 ug/mg - 35,000 ug/L
207
-------
c
i
too
>00
400
>00
»oe
Mqt*l
f » melt 1
20 «o to to 1 os ne 1*0 1*0
Duration of experiment, wk
The weight curves of the rats receiving 0, 1.7, 5.0 or 14.1 ng
VCM/kg body weight/day from the 10% PVC diets fed for four hours
each da'v all lie vithin the shaded area.
Adapted from Feron et al. 1961.
figure 1 Average Body Weights of the Extra Controls Fed the
10%-PVC Diet Ad Libitum (-) and of the Rats Given
300 tug VCi37kg Body Weight in Oil by Gavage
208
-------
If we set R ¦ 10 ' then
d - (-35,000/q*) In <1-10"5) (ug/L).
—1 —5
For the highest value of qj » 2.3 (nig/kg/day) (Table 2), setting R » 10
yields a value of d * 0.15 ug/L. Setting R - 10**^ or 10~® yields values of d
¦ 1.5 ug/L and d - 0.015 ug/L, respectively.
For comparison purposes only we compare the potency of vinyl chloride by
the diet versus the inhalation routes. A previous memo we sent you estimated
the 95% upper limit of potency for VCM as • 1.7 x 10 (mg/kg/day) based
on an Inhalation study showing angiosarcomas and other tumors in rats. That
potency estimate was derived for water quality criterion purposes. In that
document an inhalation to ingestion by gavage relationship of 1 ppm inhaled *
2.28 mg/kg/day Ingested was derived for 200 g rats based on VCM uptake study.
Without that adjustment for route differences, a direct transformation based
on a 70 kg human breathing 20 m /day would have yielded a 1 ppm inhaled •
-»2
0.76 mg/kg/day relationship and a q| ¦ 5.2 x 10 mg/kg/day, still 44 times
less than the estimate from the diet study.
In summary, the VCM potency estimates are reported in Table 3.
209
-------
Table 3 VCM Potency Estimate*
952 lower Unit concentration
Route Potency associated vlth risk (ug/L)
qfCag/kg/day)"1 10"4 10"5 10"6
Oral
Based on
diet study 2.3 1.5 0.15 0.015
Based on
inhala
Inhalation
Inhalation study 1.7 x 10~^ 200 20.0 2.0
Based on «
Inhalation study 5.2 x 10~ 67.3 6.7 0.7
210
-------
PART III
REGULATIONS AND ASSESSMENT OF RADIONUCLIDES IN DRINKING WATER
211
-------
Phase III
Radionuclides
-------
Alpha Decay
to
" Beta Decay
228 Ra
Electron
-------
CONSIDER 238y AND 228Ra
BOTH ARE RADIOACTIVE AND GO TO THE BONE
BUT -THEY ARE DIFFERENT
HALF LIVES 4.5 x 109 yr vs 6.7 yr
PARTICLE EMITTED Alpha vs Beta
NEED UNITS TO DESCRIBE
NUMBER OF PARTICLES/SEC -ACTIVITY
1 CURIE = NUMBER OF PARTICLES/SEC FROM
ONE GRAM OF RADIUM
TVPE AND ENERGY OF PARTICLE -DOSE
1 RAP IS 100 ERGS/GRAM OF ENERGY DEPOSITED
(REM IS DOSE EQUIVALENT SINCE Alpha IS MORE
EFFECTIVE THAN Beta}
-------
K)
u
Ul
r.
/
s
-------
GREEK PREFIX
mega M
kilo k
mHH m
micro t*
nano n
Pico p
fomto f
VALUE
1.000,000
14)00
1
1000
1
1,000,000
1
1.000.000.000
1/1,000,000,000,000
1 /1.000.000.000.000.000
EMOINEERINQ
SHORTHAND
vf
10"
10"* ONE PART PER THOUSAND
10"* ONE PART PER MILUON(ppm)
10T* ONE PART PER BIUJON(ppb)
10""
10"*
-------
THE URANIUM SERIES
»*Th
•0
Pb
m
-------
THE THORIUM SERIES
212p0
84
3.0x10"*sec
228Th
90
1.9yr
a
'
\
'
224Ra
88
3.6da
or
220Rn
86
SSsec
a
1
'
1.4x1010yr
B.lhr
0.15 sec
60min
Stable
3.1min
-------
AVERAGE ANNUAL EFFECTIVE DOSE EQUIVALENT
TO HUMANS FROM NATURAL BACKGROUND
Organ
Gonads
Breast
Lung
Mean Dose
T rachial / Bronchial
Pulmonary
Total
Red Bone Marrow
Bone Surfaces
Thyroid
Other
Weighting
factor
0.25
0.15
0.12
0.06
0.06
0.12
0.03
0.03
0.30
Annual dose
equivalent
(mSv/y)
0.97
0.95
0.96
14.0
1.8
1.1
1.9
0.88
0.97
Annual effective
dose equivalent
(mSv/y)
0.24
0.14
1.0
0.13
0.057
0.026
0.29
Total = 1.9 mSv/y
(or approximately
200 mrem/y)
-------
RADIONUCLIDES: DEFINITIONS
Types of nuclear radiation: alpha, beta and gamma
Activity - rate at which nuclear radiations are emitted
- Curie (Ci) - one gram of radium-226; equal to 3.7 x 1
-------
INTERIM REGULATIONS FOR
RADIONUCLIDES IN DRINKING WATER
• Gross Alpha Particle Activity - 15 pCi/l (excludes
uranium and radon)
• Combined 226Ra and 228Ra - 5 pCi/l
• Gross Beta Particle Activity - 50 pCi/l (for surface
water supplies that have population exceeding 100,000)
• Man-Made Radionuclides - 4 mrem/yr (approximately
200 radionuclides)
-------
MEASURE
GROSS ALPHA
IS ALPHA
5pCi/l
MEASURE
Ra-226
i
i
YES
MEASURE
Ra-228
T
IS Ra-226
PLUS Ra-228
> 5pCi/l
YES
IS Ra-226
NO
> 3pCi/l
NO
NO
COMPLIANCE
NON-COMPLIANCE
IS ALPHA
> 15pCi/l
I
YES
MEASURE
RADON &
URANIUM
Is ALPHA
MINUS
RADON &
URANIUM
ALPHA
> 15p Cl/I
YES
222
-------
STRENGTH OF EVIDENCE OF
CARCINOGENICITY: RADIONUCLIDES
K>
Ui
Radionuclide EPA Guidelines Category
radium-226 A
radium-228 A
natural uranium A*
radon A
gross alpha A
gross beta and
photon emitters A
*by inference
-------
PROPOSED MCLGs FOR RADIONUCLIDES
ro
Radionuclide MCLG
Radium-226 zero
Radium-228 zero
Radon zero
Uranium-natural zero
Gross Alpha Emitters zero
Gross-Beta and Photon Emitters zero
-------
RADIUM OCCURRENCE
compliance data
approximately 500 exceed 5 pCi/L
to
226Ra & 228Ra similar
MDL 1 pCi/L
max 100 pCi/L
-------
DISTRIBUTION OF COMBINED
RADIUM IN DRINKING WATER
•'i.-S.'..-. 5 S: :SS ::: . ..::V .... «»;¦ -a®?®. . :v:.:::5K . : .k;;*®:
NUMBER OF CASES
COMBINED
RADIUM
CONCENTRATION
-------
DISTRIBUTION OF GROSS ALPHA
PARTICLE ACTIVITY IN DRINKING WATER
GROSS ALPHA
PARTICLE
ACTIVITY
pCUl
{LESS URANIUM
AND RADON
ACTIVITY)
15
20
25
30
35
Number of Cases
5 10
I
SSbsSSSx •; ris-SSSSSSiSs-
TO:
15
• ¦ ••:
40
-------
URANIUM OCCURRENCE
USGS/NURE
89,000 ground and surface
approximately 20,000 domestic
MDL 1 pCi/L
max 600 pCi/L
average 2 pCi/L
234u/ 238u
-------
DISTRIBUTION OF URANIUM
OCCURRENCE IN DRINKING WATER
NUMBER OF SAMPLES
0 1000 2000 3000 4000 5000
fO
V0
URANIUM
CONCENTRATION
pCi/f
-------
RADON OCCURRENCE
- EERF survey
- workshop report
-private wells - factor of 3 to 4 higher
- ground water
- MDL 10 pCi/L
-max 2,000,000 pCi/L
-------
DISTRIBUTION OF RADON
IN DRINKING WATER
to
Ui
222
Rn
CONCENTRATION
0>a/n * 103
50.00
100.00
FREQUENCY (%)
10 20
30
40
50
10.00
15,00
20.00
;»
";-:y
-------
AREAS OF NATURAL RADIOACTIVITY IN DRINKING WATER
KEY
= Radium
= Uranium
I I -Radon
Source Author 1984
-------
DISTRIBUTION OF AREAS OF RELATIVE RISK
OF HAVING ELEVATED Ra-228 IN COMMUNITY
GROUND WATER SUPPLIES
JS
HIGH
~ MEDIUM
~ LOW
-------
POPULATION WEIGHTED AVERAGE
{concentration) X /"umber of people exposed\
\ / \ to that concentration /
(O
U)
A
total number of people
-------
OCCURRENCE OF NATURAL RADIONUCLIDES
IN DRINKING WATER SUPPLIES
Average population-weighted concentrations
(average of surface and ground water supplies)
Radionuclide
(pCi/l)
Radium-226
0.3-0.8
Radium-228
0.4-1.0
Uranium-natural
0.3-2.0
Radon-222
50-300
Lead-210
<0.11
Polonium-210
<0.13
Thorium-230
<0.04
Thorium-23 2
<0.01
-------
AVERAGE RELATIVE SOURCE CONTRIBUTION
TO THE DAILY INTAKE OF NATURAL RADIONUCLIDES
i,.¦ ^^rriffl'fwiwiiwmTfifr^^
Radionuclide Source pCi / d
226r3 air... 0.007
food . 1.1-1.7
drinking water. 0.6-2
228Ra air..... 0.007
food 1.1
drinking water. 0.8-2
234y+ 238y air 0.0007
food 0.37-0.9
drinking water. 0.6-4
210pb air 0.3
food 1.2-3.0
drinking water <0.22
-------
to
w
AVERAGE RELATIVE SOURCE CONTRIBUTION TO THE
DAILY INTAKE OF NATURAL RADIONUCLIDES (Continued)
|i |'Tlf IP f II'f III f" I" I f f I'rfflMilWIII
Radionuclide Source pCi / d
210po air 0.06
food 1.2-3.0
drinking water <0.26
230jh air 0.0007
food probably negligible
drinking water <0.08
232 jj! air 0.0007
food negligible
drinking water <0.02
222Rn outdoors (1.8 Bq/m3) 970
indoors (15 Bq/m3Kg) ....8,100
drinking water 100-600
-------
GENERAL RADON INFORMATION
n r r" w *ffWitf *f*' r tf*f ff—w y r IT '^r ii wtiwwwfirffwwiir*fWiT>>riwiwT»wrrtiiiWMHMWWMiiwwwBwi fw nrr * rp f r nr rr rrarr r*" rp r p**af*tiwraafi*fi*T,^ffiiPfffr*T***p*T*if ti ***ffTfiMWPtrTiitri t*t nnr i r m m w wm
indoor 1pCi/L(air)
outdoor 0.1 pCi/L(air)
[or about 1,000 pCi/L (water)]
national average in water
200 to 600 pCi/L
10~4 risk level - few hundred pCi/L
-------
RADIUM HEALTH EFFECTS
bone
watch dial painters
bone sarcoma/head carcinoma
leukemia/red bone marrow
-------
URANIUM HEALTH EFFECTS
bone
kidney
uptake 1 to 20%
use radium as surrogate
-------
URANIUM
(NOAEL)(animal f 1 )(adult weight)
DWEL* =
(safety factor)(water consumption/day)(human
N>
A
(1 mg / kg / day)(0.01 )(70kg)
DWEL
(100)(2L/day)(0.05)
DWEL = 60 micrograms/L or 40 pCi/L
* Drinking Water Equivalent Level
-------
RADON HEALTH EFFECTS
lung cancer
hard rock miners
Colorado, Czechoslovakia, Sweden,
Newfoundland
support from animal studies
-------
LEGEND
O COLORADO PLATEAU URANIUM MINERS ~ SWEDISH METAL MINERS
A CZECHOSLOVAKS URANIUM MINERS O NEWFOUNDLAND FLUOSPAR MINERS
SOLID MARKS ARE DATA - OPEN ONES IDENTIFY CURVES
MULTISTAGE
>
-I
X
10z.~
PROBIT
WEIBULL
I
UNSCEAR 1977
X BEIR III
m
¦0
3 nr®
•9
o
z
to
&
u»
>
30
a»
x
IT5 -
CUMULATIVE WLM
-------
cause
active smoking
passive smoking
radon
- soil
- drinking water
lyaftfftftwinnii nnwnrinnMiMiniwrirfrr'irrr ruur fliwru-' jt n r>,\
annual number
of fatal lung cancers
100,000
5,000
5,000 to 20,000
100 to 1,500
-------
RADIONUCLIDES RISK
CALCULATIONS: EXAMPLES
Population Risk = occurrence in drinking water X cancer risk rate
X U.S. population
Radium
(0.3 - 0.8) pCi/l X (2.2 - 35) X 10'6 excess cases/lifetime/person/pCi/1
X 216 X 106 people
= 200 - 4000 excess cases/lifetime in the U.S.
Radon
(50 - 300) pCi/IX(0.2 - 60) X 10~7 excess cases /lifetime/ person / pCi /1
X 216 X 10° people
= 2000 - 40,000 excess cases/lifetime in the U.S.
-------
POPULATION RISK FOR RADIONUCLIDES
IN DRINKING WATER
Radionuclide
Radium-226
Radium-228
Uranium-natural
Radon-222
Strontium-90
Lead-210
Polonium-210
Thorium-230
Thorium-232
Estimates of Lifetime Population Risk
(number of fatal cancers due to current
exposures in drinking water)
200-4,000
200-4,000
40-1,000
2,000-40,000
60-130
<100
<300
< 20
< 4
-------
absolute risk
months to years
WL to pCi / La
water to air
transport
non- equilibrium
years / lifetime
occurrance
population
TOTAL
RADON
(3.8-15.2)x10*4 /WLM
12-24 months/years
1 WL/100 pCi/La
(0.17-3.5)x10"4 La/Lw
0.3-0.7
70 years/lifetime
200-600 pCi/Lw
216x10 6 people
4,000-150,000 per lifetime
or 50-2,000 per year
-------
SOME POPULATION RISK RATE BENCH MARKS
to
oo
CAUSE
FATALITIES/YEAR
(ORDER OF MAGNITUDE)
LUNG CANCER
100,000
RADON IN HOMES
10,000
RADON IN DRINKING WATER
1,000
COKE OVENS
100
BENZENE IN AIR
100
VINYLCHLORIDE IN AIR
BEFORE REGULATION
10
AFTER REGULATION
1
CADMIUM IN AIR
10
ARSENIC IN AIR
10
VOLATILE ORGANIC CHEMICALS
IN DRINKING WATER (TOTAL)
10
-------
SUMMARY OF RISK LEVELS FOR
RADIOACTIVITY IN DRINKING WATER
Annual
Estimated effective dose
lifetime
risk level
equivalent
(mrem/year)
226Ra
pCi /1
228Ra
pCi/l
Unat
pCi/l
222r0
pCi/l
10"3
100
100
200
700
10,000
10"4
10
10
20
70
1,000
10-5
1
1
2
7
100
10-6
0.1
0.1
0.2
0.7
10
-------
mmMMfiftBBg
OCCURRENCE OF RADIUM-226
IN DRINKING WATER
to
at
o
Lifetime
Risk Level
10
-3
10"
10
-5
Radium-226
Concentration
(pCi/l)
100
10
1
Annual
Effective
Dose
Equivalent
(mrem / yr)
100
10
Number of Public
Drinking Water
Supplies That Exceed
the Concentration
in Column 2
1-10
30-300
300-3,000
10
-6
0.1
0.1
Below detection
-------
OCCURRENCE OF RADIUM-228
IN DRINKING WATER
w—Diii frwmi wi Ksim»msiamm»mMmmmeummmmMmM»&ss£stMMmi»iaiMiuaciWMas»ueaaiaimsaait*it6ittmssiesHaiMmiiem)sss£tt&STti#riim->r*Kmstmsmss3SGn&xii*G
M
Ul
Lifetime
Risk Level
10'3
Radium-228
Concentration
(pCi/l)
100
Annual
Effective
Dose
Equivalent
(mrem I yr)
200
Number of Public
Drinking Water
Supplies That Exceed
the Concentration
in Column 2
1-10
10"
10
-5
10
-6
10
1
0.1
20
0.2
30-100
300-3,000
Below detection
-------
OCCURRENCE OF URANIUM
IN DRINKING WATER
tjetmrmmmMmrismjrsji
K)
Ul
to
Lifetime
Risk Level
10
-3
10
-4
10
-5
Uranium
Concentration
(pCi/l)
700
70
7
Annual
Effective
Dose
Equivalent
(mrem/yr)
100
10
1
Number of Public
Drinking Water
Supplies That Exceed
the Concentration
in Column 2
1-10
20-500
100-2,000
-------
OCCURRENCE OF RADON
IN DRINKING WATER
Number That Exceed the
Concentration in Column 2
Lifetime
Risk Level
Radon
Concentration
(pCi/l)
Public Drinking
Water Supplies
Population
(thousands)
10'3
10,000
500-4,000
20-300
10'4
1,000
1,000-10,000
200-4,000
10-5
100
5,000-30,000
10,000-100,000
10'6
10
10,000-40,000
50,000-100,000
-------
ANALYTICAL METHODS FOR RADIONUCLIDES
to
Radium
Alpha-Emitting
Radium Isotopes
(Method 903.0)
Radium-226-Radon
Emanation Technique
(Method 903.1)
New York State
Department of
Health
(Ra-226 and -228)
Total Radium
(Method 304)
Coincidence
Spectrometry
Gamma Ray
Spectrometry
(Ra-226 and -288)
Solid State Nuclear
Track Detector
Radiochemical
Determination of
Ra-226 in Water
Samples
(Method Ra-03)
Radiochemical
Determination of
Ra-228 in Water
Samples
(Method Ra-05)
Ra-228 by Liquid
Scintillation
Counting
(Method 904.1)
Radium-228
(Method 904.0)
Radium-226
(Method 305)
-------
ANALYTICAL METHODS FOR RADIONUCLIDES
(Continued)
K)
Ul
in
Gross Alpha Particle Activity
Gross Alpha and
Gross Beta
Radioactivity
(Method 900.0)
Gross Radium
Alpha Screening
Procedure
(Method 900.1)
Gross Alpha
Activity in
Drinking Water
by Coprecipitation
(Method 00-02)
Gross Alpha and Beta
(Method 703)
Gross Alpha Particle
Activity
(Method D-1943)
Gross Beta Particle Activity
Gross Alpha and
Beta Radioactivity
(Method 900.0)
Gross Beta Particle
Activity
(Method D-1890)
-------
ro
ui
as
ANALYTICAL METHODS FOR RADIONUCLIDES
(Continued)
Uranium
Radiochemical
(Method 908.0)
Fluorometric
(Method 908.1)
Laser Induced
Fluorometry
(Method 908.2)
ASTM Method
D-2907
Man-made Radionuclides
Radioactive
Cesium
(Method 901.0)
Gamma Emitting
Radionuclides
(Method 901.1)
Radioactive
Iodine
(Method 902.0)
Radioactive
Strontium
(Method 905.0)
Tritium
(Method 906.0)
Strontium 89, 90
(Method 303)
Tritium
(Method 306)
Gamma Ray Spectroscopy
(Method D-2459)
Radon
Liquid Scintillation
(including modification
using mineral oil so
sample can be mailed)
Solid State Nuclear
Track Detector
Lucas Cell
-------
COSTS OF ANALYTICAL METHODS
radium-226 $100
radium-228 $100
uranium $ 25
radon $ 25
gross alpha $ 25
gross beta $ 25
-------
RADIONUCLIDE
TREATMENT METHODS
(g
Qi
00
Radium
lime softening
reverse osmosis
iron and manganese
ion exchange
Uranium
anion exchange
lime softening (high pH)
reverse osmosis
Radon
aeration
granular activated
carbon
Man-Made
ion exchange
-------
COSTS IN CENTS/1000 GALLONS FOR CONTROLLING
RADIUM IN DRINKING WATER (MID 1982 DOLLARS)
Population Served
Removal
100-
10,000-
Treatment Methods
Eff. %
500
100,000
Coagulation / Filtration*
>75
28
7
Lime Softening*
>85
-
10
Ion Exchange (anion)
>95
210
160
Ion Exchange (cation)
>90
80
33
Iron and Manganese
<40
110
30
Lime Softening - new
<90
-
50
Reverse Osmosis
>90
320
160
'Modified in existing facility.
-------
COSTS FOR REMOVING RADON FROM DRINKING
WATER BY PACKED TOWER AERATION (99% REMOVAL)
K>
01
O
Population Served
100- 3,300- 75,000-
500 10,000 100,000
Total Capital
Cost ($1,000) 67 250 2,200
O&M Cost
($1,000 per year) 1.2 15 230
Cost
0/1,000 gallons 75
14
9
-------
POINT OF USE: RADON TREATMENT
COSTS GAC (200gpd)
Influent
Effluent
Capital
Operating
Radon
Radon
Costs
Costs
pCi/l
pCi/l
$
$/year
15,000
1,350-3,300
$430-760
$20
30,000
2,700-6,600
$430-760
$20
150,000
1,200
$1,500
$40
-------
POINT OF USE: RADON TREATMENT
COSTS AERATION (200gpd)
K>
o>
N)
Influent Effluent Capital Operating
Radon Radon Costs Costs
pCi/l pCi/l $ $/year
15,000 750 $ 900 $60
30,000 1,500 $ 900 $80
150,000 <7,500 $1,000 $80
-------
MAN MADE RADIONUCLIDES
MMMtirtTiTn>rrr»iinTiirrnrrn'rnnrrrrrinfiiirrrninn«nnw«M^mwi^^
approximately 2,000
limit to 200 due to
- half life
- solubility
- pharmacokinetics
- health effects
fission fragments
transuranics
-------
PART IV
RISK MANAGEMENT
A. Overview of Risk Management and Control Strategies
B. Inorganics Treatment: Overview and Case Studies
C. Organics Treatment: Overview and Case Studies
D. Case Study on Risk Management of Aldicarb, Trichloroethylene,
and Vinyl Chloride in Drinking Water
E. Aldicarb Health Advisory
F. Trichloroethylene Health Advisory
G. Vinyl Chloride Health Advisory
264
-------
A. OVERVIEW OF RISK MANAGEMENT AND CONTROL STRATEGIES
Scope: Provide an overview of risk management and the alternatives
available for controlling contaminants in drinking water.
While the scope of this talk does not include EPA's
existing and proposed regulations, questions concerning
the technology portions of these regulations are invited.
A. RISK MANAGEMENT
1. Definition — The process of deciding what to do about
a problem.
2. Involves a broader array of disciplines than risk
assessment (which is finding out what the problems are).
3. Assumes knowledge of health risks.
4. Factors in feasibility, cost, and reexamines exposure
issues previously dealt with in risk assessment.
5. Done on a national level through drinking water standards
(maximum contaminant levels), but can be carried out on
a local level for cleanup of unregulated contaminants.
B. TWO IMPORTANT CONCEPTS
1. Chemicals degrade in the environment — sometimes the
intermediate products are more toxic (e.g., tetrachloro-
ethylene to vinyl chloride).
2. For some chemicals (esp., carcinogens) measurement
becomes a constraint on treatment goals (maximum contami
nant levels).
Two concepts:
a. minimum detection limit (MDL): 99% assurance the
value is not zero.
b. practical quantification limit (PQL): generally,
5 to 10 times the MDL — this is a concentration at
which a sufficient number of laboratories can report
results within a reasonable range of the true value
(say, ±20 to 40%).
265
-------
C. OVERALL APPROACH
1. Development of a reliable data base.
a. Routine monitoring.
b. Utilize other existing nearby wells for more
comprehensive monitoring, e.g., private/industrial/
abandoned.
c. Supplemental monitoring wells. (Figure 1)
d. Existing hydrogeologic data.
2. Use data base to understand situation.
a. Model ground water in attempt to determine location
of source.
b. Project future conditions, e.g., impact of continued
pumping, impact of stopping pumping.
3. Recognize that the most cost effective treatment
solutions are site-specific.
a. Dual utilization of existing facilities (e.g., air
stripping in existing reservoirs).
b. Impact on system hydraulics.
c. Energy considerations.
4. General considerations. (Figure 2)
a. Type of contaminant!
- inorganic
- organic
- other water quality data
b. Contaminant levels:
- historical levels
- mix of contaminants
- design influent levels
- design effluent levels
c. Characteristics of water supply:
- surface or ground water
- number of wells
- location of wells
- system configuration (reservoir, booster pumps)
d. Safety:
- plant operators
- community
- consumers
e. Costs:
- capital
- operating
266
-------
FIGURE 1: MONITORING WELLS
RECHARGE AREA
NESTED
SYSTEM
WATER
TABLE
CONTINUOUS SLOTTED
DISCHARGE AREA
Stream or Lake
to
AQUIFER
BACKGROUND
WELL
WATER
TABLE
' " * 'V?;-**/
^ *»u,— « < .. V * * •' * ?
1/- * A-"r."t V-'
/* W-v t > /
• • * • r •> /
' * '-V- !/
CONTAMINANT
PLUME
FLOW LINES
-------
ug/l
TETRACHLOROETHYLENE
248
1,2-DICHLO R OETH Y LENE
10
TRICHLOROETHYLENE
S
CHLOROFORM
2
1,1,1-TRICHLOROETHANE
2
jig/l
TRICHLOROETHYLENE
71
TETRACHLOROETHYLENE
25
1,2-DICHLOROETHYLENE
8
CHLOROFORM
9
1,1,1-TRICHLOROETHANE
9
TO
DISTRIBUTION
WELL
TO DISTRIBUTION
TK£9*-
AOUVFEft
WELL
Jifl/I
1,2-DICHLOROETHYLENE
24
CHLOROFORM
16
TETRACHLOROETHYLENE
8
TRICHLOROETHYLENE
3
1,1,1-TRICHLORQETHANE
1
TO DISTRIBUTION
WELL
FIGURE 2: EXAMPLE OF
A CONTAMINATED GROUND WATER SUPPLY
SMALLTOWN, U. S, A.
-------
f. Reliability:
- simplicity
- back-up
- standard equipment
- training
D. BASIC CATEGORIES OF CONTROL STRATEGIES
1. Source Control Strategies — controlling raw water
source to reduce concentration or eliminate compound.
a. Eliminate contaminant source.
b. Locate new source of supply or reduce demand.
c. Blend existing new sources.
d. Operate interceptor well.
2. Treatment Strategies — involves the use of a treatment
technique to reduce concentrations in the water supply.
a. Inorganics Removal Processes
- conventional treatment
- lime softening
- ion exchange
- reverse osmosis
- activated alumina
- electrodialysis
b. Organics Removal Processes
- conventional treatment
- aeration (diffused air, packed column, slat-tray)
- adsorption (GAC, PAC, resins)
- biodegradation
- reverse osmosis
- oxidation
- boiling
3. Combined Strategies — involves the use of a combination
of a source control strategy and a treatment strategy.
4. Short-term Strategies — bottled water or point-of-use
treatment.
E. ELIMINATE CONTAMINANT SOURCE
1. Involves identification of the contaminant source and,
subsequently, eliminating the source.
2. Example - source is a leaking underground storage tank;
fix or remove tank; pump well to waste until contaminant
concentration drops.
269
-------
3. Disadvantages of this control strategy;
Sources of the compound may not always be easily
determined because chemicals can migrate long
distances from the source to a well.
Size of the affected supply and the degree of
infiltration may be such that many years would be
required to purge the supply even after the source
is identified and eliminated.
LOCATE NEW SOURCE OF SUPPLY OR REDUCE DEMAND
1. Involves abandoning the affected well(s) and locating
an alternative supply source or reducing water demand.
2. New supply source may be:
new well in an unaffected aquifer. (Figure 3)
- tap surface supply source.
- purchase water from a neighboring community.
3. Disadvantages with this control strategy are:
- An unaffected source of supply may not be available
nearby, and the cost of developing a new source
which is far removed from the service area may be
prohibitive.
Developing a new ground water supply may not eliminate
the potential of the compound migrating to the new
supply.
- A neighboring community's supply may not be capable
of providing additional water to replace a large
affected supply.
BLENDING EXISTING AND/OR NEW SOURCES
1. Involves blending water from several wells, to reduce
the concentration of the compound via dilution.
2. Figure 4 illustrates three examples of blending:
- Blend water from one affected well and two unaffected
wells.
- Blend water from three affected wells and treat at
one location.
Blend water from two unaffected wells with treated
water from an affected well.
270
-------
GROUND-WATER DIVIDE
DISPOSAL AREA
/
BEDROCK FLOOR
FIGURE 3: DRILL NEW WELL
-------
FIGURE 4: BLENDING EXISTING
SOURCES
WELL
FIELD
well no. 3
272
-------
3. Disadvantages of this control strategy are:
The ground water system may not be flexible enough
to permit sufficient blending.
The contaminant concentrations may be too high to
achieve an acceptable level via dilution.
Consumers may not accept this alternative because it
does not involve removal of the compound from the water.
H. OPERATE INTERCEPTOR WELL
1. Involves pumping a well(s) to waste which is "upstream"
from other wells in the system, removing the chemical
from the aquifer before the water reaches the "good"
wells. (Figure 5)
2. Currently being used in several locations. Without
interceptor wells operating, compound levels are between
50 and 100 ug/L. With interceptor wells operating,
levels drop to less than 50 ug/L.
3. Disposal of "wastewater" from interceptor well may be a
problem.
I* SHORT TERM STRATEGIES TO REDUCE EXCESSIVE RISKS
1. Bottled Water.
Home delivery.
Central pickup.
Quality — should meet all MCLs.
- Cost — home delivery approximately $50 per month.
2. Point-of-Use Devices.
Definition — treats water at a single tap.
- Many types available — activated alumina, granular
activated carbon, reverse osmosis, etc.
Not recommended for waters with microbiological
contamination (esp., excessive turbidity).
Suitable for reducing risks of exposure for short-
term emergencies.
- Costs: $20-$60 per month per household.
273
-------
GROUND-WATER DIVDE
DISPOSAL AREA
(UVEA
\
\?
V\
BEDROCK FLOOR
FIGURE 5: INTERCEPTOR WELL
-------
FIGURE 6: POINT-OF-USE-DEVICES
Y~J
V
>=r
St
T
LEGEND
1. ION EXCHANGE
2. DRINKING WATER FAUCET
(1)
ION EXCHANGE TREATMENT UNIT
wa *^r
7
LEGEND
1. BOOSTER PUMP
2. REVERSE OSMOSIS MODULE
3. WATER STORAGE TANK
4. DRINKING WATER FAUCET
REVERSE OSMOSIS TREATMENT UNIT
275
-------
J. CONCLUSIONS
1. Understand the hydrogeology of your supply systems.
2. Evaluate present and probable future contaminant
concentrations.
3. Determine and evaluate alternative control strategies.
- short- (Figure 6) and long-term (Figure 7) strategies,
capital and operating costs. (Figure 8)
time required to implement.
276
-------
WELL
AERATOR
fir
1
CORROSION
INHIBITOR
to
-si
DISTRIBUTION
SYSTEM
2 WELLS
Cl2 NaoH
FIGURE 7: NORWALK, CT. ORGANICS
REMOVAL SYSTEM
-------
^TREATMENT
TECHNIQUE
100.0
0.01
1000.0
MANAGEMENT
TECHNIQUE
SYSTEM SIZE (MGD)
FIGURE 8: comparison of costs
FOR VOC CONTROL ALTERNATIVES
278
-------
REFERENCES
1. Love, O.T., Jr., R.F. Miltner, R.G. Eilers, and C.A. Fronk-
Leist. 1983. "Treatment of Volatile Organic Compounds in
Drinking Water." EPA 600/8-83-019. U.S. EPA Drinking
Water Research Division. Cincinnati, Ohio.
2. Parsons, F., P.R. Wood, and J. DeMarco. 1984. "Transforma-
tions of Tetrachloroethylene and Trichloroethylene Microcosyms
and Groundwater." Journal American Water Works Association.
Vol. 76, No. 2, p. 56.
3. James M. Montgomery, Consulting Engineers, Inc. 1985. Water
Treatment Principles and Design. John Wiley and Sons. New York.
4. Environmental Science and Engineering, Inc. 1985. Draft
Report "Techniques and Costs for the Removal of VOCs from
Potable Water Supplies." EPA Contract #68-01-6947. Office
of Drinking Water. Washington, D.C.
5. Westrick, J.J., J.W. Mellow, and R.F. Thomas. 1984. "The
Ground Water Supply Survey." Journal American Water Works
Association. Vol. 7j>, No. 5, pT 52.
6. Dyksen, J.E., A.F. Hess, and J.K. Schaeffer. 1986. "The
Capabilities of Standard.Water Treatment Processes to Meet
Revised Drinking Water Regulations." Paper presented at
the 1986 Annual Conference of the American Water Works
Association held June 22-26, 1986 in Denver, Colorado.
7. USEPA. 1978. "Manual of Treatment Techniques for Meeting
the Interim Primary Drinking Water Regulations." EPA 600/8-
77-005. Office of Research and Development, Water Supply
Research Division, Cincinnati, Ohio.
8. USEPA. 1985. "Technologies and Costs for the Removal of
Fluoride from Potable Water Supplies." Office of Drinking
Water. Washington, D.C.
9. USEPA. 1985. "Technologies and Costs for the Removal of
Nitrates from Potable Water Suplies." Office of Drinking
Water. Washington, D.C.
10. USEPA. 1985. Revised Draft "Technologies and Costs for
the Removal of Synthetic Organic Chemicals from Potable
Water Supplies." Office of Drinking Water. Washington, D.C.
11. AWWA Research Foundation. "Occurrence and Removal of Volatile
Organic Chemicals from Drinking Water." Cooperative Research
Report with KIWA. AWWA Research Foundation. Denver, Colorado*
12. USEPA. 1984. "Risk Assessment and Management: Framework
for Decision Making." EPA 600/9-85-002. Washington, D.C.
219
-------
B.
INORGANICS TREATMENT
OVERVIEW AND CASE STUDIES
I. CONVENTIONAL TREATMENT
LIME SOFTENING
REVERSE OSMOSIS
II. ION EXCHANGE
III. ACTIVATED ALUMINA
IV. PROCESS SELECTION
280
-------
I. CONVENTIONAL TREATMENT, LIME SOFTENING AND REVERSE OSMOSIS
Provide a review of the use of conventional, lime softening and
reverse osmosis treatment technologies for removing inorganics from
drinking water supplies, including process design considerations and
limitations. Provide case studies of conventional treatment and
reverse osmosis systems for inorganics removal.
Conventional Treatment
1. Process used for the removal of color and turbidity in surface
waters. Inorganic removal occurs through absorption or enmeshment
in the floe. A process schematic is presented as Figure 1-1.
2. Typical processes include:
- Raw water pumpage
- Flash mixing with coagulants such as alum, ferric salts or
cationic/anionic polymers
- Flocculation
- Sedimentation
- Filtration
- Disinfection
- Storage and distribution
3. Process design considerations:
- pH
- Coagulant aids
4. The process is generally effective for the treatment of the follow-
ing inorganic species:
Alum Coagulation: Good to Excellent for
AS(V)...at pH below 7.5
Cd at pH above 8.5
Cr(III)
Pb
Ag at pH below 8
Iron Coagulation: Good to Excellent for
281
-------
FIGURE 1-1
CHEMICALS
DISINFECTANT.
RAPIO MIX
FLOCCUL ATION
FILTRATION
SIOIMCNTATION
FIGURE - SCHEMATIC OF
COAGULATION/FILTRATION PROCESSES
r— CHEMICALS
/
DISINFECTANT
2
RAPID MIX
RECARSONATION
FLOCCULATION SEDIMENTATION FILTRATION
FIGURE - SCHEMATIC OF
LIME SOFTENING PROCESSES
282
-------
As (V)
Cd at pH above 8
Cr(III)
Cr(VI)..with ferrous salts
Pb
Ag
5. Limitations: In general, this process is effective in removing many
of the cationic inorganic chemicals. For nitrate, nitrite, barium
and sulfate the process is virtually ineffective.
B. Case Study: Conventional Treatment — Northeastern Illinois
1. Background Information:
a. System Characteristics:
1) Ground water supply.
2) Small regional areas of barium contamination, as illus-
trated on Figure 1-2.
3) Contaminated water drawn from Cambrian-Ordovician Aquifer.
4) No barium contamination where sulfate >50 mg/L.
b. Water Quality:
1) Barium: 0.4 - 8.5 mg/L
c. Maximum Contaminant Level:
1) Barium: 1.0 mg/L
2. Treatability Tests, Chemical Precipitation - Direct Filtration:
a. Test Description:
1) 500 ml jar tests
2) Gravity filtration with paper filters
3) Initial Barium concentration: 7.4 mg/L
4) Chemicals tested:
Chemical Operational Purpose
Alum Coagulant-precipitant
Sulfuric acid pH adjustment-precipitant
Hydrochloric acid pH adjustment
Sodium hydroxide pH adjustment
Potassium hydroxide pH adjustment
Calcium hydroxide Precipitant-pH adjustment
283
-------
BARIUM CONTAMINATION - NORTHEASTERN ILLINOIS
n
STUDY
WELL
<—-100—s. SULFATE ISOLtNE - mfl/L
40) BARIUM >1 mfl/L
LAKE
MICHIGAN
284
-------
Chemical
Operational Purpose
Calcium sulfate
(gypsum) Precipitant
Ferrous sulfate Coagulant-precipitant
Sodium bisulfate Precipitant
Commercial gypsum Precipitant
Anionic polymer Flocculant-filter aid
Diatomaceous earth Filter precoat
b. Test Results:
1) Optimum Barium removal using calcium sulfate (gypsum)
2) Optimum Dosage: 75 to 175 mg/L of gypsum
3) Optimum pH: = 11.0
Pilot Tests:
a. Pilot Plant Description:
1) Precipitation
2) Direct Filtration
3) Tested:
- 2 gypsum doses
- 3 anionic polymer filter aids
- Various raw water Barium concentrations
4) Pilot plant schematic shown on Figure 1-3.
b. Results:
1) Reliable reduction of barium to acceptable levels
2) Barium reduction from 6 to 0.5 mg/L, or 91%
3) Chemical Dosages:
Gypsum - 100 mg/L
Polymer - 0.25 mg/L
c. Operating Parameters:
1) pH - 11.0
2) Filter loading =1.5 gpm/ft
'Cost Data-Full Scale Estimates:
a. Capacity = 1050 gpm = 1.5 MGD
285
-------
PILOT PLANT SCHEMATIC
.CHEMICAL FEED PUMPS
f (VARIABLE SPEED)
CHEMICAL FEED PUMP
(VARIABLE SPEED),
GRAVITY
^-FILTER
/ SODIUM OR
POTASSIUM
HIGH-SPEED MIXER
HYDROXIDE
POLYMERY
GYPSUM
VARIABLE-SPEED
PADDLE DRIVE
FILTERT
FEED
PUMP
Rotameter
rapid MIX
TANK
WET WELL
FLOCCULATION
REACTOR
BACKWASH
PUMP
DISCHARGE
HEADER
TO GROUND STORAGE
RESERVOIR
FINISHED WATER
(UNSTABILIZED)
¦&-
BACKWASH
WASTE
AIR COMPRESSOR
286
-------
b. Components:
1)
Aerator
2)
Rapid mix tank
3)
Flocculation basin
4)
Gravity filter
5)
Recarbonation system
6)
Transfer pumps
7)
Potassium hydroxide system
8)
Gypsum system
9)
Polymer system
10)
Appurtenances
c. Costs (1980 dollars):
1) Construction costs:
2) Total capital costs:
3) Annual O&M costs:
$1,068,100
$2,366,000
$ 155,900
C. Lime Softening
1. Process used for the removal of hardness from ground and surface
water. Inorganic chemical removal through floe absorption or
enmeshment.
2. Typical unit processes include:
- Raw water pumpage
- Softening with lime and occasionally soda ash
- Sedimentation
- Filtration
- Disinfection
- Storage and distribution
3. Process design considerations:
- pH coagulants
4. This process is generally effective for the treatment of the follow-
ing inorganic species:
Good to Excellent for:
As(V)...at pH ¦ 10-10.8
Ba at pH - 9.5-10.8
Cd
Cr{III).at pH above 10.5
Pb
Ag
287
-------
5. Limitations: In general the process is effective in removing
cations and fluoride. The process does not effectively remove Cr
(IV), nitrate, selenium or mercury.
Reverse Osmosis
1. Process used for the desalting of sea water or brackish ground
waters. Inorganic chemicals are removed by retention in the brine
by the membrane. Several types of membranes are available including
spiral wound and hollow fiber with some membranes designated as high
pressure (greater than 350 psi) or low pressure (below 250 psi).
Examples of spiral wound and hollow fiber membranes are presented on
Figure 1-4. A process schematic is presented as Figure 1-5.
2. Typical unit processes include:
- Raw water pumpage
- Pretreatment
- Membrane desalination
- Disinfection
- Storage and distribution
3. Process design considerations:
- Influent suspended solids
- Competing ions
- Ionic size
- Membrane pore size
- Membrane type
4. This process is generally effective for the treatment of the follow-
ing inorganic species:
Good to Excellent for:
5. Limitations: The process is generally effective in removing all
inorganic chemicals.
Case Study: Reverse Osmosis — Sarasota County, Florida
1. Background Information
a. System Characteristics
As(III)
As (V)
Ba
Cd
Cr(III)
Cr(VI)
F
Pb
Hg
Nitrate
Se (IV) , (VI)
Ag
Ground water supply
Eight RO systems tested
Flow ranges 0.0008 to 1.0 mgd
288
-------
FIGURE 1
TYPES OF REVERSE OSMOSIS MEMBRANES
^^Antl-telescoping
Brine ' device
Product
Brine
Feed-channel
spacer
Product tube
^Fiberglass
y' outerwrap
Membrane
surface
Tricof
product-
water ,
collection ' ^ 'x- ,,
channel I /\"\ ~""Meml?ran1e
\/ \ \ support-backing
Product > \ ...
flow • "Adhesive
Membrane Brine-seal
/Brine seal
Feed
Product
surface
carrier
SPIRAL WOUND
Segmented
ring \
O-ring
seals
Epoxy
,'nub
123 > ; «. \
/Shell
Sample
End plate
i \ Permeator sleeve
End plate \f
sleeve
HOLLOW FIBER
289
screen
End plate
Flow Fiber
screen"! bundle
i i
O-ring
seal
Support
0 ring
seal
Product
Distributor'
Epoxy
tube-sheet
'Porous ^"-Segmented
( support block rin9
-------
FIGURE 1-5
REVERSE OSMOSIS
raw water
DISINFECTION
PRETREATMENT
REVERSE OSMOSIS
ELECTRODIALYSIS
BRINE
290
-------
Radium concentrations high due to phosphatic limestone
b. Water Quality
Radium: 3.4 to 20.2 pCi/L
Plant Description
a. Plant Capacity: 800 to 1,000,000 gpd
b. Percent Recoveries: 28 percent to 54 percent
c. Operating Pressures: 200 psi to 425 psi
d. Membrane Type: Hollow Fiber & Spiral Wound
e. Treatment processes:
- Pretreatment
- Cartridge filtration
- pH adjustment
- Ion sequestration
- Reverse Osmosis
- Posttreatment
- pH adjustment
- Degasification
- Chlorination
f. Process schematic for a typical RO system is presented
Figure 1-6.
Plant Performance
a. Raw Water Concentration: 3.2-20.2 pCi/L
b. Product Water Concentration: 0.14 - 2.0 pCi/L
c. Reject Water Concentration: 7.8 - 37.8 pCi/L
d. All product waters below regulatory limit of 5.0 pCi/L
Costs
a. Operating Costs: $0.60 - $1.54 per 1,000 gallons
b. Components:
- Chemicals
- Electrical power
291
-------
FIGURE 1-6
TYPICAL RO SYSTEM
GENERATOR SET
A BRINE TO
> PERCOLATION
POND
HIGH SERVICE
PUMPS
PERMEATORS
CONTROL PANEL]
AND PUMPS
PRODUCT
TO DEGASIFIER
AND RESERVOIR
ACID
FEED
FILTER
MIXING
TANK
FEED
CLEANING
SOLUTION
SODIUM SILICATE FEED
292
-------
- Filter cartridge replacement
- Labor
5. Summary
a. Advantages:
- High removal of radium
- High removal of other cations & anions
- Small space requirement
b. Disadvantages:
- High operating costs
High capital costs
- Disposal of reject waters
c. Process Comparisons:
- Reverse Osmosis: 96 percent removal
- Lime Softening: 75 - 96 percent, removal
- Ion Exchange: 81 - 97 percent removal
293
-------
II. ION EXCHANGE
Scope: Provide a review of the use of ion exchange technology for removing
inorganics from drinking water supplies, including design
considerations and limitations. Provide a case study of an
operating ion exchange facility, highlighting the design
considerations and costs.
A. Design Considerations
1. Process used to remove hardness and nitrate from groundwaters.
Inorganic removal occurs by absorption to resin exchange sites.
2. Typical unit processes include:
- prefiltration
- ion exchange
- disinfection
- storage and distribution
3. Process design considerations
- influent suspended solids
- competing ions (Ca & Mg)
- resin exchange capability
- resin break through times
4. This process is generally effective for the treatment of the
following inorganic species:
Good to Excellent for:
Cationic Anionic
Ba As(V)
Cd Cr(VI)
Cr(III) Nitrate
Ag Se(IV)
Se(VI)
5. Limitations - the process is effective for removing Ba and Ra
as well as other cations using cationic resins while anionic
resins are effective for nitrate and selenium.
B. Case Study - McFarland, California
1. Background Information
a. System Characteristics
1) Ground water supply
2) 4 wells (No.'s 1,2,3 and 4)
3) All wells affected by nitrate
4) Well No. 3 abandoned
294
-------
5) Wells No.'s 1 and 4 used for current water supply,
composite sample below 10 mg/L nitrate.
6) Well No- 2 treated
b. Water Quality (Raw)
1) Nitrate: 6.8 to 22.1 mg/L as N
Plant Description
a. Plant Capacity: 695 gpm (1 MGD)
b. Current Finished Water Flow
- Treated water: 500 gpm (71% of total)
- Blend water: 200 gpm (29% of total)
c. Waste water
- Saturated brine rates 36 gpm
- Diluted brine rate: 190.5 gpm
d. Treatment Processes
- Anion exchange resin
- Sodium chloride regeneration with slow rinse and resin
declassification
- Aerated lagoons and spray irrigation for brine waste
treatment
- Process schematic presented on Figure II-l
Treatment Design
a. Nitrate level (basis for design)
- Raw water: 16 mg/L (average)
- Treated flow: 2.6 mg/L (average)
- Finished flow (blend): 7.0 mg/L (average)
10.0 mg/L (maximum)
b. Media
- Anion exchange resin (A.-101-D, Duolite, Rohm and Haus
Company, Philadelphia, PA.)
c. Bed Characteristics and Target Flows
- Reaction vessels: 3, each 6 ft. diameter by 10 ft. high.
- Bed depth: 3 feet (operating)j 5 feet (maximum)
- Treatment flow rate: 250 gpm
- Empty Bed Contact Time: 2.54 minuses
- Service loading rate: 9.03 gpm/ft
Regeneration
a. Regeneration material
- 6% sodium chloride brine (2.6 lbs/gal or 259 g/L)
b. Regeneration procedure
- Saturated brine rate: 12.0 gpm
- Diluted brine rate: 63.5 gpm
- Brine rinse duration: 15 minutes
- Bed volume treated per regeneration: 250
- Downflow regeneration flow direction
295
-------
McFARLAND, CA.
TREATMENT PLANT FLOW DIAGRAM
SALT
OAPINO
BRINE
HAW WATER
VE8SEL
VE8SEL
VE88EL
BLENDING
VALVES
TREATED WATER
PRESSURE
TANK
BACKWA8H
NITRATE
ANALYSIS
WASTE TO
DISPOSAL
OtSTMBUTION
SYSTEM
ALARM AND
SHUTDOWN
-—CONDUCTIVITY
MONITOR
WELL SUPPLY
3D
m
-------
c. Slow Rinse procedure
- Slow rinse rate: 64 gpm
- Slow rinse durations 30 to 50 minutes
- Downflow slow rinse flow direction
d. Resin declassification procedure
- Declassification flow rate: 140 gpm
- Declassification service rate: 5 gpm/ft
- Upflow declassification flow direction
Waste Handling
- Brine discharge to municipal wastewater treatment plant
- Brine treated by aerated lagoons with spray irrigation for
animal feed crops and cotton.
Operations Data
a. Staggered reaction vessel operation; two operating and one
regenerating at any given time.
b. Vessel regeneration
- Every 159,000 gallons per vessel at current operating
conditions
- 1.47 times per day at current operating conditions
- 5.55 milliequivalents of chlorine per milliequivalent of
nitrate removed
- 2162 lbs. salt required per day at continuous operation.
c. Plant performance
- Toleration of some nitrate leakage in treated water (2-5
mg/L)
- Finished water nitrate range: 6.2 to 8.3 mg NO -N/L
- Finished water chloride concentration: 166 mg/L
- 270.7 milliequivalents of nitrate removed per liter of
resin
- Average nitrate removal before breakthrough: 14.33 mg/L
- Resin replacement 20% per year
d. Plant operations
- Microprocessor control with flow, product water nitrate
and product water conductivity sensors
- At full automation once a day plant monitoring required
Costs
a. Construction (1983): $354,638 which includes:
- Ion Exchange vessels: 111,741
- Brine tank 18,700
- On-site construction 81,154
- Other 40,045
- Resin 56,610
- Engineering 46,388
b. Operating and Maintenance Costs: 12.8$ per 1000 gallons
which includes:
- Operator: 1.3fc per 1000 gallons
- Power: 2.2$ per 1000 gallons
297
-------
- Resin replacement:
- Salt:
- Normal O & M:
- Miscellaneous
3.2$ per 1000 gallons
3.4$ per 1000 gallons
1.9$ per 1000 gallons
0.8$ per 1000 gallons
298
-------
III. ACTIVATED ALUMINA
Scope: Provide a review of the use of ion exchange technology for removing
inorganics from drinking water supplies, including design
considerations and limitations. Provide a case study of an
operating ion exchange facility, highlighting the design
considerations and costs.
A. Design Considerations
1. Process used to remove fluoride from groundwaters. Inorganic
chemical removal occurs through absorption on the activated
alumina. A process schematic is presented as Figure III-l.
2. Typical unit processes include:
- raw water pumpage
- pretreatment
- activated alumina contact
- disinfection
- storage and distribution
3. Process design considerations
- influent suspend solids (pretreatment)
- competing ions
- alumina exchange ability
4. This process is generally effective for the treatment of the
following inorganic species:
Good to Excellent for:
As (V)
F
Se(IV)
5. Limitations - the process is effective in removing fluoride,
arsenic and selenium. The system is not effective in removing
Ba, Ra, or Cd.
B. Case Study - Gila Bend, Arizona
1. Background Information
a. System Characteristics
- ground water supply
3 wells (Nos. 1, 2 and 4)
- chlorination of selected wells
- wells affected by high fluorides
- Well No. 4 treated
299
-------
ACTIVATED ALUMINA
RAW WATER
DISINFECTION
PRETREATMENT
ACTIVATED ALUMINA
ION EXCHANGE
-------
b. Water Quality
- Fluoride: 4 to 6 mg/L
Plant Description
a. Plant Capacity: 600 gpm (900 gpm max.)
b. Treated water total flow - 90 percent raw water flow -
750,000 gpd
c. Waste water - 10 percent raw water flow - 75,000 gpd
d. Treatment Processes
- activated alumina
- caustic regeneration
- acid neutralization
- evaporation pond for regenerant waste treatment
- flow schematics presented in Figure III-2
Treatment Design
a. Fluoride levels (basis for design)
- Raw Water - 5.0 ppm (ave.)
- Treated Water - 0.7 ppm (ave.)
1.4 ppm (max.)
b. Media
- Material Spec. - Alcoa Activated Alumina -
Grade F-l, -28 + 48 mesh
- Bed material capability to remove fluoride - 1,000
grains/ft
3
- Desert Center, California - 1,000 + grains/ft with
7.5 ppm fluoride
3
- Alcoa Laboratory - 700 grains/ft with 22 ppm fluor-
ide
3
- X9 Ranch - 1,000 + grains/ft with 4 ppm fluoride.
c. Bed Design
- Number of treatment units - 2, each 10 ft diameter by
10 ft high
- Bed depth - 5 feet - 0 inches
- Bed expansion during backwash - 50 percent e 2 feet -
6 inches
- Tank free board - 6 inches
- Superficial residence time of raw water flowing
through bed - 5 minutes (min.)
2
- Treatment unit flow rate - 7 gpm/ft (max)
2
- Treatment unit backwash flow rate - 11 gpm/ft (max)
301
-------
BASIC OPERATING MODE
FLOW SCHEMATICS
o
ro
RAW WATER
ACID
^TREATED WATER
TREATMENT
UNIT
J
TREATMENT AND
DOWNFLOW RINSE
RAW WATER
TREATMENT
#NIT
~WASTE
BACKWASH AND
UPFLOW RINSE
RAW WATER
^CAUSTIC
RAW WATER
WASTE
UPFLOW
REGENERATION
CAUSTIC
TREATMENT
UNIT
WASTE
DOWNFLOW
REGENERATION
0
s>
m
i
K»
-------
Regeneration and Neutralization
a. Regeneration material - 1 percent NaOH
- Blend of 50 percent NaOH and raw water in "mixing T"
at treatment unit
- Fifty percent NaOH procured directly from caustic
manufacturer, delivered to plant in tank trucks
b. Regeneration process
2
- Flow rate through treatment unit - 2-1/2 gpra/ft
(max)
- Residence time in treatment bed - 24 minutes (min.)
- Amount of caustic required/regeneration - 200
gallons/lb fluoride in bed
- Incorporate provision for upflow or downflow through
bed
c. Neutralization material - 0.04 percent H2S04
- Blend of 93 percent H2S04 and raw water in "mixing T"
at treatment unit
- Ninety-three percent H SO procured directly from
acid manufacturer, delivered to plant in tank trucks
d. Neutralization process
2
- Flow rate through treatment unit - 7 gpm/ft (max.)
- Amount of acid rinse required - sufficient to adjust
pH within acceptable pH limits 6.5 - 8.5
- Incorporate provision for upflow or downflow through
bed
Waste Handling
a. Nontoxic wastes (backwash, neutral rinse water) discharged
to sewer
b. Regenerant waste discharge to lined evaporation pond (240
ft by 440 ft by 9 ft deep)
Operating Data
a. Regenerate every 3.5 to 4 mg of water treated
b. Ten hours to regenerate
303
-------
c. Activated alumina media lost: 10-12 percent per year
d. Water temperature: 107 P
e. Operating data presented in Figure III-3
7. Costs
a. Construction (1977-78): $285,000 which includes:
treatment facility
- well
- 0.5 mg steel tank
- pond
- booster pumps and standby generator
- chlorine facilities
b. Operating costs: 27 to 28^ per 1,000 gallons
salary
- power
chemicals
- media replacement
304
-------
TYPICAL OPERATING RUN
AT GILA BEND, AZ.
—18
ss
U1
x
a
Treated Water pH
Raw Water pH
Treated Water F Content
2 4 6 8 10
Water Flow Through Treatment Bed - 100m3
-------
IV. PROCESS SELECTION
Scope: Review the various factors that must be considered when selecting a
treatment process for removing inorganics from drinking water
supplies.
1. Historical IOC concentration
a. Dependency on raw water concentration level since most
technologies rely on a percent removal basis.
b. Valence state of the metal very important to the design
strategy.
c. Type and concentration of the asbestos fiber present
critical to effective design.
2. Process residues or waste products Disposal of wastes need
special consideration since the residuals are often considered
hazardous wastes and may be regulated under CERCLA.
a. Conventional processes produce sludges
b. Lime softening processes produce sludges
c. Ion exchange produces brines
d. Reverse Osmosis produces brines
e. Activated Alumina produces brines
3. Existing Process may be modified using one of the above tech-
nologies.
4. Pretreatment Requirements
a. Surface waters require filtration prior to membrane or ion
exchange processes.
b. Stability requirements
c. Ground water systems may have little in existing conven-
tional treatment-generally leaving choices more open.
5. Flow versus Type of Treatment
a. Size of plant determines the feasible treatment method
(economy of scale)
b. Process selection depends on not only flow but the
presence of other, undesired contaminants such as Secon-
dary Drinking Water parameters.
306
-------
6. Other Considerations
a. Availability of local supply of process chemicals
b. Power costs
307
-------
MOST PROBABLE APPLICATION
PROCESS
CONVENTIONAL
LIME SOFTENING
CATION EXCHANGE
ANION EXCHANGE
ACTIVATED ALUMINA
POWERED ACTIVATED
CARBON
GRANULAR ACTIVATED
CARBON
REVERSE OSMOSIS
AND ELECTRODIALY!
REMOVES
Cd, Cr. As, Ag, Pb
Ba, Cd, Cr, (III), F,
As, V, Pb
Ba
NO 3
F, As, Se
Hg
Hg
ALL INORGANICS
FROM
SURFACE WATER
GROUNDWATER, HARD
SURFACE WATER
GROUNDWATER
GROUNDWATER
GROUNDWATER
SURFACE WATER
(SPILLS)
SURFACE OR
GROUNDWATER
GROUNDWATER
308
-------
INORGANICS TREATMENT
REFERENCES
1. Krause, T. L.; and Storer, E. L. "Evaluating Water
Treatment Techniques for Barium Removal." Journal
AWWA, 74 : 9 : 478 (Sept. 1982).
2. Lauch, R. P.; and Cuter, G. A. "Ion Exchange For the
Removal of Nitrate from Well Water." Journal AWWA,
78:5:83 (May 1986) .
3. McGuire, M. J.; Bowers, A. E.; and Bowers, D. A.
"Optimizing Large-Scale Water Treatment Plants for
Asbestos-Fiber Removal." Journal AWWA, 75:7:364 (Julv
1983) .
4. Rubel, F. Jr. "Design Manual: Removal of Fluoride fr :a
Drinking Water Supplies by Activated Alumina."
EPA-600/2-84-134. USEPA, Cincinnati, Ohio (August
1984).
5. Rubcl, F. Jr.; and Woolsey, R. D. "Removal of Excess
Fluoride from Drinking Water." Technical Report
EPA-530/9-78-001. USEPA, Washington, D. C. (1978).
6 i Rubel, F. Jr.; and Woolsey, R. D. "The Removal of
Excess Fluoride from Drinking Water by Activated
Alumina." Journal AWWA, 71:1:45 (January 1979).
7. Sorg, T. J. "Treatment Technology to Meet the Interim
Primary Drinking Water Regulations for Inorganics."
Journal AWWA, 70:2:105 (February 1978).
8. Sorg, T. J.; and Logsdon, G. S. "Treatment Technology
to Meet the Interim Primary Drinking Water Regulations
for Inorganics: Part 2." Journal AWWA, 70:7:379 (July
1978).
9. Sorg, T. J.; Csanady, M.; and Logsdon, G. S. "Treatment
Technology to Meet the Interim Primary Drinking Water
Regulations for Inorganics: Part 3." Journal AWWA,
70:12:680 (December 1978).
10. Sorg, T. J. "Treatment Technology to Meet the Interim
Primary Drinking Water Regulations For Organics: Fart
4-" Journal AWWA, 71:8:454 (August 1979).
11. Sorg, T. J.; and Longdon, G. S. "Treatment Technology
to Meet the Interim Primary Drinking Water Regulations
for Inorganics: Part 5." Journal AWWA> 72:7:411 (Julv
1980).
309
-------
12. V. J. Ciccone and Associates, Inc. "Technologies and
Costs for the Removal of * from Potable Water Sup-
plies." Science and Technology Branch, Criteria and
Standards Division, Office of Drinking Water, U. S.
Environmental Protection Agency, Washington, D. C.
~Arsenic
Asbestos
Barium
Cadmium
Chromium
Cyanide
Lead
Mercury
Molybdenum
Nickel
Nitrates and Nitrites
Selenium
Silver
Sodium
Sulfates
310
-------
c.
ORGANICS TREATMENT
OVERVIEW AND CASE STUDIES
I. GRANULAR ACTIVATED CARBON - TREATMENT OVERVIEW
II. GRANULAR ACTIVATED CARBON - CASE STUDIES
III. AERATION - TREATMENT OVERVIEW
IV. AERATION - CASE STUDY
311
-------
I. GRANULAR ACTIVATED CARBON - TREATMENT OVERVIEW
Present a review of the use of granular activated carbon adsorption
technology for removing organics from drinking water supplies,
including adsorption principles, process design considerations,
facility design considerations, and costs.
PRINCIPLES OF ADSORPTION
1. Adsorption - the transfer of a dissolved contaminant (adsor-
bate) from a solvent (solution) to the surface of an adsorbent
(carbon). See Figure 1-1 for schematic of an adsorption
system.
2. Attractive Adsorption Forces
- physical: Van der Waals forces
- chemical
- electrical
3. Factors Affecting Adsorption Process
a. Adsorbate * see Tables 1-1 and 1-2 for lists of readily
adsorbed and poorly adsorbed organics, respectively.
- bran,ched-chain compounds more adsorbable than
straight-chained compounds
- increasing molecular weight increases adsorption
- lower solubility increases adsorption.
- greater concentration, increased adsorbability
b. Adsorbent
- high degree of porosity
- extensive internal surface area
- affinity of adsorbate for absorbent(polar, nonpolar)
c. Aqueous Solution
- temperature
- pH
- dissolved solids
- other adsorbates
4. Forms of Activated Carbon
a. Granular
b. Powdered
312
-------
FIGURE I- 1
Solvent
Adsorbs! e
Adsorbent
mm
Attached
Adsorbate
THE ADSORPTION SYSTEM
313
-------
TABLE 1-1
READILY ADSORBED ORGANICS
Aromatic Solvents
Benzene, toluene, nitrobenzenes
Chlorinated Aromatics
PCBs, chlorobenzenes, chloronapthalene
Phenol and chlorophenols
Polynuclear Aromatics
Acenapthene, benzopyrenes
Pesticides and herbicides
DDT, aldrin, chlordane, heptachlor
Chlorinated non-aromatics
Carbon tetrachloride, chloroalkyl ether
High MW Hydrocarbons
Dyes, gasoline, amines, humics
TABLE 1-2
POORLY ADSORBED ORGANICS
Alcohols
Low MW Ketones, Acids, and Aldehydes
Sugars and Starches
Very High MW or Colloidal Organics
Low MW Aliphatic*
314
-------
B. GAC PROCESS DESIGN CONSIDERATIONS
1. GAC process design considerations:
a. contaminant
b. levels
c. GAC
d. carbon usage rate - pounds of carbon per gallon of water
treated
e. empty bed contact time (5-30 minutes)
f. surface loading rate (2 to 10 gpm/sf)
g. carbon depth (10-30 ft)
2. Empty Bed Contact Time
a. Affects capital costs
b. 5 to 30 minutes
c. Average - 10 minutes for most organic*
d. Radon - 100 to 200 minutes
3. Carbon Usage Rate
a. Rate of carbon adsorption
b. Affects O&M cost
c. 100 to 300 lb/mg for most organics
4. Carbon Usage Rates for Several Organic*:
a. Volatile Organics
lb/MG
TCE - 200
PCE - 70
Vinyl Chloride - NA
Ci*-l#2-Dichloroethylene - 250
b. Pesticides
Aldicarb - 25
Chlordane - 5
DBCP - 15
315
-------
lb/MG
c. Chlorinated Aromatics
PCB - 5
Dichlorobenzene - 10
4. Carbon Adsorption Testing
a. Isotherm (laboratory) - Figure 1-2 indicates isotherms for
several organic chemicals
b. Freundlich Isotherm Relationship:
x/m » kc*^n
x/m » equilibrium capacity (mg SOC/gm carbon)
k - capacity at 1 mg/L SOC concentration
c * SCX: effluent concentration (mg/L)
1/n « exponent
c. Minicolumns (laboratory) see diagram on Figure 1-3
d. Dynamic columns (field)
5. Effects of Different Organics on GAC Designs
a. Contaminant levels - see Figure 1-4
b. Type of Compound - see Figure 1-5
C. GAC FACILITY DESIGN CONSIDERATIONS
1. Major Process Elements
a. Carbon contactors
b. Transfer system
c. Regeneration system
2. Carbon Contactor Configuration
a. Upflow
- long contact times
- suspended solids removal
b. Dovmf low
- Pressure - see diagram on Figure 1-6
- Gravity - see diagram on Figure 1-7
316
-------
FIGURE 1-2
PENTACHLOROPHENOL (866)
I ^
TRtCHLORJOETHANE flffi,
jf 0.000I O.OOI O.OI O.I l.o
* RESIDUAL CONCENTRATION jug/I
NOTE: NUMBER IN PARENTHESIS (166) INDICATES
THE MOLECULAR WEIGHT OF THE COMPOUND
ADSORPTION ISOTHERMS FOR SEVERAL ORGANIC
COMPOUNDS FOUND IN GROUND WATER SUPPLIES
317
-------
OMCAT COLUWM
DIAGRAM OF DYNAMIC MINI-COLUMN ADSORPTION
TECHNIQUE SYSTEM
-------
FIGURE 1-4
200 -
CO
>
<
o
uu
U.
z
o
ID
AC
<
o
100
TRICHLOROETHYLENE
10 MINUTE EBCT
EFFLUENT CONCENTRATION
50 jug/I
10 jug/I
yr—1 jug/l
_L
JL
_L
-L
I00 200 300 400 500 600 700 800 900 I000
INFLUENT CONCENTRATION, jug/l
EFFECT OF CONTAMINANT LEVELS
ON CARBON LIFE
319
-------
FIGURE
400-
EFFLUENT CONCENTRATION 10ufi/l
EBCT-10 MINUTES
TETRACHLOROETHYLENE
TRICHLOROETHYLENE
1,1,1,-TRICHLOROETHANE
I00 200 300 400 500600 700 800 900 I000
INFLUENT CONCENTRATION/mq/I
EFFECT OF TYPE OF COMPOUND ON CARBON LIFE
320
-------
FIGURE 1-6
INFLUENT
BOptl
}«r rf®
20,000 LB EA.
GRANULAR
ACTIVATED CARBON
COLLECTOR
SYSTEM
TREATED WATER
GAC CONTACTORS
SCHEMATIC OF TREATMENT PROCESSES
321
-------
FIGURE 1-7
SURFACE
WASH
influent
FRESH CARBON
SPENT
CARBON
CARBON
BACKWASH
EFFLUENT
GRAVEL
filter blooks
'DRAIN
DOWNFLOW GRAVITY CONTACTOR
322
-------
3. Transfer System
a. Hydraulics
b. Velocities
c. Materials of construction
d. GAC loss
4. GAC regeneration:
a. On-site Regeneration - economical where carbon exhaustion
rate is greater than 2,000 pounds per day.
b. Off-Site Regeneration - economical where carbon exhaustion
rate falls between 500 and 2,000 pounds per day.
c. Off-Site Disposal - economical where carbon exhaustion
rate is less than 500 pounds per day.
5. Operational Issues
a. Desorption
b. Replacement
c. Bacterial growth
d. Mass transfer - defines breakthrough curve or wavefront
(see Figure 1-8)
6. Waste Disposal
a. Backwash
b. Spent carbon
D. GAC TREATMENT ECONOMICS
Capital cost components include:
Basic
Site Specific
contactors
activated carbon
piping
special sitework
raw water holding tank
new/restaged well pump
GAC contactor building
chemical facility
clearwell
finished water puii¥>(s)
backwash storage
2. Capital costs are shown on Figure 1-9 at end of this section.
323
-------
FIGURE 1-6
INFLUENT
WAVEFRONT
C.
EFFLUENT
GAC CONTACTOR
324
-------
CAPITAL COSTS FOR
GAC SYSTEMS
400-
CO 350 -
O
5 300-
o
ws
I— 200-
(/)
8 150
100 •
50-
i
1.5
1.0
2.5
2.0
0.5
SYSTEM SIZE
(MGD)
-------
3. Operating costs are shown on Figure 1-10 at end of this sec-
tion.
4. Relative costs for organics removal
Chlorinated aromatics - least costly
Pesticides - J
VOCs - most costly
326
-------
0 & M COSTS FOR GAC SYSTEM
u>
to
o
O
O
**
2
CO
h
0)
o
o
60
55
50
45
40
35
30
25
20
15
10
5
0
0.5 1.0 1.5 2.0 2.5 3.0
SYSTEM SIZE (MGD)
-------
II. GRANULAR ACTIVATED CARBON - CASE STUDIES
Scope: Describe experiences of two water supplies in dealing with organics
contamination, including the use of granular activated carbon to
treat their supply.
A. GAC ADSORPTION - WASHINGTON, NEW JERSEY
1. System Characteristics
a. ground water supply
b. 1 well
c. 550 gpm, 0.792 mgd
2. Water Quality
a. PCEs 50-500 ug/L
b. TCEs 1-10 ug/L
c. 1,1,1-Trichloroethane: 1-20 ug/L
d. Carbon Tetrachloride: 1-5 ug/L
e. See Figure II-l for plot of VOC influent variations
3. Alternatives Considered
a. GAC (selected)
b. Resin
c. New source of supply
4. GAC Design
a. No. of Contactors: 2
b. Mode of Operation: Series or Parallel,
downflow, pressure
c. Diam (ft): 7
d. Carbon depth:
(ft) 10
e. Hydraulic
Loadingi
(gpm/ft ) 7.1
f. EBCT (min): 10.5
g. Washwater: sand-filtered and recycled
h. See Figure I1-2 for schematic of Vannatta Street Station
328
-------
CONCENTRATION OF
CONTAMINANTS IN THE RAW WATER
550
470
390
PCE
3 310-
230
AVERAGE
150 -
1,1. 1-TCEA
20-
AVERAGE
10
0-H
0
20
10
30
40
50
60
HOURS OF OPERATION
-------
GAC TREATMENT PLANT SCHEMATIC
VANNATTA STREET STATION
CARBON
CARBON
CHLORINE
SAND
7m i
Oo-G
WASTEWATER RECYCLE
FILTERED WATER TO
DISTRIBUTION SYSTEM
-------
5. Carbon Usage Rates
lbs GAC/mg
PCE
Breakthrough 102
5 ug/L 91
1,1,1-TCEA
Breakthrough 271
10 ug/L 209
6. Costs
a. Capital: $506,500 (1981)
b. Operating: $80,000/year
GAC ADSORPTION - CINCINNATI. OHIO
1. System Characteristics
a. supply: Ohio River
b. capacity: 220 mgd
c. existing treatment includes: high-rate pretreatment, presett
ling, conventional treatment (See Figure II-3)
2. Water Quality - see Figure 11-4 for influent TOC variations
3. Cincinnati Project Goals
a. Finished water TOC <1.0 mg/L
b. Maximum use of existing WTP facilities
c. Flexible system to accommodate future regulations
d. System costs within reasonable limits
4. GAC Design Concepts
a. Post-filtration adsorption using downflow deep-bed contactors
b. Post-GAC chlorination.
c. On-site carbon regeneration utilizing fluidized bed furnaces.
d. Minimization of carbon losses.
5. See Figure 11-5 for schematic of Cincinnati treatment train
331
-------
FIGURE H-3
CINCINNATI TREATMENT TRAIN
PRESETTLINQ
BASIN
PRESETTLINQ
BASIN
LAMELLA *—*
SETTLER PUMPING
STATION
i >
PLOCCULATION/
SEDIMENTATION
BASINS
EAST
CHEMICAL
BUILDING
CLEARWELL DISTRIBUTION
„ SYSTEM
332
-------
TYPICAL TOO REDUCTION CURVE
DURING PILOT STUDY
Lo
U>
U?
-J
4000
3500
3000
< 2000
h-
o 1500
o 1000
500
INFLUENT
St
m
1
m
CONTACTOR EFFLUENT
TIME, DAYS
-------
figure ii-©
CINCINNATI TREATMENT TRAIN
PRESETTLINQ
BASIN
PRESETTLINQ
BASIN
LAMELLA * *
SETTLER PUMPING
STATION
FLOCCULATION/
SEDIMENTATION
EAST
CHEMICAL BASINS
BUILDING ———
FILTERS CLEAR WELL DISTRIBUTION
SYSTEM
PROPOSED
PUMPING
STATION
PROPOSED
GAC
FACILITIES
334
-------
6. GAC design criteria:
Plant Flowrate (mgd):
Annual Average
Maximum Day
124
175
Empty Bed Contact Time (min)
15
GAC Bed Depth (feet)
11
Maximum Loading Rate (gpm/sf)
5.5
Carbon Usage Rate (lb/day):
Annual Average
Peak Period
54,000
92,000
7. Carbon contactor building layout - Figure II-6
8. Carbon contactor building floor plan - Figure II-7
9. GAC contactor cross sections - Figures II-8 and II-9
10. GAC transport system design
a. all transport pipe is Schedule 10 316L stainless Steel
b. bends
c. velocities - 3 to 5 fps
11. Regeneration System - see Figure 11-10 for schematic of system
12. Capital Costs
a. GAC Contactors
b. Regeneration Equipment
c. Intermediate Pumping Facilities
d. Outside Piping
je. Modification of Existing Facilities
3" pipe - 24" radius
4" pipe - 36" radius
8" pipe « 48" radius
Capital Cost « §40 Million
13. O&M Costs
a. Labor
b. Power
c. Natural Gas
335
-------
INLET CHAMBER
EXISTING FILTER BUILDING
WEIR CHAMBER
FILTERED WATER
CARBON
CONTACTED
WATER
CARBON
CONTACTOR
BUILDING
WASTEWATER
RECOVERY TANK-
OVERFLOW
TO RIVER
CARBON CONTACTOR BUILDING LAYOUT
-------
SEAL WELL
(TYP.)
CARBON
CONTACTED
WATER
EFFLUENT
CARBON
CONTACTORS
CARBON
CONTACTORS
i nitn ~ ri ~
REGENERATION
AREA
Tdoro
FILTERED WATER
CLEARWELL (BEL.
1 ¦
FILTERED
WATER
INFLUENT
TT n
CARBON STORAGE
I l
STORE ROOM
lLl
CARBON
CONTACTORS
CARBON
CONTACTORS
CARBON CONTACTOR BUILDING
FLOOR PLAN
-------
^ PIPE GALLERY
INFLUENT FLUME
EL. 124.00
^WATERJ>URFACE EL.120.00
I /-CARBON FILL PIPE
TOP OF CARBON EL.110.00
G. A. C.
BUTTERFLY T/
VALVE (TYP.)-7
EL 97 75
BACKWASH
INFLUENT
S S. UNDERORAIN
HEADER
WASTEWATER
DRAIN
CARBON
CONTACTED
WATER
GAC CONTACTOR SECTION -
O
c
u
m
T
00
-------
-------
REGENERATION SYSTEM SCHEMATIC
DRYER
OFF-GAS
DEWATERED
SPENT CARBON
CYCLONE
TO SCRUBBERS
AND STACK
GRINDER
REGENERATION
FURNACE
FURNACE'
OFF-GAS
RECUPERATOR
RECYCLE
DRIED SPENT
CARBON
AFTERBURNER
3V
m
o
-------
d. Make-up GAC
O&M Cost • $3 to 4 Mi11ion/yr
Cost Impact of GAC
a. Average Bills Before Installation of GAC
3
Quarterly: $ B.10 for first 1,200 ft,
10.80 for next 1,600 ft
$18.90 3,000 ft
Annual: $8.0.00
b. Projected Annual Bills After Installation of GAC
- If 30 percent increase, $80 + 30 percent ¦ $105
- If 40 percent increase, $80 + 40 percent « $115
341
-------
111. AERATION - TREATMENT OVERVIEW
Scope; Present a review of the use of aeration to remove organic chemicals
from drinking water, including aeration principles, equipment,
process design, facility design and costs.
A. PRINCIPLES OF AERATION
1. Rate of mass transfer proceeds according to following equation:
M » K. a A P
b
Where: M ¦ mass of substance transferred per unit time and
volume (lb/hr/cf)
K " coefficient of mass transfer (lb/hr/sf)
a * effective area (sf/cf)
AP » concentration difference or driving force
2. Driving force is the difference between actual conditions in the air
stripping unit and conditions associated with equilibrium between
the gas and liquid phases. See Figure III-l for example of driving
force.
3. Equilibrium concentration follows Henry's Law, which states that the
amount of gas that dissolves in a given quantity of liquid, at
constant temperature and total pressure, is directly proportional to
the partial pressure of the gas above the solution. Henry's con-
stant calculated as follows:
H (dimensionless units) » <16.04)(P)(M)
(T) (S)
P - vapor pressure in mm
M ¦ gram molecular weight of solute
T ¦* temperature in degrees Kelvin
S ¦ solubility in mg/L
4. A compound's Henry's Law constant indicates relative volatility of
the compound; high Henry's Law constant - easily removed by air
stripping.
342
-------
P'OURE in- ,
ELOWER
A IF, FLOW
PATTERN
intake
343
-------
5. Henry's Constants for several organic chemicals:
a. VOCs
Dimensionless Units
- Vinyl chloride: 265
- TCE: 0.44
- PCE: 0.88
- Cis-l,2-Dichloroethylene: 0.18
b. Pesticides
- Aldicarb: 1 x 10 '
- Chlordane: 0.015
- DBCP: 0.011
c. Chlorinated Aromatics
- PCBs 0.021
- Dichlorobenzene: 0.086
B. AERATION EQUIPMENT
1. Two types of aeration equipment:
a. diffused air * inject air bubbles into water
b. waterfall - cause water to fall through air
- Cascade
- Multiple tray
- Spray no»tl«s
- Packed column
2. Diffused air system - Figure 11-2 at end of this section is a
diagram of diffused air basin.
3. Waterfall Aerators
a. Multiple tray - see Figure III-3 for diagram.
b. Packed column - diagram of packed column is shown on Fig-
ure II1-4.
c. Catenary grid unit - diagram shown on Figure XII-5.
d. Higee System - diagram shown on Figure II1-6.
344
-------
FIGURE III- 2
AIR SUPPLY
DIFFUSES! Oslo
EFFLUENT
DIFFUSED AIR BASIN
345
-------
FIGURE"!*-J
INLET
CHAMBER
DISTRIBUTOR
NIPPLES
STAGGERED -
SLAT TRAYS
AIR INLET
BLOWER
AIR WATER
-SEAL -x INLET j
\j.L ^ j r
F^rFip ja. .crw^zi
4
« 1 1
SWf "'1
i' > \ ' \-: * > • * rt r \ !i\
>M»C3cac3Cai-»i-M-Tt^»^aDtoi
pi—ii—i pa trachea
cqcibOE!^eai^>J
a «=> eSi «=> ilte c*J
cx=» e±» ea esa ei, £*-. J
:» eS» cia eia eta ii±> ctj
ee» ek «ae» bo J
^oucai^aa
.ciicticat^e
itoe^rV^i—
I fctj «—«e±i eta e:
Leeacb>e^cbiS»±>d
Jai-.i^irSpi—r»erj r—j
I da C=3 e=eb eta «=a «2
rta ca ate cite rftook «2i>
t> tiia r±±3 rtra c~> <=a e^a a
oebtibesaiiocsca
o f - a en era
*.«—>—¦-j
saocaeba
*c£=ae±aesses^
• k cto iSa efb c£=* dSa i±> c±=» e£±» c
ipta cba i±=i i±5> c±» c5=» Sti ti2a afca ti=3 «2b cti
A eita ea» c£±a csb r£» eb» esia c4±a c±x» dm tsim mtim J
1 «£^» d±a c2±a cira c±> e==> c*a <±» c±i» c^a c±30d era
L cs» «±£a si±a c±» d±» «^n Ma «t£a nta» cki> t±i» km c±£» t£U c±!b cfba c£as atmm
> fS1 Ca ctS r^s c!b cft» c^n a±^» ct±» atca «±a csc» a±m *.
]* eaj^=>-eta i. «ba <£i> iAa da atak c±=i
i,l U I* .H L *1 it |1 <
' ;> I !< P™3' * '» 1 :i'
'«' v Info rrf, '.} .! '•, h
AIR SEAL
AIR
— OUTLET
BAFFLES
AIR STACKS
DIAGRAM OF A REDWOOD SLAT
TRAY AERATOR
346
-------
FIGURE ltl-4
INFLUENT
rssi&i£
LIQUlO DISTRIBUTOR
PACKING MATERIAL
PACK I HQ SUPPORT
EFFLUENT
XTV
AIR IN
DIAGRAM OF PACKED COLUMN
347
-------
FIGURE 111- 6
DEMISTER
WATER INLET
(TYR )
FLUIDIZED
ZONE
CATENARY
GRID (TYP.)
TREATED WATER
SAMPLE COLLECTOR
MANOMETER FOR
AIR FLOW RATE
MEASUREMENT-
RAW WATER
ROTAMETER
RAW WATER
SAMPLE TAP
BLOWER
TREATED WATER
SAMPLE TRAP
f WATER FLOW
METERING VAL
AIR FLOW
DAMPER
RAW WATER
FROM WELL
TREATED WATER
TO DRAIN
Malcolm
PIRNIE
DIAGRAM OF PILOT-SCALE:
348 CATENARY GRID UNIT
-------
EXHAUST AIR
AIR IN
BLOWER
i .
NIGEE
=(~)
GROUNDWATER
PRODUCT
WATER
FILTER
—8~
PUMP
HIGEE SYSTEM
O
C
J}
cn
-------
C. PROCESS DESIGN CRITERIA
1. Diffused air system - improving process design:
a. increase basin depth
b. produce smaller air bubbles
c. optimize basin geometry
d. increase gas flow
2. Packed column design parameters:
a. type of compound
b. VOC concentrations (ug/L)
c. type of packing material
d. A:W ratio (cubic feet per cubic feet)
e. Liquid loading rate (gpm/sf)
f. Packing height (ft)
g. water temperature
3. Figure III-7: effect of compound on packed column design
4. Figure III-8: effect of temperature on removal efficiency
D. FACILITY DESIGN CONSIDERATIONS
(Packed Column Facility Components Shown on Figure III-9)
1. Design Considerations
a. Location and site constraint
b. Noise
c. Aesthetics
d. Housing and type of construction
e. Air quality
f. System hydraulics
g. Instrumentation and control
h. Column and column internals
i. Clogging of packing
2. Location/Site Constraints
a. Zoning requirements
b. Height restrictions
c. Location of air intake louvers
3. System Hydraulics
a. Festaging well pumps
b. Flow and system pressure
c. Repumping to distribution system
350
-------
toor
^ 80
m
H
flL
HI
o
C*3 —
2 O
o
<
0.
60
40
20
CHLOROFORM
20/1
40/1
EFFECT OF COMPOUND
ON PACKED COLUMN DESIGN
95% REMOVAL
55°F
1,2 DICHLOROETHANE
55°F
OETHANE
1 ¦ '
60/1 80/1 100/1 120/1
A/W RATIO
-------
FIGURE lli-e
LIQUID LOADING RATE-30gpm/«f
AIR: WATER RATIO = 3011
SITE 0
(55 F)y
L SITE A
(79 F)
50
75
90 95 97.5 99
REMOVAL EFFICIENCY (%)
99.5
99.8
PACKING HEIGHT VS REMOVAL EFFICIENCY
TCE
352
-------
PACKED
COLUMN
Txrrx
| TO ATMOSPHERE
~y\
SPRAY
HEADER
PLASTIC
MEDIA
HIQH SERVICE
VERTICAL
AIR TURBINE PUMPS
^— BLOWER
ASSEMBLY
CLEAR HELL
FINISHED WATER
TO SYSTEM
rrQP
iFZTPrr
WELL
PACKED COLUMN SYSTEM COMPONENTS
-------
4. Housing
a. Freezing potential (see Figure IIX-10 for examples of tempera-
ture effects on aeration system)
b. Noise
c. Security
d. Equipment maintenance
5. Column and Column Internals
a. Column Construction
- FRP (fiberglass-reinforced plastic)
- Aluminum
- Stainless steel
- Concrete
b. Mist eliminator
c. Liquid distributor
- orifice plate (see Figure III-ll)
- trough-type distributor (see Figure II1-12)
- orifice headers
- spray nozzles
d. Support grid
e. Packing Media
6. Air Quality
a. Intake air - air-bourne contaminants
b. Exist air - discharge regulations
7. VOC Emissions
a. Discharge rate - pound/hour
b. Ambient concentrations
c. Modeling
d. Column modifications
- Height
- Air flowrate
- Exist velocity
354
-------
FIGURE III- 1 0
TEMPERATURE EFFECTS
ON AERATION SYSTEM - JANUARY 1983
WATER IN
51°F
I
rr
-4-4-
WATER OUT
49#F
]
a AIR OUT
i r
[ ' i i !: i
-H-
-<4-
AMBIENT AIR
18°F
AIR IN
355
-------
FIGURE III- 1 1
Orifice-type distributor
356
-------
Tnn
\W'^
-^P
p.
\0f
tf>1
-------
e. Vapor phase carbon (see Figure II1-13)
8. Clogging of Packing
a. Iron
b. Solids
c. Biological growth
d. Pretreatment requirements may have to be considered for any one
of these problems
9. Corrosivity of Treated Water
a. Problem: increase DO, reduce CO
b. Solution: reduce pH; provide post treatment
E. ECONOMICS
1. Packed column cost components.
Basic
Site Specific
Column Structure
Internals
Packing
Blower(s)
Clearwell
Booster puiqp(s)
Piping
Special citework
Raw water holding tank
New/restaged well pump
Blower building
Booster pump building
Chemical facility
Noise control installation
Air emissions control
2. Capital costs of packed columns - see Figure 111-14.
3. O&K costs of packed columns - see Figure IXI-15
4. Relative costs for removal:
Vinyl Chloride
least costly to remove
PCE
TCE
Carbon Tetrachloride
1,2-Dichloroethane
DBCP
most costly to remove
358
-------
TREATED AIR
CONTAMINATED
AIR
RAW WATER
CLEAN
AIR
PACKED
COLUMN
HEATING BLOWER
ELEMENT
BLOWER
TREATED
WATER
VAPOR PHASE CARBON
-------
ANNUAL O&M COSTS
FOR PACKED COLUMN SYSTEMS
» 100
o
o
o
80
in
Lo
o
o
h
(0
o
o
2
4
O
60
40
< 20
1.0 2.0 3.0 4.0
SYSTEM SIZE (MGD)
5.0
O
c
2)
m
i
-------
ANNUAL O&M COSTS
FOR PACKED COLUMN SYSTEMS
m 100
O
O
O
tT 80
<*
I-
(0
o
o
s
«0
o
60
40
20
Z'
<
1.0 2.0 3.0 4.0
SYSTEM SIZE (MGD)
5.0
-------
IV. AERATION - CASE STUDY
Scope; Describes experience of a water supplier in dealing with organic
contamination of its supply U6ing packed column aeration.
k. PACKED COLUMN AERATION - SCOTTSDALE, ARIZONA
1. System characteristics
- ground water supply
- 24 wells
- 40 mgd capacity
2. Water Quality
a. Well No. 6 (1,200 gpm), TCE: 18 to 200 ug/L
b. Well No. 31 (2,500 gpm), TCE: 5 to 43 ug/L
3. Evaluation of Alternatives
a. GAC adsorption - $0.17 - 0.38/1,000 gal.
b. packed column aeration - $0.07/1,000 gal.
4. Pilot tests conducted on-site to evaluate packed column aeration;
mini-column tests conducted in laboratory to evaluate GAC adsorption
5. Design Considerations
a. TCE removal
b. Air quality
c. Aesthetics
d. Noise
6. Process Design Criteria
a. Flow: 1,200 9pm
b. Packing Height: 12 feet
c. AtW Ratio 50>1
d. Column Diameter: 10 feet
e. Removal Efficiency: 97 percent of TCE
7. Facility Schematic - see Figure IV-1
8. Facility Layout - see Figure IV-2
9. Air Quality Monitoring Study
a. review local meteorological conditions
b. simulate impact of packed column operation
362
-------
EXHAUST
TREATED WATER
TO RESERVOIR
INFLUENT
WATER
WELL NO.6
BOOSTER
PUMP
BLOWER
CLEARWELL
//4yYW
SCHEMATIC DIAGRAM
SCOTTSDALE PACKED COLUMN
-------
SCOTTSDALE FACILITY LAYOUT
£
-.o
BLOWER
ROOM
PACKED
COLUMN
PUMP ROOM
• ¦
i
-------
c. establish background TCE levels
d. monitor air quality during operation
e. recommend long-term monitoring program
10.
11.
12.
Proposed Packed Column Operating Schedule (see Figure IV-3)
Air Quality Monitoring
Date
2/20/85
Weather
Conditions
Sunny, breezy
3/6/85 Overcast, calm
Distance
Downwind (m)
20
48
16
48
61
95
TCE
Concentration (ug/m )
<0.01
<0.01
0.05
0.04
<0.01
<0.01
Full-scale Operating Results
Date
2/20/85
3/6/85
3/17/85
3/19/85
TCE Concentration (ug/L) Percent. .
Influent Effluent Removed
67.3
89.1
190
200
0.5
1.1
1.1
1.2
99.3
98.7
99.4
99.4
fl) Design percent removal * 97%.
13. Costs
a. Capital: $300,000
b. O&M: $25,000/year
14. Interaction with Public
a. media coverage
b. public meeting
c. formation of citizen groups
d. tour of facilities
• . recommendations of citizen groups
15. Conclusions
a. Packed column aeration is effective
b. Obtain public comment early
c. Encourage positive media coverage
d. Be prepared to address air quality impacts
365
-------
CITY OF SCOTTSDALE
PROPOSED PACKED COLUMN
OPERATING SCHEDULE
MONTH
JAN FEB MAR APR MAY JUN JUL AUG SEP OCT MOV DEC
u>
ON
O*
¦
D
C
31
m
<
i
u
-------
ORGAN ICS TREATMENT
REFERENCES
I. GRANULAR ACTIVATED CARBON - TREATMENT OVERVIEW
1. Peel, R.G. and A. Benedek, "Attainment of Equilibrium in Activated Carbon
Isotherm Studies," Environmental Science and Technology, 14:66-79, 1980.
2. U.S. EPA, "Process Design Manual for Carbon Adsorption," Technology
Transfer, U.S. EPA, October 1973.
3. Ruggiero, D.D. and R. Ausubel, "Removal of Organic Contaminants from
Drinking Water Supply at Glen Cove, New York, Phase II," Report
No. EPA-600/2-82/027, U.S. EPA, March 1982, and Phase I, Report
No. EPA-600/2-80-198, 1980.
4. Dobbs, R.A. and J.M. Cohen, "Carbon Adsorption Isotherms for Toxic
Organics," EPA Report 600/880-023, Office of Research and Development,
MERL, Cincinnati, Ohio, April 1980.
5. Love, O.T. and R.G. Ellers, "Treatment for the Control of
Trichloroethylene and Related Industrial Solvents in Drinking Water,"
Drinking Water Research Division, U.S. EPA, Cincinnati, Ohio, February
1981, JAWWA. 74i413, 1982.
6. Weber, W.J., Jr. and M. Pirbazari, "Adsorption of Toxic and Carcinogenic
Compounds from Water," JAWWA, 74:203, 1982.
7. Symons, J.M., "Removal of Organic Contaminants from Drinking Water Using
Techniques Other than Granular Activated Carbon Alone - A Progress
Report," Drinking Water Research Division, U.S. EPA, Cincinnati, Ohio,
May 1979.
8. Randtke, S.J. and C.P. Jepsen, "Lffects of Salts on Activated Carbon
Adsorption of Fulvic Acids," JAWWA, 74»84-93, February 1982.
9. Hess, A.F., "GAC Treatment Designs and Costs for Controlling Volatile
Organic Compounds in Ground Water," Malcolm Pirnie, Inc., Paraous, New
Jersey. Paper presented at the National American Chemical Society
Meeting, Atlanta, Georgia, March 30 - April 3, 1981.
10. Sontheimer, H., "Applying Oxidation and Adsorption Techniques: A Summary
of Progress," JAWWA, 71:612-617, November 1979.
11. Schalekamp, M., "The Use of GAC Filtration to Ensure Quality in Drinking
Water from Surface Sources," JAWWA, 71:638-647, November 1979.
12. Meijers, A.p., "Objectives and Procedures for GAC Treatment," JAWWA,
71:628, 1979.
13. Fiessinger, F. and Y. Richard, "International Experience with Granular
Activated Carbon." Paper presented at the AWWA meeting, Atlanta,
Georgia, June 15-20, 1980.
367
-------
14. McCarty, P.L., D. Argo and M. Reinhard, "Operational Experiences with
Activated Carbon Adsorbers at Water Factory 21," JAWWA, 71:683-689,
November 1979.
15. Roberts, P.V. and R.S. Summers, "Performance of Granular Activated Carbon
for Total Organic Carbon Removal," JAWWA, 74:113-118, February 1982.
16. Schulhof, P., "An Evolutionary Approach to Activated Carbon Treatment,"
JAWWA, 71:648, 1979.
17. Sontheimer, H., "Design Criteria and Process Schemes for GAC Filters,"
JAWWA, 71:618, 1979.
18. Malcolm Pimie, Inc., "Preliminary Treatment Designs and Costs for
Control of Organic Compounds." Report prepared for the Office of Drink-
ing Water, U.S. EPA, Washington, D.C., April 1981.
19. O'Brien, R.P., D.M. Jordan and W.R. Musser, "Trace Organics Removal from
Contaminated Ground Waters with Granular Activated Carbon," Calgon
Corporation, Pittsburgh, Pennsylvania. Presented at the National Ameri-
can Chemical Society Meeting, Atlanta, Georgia, March 29 - April 3, 1981.
20. Weber, W.J., Jr. and B.M. VanVliet, "Synthetic Adsorbents and Activated
Carbons for Water Treatment: Overview and Experimental Comparisons,"
JAWWA, 73:420, 1981.
II. GRANULAR ACTIVATED CARBON - CASE STUDIES
1. Chrobak, R.S., D.L. Kelleher and I.H. Suffet, "Full Scale GAC Adsorption
Performance Compared to Pilot Plant Predictions." Paper presented at the
1985 Annual Conference of the American Water Works Association held in
Washington, D.C., June 27, 198S.
2. Pawley, J.D., "Ground Water Pollution; A Case Study," JAWWA, 74:8:405,
August, 1982.
3. Stover, E.L. and D.F. Kincannon, "Contaminated Ground Water Treatability:
A Case Study," JAWWA, 75>6:292, June 1983.
4. Woodhull, R.S., "Ground Water Contamination in Connecticut," JAWWA
73:4:188, April 1981.
5. DeMarco, J., "Experiences in Operating a Full-Scale Granular Activat-
ed-Carbon System with On-Site Reactivation," "Treatment of Water by
Granular Activated Carbon," edited by I.H. Suffet and M.J. McGuire,
Advances in Chemistry Series, American Chemical Society Books, 1983.
6. Tucker, R.K. "Ground Water Quality in New Jersey - An investigation of
Toxic Contaminants," New Jersey Department of Environmental Protection,
Office of Cancer and Toxic Substances Research, March 1981.
368
-------
7. Suffet, I.H. et al., "Applying Analytical Techniques to Solve Ground
Water Contamination Problems," JAWWA, 77:1:65, January 1985.
8. Chrostowski, P.O., Chrobak, R.S., Deitrich, A.m., and Suffet, I.H., "A
Comparison of Granular Activated Carbon and a Carbonaceous Resin for
Removal of Volatile Halogenated Organics from a Ground Water," "Treatment
of Water with Granular Activated Carbon," edited by I.H. Suffet and
M.J. McGuire, Advances in Chemistry Series, American Chemical Society
Books, 1983.
9. Westerhoff, G.P. and R. Miller, "Design of the Nation's First Major GAC
Facility for Drinking Hater Treatment at Cincinnati, Ohio." Paper
presented at the 1985 Annual Conference of the American Water Works
Association held in Washington, D.C., June 1985.
10. Miller, R., D. Hartman, J. DeMarco, "Cincinnati Full Scale Research
Project with Granular Activated Carbon."
11. DeMarco, J., R. Miller, D. Davis, C. Cole, "Experiences in Operating a
Full-Scale Granular Activated-Carbon System with On-site Reactivation in
"Treatment of water by Granular Activated Carbon," American Chemical
Society, 1983.
12. Howes, J.E., F.Ii. DeRoos, D. Aichele, D. Kohler, M. Larson, B.W. Lykins,
"Determination of Dioxin Levels in Carbon Reactivation Process Effluent
Streams."
111• AERATION - TREATMENT OVERVIEW
1. Langelier, W.F., "Theory and Practice of Aeration," JAWWA, 24:1:62, 1932.
2. Harney, Paul D., "Theoretical Principles of Aeration," JAWWA, 4o:4t353,
1954.
3. Camp, T.R., "Gas Transfer To and From Aqueous Solutions," Journal Sani-
tary Engineering Division, Proc. ASCE, 84:SA4:1701, 1958.
4. McCarty, F.L., K.H. Sutherland, J. Graydon and M. Reinhard, ".olatile
Organic Contaminants Removal by Stripping," Proc. AWWA Seminar, Control-
ling Organics in Drinking Water, San Francisco, June 1979.
5. Singley, J.E., A.L. Ervin, M.A. Mangone, J.M. Allan and H.H. Land, "Trace
Organics Removal by Air Stripping," AWWA Research Foundation, 1980.
6. Treybal, R.E., "Mass Transfer Operations," McGraw-Hill Book Co., New York
(3rd edition), 1980.
7. Kavanaugh, M.C. and R.R. Trussel, "Design of Aeration Towers to Strip
Volatile Contaminants from Drinking Water," JAWWA, 72:12:684, 1980.
369
-------
8. Warner, H.P., J.M. Cohen and J.C. Ireland, "Determination of Henry's Law
Constants of Selected Priority Pollutants," Wastewater Research Division,
Municipal Environmental Research Laboratory, Cincinnati, Ohio, 1980.
9. Symons, J.M., A.A. Stevens, R.M. Clark, E.E. Geldreich, O.T. Love and
J. DeMarco, "Treatment Techniques for Controlling Trihalomethanes in
Drinking Water," U.S. EPA, Drinking Water Research Division, 1981.
10. Dyksen, J.E. and A.P. Hess, "Aeration Techniques for Removing Trace
Organic Compounds from Drinking Water." Paper presented at the 1981 ASCE
National Conference on Environmental Engineering, Atlanta, Georgia, July,
1981.
11. Dyksen, J.E., A.P. Hess, M.J. Barnes and G.C. Cline, "The Use of Aeration
to Remove Volatile Organics From Ground Water." Presented at the 1982
Annual Conference of the American Water Works Association, Miami Beach,
Florida, May 1982.
12. Love, O.T. and R.G. Eilers, "Treatment for the Control of
Trichloroethylene and Related Industrial Solvents in Drinking Water,"
U.S. EPA, Drinking Water Research Division, Cincinnati, Ohio, October
1980.
13. Nebolsine, Kohlman and Ruggiero Engineers, "Removal of Organic Contami-
nants from Drinking Water Supply at Glen Cover New York," Interim Report
on U.S. EPA Agreement No. CR806355-01, Office of Research and Develop-
ment, MERL, Drinking Water Research Division, Cincinnati, Ohio, July
1980.
14. Hess, A.F., J.E. Dyksen and G.C. Cline, "Case Studies Involving Removal
of Organic Chemical Compounds from Ground Water." Presented at the 1981
Annual Conference of the American Water Works Association St. Louis,
Missouri, June 1981.
15. Metcalf and Eddy, Inc., "Volatile Organics Removal! Two Ground Water
Supply Case Histories." Presented at the New York Section AWWA, 1980.
16. Kavanaugh, M.C. and R.R. Trussel, "Air Stripping as a Treatment Process."
Paper presented at the AWWA conference, July 1981.
17. Cummins, M.D. and J.J. Westrick, "Packed Column Air Stripping for Removal
of Volatile Compounds." Presented at the 1982 Conference on Environ-
mental Engineering, ASCE, July 14-15, 1982.
18. McKinnon, R.J. and J.E. Dyksen, "Aeration Plus Carbon Adsorption Remove
Organics from Rockaway Township (NJ) Ground Water Supply." Presented at
the 1982 Annual Convention of the American Society of Civil Engineers,
New Orleans, Louisiana, October 25-27, 1982.
370
-------
19. Mackay, D. et al., "Determination of Air-Water Henry's Law Constants for
Hydrophobic Pollutants/" Environmental Science and Technology, 13(3),
33-337, 1979.
20. Munz, C. and P.V. Roberts, "Transfer of Volatile Organic Pollutants into
a Gas Phase During Bubble Aeration," Technical Report No. 262, Depart-
ment of Civil Engineering, Stanford University, 1982.
21. Raczko, R.F., J.E. Dyksen and M.B. Denove, "Pilot Scale Studies of Air
Stripping for Removal of Volatile Organics from Ground Water." Presented
at the 14th Mid-Atlantic Industrial Waste Conference, University of
Maryland, College Park, Maryland, 1982.
22. Roberts, P.V. and P. Dandliker, "Mass Transfer of Volatile Organic
Contaminants During Surface Aeration." Presented at the 1982 Annual
Conference of the American Water Works Association, Miami Beach, Florida,
May 1982.
IV. AERATION - CASE STUDY
1. Cline, G.C., T.J. Lane and M. Saldamando, "Packed Column Aeration for
Trichloroethylene Removal at Scottsdale, Arizona." Paper presented at
the 1985 Annual Conference of the American Water Works Association held
in Washington, D.C., June 1985.
2. Malcolm Pimie, Inc., Report on Organic Chemical Treatment of Ground
Water Supply, Well No. 31, prepared for the City of Scottsdale, Arizona,
March 1983.
370 A
-------
D.
RISK MANAGEMENT PROBLEM
GROUNDWATER CONTAMINATED WITH ALDICARB,
TRICHLOROETHYLENE AND VINYL CHLORIDE
371
-------
RISK MANAGEMENT CASE STUDY
Introduction to Case Study
I. Background information on Aldicarb, Trichloroethylene
and Vinyl Chloride
II. Drinking Water Regulations: Statutory and Institutional
Background
III. Background on the Water Supply System
IV. Calculating Human Exposure and Risk
V. Options for Reducing Risks
372
-------
INTRODUCTION TO THE RISK MANAGEMENT CASE STUDY
You are a group of experts called together by the water supply manager
of a small town to advise her on a possible case of drinking water contamination.
You will be required to analyze the situation and make a brief presentation
of your findings at a public meeting. Earlier you were presented with
information concerning the health risks associated with exposure to the
three compounds. You are aware that, although the risk assessment is
fairly complete, there are a host of other factors that must be considered
in implementing a permanent solution, lhese factors will be a part of
your risk managment problem. While risk assessment considers the nature
of the risk, risk management must consider taking appropriate action to
alleviate that risk.
Most of you probably are familiar with the work of Dr. John Snow in
London, 1854. Dr. Snow, through a very thorough epidemiological study,
proved that the Broad Street pump was the source of an outbreak of cholera.
He did this by statistically correlating incidence of disease with exposure
to drinking water at that well. This example was an early form of risk
assessment. Later, Snow removed the handle from the pump and observed
that, as the people drank water from other sources, the incidence of cholera
declined. This later act was what we are calling risk management. Dr.
Snow took positive action to correct the problem. Unfortunately, today's
drinking water contamination problems are not solved as readily.
Snow had a relatively simple problem to solve by modern standards,
but remember, he accomplished this twenty years prior to the discovery of
the germ theory of disease by Koch and Pasteur. The public health aspect
of drinking water has come upon the reverse of Snow's problem. He knew
the risk of drinking water from the Broad Street Pump, but could not identify
the contaminant.
Today we can identify many more contaminants, but are unable to
determine the exact nature of the potential adverse human health effects.
Further, quantifying those risks is itself a risky business, projection
of human risk exposure from data on animal carcinogens would appear to be
straight forward. But, as you saw in the risk assessment problem, even
the "experts" cannot agree on validity of extrapolation of animal data
to human health risks. Even the most experienced scientists cannot
predict the exact nature of the risk of exposure to chemical contaminants.
In the problem described here, the risk assessment would likely
conclude that one contaminant is an animal carcinogen, another, a human
carcinogen, and the third, a neurotoxin. Large uncertainties surround the
projection of human risks from animal data. Six or more orders of magnitude
(106 or one million times) of uncertainty are associated with the use of
models extrapolating animal data to human data. Everyone would feel more
comfortable if there were more certainty in the risk assessment, but there
is very seldom a straight answer to a chemical contaminant safety issue.
All of thie uncertainty becomes part of the evaluation and analysis conducted
in the process called risk management.
373
-------
YOUR ROLE
You, as an expert consultant, must advise the town manager and recommend
an appropriate course of action to protect the public health, both long and
short term. Specifically, you are concerned with mitigating people's exposure
to the toxic chemicals in drinking water.
This case study focuses on your ability to use the information presented
in this course to solve a drinking water contamination problem. Tlie review
and evaluaton will take place with a group of 10 to 15 people. You will
realize that there is no one right or wrong answer and common sense should
prevail. The process by which you arrive at your conclusions is very important.
The group should attempt to come to a concensus about what action can be
taken. If you cannot come to a concensus, present the alternative views.
The conclusions of each work group will be compared and contrasted at a
final plenary session.
NATURE OP THE MATERIAL
You will focus on several types of information. Results of the previously
completed risk assessments will be reviewed briefly, in addition, both
qualitative and quantitative information will be provided on various courses
of action. This information will include political and social factors as
well as treatment, economic and environmental data. You must consider the
interests of various economic and public interest groups in your recommendation.
The case study package is divided into five sections. Each package
also contains the Health Advisory documents for aldicarb, vinyl chloride and
trichloroethylene. lhe Health Advisory documents contain occurrence, health
effects, analytical chemistry and treatment data on each chemical. Use this
information as appropriate in formulating your respose to the questions that
appear in the latter sections of the case study. The discussion of drinking
water regulations focuses on proposed rulemaking for the volatile synthetic
organic chemicals and some pertinent legislative background. This information
should prove useful in organizing your thoughts, but should not be viewed as
providing the exact answer or constraining your response. Remember, this is
proposed rulemaking and you are required to respond immediately. The following
three sections provide site-specific information, questions to be answered
and calculations to be performed. It might be helpful if someone in each
group could provide a calculator, but this is not required. We also will
provide a facilitator for each group. He should not lecture, nor should you
look to him foj> providing answers.
The focus of this exercise is risk management and risk communication.
Try to use the conclusions from your risk assessment of the relevant chemicals,
as well as the information provided here and in the lectures.
374
-------
I. BACKGROUND INFORMATION ON CHEMICALS
the Health Advisories for aldicarb, trichloroethylene and vinyl
chloride are located in this workbook in the next section immediately
following this problem. Additional information concerning the chemicals
will appear as appropriate throughout this document and in some of the
lecture outlines.
375
-------
II. DRINKING WATER REGULATIONS: STATUTORY AND INSTITUTIONAL CONCERNS
INTRODUCTION
In thinking about how to manage a drinking water contamination incident
it would be useful to understand the framework provided by the Safe Drinking
Water Act as amended through 1986. This Act provides a two step approach to
setting drinking water standards. The first step is to set a maximum contaminant
level goal (MCLG), formerly called the recommended maximum contaminant level
(RMCL). EPA must also set the maximum contaminant level (MCL) as close to
the MCLG as is feasible. Simply put, MCLGs are health-based goals and MCLs
are technologybased standards. Standards are enforceable and goals are not.
MCLGs are non-enforcable health goals. MCLGs are "set at the level at
which no known or anticipated adverse effects on the health of persons occur
and which allow an adequate margin of safety". The House Report on the Safe
Drinking Water Act provides Congressional guidance on developing RMCLs (MCLGs):
"... the recommended maximum level must be set to
prevent the occurence of any known or anticipated
adverse effect. It must include an adequate margin
of safety, unless there is no safe threshold for
a contaminant, in such a case, the recommended max-
imum contaminant level should be set at zero level".
The RMCLs (MCLGs) for a number of carcinogenic volatile organic chemicals
were proposed at zero based on this language. Obviously, the MCL or enforceable
level cannot be zero since zero cannot be measured. The MCL or enforceable
level must be a non-zero number.
The MCL must be set as close to the RMCL (MCLG) as is feasible. Feasible
means with the use of the best technology, treatment techniques and other
means available taking cost into consideration. Hie 1986 Amendments include
language indicating that these technologies must be tested under field conditions.
The Amendments also state that technologies, for the control of synthetic
organic chemicals (SOCs), must be at least as effective as granular activated
carbon.
The general approach used in setting MCLs for the volatile organic
chemicals (VOCs) or any other contaminant is to determine feasibility. This
requires an evaluation of: (1) the availability and cost of analytical methods,
(2) the availability and performance of treatment technologies and (3) an
evaluation of the cost and feasibility of achieving various levels. A brief
non-technicalydescription of each component of the regulatory analysis follows.
ANALYTICAL METHODS
The analytical method constraints include considerations of precision
and accuracy at low (ppb-part per billion) levels. The numbers produced by
the analyst must be within some reasonable proximity of the true value (accuracy)
and must be reproducible (precision).
376
-------
The analytical methods for the volatile organic chemicals include gas
chromatography (GC) with either conventional detectors or a mass spectrometer
(GC/MS). These analytical methods use the purge and trap technique for
extraction from the liquid phase and concentration on a columnn containing a
sorbent. Hie higher molecular weight organic chemicals (e.g., pesticides)
generally require extraction with a solvent (e.g., hexane or methylene chloride).
The sample or solvent extract is injected into the entrance port of the GC
column. Purging of the volatile chemicals is accomplished using an inert gas.
The organic chemicals of interest are then sorbed to the wall or special packing
material within the column, Hie compounds are desorbed from the column by
heating and backflushed into the head of the GC column. Hiis is followed by
separation of constituents in the GC column and measurement with a specific
detection system. Detection systems include photo-ionization and electrolytic
conductivity. Hie detection system generates an electrical signal which is
amplified and transformed to a peak on a strip chart recorder. The position
and height of the peak is then compared to internal standards for identification
and quantification.
Each step of this process is subject to some error. Hiese errors are
expressed as precision and accuracy. For the single lab this is sufficient.
But, in developing national standards, one must consider interlaboratory
variablity. In general, EPA defines the method detection limit (MDL) as the
minimum concentration of a substance that can be measured and reported with 99
percent confidence that the true value is not zero. Hiis detection limit
differs for different labs, different instruments, different analysts, and is
not necessarily reproducible over time if all these factors remain the same.
Traditionally, quantification limits are five to ten times the method detection
limit. Hie importance of this is that it is not possible to determine compliance
or noncompliance with an MCL unless there is reasonable assurance that the
reported value is close to the true value.
The remaining component of the use of analytical measurements in solving
drinking water contamination problems is that of acceptable laboratory performance.
The criteria for EPA certified labs for the types of gas chromatography (GC)
analyses under consideration in this problem are +_ 40% at concentrations under
10 ug/L and +_ 20% at concentrations above 100 ug/L. Consider these limitations
in determining what levels will be acceptable in solving the case study problem.
TREATMENT TECHNOLOGIES
Once the lowest level that can be quantified has been determined, the
next constraint for determination of the MCL is the performance of the Best
Available Technologies (BAT). Hie obvious first step would be to list all
technologies that have ever been used to remove a particlar compound or class
of contaminants. For example, for the volatile organic chemicals, there are
data available on ozonation, ultraviolet Irradiation, aeration and adsorption.
Conventional coagulation and softening treatment provides little to no removal
of these compounds. However, there is limited evidence that ozonation and
ultraviolet irradiation can break down chlorinated ethylenes and other organic
molecules with double bonds. Hie kinetics of oxidation of organic contaminants
is not understood well enough to determine the cost of various levels of removal.
377
-------
Packed tower aeration and, to a lesser extent, granular activated carbon
(GAC) adsorption have been shown to be highly effective (>99.9% removal) for
the removal of volatile organic chemicals. The BAT determination for the
volatile organic chemicals is then based on these two processes.
Aeration Treatment
The performance potential of a properly designed packed tower aeration
system is quite good for VOC removal. Both field and laboratory experiments
and theoretical calculations indicate that at the concentrations generally
found in drinking water (a few hundred parts per billion or less) aeration
can produce treated water with sub-part per billion concentrations. Aeration
processes provide a fixed percent removal of contaminants. As a consequence
the concentration in the treated water can be affected by fluctuations in
the raw water concentration. Volatile organic chemical contamination of
ground waters is generally due to poor waste disposal practices and many
times the exact source can never be found. The hydrogeological factors
affecting the fate and transport of these chemicals are complex. Modeling
them is an inexact science. As a result, historic information on changes in
concentrations should be considered in the design of an aeration treatment
system. Traditionally, a safety factor of two times the raw water concentration
has be used in a conservative design. If these and other design factors are
properly considered, the treated water should meet a concentration goal
below the analytical quantification levels.
Transfer of volatile organic chemicals from air to water might be a
concern depending on the proximity to human habitation, treatment plant
worker exposure, local air quality, local meteorological conditions, daily
volume of water processed and the concentration of the contaminant. EPA
evaluated a number of existing and planned packed tower installations using
an air dispersion/human exposure model. The results of this evaluation
indicated that lifetime exposure to small amounts of carcinogenic chemicals
in air did not result in a significant increase in individual risk of cancer
(generally, less than one in 10® or 10?). These were the highest risks
and occurred for persons exposed to 70 years of worst case air concentration
conditions at less than two hundred meters from the source. As the distance
grows, the population exposed increases, but the concentration declines so
rapidly that projected cancer risks become very small. Using very conservative
assumptions these kinds of analyses resulted in a projection of less than
one possible cancer incidence nation-wide over seventy years. Since drinking
water contaminated with the carcinogenic chemicals of concern was the projected
cause of approximately 50 excess cases of cancer, one could conclude that
air emissions from aeration treatment facilities are not a major national
concern. ^
If necessary, control of volatile organic chemical emissions from
packed tower aeration installations is feasible using air phase GAC adsorption.
EPA currently has full-scale field evaluations of this technology under way.
Preliminary evidence indicates that installation of this equipment would
approximately double the cost of water treated by packed tower aeration.
378
-------
GAC Adsorption Treatment
GAC adsorption removal of moat organic contaminants from drinking
water, especially ground waters, is very good. There are a few exceptions
including low molecular weight compounds such as vinyl chloride. Experiments
with this chemical have shown removal of it from water to be erratic using
GAC adsorption columns.
The capacity of carbon for removing a contaminant from water can be
determined empirically. Generally, GAC adsorption removes the contaminant
to below its detection limit until the capacity of the fixed bed adsorber is
reached. The point at which the contaminant is detected in the effluent
water is termed breakthrough. After breakthrough the GAC may remain in
service for some time until the treatment goal is reached. Carbon is replaced
at intervals of three to six months or longer in practice.
Background organics, sometimes measured as total organic carbon or
TOC, can increase the amount of carbon required to treat a given volume of
water. This is especially a problem in surface waters. But, since the
volatile organic chemicals do not occur often above one part per billion in
surface waters, this may not become a major issue. It also should be noted
that empirical determination of carbon usage rates at the site takes into
account the competitve effects of background naturally-occurring organics
(i.e., TOC).
Once the treated water goal is reached by a GAC treatment system, the
carbon must be replaced or reactivated. Small systems generally have a
contract with a supplier who delivers fresh carbon and removes the spent
carbon. The supplier may then reactivate the carbon for use in waste water
treatment. Larger systems can reactivate the GAC on-site using heat. Fluid-
ized bed reactivation furnaces are popular for this. This thermal reactivation
process can result in the discharge of particulates and combustion products
of both the fuel and the adsorbed organics to air. Experiments at Cincinnati,
Ohio revealed that toxic (carcinogenic) dioxins were in the stack gases of
the reactivation furnace. Afterburners typically installed with reactivation
furnaces remove the dioxins and other air pollutants. These concerns are
not likely to limit the applicablity of GAC adsorption as BAT for the control
of organic chemical contaminants in water.
Cost Considerations
The Safe Drinking Hater Act requires EPA to take cost into consideration
in setting standards. The objective is to set the maximum contaminant level
as close to the goal (zero for carcinogens) as is feasible taking cost into
consideration. Tables 1 and 2 contain cost estimates for 99% removal of
nine volatile organic chemicals using GAC and aeration. For perspective,
the average cost of treated drinking water in the U.S. ranges from about one
dollar to a dollar and a half per 1000 gallons. Figure 3 is a table of the
cost of removing trichloroethylene to various concentrations. Notice that
the rate of increase of cost does not change dramatically as the percent
removal increases nor are the actual costs significantly higher than that
paid for treated water today. It would not be inordinate to conclude that
the cost of removing volatile organic chemicals down to the analytical
quantification level is reasonable.
379
-------
The previous paragraph discussed the system level costs of removing
volatile organic chemicals. At the national level total national costs
are an obvious concern. Table 5 presents a summary of the national cost
as a function of the selection of maximum contaminant level. A major
conclusion that may be drawn is that, as the level decreases, the total
number of systems required to treat increases and consequently the cost
increases, lhe total national cost was not the major determinant in the
selection of the maximum contaminant level, but was considered in the
overall analysis.
FINAL RULE
The final rule promulgating maximum contaminant levels for the nine
volatile organic chemicals has not been published. The EPA may change the
numbers or the methodology used in determining those numbers, The solution
to the risk management problem should consider that regulations for tri-
chloroethylene and vinyl chloride aire due out shortly and that a rule for
aldicarb and other pesticides is also forthcoming. But, do not restrict
your response to what EPA may or may not do. In other words, you must
take the Health Advisory and risk assessment/management problem data and
develop your own solutions and numerical goals.
380
-------
Table 1
Cost for 99 percent removal (from 500 ug/1 to 5 ug/1)
of the nine VOCs using packed tower aeration in
August 1983 dollars.
Costs by System Size Category*
100 - 500 3300 - 10,000 100,000 - 500,000
Compound (0.037 mgd) (0.95 mgd) (36.8 mgd)
Tr ichloroethylene
Capital cost 69,000 264,000 4,789,000
Annual 0 £ M cost 1,400 18,000 617,000
total cost (£/1000 gallons) 79.0 15.5 9.4
Tetrachloroethylene
Capital cost 67,000 252,000 4,607,000
Annual O & M cost 1,200 15,000 513,000
total cost (0/1000 gallons) 75.0 14.2 8.4
Carbon tetrachloride
Capital cost 66,000 249,000 4,536,000
Annual O & M cost 1,200 15,000 509,000
total cost (0/1000 gallons) 75.0 14.0 8.3
1,2-Dichloroethane
Capital cost 84,000 461,000 10,221,000
Annual 0 & M cost 2,400 37,000 1,149,000
total cost (0/1000 gallons) 101.0 28.5 18.7
Vinyl chloride
Capital cost 60,000 201,000 3,453,000
Annual 0 & M costs 900 11,000 377,000
total cost ($6/1000 gallons) 66.0 11.0 6.2
1,1-Dichloroethylene
Capital cost 64,000 229,000 3,975,000
Annual 0 6 M costs 1,000 13,000 428,000
total costs (0/1000 gallons) 71.0 12.5 7.1
~Number of persons served and million gallons per day
381
-------
Costs by System Size Category
100 - 500 3300 - 10,000 100,000-500,000
Compound (0.037 mgd) (0.95 mgd) (36.80 mgd)
Benzene
Capital cost 74,000 325,000 6,538,000
Annual O & M cost 1,700 23,000 781,000
total cost (jji/1000 gallons) 86.0 19.2 12.3
p-Dichlorobenzene (1000 ug/1 to 750 ug/1)
Capital cost 51,000 146,000 2,489,000
Annual O & M cost 700 8,000 283,000
total cost (jg/1000 gallons) 56.0 8.1 4.6
1,1,1-Trichloroethane (500 ug/1 to 200 ug/1)
Capital cost 52,000 150,000 2,500,000
Annual O & M costs 700 8,500 290,000
total cost (£/1000 gallons) 57.0 8.2 4.7
382
-------
TABLE 2
Cost for 99 percent removal (from 500 ug/1 to 5 ug/1) of the
nine VOCs using granular activated carbon adsorption in
August 1983 dollars
Coats by System Size Category*
100 - 500 3300 - 10,000 100,000-500,000
Compound (0.037 mgd) (0.95 mgd) (36.8 mgd)
Trichloroethylene
Capital cost 24,000 240,000 9,000,000
Annual 0 & M cost 4,500 86,000 710,000
Total cost (ff/1000 gallons) 57.0 34.0
Tetrachloroethylene
14.0
Capital cost 24,000 240,000 7,700,000
Annual 0 fi M cost 2,800 45,000 400,000
Total cost (£/1000 gallons) 45.0 22.0 11.0
Carbon tetrachloride
Capital cost 24,000 240,000 9,800,000
Annual O & M cost 5,700 85,000 930,000
Total cost (^/1000 gallons) 66.0 34.0 17.0
1,2-Dichloroethane
Capital cost 24,000 240,000 11,000,000
Annual 0 & M cost 9,400 150,000 1,500,000
Total cost (£/1000 gallons) 93.0 52.0 23.0
Vinyl chloride
Capital cost NA NA HA
Annual 0 £ M cost NA NA NA
Total cost (f*/1000 gallons) NA NA NA
1,1-Dichloroethylene
Capital cost 24,000 240,000 9,100,000
Annual 0 & M cost 4,600 90,000 740,000
Total cost (0/1000 gallons) 58.0 35.0 15.0
~Number of persons served and million gallons per day
383
-------
Coats by System Sige Category
100 - 500 3300 - 10,000 100,000-500,000
Compound (0.037 mgd) (0.95 mgd) (36.8 mgd)
Benzene
Capital cost 24,000 236,000 17,200,000
Annual 0 £ M cost 15,700 258,000 2,800,000
Total cost (£/1000 gallons) 150 83.3 37.6
p-Dichlorobenzene (1000 ug/1 to 750 ug/1)
Capital cost 24,000 240,000 5,100,000
Annual 0 & M cost 1,900 22,000 230,000
Total cost (0/1000 gallons) 38.0 15.0 6.9
1,1,1-Trichloroethane (500 ug/1 to 200 ug/1)
Capital cost 24,000 240,000 10,000,000
Annual 0 £ M cost 6,600 100,000 1,100,000
Total cost (0/1000 gallons) 73.0 38.0 18.0
384
-------
Table 3: Comparsion of Various Levels of Removal of Trichloroethylene (as
percent versus total costs (cent per thousand gallons)
%
removed
50
90
99
Total Cost (cents per
using packed
tower aeration
5.9
8.5
12.0
thousand gallons)
using GAC
adsorption
18.5
22.7
25.3
Table 4: Summary of Impacts of the Regulatory Options for Controlling Volatile
Organic chemicals (Federal Register, November 13, 1985, p.46927)
Reg
ulatorv Options
1 ug/L
5 ug/L
10 ug/L
Number of Systems
3,800
1,300
800
Total cost ($M)
1 ,300
280
150
Annual cost ($M)
100
21
11
Compliance ($M)
9
Unregulated ($M)
(1445)
2
Annual cost per
very small (25-500)
small (501-3300)
medium (3301-5010
large (>50k)
96
47
12
91
41
12
90
40
11
Annual Cancer Cases
Avoided
42
32
31
385
-------
Table 5: Costs Impacts of MCLs At Various Levels
Estimated
National cost
Annual cost per family per size
#
($ mill]
Lons)
of system
dollars
per year)
systems
MCL Opts. ug/L
impacted
Total
Annual
Very
Small
Medium
Large
capital
small
3,800
1,300
100
96
47
12
8
1,300
280
21
91
41
1 2
3
800
150
11
90
42
11
1
386
-------
III. BACKGROUND ON THE CONTAMINATED WATER SUPPLY SYSTEM
Existing Water System
Population served: 30,000 people
Capacity: 5.1 million gallons per day
Average Demand: 3.0 million gallons per day
Maximum Day Demand: 4.2 million gallons per day
Source:
Storage:
Treatment:
Constructed:
0 three wells approximately 500 feet deep
0 capacity of each well is 1.8 million gallons per day
0 screened between 400 - 500 feet with gravel pack
° 18" steel casing from 0 - 400 feet
° portland cement grout from 0 - 200 feet
° all wells are pumped to a common manifold which
flows to the water treatment plant
0 soil profile: 0-100 ft., sandy soil; 100 -
400 ft., sand clay mixture; 400 -500 ft., wet sand
and gravel? 500 feet, bedrock
3.5 million gallons
Iron removal using chlorine oxidation, alum
coagulation, sedimentation, and rapid pressure
sand filtration. Disinfection (chlorine),
fluoridation and corrosion control (lime and
metallic phosphates) are also practiced.
1957
Mechanical/Struc-
tural Condition:
Excellent
Indebtedness:
Rates:
Major Employersj
None
$1.05 per thousand gallons -
$ .85 per thousand gallons -
- commercial/industrial
residential
printing plant (50 people)
potato farming (4000 Acres)
machinery manufacturing (20 people)
shopping center (30 people)
plastic bag manufacturer (10 people)
soda bottler (50 people)
US Air Force Base (10,000 including residents)
387
-------
All of the above employers are on the town water system (except the
Air Force base) and are within three miles of the the water wells. The Air
Force base has its own drinking water treatment plant which is supplied by a
surface water source.
Water Quality Results
parameter
WELL # 1
WELL #2
WELL#3
raw
treat
raw
treat
raw
treat
iron [mg/L]
3.0
0.05
2.2
0.05
2.0
0.05
PH
6.0
7.8
5.9
7.8
6.2
7.8
alkalinity [mg/L]
10
110
14
110
12
110
vinyl chloride
40
20
14
20
6
20
tug/L]
trichloroe thylene
50
60
30
60
100
60
tug/L]
aldicarb (total)
30
30
30
30
30
30
[ug/L]
Total Organic
Carbon [mg/L]
3.0
1.0
2.1
1.0
1.0
1 .0
The above analyses were reported by the State Health Department lab.
Since then, repeat samples have been analyzed and the results were not found
to be significantly different. The health officer wants you to notify the
public immediately, but will not tell you what to say. He says that no one
should use the water because it contains carcinogens and other toxic chemicals.
This is not all that acceptable to the town government, since they cannot
provide an alternate water supply in a short time frame.
388
-------
IV. DETERMINING HUMAN EXPOSURE AND RISKS
Exposure
In order for human health effects to occur as a result of environmental
contamination, there must be a level of exposure to the contaminant high
enough to reach the target organs in toxic concentrations. Some systems
have been designed to directly measure human exposure to potentially harmful
agents, but they are not generally available for situations like this.
Exposure to possible toxins in drinking water cannot be determined precisely
in the general population.
In the case at hand, we have three contaminants, two of which are
volatile synthetic organic chemicals normally used in industry and one is
an agricultural pesticide. This opens up a number of possible means and
routes of exposure for various individuals. First, a number of people
might be exposed to trichloroethylene in the work place, since it is frequently
used to degrease machinery parts. Agricultural workers might be expose to
aldicarb during application to the fields. These are specialized sub-
populations which might be considered in determining the "safe" dose for
the general population. We might have to do some research to find approxi-
mations for the exposures in the work place.
° Should we consider occupational exposures in
determining a "safe" level in drinking water?
0 Which people might be receiving occupational
exposure? (see major employers list, p. III-2)
Why?
Concentrating on exposure in the home, we have three major routes of
exposure: breathing, oral consumption and dermal exposure. We generally
assume that the average adult drinks two liters per day and breathes 20
cubic meters of air. Another standard assumption for volatile contaminants
is half of the exposure is due to volatilization.
0 For which contaminants might sources of exposure
other than drinking water be a concern? Name the
sources. What are the routes?
0 Would a 20% relative source contribution from
drinking water be a satisfactory assumption
in this case?
° Is there any way for the residents to mitigate
some of the exposure? Would boiling the water
help? How should the boiling be done?
° The town has a central sewer system with an activated
sludge treatment system, ttie activated sludge process
includes four to five hours of vigorous aeration of the
waste water. What is the ultimate sink (air, water, or
land) for each contaminant?
389
-------
Risks
In the risk assessment case study and the risk communication video
tape you learned some basic principles that now need to be applied to risk
management.
0 In layman terms, describe the individual and
population risks incurred from various sources of
exposure. Describe the fate and transport of the
contaminants and the relationship of this to the
human risk of disease.
0 How did you calculate individual and population
risks for this exercise?
0 What are your target numbers for correction?
9 How would you quantitate and articulate the
uncertainties surrounding your risk estimates?
390
-------
V. OPTIONS AVAILABLE FOR REDUCING RISK
SHORT TERM
0 point-of-use carbon treatment units @ $400 per year per home
0 bottled water delivered to the doorstep @ $600 per home per year
0 issue a boil water order @ $ 0 per year
° do nothing @ $ 0 per year
LONG TERM
0 regional water supply with the Air Force @ $500,000 per year
(this water contains an annual average concentration of 98 ug/L
of Total Trihalomethanes)
0 drill new wells @ $200/000 per year (extensive studies would be
required to find an uncontaminated source)
0 install point-of-entry GAC adsorption treatment units in each
home § $1,000,000 per year
0 install central GAC treatment to meet the following levels of
trichloroethylene:
1.0 ug/L @ 19.5
-------
September 30, 1985
E.
ALDICARB
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
The Office of Drinking Water's non-regulatory Health Advisory Program provides
information on health effects, analytical methodology and treatment technology that
would be useful in dealing with contamination of drinking water. Health Advisories
also describe concentrations of contaminants in drinking water at which adverse
effects would not be anticipated to occur. A margin of safety is included to
protect sensitive members of the population.
Health Advisories are not legally enforceable Federal standards. They are
subject to change as new and better information becomes available. The Advisories
are offered as technical guidance to assist Federal, State and local officials
responsible for protection of the public health.
The Health Advisory numbers are developed from data describing non-carcinogenic
end-points of toxicity. They do not incorporate quantitatively any potential
carcinogenic risk from such exposure. For those chemicals which are known or
probable human carcinogens according to the proposed Agency classification scheme,
non-zero One-day, Ten-day and Longer-term Health Advisories may be derived, with
attendant caveats. Health Advisories for lifetime exposures may not be recommended.
Projected excess lifetime cancer risks are provided to give an estimate of
the concentrations of the contaminant which may pose a carcinogenic risk to
humans. These hypothetical estimates usually are presented as upper 95% confidence
limits derived frcm the linearized multistage model which is considered to be
unlikely to underestimate the probable true risk.
[Summary Table-to be added]
392
-------
Aldicarb
September 30, 1985
This Health Advisory (HA) is based upon information presented in the Office
of Drinking Water's draft Health Effects Criteria Document (CD) for Aldicarb
(U.S. EPA, 1985). The HA and CD formats are similar for easy reference. Individuals
desiring further information on the toxioological data base or rationale for risk
characterization should consult the CD. The CD is available for review at each
EPA Regional Office of Drinking Water counterpart (e.g., Water Supply Branch or
Drinking Water Branch), or for a fee from the National Technical Information
Service, U.S. Department of Commerce, 5285 Port Royal Rd., Springfield, VA.,
22161, PB # 86-117751/AS.. The toll free number is (800) 336-4700; in Washington,
D.C. area: (703) 487-4650.
H. GENERAL INFORMATION AND PROPERTIES
Synonyms: 2-methyl-2~(methylthio)propionaldehyde 0-flethylcarbamoyl oxime
Temik*
Use: Pesticide (nematocide, acaracide)
Properties:
CAS #
Chemical formula
Molecular weight
Physical state (rocm temp.)
Melting point
Boiling point
Vapor pressure
Specific gravity
Water solubility
Taste threshold (water)
Odor threshold (water)
Odor threshold (air)
Structural formula
Occurrence
0 EPA estimated that aldicarb production ranged from 3.0 to 4.7 million
lbs per year during 1979-1981. Aldicarb is applied both to the soil
and directly to plants.
0 Aldicarb is considered to be moderately persistent as a pesticide.
Aldicarb is metabolized rapidly by plants after application to its
sulfoxide and sulfone. Once in the soil, aldicarb is degraded by
both aerobic and anaerobic bacteria. Aldicarb has a soil half life of
2 to 6 weeks, with residual levels found up to 6 to 12 months later.
Aldicarb in pond water was reported to degrade more rapidly, with a
half life of 5 to 10 days. Aldicarb is expected to hydrolyze slowly
over months or years in most ground and surface waters. Aldicarb and
116-06-3
C7H14O2N2S
190.3
white crystals
100°C
decomposes above 100°C
0.05 torr at 20°C
1.195 at 25°C
6 g/1 (roam temp.)
odorless to light sulfur amell
393
-------
Aldicarb
September 30, 1995
its sulfoxide and sulfone degradation products do not hind to soil
or sediments and have been shown to migrate extensively in soil.
Aldicarb does not bioaccumulate to any great extent.
0 Aldicarb has been reported to occur widely in ground water at levels
in the low ppb range. New York, Florida, Wisconsin and Maine, among
other states, have restricted the use of aldicarb based upon its
potential for ground water contamination. Aldicarb has not been
analyzed for in Agency surveys of drinking water and estimates of
national exposures are unavailable. Because of aldicarb's relatively
rapid degradation rate, it is expected to occur more often in ground
waters than surface waters (U.S. EPA, 1983).
0 Monitoring of aldicarb residues on foods have found only occasional
low levels of the pesticide and its metabolites (U.S. FDA, 1984).
The Agency has set limits for residues which would result in an adult
receiving a daily dose of 100 ugAg a day. For drinking water exposures
to exceed this dose, concentrations would need to exceed 50 ug/L.
III. PHARMACOKINETICS
Absorption
° Aldicarb, as well as its sulfoxide and sulfone metabolites, has been
shown to be absorbed readily and almost completely through the qut
in a variety of mammalian and non-mammalian species (Knaak, et
al., 1966; Andrawes, et al., 1967; Thorough and Ivie, 1968; Dorough,
et al., 1970; Hicks, et al., 1972? Cambon, et al., 1979).
0 Dermal absorption of aldicarb has been demonstrated in rabbits
(Kuhr and Dorough, 1976; Martin and Worthing, 1977) and rats (Gaines,
1969), and would be expected to occur in unprotected humans in manu-
facturing and field application settings.
Distribution
0 Aldicarb is distributed widely in the tissues of Holstein cows when
administered in feed (Dorough, et al., 1970). Highest residues were
found in the liver. When aldicarb was administered at a lower level,
residues were detected only in the liver.
• In rats administered aldicarb orally, residues were found in all 13
tissue types analyzed. Hepatic residue levels were similar to those
of many other tissues (Andrawes, et al., 1967).
° Aldicarb, in a ltl molar ratio of the parent compound to the sulfone,
administered orally to laying hens in a single dose or for 21
consecutive days resulted in similar patterns of distribution with
the liver and kidneys as the main target organs (Hicks, et al., 1972).
394
-------
Aldicarb
September 30, 1985
Residues also were present in both the yolks and whites of the eggs
laid by these hens.
Metabolism
° The metabolism of aldicarb involves both hydrolysis of the carbamate
ester and oxidation of the sulfur to sulfoxide and sulfone derivatives
which have been shewn to be active cholineaterase inhibitors (Andrawes,
et al., 1967; Bull, et al., 1967).
° Metabolic end products of aldicarb detected in both the milk and
urine of a cow included the sulfoxides and sulfones of the parent
compound, oxime and nitrile, as well as a number of unknown metab-
olites (Dorough and Ivie, 1968).
Excretion
° elimination of aldicarb and its metabolism products occurs primarily
via the urine as demonstrated in rats (Knaak, et al., 1966)
cows (Dorough and Ivie, 1968) and chickens (Hicks, et al., 1972).
° Excretion of aldicarb via the lungs as CO2 has been demonstrated
as a minor route in rats (Knaak, et al., 1966) and in the milk of
cows (Dorough and Ivie, 1968).
0 Excretion of aldicarb is relatively rapid with reported 24-hour
elimination values in rats and cows of approximately 80% to 90% of
the administered dose (Knaak, et al., 1966? Dorough and Ivie, 1968).
HEALTH EFFECTS
Humans
® In two related incidents in 1978 and 1979, ingestion of cucumbers
presumed to contain aldicarb at about 7 to 11 ppm resulted in complaints
of diarrhea, abdominal pain, vomiting, nausea, excessive perspiration,
dyspnea, muscle fasciculation, blurred vision, headaches, convulsions
and/or temporary loss of limb function in a" total of fourteen residents
of a Nebraska town (CDC, 1979; Goes, et al., 1980). Onset of symptoms
occurred within 15 minutes to 2.25 hours and they continued for
approximately 4 to 12 hours.
0 Industrial exposure by a man bagging aldicarb for one day resulted in
nausea, dizziness, depression, weakness, tightness of chest muscles,
and decreases in plasma and red blood cell cholinesterase activity
(Sexton,1966). The symptoms lasted more than six hours but the subject
returned to work the following day without synp tarns.
0 In a laboratory study, four adult males orally administered aldicarb
at 0.1 mg/kg experienced a variety of cholinergic symptoms including
malaise, weakness in their limbs, pupil contraction and loss of photo-
395
-------
Aldicarb
September 30, 1985
reactivity, epigastric cramps, sweating, salivation, nausea, vomiting
and "air hunger" (Haines, 1971). These symptoms did not occur at 0.025 or
0.05 mg/kg. Depression of cholinesterase activity occurred in a
dose-dependent manner with values as low as 25% of the control valuo
measured in two subjects dosed at 0.1 mgAq-
Animals
Short-term Exposure
° NAS (1977) stated that the acute toxicity of aldicarb is probably
the greatest of any widely used pesticide.
0 Reported oral LD50 values for aldicarb administered to rats in corn or
peanut oil range from about 0.65 to 1 mgAg (Weiden, et al., 1965;
Gaines, 1969). Females appear to be more sensitive than males. The
oral LD50 in mice is 0.3 to 0.5 mgAg (Black, et al., 1973).
0 Oral LD50 values for aldicarb were higher when using a vehicle other
than corn or peanut oil. Weil (1973) reported an oral LD50 of 7.07
mgAg in rats administered aldicarb as dry granules. Carpenter and
Smyth (1965) reported an LD50 of 6.2 mgAg in rats administered aldicarb
in drinking water.
0 Dermal toxicity also is high with 24-hour LD50 values of 2.5 and 3
mgAg reported for female and male rats, respectively (Gaines, 1969)
and 5 mgAg in rabbits (Weiden, et al., 1965).
0 The principal toxic effect of aldicarb and its sulfoxide and sulfone
metabolites in rats has been shown to be cholinesterase inhibition
(Weil and Carpenter, 1963; Nycum, 1968; Weil, 1969).
0 Feeding studies of short duration (7 to 15 days) have been conducted
by various authors using aldicarb and/or its sulfone and sulfoxide.
Statistically significant decreases in cholinesterase activity were
observed in rats at dosage levels of 1 mgAg/day (the approximate
LDcg in rats) (Nycum and Carpenter, 1970) and at 2.5 tng/kg/day in
chickens (Schlinke, 1970). The latter dosage also resulted in seme
lethality in test animals.
0 A NQAEL has been determined for a mixture of aldicarb oxidation
products based on data reported by Mirro, et al. (1982) who administered
aldicarb sulfone and sulfoxide in a 1 si ratio in the drinking water
of young rats for 8 to 29 days. Doses ranged up to 1.67 mgAg/day
for males and 1.94 mgAg/day for "females. Based on statistically
significant reductions in cholinesterase activity in brain, plasma
and RBs at higher dosage levels, a NQAEL of 0.12 mgAg/day was determined.
396
-------
Aldicarb
September 30, 1985
Longer-term Exposure
0 Aldicarb administered for two years in the diets of rats or dogs at
dosage levels up to 0.1 mg/kg/day resulted in no significant increases
in adverse effects based on a variety of toxicologic encjpoints (Weil
and Carpenter, 1965, 1966a). In another two-year study, levels of up
to 0.3 mgAg/day resulted in no adverse effects in rats (Weil, 1975).
0 Feeding studies using aldicarb sulfoxide at 0.6 mgAg/day for two
years resulted in an increase in the mortality rates of female rats
(Weil, 1975).
° Higher dosages of aldicarb sulfoxide (i.e., 0.25 to 1.0 mg/kg/day) or
aldicarb suifone (1.8 to 16.2 mgAg/day) administered in the diets of
rats for three or six months resulted in decreases in cholinesterase
activity in plasma, RBCs and brain (Weil and Carpenter, 1968a,b). No
increases in mortality or gross or microscopic histqpathology were
noted in any group, however. Data derived from the lower dosage
levels of this study have been used by the World Health Organization
Cormittee on Pesticide Residues (FAOAJHO, 1980) to derive a HQAEL of
0.125 mgA9 NOEL for aldicarb sulfoxide in the rat.
Teratogenicity/Reproductive Effects
° No teratogenic or reproductive effects have been demonstrated to
result from the a
-------
Aldicarb September 30, 1985
Carcinogenicity
° Neither aldicarb nor its sulfoxide or sulfone have been demonstrated
to increase significantly the incidence of tumors in mice or rats in
feeding studies (Weil and Carpenter, 1965; NCI, 1979). Bioassays
with aldicarb in which rats and mice were fed either 2 or 6 ppm in
the diet for 103 weeks revealed no tumors that could be attributed
solely to aldicarb administration (NCI, 1979). It was concluded that,
under the conditions of the bioassay, technical grade (99+%) aldicarb was
not carcinogenic to F344 rats or 06C3F^ mice of either sex. A two-year
feeding study reported by Weil and Carpenter (1965) also produced no
statistically significant increase in tumors over controls when rats were
ackninistered aldicarb at equivalent doses of 0.005, 0.025, 0.05 or 0.1
mgAg bw/day in the diet. Weil (1975) similarly reported no adverse effects
in Greenacres Laboratory Controlled Flora rats fed aldicarb at 0.3 mgAg
bw/day for 2 years.
° In the only skin-painting study available to date, Weil and Carpenter
(1966b) found aldicarb to be noncarcinogenic to male C3H/H3J mice
under the conditions of the experiment.
° Intraperitoneal^ administered aldicarb did not exhibit transforming
or tumorigenic activity in a host-mediated assay using pregnant
hamsters and nude (athymic) mice (Quarles, et al, 1979).
V- QUANTIFICATION OF TCXICCLOGICAL EFFECTS
Health Advisories are based upon the identification of adverse health
effects associated with the most sensitive and meaningful non-carcinogenic
end-point of toxicity. The induction of this effect is related to a particular
exposure dose over a specified period of time, most often determined fran the
results of an experimental animal study. Traditional risk characterization
methodology for threshold toxicants is applied in HA development. The general
formula is as follows:
(NOAEL or LOAEL) (BW) . UCJ Aj
(UF(s)) ( L/day)
Where: NOAEL or LOAEL » No-Observed-Adverse-Effect-Level
or
Lowest-Observed-Adverse-Effect-Level
(the exposure dose in mgAg bw)
BW ¦ assumed body weight of protected individual
in kg (10 or 70)
UF(s) « uncertainty factors, based upon
quality and nature of data
398
-------
Aldicarb
September 30, 1985
L/day 3 assumed daily water consurrption (1 or 2), in liters
The available data suggest that the appearance of cholinergic syirptoms
indicative of cholinesterase enzyme inhibition is the moat sensitive indicator
of the effects of exposure to aldicarb. Adverse health effects appear to be
related primarily to the depression of cholinesterase activity, as no other
biochemical, morphological, reproductive, mutagenic or carcinogenic effects
have been reported, even after chronic dosing.
Given the nature of the primary toxicity (rapidly reversible cholinesterase
inhibition) of aldicarb and its oxidative metabolites/degradation products,
it is apparent that the same NQAEL can be used as the basis for the derivation
of acceptable levels over virtually any duration of exposure. In addition,
the Health Advisories calculated in this document are appropriate for use in
circumstances in which the sulfoxide and/or sulfone may be the substance(s)
present in a drinking water sample. Depending upon the analytical method
applied, it may not be possible to characterize specifically the residue(s)
present. By establishing Health Advisories based upon data from valid
studies with the most potent of the three substances, there is greater
assurance that the guidance is protective to human health.
As described above, a NQAEL of 0.125 mgAg bw/day can be determined frcm
the Wail and Carpenter (1968b) and Mirro, et al., (1982) studies. From this
NQAEL, all HA values can be determined.
One-day Health Advisory
For the 10 kg child:
One-day HA 3 (0.125 mg/kg/day) (10 kg) . 0.012 mg/t, (12 uq/L)
(100)(1 L/day)
Wheres
0.125 wjAg/day - NQAEL, based upon lack of significant decreases
in cholinesterase activity in rats
» assumed weight of protected individual
» uncertainty factor, appropriate for use with
animal NQAEL
= assumed volume of water consumed/day by 10 kg
child, in liters
10 kg
100
1 L/day
399
-------
Aldicarb
September 30, 1985
Ten-day Health Advisory
Since aldicarb is metabolized and excreted rapidly (>90% in urine
alone in a 24-hour period following a single dose), the One- and Ten-day HA
values would not be expected to differ to any extent. Therefore, it is
the Ten-day HA will the same as the One-day HA (12 ug/L).
Longer-term Health Advisory
For the 10 kg child:
Longer-term HA » (0.125 WQ/kq/day)(10 kg) „ 0>012 mq/L (12 ug/L)
(100)(1 L/day) ^
Where:
0.125 mgAg/day = NQAEL, based upon lack of significant decreases
in cholinesterase activity in rats
10 kg * assumed weight of protected individual
100 = uncertainty factor, appropriate for use with
animal NQAEL
1 L/day = assumed volume of water consumed/day by 10 kg
child
For the 70 kg adult:
Longer-term HA = (0.125 rngAq/day) (70 kg) . 0>042 mg/L (42 ug/L)
(100)(2 L/day)
Where:
70 kg * assumed weight of protected individual
2 L/day = assumed volume of water consumed/day by 70 kg
adult, in liters
(Other factors as described above for 10 kg child)
Lifetime Health Advisory
Step 1: Determination of RRfD
RRfD* « (0.125 mqAq/day) m 0.00125 mgAg/day
(100)
400
-------
Aldicarb
September 30, 1985
Where:
0.125 mg/kg/day 38 NOAEL
100 = uncertainty factor appropriate for use
with NQAEL fran animal stucfy
* RRfd » Risk Reference Dose: estimate of daily exposure
to the human population which appears to be
without appreciable risk of deleterious
non-carcinogenic effects over a lifetime of
exposure
Step 2: Determination of Lifetime HA
Lifetime HA » (0.00125 mgAg/day) (70 kg) „ 0#042 m/L = 42 yg/L
(2 L/day)
Where:
0.00125 mg/kg/day = RRfD
70 kg * assumed weight of protected individual
2 L/day * assumed volume of water ingested
per day by 70 kg adult
The Lifetime Health Advisory proposed above reflect the assumption that
100% of the exposure to aldicarb residues is via drinking water. Since aldi-
carb is used on food crops, the potential exists for dietary exposure also.
Lacking compound-specific data on actual relative source contribution, it may
be assumed that drinking water contributes 20% of an adult's daily exposure to
aldicarb. The Lifetime"Health Advisory for the 70 kg adult would be 9 uq/1,
taking this relative source contribution into account.
Evaluation of Carcinogenic Potential
Since aldicarb has been found to be noncarcinogenic under all conditions
tested, quantification of carcinogenic risk for lifetime exposures through
linking water would be inappropriate.
The International Agency for Research on Cancer (IARC) has not classified
the carcinogenic potential of aldicarb.
Applying the criteria described in EPA's proposed guidelines for assessment
of carcinogenic risk (U.S. EPA, 1984a), the Agency has classified aldicarb in
Group E: No evidence of carcinogenicity in humans. This category is used for
agents that show no evidence of carcinogenicity in at least two adequate
animal tests in different species or in both epidemiologic and animal studies.
401
-------
Aldicarb
September 30, 1985
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The National Academy of Sciences proposed an ADI of 0.001 mgAg/day
based upon the two-year feeding studies in rats and dogs (NAS, 1977).
NAS reaffinned this ADI in 1983 (NAS, 1983).
° In addition, NAS also derived a chronic suggested-no-adverse-effect-
level (SNARL) of 7 ug/1, using the studies mentioned above with an
uncertainty factor of 1000 (NAS, 1977). The SNARL is protective of a
70 kg adult, consuming 2 liters of water per day and for whan drinking
water is assumed to contribute 20 percent of the daily exposure to
aldicarb residues.
0 EPA's Office of Pesticide Programs established an ADI of 0.003
mgAg/day based upon the data from the six-month rat feeding study
with aldicarb sulfoxide (U.S. EPA, 1981).
° The FAD/WHO proposed ADIs for aldicarb residues of 0-0.001 mgAg/day
in 1979 and 0-0.005 mgAg/day in 1982.
VI. ANftLYSIS
0 Analysis of aldicarb is by a high performance liquid chromatographic
procedure used for the determination of N-methyl carbamoyloximes and
N-methylcarbarvates in drinking water (Method 531. Measurement of
N-methyl carbamoyloximes and N-methylcarbamates in Drinking Water
by Direct Aqueous Injection HPLC with Post Column Derivatization.
U.S. EPA, 1984b). In this method, the water sample is filtered
and a 400 uL aliquot is injected into a reverse phase HPLC column.
Separation of compounds is achieved using gradient elution
chromatography. After elution from the HPLC column, the compounds
are hydrolyzed with sodium hydroxide. The methylamine formed
during hydrolysis is reacted with o-phthalaladehyde (OPA) to form
a fluorescent derivative which is detected using a fluorescence
detector. The method detection limit has been estimated to be
approximately 1.3 ug/L for aldicarb.
VUL TREATMENT
0 Techniques which have been used to remove aldicarb from water are
carbon adsorption and filtration. Since aldicarb is converted
into aldicarb sulfoxide and sulfone, all three compounds must be
considered when evaluating the efficiency of any decontamination
technique.
0 Granular activated carbon (GAC) has been used in two studies of aldicarb
removal from contaminated water (Union Carbide, 1979; ESE, 1984). Both
studies utilized home water treatment units rather than large scale
water treatment systems. Union Carbide tested the Hytest Model HF-1
402
-------
Aldicarb
September 30, 1985
water softener in which the ion exchange ion was replaced with 38.5
lb Filtrasorb * 400 (Calgon GAC). The unit was operated at a flow rate
of 3 gal^nin. Water spiked with 200 ppb or 1000 ppb of a mixture of
aldicarb, aldicarb sulfoxide and aldicarb sulfone in a 10:45:45 ratio
was treated. Under these conditions, the total aldicarb residue
level was reduced by 99% to 1 ppb for the treatment of 13,500 gallons
of water with 200 ppb of residues and 41,500 gallons with 1000 ppb
total residues. No breakthrough of aldicarb occurred. When the
study was terminated, the carbon had adsorbed 9 mg aldicarb residue
per gran. This value can be compared with an equilibrium loading
value of 21 mg per gram of carbon at 16*> determined using 200 ppb
aldicarb residues. In the second study, ESE (1984) did a fieid
study in Suffolk County, NY. Nineteen units using type CW 12 x 40
mesh carbon were tested. After 38 months of use, breakthrough of.
aldicarb occurred to levels over 7 ug/L in eight units tested.
The range of usage values can be attributed to the fact that the
natural well samples contained a variety of adsorbable substances
in addition to aldicarb.
0 Chlorination also appears to offer the potential for aldicarb
removal (Union Carbide, 1979}. The corpany reported that 1.0 ppm
free chlorine caused a shift in the ratio of aldicarb, its sulfoxide and
its sulfone so that all residues were converted to the sulfoxide within
five minutes of chlorine exposure. Normal conversion of aldicarb to
aldicarb sulfone did not appear to be affected. On standing, the
sulfoxide and sulfone decomposed. The decomposition products were
not identified. However, should these be non-toxic, then chlorination
could be feasible as an aldicarb removal technique.
° Aeration or air stripping which is ccmonly used to remove synthetic
organic chemicals is not a good technique for the removal of aldicarb
(ESE, 1984). This is because aldicarb has a low Henry's Law Constant
(2.32 x 10-4 atari).
403
-------
Aldicarb
September 30, 1985
IX. REFERENCES
Andrawes, N.R., H.W. Dorough and D.A. Lindcjuist. 1967. Degradation and
elimination of Temik in rats. J. Econ. Entomol. 60(4):979-987.
Black, A.L., Y.C. Chiu, M.A.H. Faftny and T.R. Fukuto. 1973. Selective
toxicity of N-sulfenylated derivatives of insecticidal methylcar-
bamate esters. J. Agr. Food Chem. 21:747-751.
Bull, D.L., D.A. Lindguist and J.R. Coppedge. 1967. Metabolism of 2-
methyl-2-(methylthio)propionaldehyde 0-(methyl carbamoyl) oxime
(Temik, UC-21149) in insects. J. Agr. Food Chem. 15(4):610-616.
Cambon, C., C. Declume and R. Derache. 1979. Effect of the insecticidal
carbamate derivatives (carbofuran, primicarb, aldicarb) in the activity
of acetylcholinesterase in tissues frcin pregnant rats and fetuses.
Toxicol. Appl. Pharmacol. 49:203-208.
Carpenter, C.P. and H.F. Smyth. 1965. Recapitulation of pharmacodynamic
and acute toxicity studies on Temik. Mellon Institute Report No. 28-78.
EPA Pesticide Petition No. 9F0798.
CDC (Centers for Disease Control). 1979. Epidemiologic notes and reports*.
Suspected carbamate intoxications — Nebraska. Morbid. Mortal. Week.
Rep. 28:133-134.
Dorough, H.W., R.B. Davis and G.W. Ivie. 1970. Fate of Temik-carbon-14
in lactating cows during a 14-day feeding period. J. Agr. Food Chem.
18(1) .-135-143.
Dorough, H.W. and G.W. Ivie. 1968. Temik-S^S metabolism in a lactating
ccw. J. Agr. Food Chem. 16(3):460-464.
Ercegovich, C.D. and K.A. Rashid. 1973. Mutagenesis induced in mutant
strains of Salmonella typhimurium by pesticides. Abstracts of Papers.
Am. Chem. Soc. p. 43.
ESE. 1984. Environmental Science and Engineering. Review of treat-
ability data Cor removal of twenty-five synthetic organic chemicals
from drinking water. Prepared for EPA's Office of Drinking Water.
FAO/WHO. 1979 and 1982. References not available.
Gaines, T.B. 1969. The acutQ toxicity of pesticides. Toxicol. Appl.
Pharmacol. 14:515-534.
Godek, E.S., M.C. Dolak, R.W. Naismith and R.J. Matthews. 1980. Ames
5almone 11 a/Microsame Plate Test. Unpublished report by Pharmakon
Laboratories. Submitted to Union Carbide June 20, 1980.
404
-------
Aldicarb
September 30, 1985
Goes, E.H., B.P. Savage, G. Gibbons, M. Aaronson, S.A. Ford and H.W.
Wheeler. 1980. Suspected foodborne carbamate pesticide intoxications
associated with ingestion of hydroponic cucumbers. Am. J. Epidemiol.
111:254-259.
Haines, R.G. 1971. Ingestion of aldicarb by human volunteers: A
controlled study of the effect of aldicarb on man. Union Carbide
Corp., Unpublished report with addendum (A-D), Feb. 11, 1971, 32
pages.
Hicks, B.W., H.W. Dorough and H.M. Mehendale. 1972. Metabolism of aldi-
carb pesticide in laying hens. J. Agr. Food Chem. 20(1):151-156.
IRDC. 1983. International Research and Development Corporation. 1983.
Teratology study in rabbits. Union Carbide Corporation.
Knaak, J.B., M.J. Tallant and L.J. Sullivan. 1966. The metabolism of 2-
methyl-2-(methylthio) propionaldehydo 0-(methyl carbamoyl) oxime in
the rat. J. Agr. Food Chan. 14(6):573-578.
Ruhr, R.J. and H.W. Dorough. 1976. Carbamate Insecticides: Chemistry,
Biochemistry, and Toxicology. CRC Press, Inc., Cleveland, OH. pp. 2-6.
103-112, 187-190, 211-213, 219-220.
Martin, H. and C.R. Wbrthing, Ed. 1977. Pesticide Manual. British Crop
Protection Council, Wbrcestershire, England, p. 6.
Mirro, E.J., L.R. DePass and F.R. Frank. 1982. Aldicarb sulfone: aldicacb
sulfoxide twenty-nine-day water inclusion study in rats. Mellon
Inst. Rep. No. 45-18.
NAS. 1977. National Academy of Sciences. Drinking Water and Health
Volume 1. National Academy Press. Washington, D.C. pp. 635-643.
NAS. 1983. National Academy of Sciences. Drinking Water and Health
Volume 5. National Academy Press. Washington, D.C. pp. 10-12.
NCI. 1979. National Cancer Institute. Bioassay of aldicarb for possible
carcinogenicity. National Institutes of Health. U.S. Pttolic Health
Service. U.S. Department of Health, Education and Welfare.
Washington, D.C. NCI-CG-TR-136.
Nycum, J.S. 1968. Toxicity studies on Temik and related carbamates.
Mellon Institute, unpublished report 31-48, 5 pages.
Nycum, J.S. and C. Carpenter. 1970. Summary with respect to Guideline
PR70-15. Mellon Institute Report No. 31-48. EPA Pesticide Petition
No. 9F0798.
Proctor, N.H., A.D. Moecioni and J.E. Casida. 1976. Chicken embryo NAD
levels lowered by teratogenic organophosphorous and methylcarbamate
insecticides. Biochem. Pharmacol. 25:757-762.
405
-------
Aldicarb
September 30, 1985
Quarles, J.M., M.W. Sega, C.K. Schenley and W. Lijinsky. 1979. Trans-
formation of hamster fetal cells by nitrosated pesticides in a
transplacental assay. Cancer Res. 39:4525-4533.
Schlinke, J.C. 1970. Toxicologic effects of five soil nematocides in
chickens. J. Am. Vet. Med. Assoc. 31:119-121.
Sexton, W.F. 1966. Report on aldicarb. EPA Pesticide Petition No.
9F0798, Section C.
Union Carbide. 1979. (Jnion Carbide Agricultural Products Company. Temik ®
aldicarb pesticide. Removal of residues frcm water. Research and
Development Department.
U.S. EPA. 1981. U.S. Environmental Protection Agency. 40 CFR 180.
Tolerances and exemptions from tolerances for pesticide chemicals in or
on agricultural camnodities: aldicarb. Federal Register 46 (224): 57047.
U.S. EPA. 1983. U.S. Environmental Protection Agency. Occurrence of pesti-
cides in drinking water, food, and air. Office of Drinking Water.
U.S. EPA. 1984a. U.S. Environmental Protection Agency. Proposed guidelines
for carcinogenic risk assessment; Request for comments. Federal Register
49(227)46294-46301. November 23.
U.S. EPA. 1984b. U.S. Environmental Protection Agency. Method 531. Meas-
urement of N-methyl carbamoyloximes and N-methylcarbamates in drinking
water by direct aqueous injection HPLC with post column derivatization.
Enviramental Monitoring and Support Laboratory, Cincinnati, Ohio 45268.
U.S. EPA. 1985. U.S. Environmental Protection Agency. Draft health effects
criteria document for aldicarb. Criteria and Standards Division.
Office of Drinking Water.
U.S. FDA. 1984. U.S. Food and Drug Administration. Surveillance Index for
Pesticides. Bureau of Foods.
Vteiden, M.H.J., H.H. Moorefield and L.K. Payne. 1965. o-(Methyl carbamoyl)
oximes: A new class of carbamate insecticides-acaracides. J. Econ.
Entanol. 58:154-155.
Weil, c.S. 1969. Purified and technical Temik. Results of feeding in
the diets of rats for one week. Mellon Institute, unpublished report
32-11, 6 pages.
Weil, C.S. 1973. Aldicarb, Seven-day inclusion in diet of dogs. Carnegie-
Mellon Institute of Research, unpublished report 36-33, 4 pages.
406
-------
Aldicarb
September 30, 1965
Weil, c.S. 1975. Mellon Institute Report No. 35-72, Section C. EPA
Pesticide Petition No. 3F1414.
Weil, C.S. and C.P. Carpenter. 1963. Results of three months of inclusion
of Compound 21149 in the diet of rats. Mellon Institute, unpublished
report 26-47, 13 pages.
Weil, C.S. and C.P. Carpenter. 1964. Results of a three-generation
reproduction study on rats fed Compound 21149 in their diet. Mellon
Institute Report Nb. 27-158. EPA Pesticide Petition Nb. 9F0798.
Weil, C.S. and C.P. Carpenter. 1965. Two year feeding of Ccrpound 21149
in the diet of rats. Mellon Institute, unpublished report 28-123, 40
pages.
Weil, C.S. and C.P. Carpenter. 1966a. Two year feeding of Compound
21149 in the diet of dogs. Mellon Institute, unpublished report
29-5, 22 pages.
Weil, C.S. and C.P. Carpenter. 1966b. Skin painting in mice. NO
reference available.
Weil, C.S. and C.P. Carpenter. 1968a. Temik sulfoxide. Results of
feeding in the diet of rats for six months and dogs for three months.
Mellon Institute Report No. 31-141. EPA Pesticide Petition No. 9F0798.
Weil, C.S. and C.P. Carpenter. 1968b. Temik sulfone. Results of feeding
in the diet of rats for six months and dogs for three months. Mellon
Institute Report No. 31-142. EPA Pesticide Petition No. 9F0798.
Weil, C.S. and C.P. Carpenter. 1974. Aldicarb. Inclusion in the diet
of rats for three generations and a dominant lethal mutagenesis test.
Carnegie-Mellon Institute of Research. Unpublished report 37-90,
46 pages.
407
-------
Septenber 30, 1985
F.
IRICHLCROETHYLENE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
The Office of Drinking Water's non-regulatory Health Advisory Program
provides information on health effects, analytical methodology and treatment
technology that would be useful in dealing with contamination of drinking
water. Health Advisories also describe concentrations of contaminants in
drinking water at which adverse effects would not be anticipated to occur.
A margin of safety is included to protect sensitive rentiers of the population.
Health Advisories are not legally enforceable Federal standards. They
are subject to change as new and better information becomes available. The
Advisories are offered as technical guidance to assist Federal, State and
local officials responsible for protection of the public health.
The Health Advisory nunbers are developed from data describing non-
carcinogenic end-points of toxicity. They do not incorporate quantitatively
any potential carcinogenic risk from such exposure* For those chemicals
which are known or probable hunan carcinogens according to the proposed
Agency classification scheme, non-zero One-day, Tan-day and Longer-term Health
Advisories may be derived, with attendant caveats. Health Advisories for
lifetime exposures may not be reconmended. Projected excess lifetime
cancer risks calculated by EPA's carcinogen Assessment Group are provided
bo give an estimate of the concentrations of the contaminant which may pose
a carcinogenic risk to humans. These hypothetical estimates usually are
presented as upper 95% confidence limits derived from the linearized multi-
stage model which is considered to be unlikely to underestimate the probable
true risk.
(Summary Table - to be added.]
408
-------
Trichloroethylene Septanber 30, 1985
This Health Advisory (HA) is based upon information presented in the
Office of Drinking Vteter's Health Effects Criteria Document (CD) for
Trichloroethylene (U.S. EPA, 1985a). The HA and CD formats are similar for
easy reference. Individuals desiring further information on the toxicological
data base or rationale for risk characterization should consult the CD. The
CD is available for review at each EPA Regional Office of Drinking Water
counterpart (e.g., Water Supply Branch or Drinking water Branch), or for a
fee fran the National Technical Information Service, U.S. Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161, PB t %L-llfllClL/AS.
$ . The toll free nunber is (800 ) 336-4700; in Washington, D.C.
area: (703) 437-4650.
. GENERAL INFORMATION AND PROPERTIES
Synonyms
TCE, trichloroethene
Uses
Solvent and degreaser for metal components
Properties
CAS#
Pornula
Physical state
Boiling point
Density at 25*C
Vapor pressure
Water solubility
Odor threshold (water)
Odor threshold (air)
79-01-6
Cl-HOC-Cl2
Liquid
86.7*C
1.4
0.5 mgA (Cherkinski, 1951)
2.5-900 mg/to3 (van Geroert and Netten-
breijer, 1977)
Occurrence
* Trichloroethylene is a synthetic chemical with no natural sources.
* Production of trichloroethylene was 200 million lbs in 1982 (U.S. ITC,
1983).
* The major source of trichloroethylene released to the environment is
from its use as a metal degreaser. Since trichloroethylene is not
consumed during this use, the majority of ell trichloroethylene
production is released to the environment. Most of the releases
occur to the atmosphere by evaporation. However, trichloroethylene
which is not lost to evaporation becomes heavily contaminated with
grease and oil and is disposed of by burial in landfills, dunping on
the ground or into sewers. Because metal working operations are
performed nationwide, trichloroethylene releases occur in all
409
-------
If ichloroethylene
September 30, 1985
industrialized areas. Releases of trichloroethylene during production
and other uses are relatively minor.
0 Trichloroethylene released to the air is degraded in a matter of a few
days. Tr ichloroethylene released to surface waters migrates to the
atmosphere in a few days or weeks where it also degrades. Tr ichloro-
ethylene which is released to the land does not degrade rapidly and
migrates readily to ground water. Trichloroethylene remains in
ground water for months to years. Under certain conditions, trichloro-
ethylene in groundwater appears to degrade to dichloroethylene and
vinyl chloride. Trichloroethylene also may be formed in ground water
by the degradation of tetrachloroethylene (Parsons, 1984; Vbgel,
1985). Trichloroethylene, unlike other chlorinated conpounds, does
not bioaccunulate in individual animals or food chains.
° Because of the large and dispersed releases, trichloroethylene occurs
widely in the environment. It ichloroethylene is ubiquitous in the air
"with levels in the ppt to ppb range. Trichloroethylene is a cannon
contaminant in ground and surface waters with higher levels found in
ground water. Surveys of drinking water supplies have found that 3%
of all public systems derived from well water contain trichloroethylene
at levels of 0.5 ug/L or higher. A mail number of systems (0.04%)
have levels higher than 100 ug/L* Public systems derived from surface
water also have been found to contain trichloroethylene but at lower
levels. Trichloroethylene has been reported to occur sane foods in
the ppn range.
0 The major sources of exposure to trichloroethylene are fran contaminated
water and to a lesser extent air. Pood is only a minor source of tri-
chloroethylene .
PHARMACOKINETICS
Absorption
* Data on absorption of ingested TCE are limited. When a dose of 200
mg/kg of l^C-TCE in corn oil was administered to rats, 97% of the
dose was recovered during 72 hours after dosing (DeKant, et al.,
1974).
Distribution
* Doses of 0, 10, 100 or 1,000 mg TCE/kg/day adninistered by gavage to
rats five days/week for six weeks (Zenick, et al., 1984). Marginal
increases In TCE tissue levels were detected in the 10 mg/kg/day and
100 mg/kg/day dose groups. Compared to controls, a marked increase
in TCE levels in most tissues was observed in the highest dose group.
TCE was distributed in all tissues examined with the highest concen-
trations in the fat, kidney, lung, adrenals, vas deferens, epididymis,
brain and liver.
410
-------
If ichloroe thylene
September 30, 1985
Metabolign
0 Studies indicate that TCE is metabolized to trichloroethylene oxide,
trichloracetaldehyde, trichloroacetic acid, monochloroacetic acid,
trichloroe thanol and trichloroethanol glucuronide (U.S. EPA, 1984a).
Excretion
0 Trichloroe thylene and its metabolites are excreted in urine, by
exhalation and, to a lesser degree, in sweat, feces and saliva
(Soucek and Vlachova, 1959).
IV. HEALTH EFFECTS
Humans
Short-term Exposure
0 Oral exposure of humans to 15 to 25 ml (21 to 35 g) quantities of TCE
resulted in vaniting and abdominal pain, followed by transient uncon-
sciousness (Stephana, 1945}.
Longer-term Exposure
0 Studies of humans exposed occupationally have shown an increase in
servxn transaminases, which indicates damage to the liver parenchyma
(Lachnit, 1971). Quantitative exposure levels were not available.
Animals
Short-term Exposure
0 The acute oral LD50 of trichloroe thylene in rats is 4.92 mgAg
(NIOSH, 1980).
Longer-term Exposure
* Rats exposed to 300 mg/ta3 (55 ppn) TCE five days/week for 14 weeks
had elevated liver weights (Kininerle and Eben, 1973).
Mutagenicity
0 Tr ichloroe thylene was nutagenic in Salmonella typhimuriun and in the
B. ooli K-12 strain, utilizing liver microsomes for activation (Greim,
et aI77 1975, 1977).
Carcinogenicity
* Technical TCE (with epichlorohydrin and other compounds) was found to
induce a hepatocellular carcinogenic response in mice (NCI, 1976).
Under the conditions of this experiment, a carcinogenic response was
not observed in rats. Ttve "time-weighted" average doses were 549 and
411
-------
Trichloroethylene
September 30, 1985
1,097 mgAg for both male and female rats. The time-weighted average
daily doses were 1,169 and 2,339 mgAg for male mice and 869 and
1,783 mgAg for female mice.
° Epichlorohydrin-free trichloroethylene was reported to be carcinogenic
in mice (NCI, 1980). It was not found to be carcinogenic in female
rats. The experiment with male rats was considered to be inadequate
since these rats received doses of 7CE that exceeded the maximun
tolerated dose.
° TCE has been shown to be carcinogenic in different strains of mice
utilizing the inhalation as well as the oral route of exposure. The
National Cancer institute (1976) and the National Toxicology Program
(1982) conducted two separate studies with TCE contaminated with
epichlorohydrin and with TCE free of epichlorohydrin. In these
studies, B6C3F} mice were used, and the results were unequivocally
positive, showing liver neoplaans.
* in an inhalation study, Henschler, et al. (1980) reported dose-related
malignant lymphomas in female mice (NMRI strain). However, the
authors downplayed the significance of this observation, indicating
that this strain of mice has a high incidence of spontaneous lymphomas.
0 Fukuda, et al. (1983) found pulmonary adenocarcinomas in female ICR
mice on exposure to TCE vapor.
0 Henschler, et al. (1984) tested Swiss (ICR/HA) mice and reported that
when the animals were gavaged with TCE in corn oil, no statistical
differences were observed in the incidence of cancers. The results
of this study can be questioned because the dose schedule was often
interrupted even with half of the original dose. Therefore, it is
very difficult to assess the exposure. A slight increase in tunors
was found in all groups treated with TCE but did not approach .statistical
significance.
* The Van Duuren study (1979) with skin applications of TCE in IOVHA
mioe does not negate the positive findings with other strains of mice
and other routes of exposure.
V* QUMTCIFICATICH OF TDXICOLOGICAL EFFECTS
Health Advisories are based upon the identification of adverse health
effects associated with the most sensitive and meaningful non-carcinogenic
end-point of toxicity. The induction of this effect is related to a particular
exposure dose over a specified period of time, most often determined from the
reeults of an experimental animal study. Traditional risk characterization
methodology for threshold toxicants is applied in HA development. The general
foraula is as follows:
412
-------
Trichloroethylene
September 30, 1985a
(NQAEL or LQAEL) (BW) - ,^,/t
(UF(s)) (__ V'day) ^
Where:
NGAEL or LQAEL ¦ No-Observed-Adverse-Effect-Level
or
Lowes t-Observed-Adverse-Ef f ec t-Level
(the exposure dose in mg/kg bw)
BW » assumes body weight of protected individual
in kg (10 or 70)
UF(s) ¦ uncertainty factors, based upon
quality and nature of data
I/day ¦ assumes daily water consumption (1 or 2) in liters
Che-day and Ten-day Health Advisory
Suitable data were not available to estimate One-day and Ten-day Health
Advisories.
Longer-term Health Advisory
No suitable data are available from which to calculate a Longer-term Health
Advisory.
Lifetime Health Advisory
Trichloroethylene ray be classified in Group B: probable Human Carcinogen,
according to EPA's proposed weight-of-evidertce scheme for the classification
of carcinogenic potential. Because of this, caution must exercised in raking
a decision on how to deal with possible lifetime exposure to this substance.
The risk manager Rust balance this assessment of carcinogenic potential
against the likelihood of occurrence of health effects related to non-carcinogenic
end-points of toxicity. In order to assist the risk manager in this process,
drinking water concentrations associated with estimated excess lifetime
cancer risks over the range of one in ten thousand to one in a million for
the 70 kg adult, drinking 2 liters of water per day, ace provided in the
following section. In addition, in this section, a Drinking Water Equivalent
Level (DWEL) is derived. A DUEL is defined as the radium-specific (in this
case, drinking water) exposure which is interpreted to be^protective for
non-carcinogenic end-points of toxicity over a life tin® of exposure. Trie
WEL is determined for the 70 kg adult, ingesting 2 liters of water ger day.
Also provided is an estimate of the excess cancer risk that would reSult it
exposure were to occur at the EWEL aver a lifetime.
413
-------
Trichloroethylene
Septeirber 30, 1985a
-7-
Neither the risk estimates nor the EWEL take relative source contribution
into account. The risk manager should do this on a case-by-case basis,
considering the circumstances of the specific contamination incident that has
occurred.
The study by Kimmerle and Eben (1973) is the most appropriate from which
to derive the DWEL. This study evaluated the subacute exposure to trichloro-
ethylene via inhalation by adult rats for some 14 weeks following exposure to
55 ppm (300 ng/m3), five days a week. Indices of toxicity include hemato-
logical investigation, liver and renal function tests, blood glucose and orgar\/
body weight ratios. Liver weights were shown to be elevated while other test
values were not different front controls. The elevated liver weights could be
interpreted to be the result of hydropic changes or fatty accumulation. The
no-observed-effect level was not identified since only a single concentration
was administered. From these results, a LOAEL 55 ppm OOOmg/m3) was identified
using the LOAEL, the DWEL is derived as follows:
Step 1: Determination of Total Absorbed Dose (TAD")
*TAD - (300 irg/m3) (8 mVday) (5/7) (0.3) - 7.35 mg/kg/day
Where: (70 kg )
300 mg/m3 » LOAEL
8 nP/day ¦ volume of air inhaled during the exposure period
5/7 ¦ Conversion factor for adjusting from 5 days/week exposure
to a daily dose
0.3 * Ratio of the dose absorbed.
70 kg * Assumed weight of adult
Step 2: Determination of RRfD*
RRfD* ¦ (7.35 mg/kg/day) « 0.00735 mg/kfl/day
(100) (10)
Where;
7.35 nQ/kfl/day ¦ TAD
100 - uncertainty factor appropriate for use with data from
an animal study.
10 « uncertainty factor appropriate for use in conversion
Of LOAEL to NOAEL
*RRfD * Risk Reference Dose: estimate of daily exposure to the human
population which appears to be without appreciable risk of
deleterious non-carcinogenic effects over a lifetime of exposure.
414
-------
Tr ichloroethylene
September 30, 1985
Step 3: Determination of the EWEL
DWEL « (0.00735 ma Aa/dav) (70 kg) « 0.26 mg/L (260 ugA)
2 I/day
Whsro*
0.00735 mgAg/day » RRfD
70 kg ¦ Assumed weight of protected individual
2 I/day " Assumed volune of water ingested by 70 kg adult
The estimated excess cancer risk associated with lifetime exposure to
drinking water containing trichloroethylene at 260 ug/L is approximately
1 X 10"'. This estimate represents the upper 90% confidence limit fran extra-
polations prepared by CPA's Carcinogen Assessment Group using the linearized,
multistage model. The actual risk is unlikely to exceed this value, but
there is considerable uncertainty as to the accuracy of risks calculated by
this methodology.
Evaluation of Carcinogenic Potential
Using the inproved nulti-stage model, it can be estimated that water
with TCE concentrations of 280 ug/L, 28 ug/L or 2.6 ug/L would increase the
risk of one excess cancer per 10*, 10s or 10® people exposed, respectively.
These estimates were calculated fran the 1976 NCI bioassay data, which utilized
TCE contaminated with epichlorohydrin. since then, an NCI bioassay utilizing
epichlorohydrin-free TCE has became available; the data from this bioassay
have been reviewed and evaluated for carcinogenicity, and epichlorohydrin-free
TCE has been reported to be carcinogenic in mice.
IARC has classified trichloroethylene in Group 3.
Trichloroethylene has been classified in Group B2: Probable Hunan
Carcinogen. This classification for carcinogenicity was determined by a
technical panel of EPA's Risk Assessment Ftorun using the proposed EPA risk
assessment guidelines for carcinogens (FR 49 (227)»46294-46301).
. OTHER CRITERIA, GUIDANCE AND STANDARDS
* The NAS (1980) recanmended one- and Seven-day SNARLS of 105 and 15 mg/L,
respectively.
* The MHO (1984) recommended a drinking water guidance level of 30 ug/L
based on a carcinogenic end point.
* The EPA (U.S. EPA, 1980) recaimended a water quality criterion of
6.77 mg/L for effects other than cancer.
415
-------
Trichloroethylene September 30, 1985
VII. ANALYSIS
0 Analysis of trichloroethylene is by a purge-and-trap gas chromato-
graphic procedure used for the determination of volatile organohalides
in drinking water (Method 502.1. Volatile halogenated organic carpounds
in water by purge and trap gas chromatography, U.S. EPA, 1985a).
This method calls for the bubbling of an inert gas through the sample
and trapping trichloroethylene on an adsorbent material. The adsorbent
material is heated to drive off the trichloroethylene onto a gas
chromatographic column. This method is applicable to the measurement
of trichloroethylene over a concentration range of 0.01 to 1500 ug/L.
Confirmatory analysis for trichloroethylene is by mass spectrometry
(Method 524.1. Volatile organic cotpounds in water by purge and trap
gas chranatography/mass spectrometry. U.S. EPA, 1985b). The detection
limit for confirmation by mass spectrometry is 0.2 ug/L.
vm. TREATMENT
* Treatment technologies which will remove trichloroethylene (TCE) from
water include granular activated carbon (GAC) adsorption, aeration
and boiling.
* Dobbs and Cohen (1980) developed adsorption isotherms for several organic
chemicals including TCE. It was reported that Fibrasorb* 300 carbon
exhibited adsorptive capacities of 7 mg, 1.6 mg and 0.4 mg TCE/gm
carbon at equilibrium concentrations of 100, 10 and 1 mg/L, respectively.
USEPA-DWRD installed pilot-scale adsorption oolunns at different
sites in New Bigland and Pennsylvania, in New England, contaminated
well water with TCE concentrations ranging fran 0.4 to 177 mg/L was
passed through GAC columns until a breakthrough concentration of 0.1
mg/L was achieved with onpty bed contact time (EBCT) of 18 and 9
minutes, respectively (Love and Eilers, 1982). In Pennsylvania, TCE
concentrations ranging from 20 to 130 mg/L were reduced to 4.5 mg/L
by GAC after 2 months of continuous operation (ESE, 1985).
* TCE is amenable to aeration on the basis of its Henry's Law Constant
o£ 550 atm (Kavanaugh, et al., 1980). in a full plant-scale (3.78
MGD) redwood slat tray aeration colimn, a removal efficiency of
50-60% was achieved from TCE initial concentrations of 8.3-39.5 mg/L
at an air-to-water ratio of 30:1 (Hess, et al., 1981). in another
full plant-scale (6*0 MGD) nultiple tray aeration column study, TCE
removal of 52« was achieved from 150 mg/L (Hess, et al., 1981). A
full plant-scale packed tower aeration column moved 97-99% of TCE
fran 1,500-2,000 mg/L contaminated groundwater at air-to-water ratio
of 25tl (ESE, 1985).
* Boiling also is effective in eliminating TCE fran water on a short-term,
emergency basis. Studies have shown 5 minutes of vigorous boiling
will wmove 95% of TCE originally present (Love and Eilers, 1982).
416
-------
Trichloroethylene
September 30, 1985
° Air stripping is an effective, sinple and relatively inexpensive process
for removing TCE and other volatile organics from water. However, use
of this process then transfers the contaminant directly to the air
stream. When considering use of air stripping as a treatment process,
it is suggested that careful consideration be given to the overall
envirormental occurrence, fate, route of exposure and various other
hazards associated with the chemical.
417
-------
Trichloroethylene
Septentoer 30, 1985a
REFERENCES
DeKant, W. Metzderm and D. Henschler. 1984. Novel metabolites of trichloro-
ethylene through dechlorination reactions in rats, mice and humans.
Biochem. Pharmacol. 33:2021-2027.
Dobbs/ R.A., and J.M. Oohen. 1980. Carbon adsorption isotherms for toxic
organics. EPA 600/8-80-023, Office of Research and Development, MERL,
Wastewater Treatnent Division, Cincinnati, Ohio.
ESE. 1985. Environmental Science and Engineering. Draft technologies and
costs for the removal of volatile organic chemicals from potable water
supplies. ESE No. 84-912-0300 prepared for U.S. EPA, Science and Technology
Branch, C5D, ODW, Washington, D.C.
Fukuda, K., K. Takemoto and H. Tsuruta. 1983. Inhalation carcinogenicity of
trichloroethylene in mice and rats. Ind. Health 21:243-254.
Greim, H., D. Bimboes, G. Egert, w. Giggelmann and M. Kramer. 1977. Muta-
genicity and chromosomal aberrations as an analytical tool for jm vitro
detection of mannalian enzyme-mediated formation of reactive metabolites.
Arch. Toxicol. 39:159.
Greim, H., G. Bonse, 2. Radwan, D. Reichert and D. Henschler. 1975. Muta-
genicity in vitro and potential carcinogenicity of. chlorinated ethylenes
as a function of metabolic oxirane formation. Biochem. Pharmacol.
24:2013.
Henschler, D., H. Elsasser, W. Ronen and E. Eder. 1984. Carcinogenicity
study of trichloroethylene, with and without epoxide stabilizers,
in mice. J. Cancer Res. Clin. Oncol. 104:149-156.
Henschler, D., W. Ronen, H.M. Elsasser, D. Reichert, E.Eder and Z. Radwan.
1980. Carcinogenicity study of trichloroethylene by long-term-inhalation
in the animal species. Arch. Toxicol. 43<237-248.
Hess, A.F., J.E. Dyksen and G.C. Cline. 1981. Case study involving removal
of organic chemical conpounds from ground water. Presented at Annual
American Water Wbrks Association Oonference, St. Louis, Missouri.
I/RC. 1982. JJRC monographs on the evaluation of the carcinogenic risk of
chemicals to humans. Supplemant 4, Lyon, Prance.
Kavanaugh, M.C., and RJt< Trussell. 1980* Design of aeration towers to
strip volatile contaminants from drinking water. JAMWA. Decentoer.
Kinrorle, G., and A. Eben. 1973. Metabolism, excretion and toxicology of
trichloroethylene after inhalation. 1. Experimental exposure on rats.
Arch. Tbxicol. 30:115.
Lachnit, V. 1971. Halogensted hydrocarbons and the liver. Wien. Klin.
Wochenschr. 83(41):734.
418
-------
Trichloroe thylene
Septerrber 30 , 1985a
Love, O.T., Jr., and R.G. Eilers. 1982. Treatment of drinking water containing
trichloroethylene and related industrial solvents. JAWWA. August.
NAS. 1980. National Acadeny of Sciences. Drinking water and Health. Volume 3.
National Academy Press. Washington, DC.
NCI. 1976. National Cancer Institute. Carcinogenesis bioassay of trichloroethylene
U.S. Department of Health, Education and Welfare, Public Health Service,
CAS No. 79-01-6 , February.
NICBH. 1980. Registry of Ttoxic Effects of Chemical substances. U.S. Depart-
ment of Health and Human Services. DHH3 (NIOSH) 81-116.
NIP. 1982. National Tbxicology Program. Carcinogenesis bioassay for tri-
chloroe thylene. CAS # 79-01-6. No. 82-1799. (Draft).
Parsons, F., P.R. WxxJ and J. DeMarco. 1984. Transformation of tetrachloro-
ethene and trichloroethene in microcosms and groundwater. JAWWA,
26 ( 2) :56f.
Perry, R.H., and C.H. Chilton. 1973. Chemical Engineers Handbook. 5th
Edition. McGraw Hill Book Oompany.
Soucek, B., and D. Vlachova. 1959. Metabolites of trichloroethylene excreted
in the urine by man. Pracoc. Lek. 11:457.
Stephens, C.A. 1945. Poisoning by accidental drinking of trichloroethylene.
Brit. Med. J. 2:218.
U.S. EPA. 1979. water Related Environmental Fate of 129 Priority Pollutants,
Office of Water planning and Standards, EPA-440/4-79-029.
U.S. EPA. 1980. Antoient water quality criteria document for trichloroe thylene.
Office of Water Research and standards. Cincinnati, Ohio.
U.S. EPA. 1983. Trichloroe thylene occurrence in drinking water, food, and
air. office of Dfinkiny Water.
U.S. EPA. 1984. Proposed guidelines for carcinogenic risk assessmant;
request for conrants. Federal Register 49(227) *46294-46301. Novenber 23.
U.S. EPA. 1985a. the drinking water criteria document on trichloroethylene.
Office of Drinking Water.
U.S. EPA. 1985b. Method 502.1. Volatile Halogenated Organic Ctornpounds in
Water by Purge and Trap Gas Chromatography, Environnental Monitoring and
Support Laboratory, Cincinnati, Ohio 45268.
U.S. EPA. 1985c. Method 524.1. Volatile Organic Qonpounds in Water by Purge
and Trap Gas Chromatography/Masa Spectrometry, Environmental Monitoring
and Support Laboratory, Cincinnati, Ohio 45268.
419
-------
Trichloroethylene
September 30, 1985a
U.S. ITC. 1983. United States International Trade Cbnrvission. Synthetic
organic chemicals. United States production, UBITC Publication 1422.
tobshington, D.C. 20436.
van Duuren, B.L., B.M. Goldschmidt, G. Lcwengart, A.C. Smith, S. Melchionne,
I. Seldman and D. Roth. 1979. Carcinogenicity of halogenated olefinic
and aliphatic hydrocarbons in mice. J. Natl. Cancer Inst. 63:1433-1439.
Vogel, T., and P. McCarty. 1985. Biotransformation of tetrachloroethylene
to trichloroethylene, dichloroethylene, vinyl chloride, and carbon dioxide
under nBthanogenic conditions. Appl. Environm. Microbiol. 49(5).
WHO. 1984. Wbrld Health Organization. Guidelines for drinking water quality.
Vol. 1 Reconrondations Geneva, Switzerland p. 63; p. 66.
Zenick, H., K. Blackburn, E. Hope, N. Richards and M.K. Smith. 1984. Effects
of trichloroethylene exposure on male reproductive function in rats.
Tbxicology. 31:237.
420
-------
September 30, 1985
G.
VINYL CHLORIDE
Health Advisory Draft
Office of Drinking Water
U.S. Environmental Protection Agency
The Office of Drinking Water's non-regulatory Health Advisory Program
provides information on health effects, analytical methodology and treatment
technology that would be useful in dealing with contamination of drinking
water. Health Advisories also describe concentrations of contaminants in
drinking water at which adverse effects would not be anticipated to occur.
A margin of safety is included to protect sensitive members of the population.
Health Advisories are not legally enforceable Federal standards. They
are subject to change as new and better information beccnves available. The
Advisories are offered as technical guidance to assist Federal, State and
local officials responsible for protection of the public health.
The Health Advisory numbers are developed frcm data describing non-
carcinogenic end-points of toxicity. They do not incorporate quantitatively
any potential carcinogenic risk frcm such exposure. For those chemicals
which are known or probable human carcinogens according to the proposed
Agency classification scheme, non-zero One-day, Terr-day and Longer-term Health
Advisories may be derived, with attendant caveats. Health Advisories for
lifetime exposures may not be recommended. Projected excess lifetime
cancer risks calculated by EPA's Carcinogen Assessment Group are provided
to give an estimate of the concentrations of the contaminant which may pose
a carcinogenic risk to humans. These hypothetical estimates usually are
presented as upper 95% confidence limits derived fran the linearized multi-
stage model which is considered to be unlikely to underestimate the probable
true risk.
I Summary table-to be added]
421
-------
Vinyl Chloride
September 30, 1985
This Health Advisory (HA) is based upon information presented in the
Office of Drinking Water's Health Effects Criteria Document (CD) for vinyl
chloride (U.S. EPA, 1985a). The HA and CD formats are similar for easy
reference. Individuals desiring further information on the toxicological
data base or rationale for risk characterization should consult the CD. The
CD is available for review at each EPA Regional Office of Drinking Water
counterpart (e.g., Water Supply Branch or Drinking Water Branch), or for a
fee from the National Technical Information Service, U.S. Department of
Commerce, 5285 Port Royal Rd., Springfield, VA 22161, PB # 86-118320/AS.
The toll free number is (800) 336-4700; in Washington, D.C. area: (703)
487-4650.
. GENERAL INFORMATION AND PROPERTIES
° Vinyl chloride and polyvinyl chloride (PVC) are used as raw materials
in the rubber, paper, glass and automotive industries. In addition,
vinyl chloride and PVC are used in the manufacture of electrical wire
insulation and cables, piping, in&istrial and household equipment,
medical supplies, food packaging materials and building and construc-
tion products. Vinyl chloride and PVC copolymers are distributed and
processed in a variety of forms, including dry resins, plastisol
(dispersions in plasticizers), organosol (dispersions in plasticizers
plus volatile solvent), and latex (a colloidal dispersion in water
used to coat paper, fabric or leather) (U.S. EPA, 1985a).
Synonyms
Q
Monochloroethylene, chloroethene
Uses
Properties
CAS #
Chemical Formula
Molecular weight
Physical state
Boiling point
Vapor pressure
Specific gravity
Water solubility
Taste Threshold (water)
Odor threshold (water)
75-01-4
HoC-CHCl
62.5
gas
-13.3°C
2,530 run at 20°C
0.91
1.1 g/L water at 28°C
not available
not available
Structural formula
H-OC-C1
H H
Occurrence
O
Vinyl chloride is a synthetic chemical with no natural sources
422
-------
Vinyl Chloride
September 30, 1985
0 Production of vinyl chloride was approximately 7 billion lbs in 1983
(U.S. ITC, 1983). Vinyl chloride is used consunptively and little is
released to the environment. Enviromental releases will be limited
to the areas where vinyl chloride is produced and used.
0 Vinyl chloride released to the air is degraded in a matter of a few
hours (U.S.EPA, 1980). Vinyl chloride released to surface waters
migrates to the atmosphere in a few hours or days where it also
degrades. Vinyl chloride which is released to the ground does not
adsorb onto soil and migrates readily to ground water. Evidence from
laboratory studies suggests that vinyl chloride in ground water may
degrade to CX>2 and Cl~ (McCarty, 1985). Vinyl chloride is expected
to remain in ground water for months to years. Vinyl chloride has
been reported to be a degradation product of trichloroethylene and
perchloroethylene in groundwater (Parsons, 1984). Vinyl chloride,
unlike other chlorinated compounds, does not bioaccumulate in indi-
vidual animals or food chains.
0 Vinyl chloride does not occur widely in the environment because of
its rapid degradation and limited release. Vinyl chloride is a
relatively rare contaminant in ground and surface waters with higher
levels found in ground water. The Ground Water Supply Survey of
drinking water supplies have found that less than 2% of all around
water derived public water systems contain vinyl chloride at levels
of 1 ug/t, or higher. Vinyl chloride almost always co-occurs with
trichloroethylene. Public systems derived from surface water also
have been found to contain vinyl chloride but at lower levels. No
information on the levels of vinyl chloride in food have been identi-
fied. Based upon the limited uses of vinyl chloride and its physical
chemical properties, little or no exposure is expected frcm food.
Vinyl chloride occurs in air in urban areas and near the sites of its
production and use. Atmospheric concentrations are in the ppt
range.
0 The major source of exposure to vinyl chloride is from contaminated
water.
PHARMACOKINETICS
Absorption
° Vinyl chloride is absorbed rapidly in rats following ingestion and
inhalation (Withey, 1976; Duprat, et al., 1977).
Distribution
° Upon either inhalation or ingestion of l^C-vinyl chloride in rats, the
greatest amount of 14C activity was found in liver followed by kidney,
muscle, lung and fat (Watanabe, et al., 1976a,b). However, another
study of inhalation exposure of rats to 14C-vinyl chloride showed
the highest ^C activity in liver and kidney, followed by spleen and
brain (Bolt, et al., 1976).
423
-------
Vinyl Chloride
September 30, 1985
Metabolism
0 Bartsch and Montesano (1975) reported two possible metabolic pathways
for vinyl chloride, one involving alcohol dehydrogenase, the other
involving mixed function oxidase. Hefner, et al. (1975) concluded
that the dominant pathway at lower exposure levels probably involves
alcohol dehydrogenase.
0 Vinyl chloride metabolism is saturable (Watanabe, et al., 1976a? Bolt,
et al., 1977).
Excretion
° Rats administered vinyl chloride by ingestion or inhalation expire
greater amounts of unmetabolized vinyl chloride as the dose is
increased (Watanabe, et al., 1976a, b).
° Vinyl chloride metabolites are excreted mainly in the urine. In rats,
urinary metabolites include N-acetyl-5-(2-hydroxyethylcysteine) and
thiodiglycolic acid (Watanabe, et al., 1976a).
° Using statistical modeling, Withey and Collins (1976) concluded that,
for rats, a total liquid intake containing 20 ppn vinyl chloride would
be equivalent to an inhalation exposure of about 2 ppm for 24 hours.
HEALTH EFFECTS
Humans
° At high inhalation exposure levels, workers have experienced dizziness,
headaches, euphoria and narcosis (U.S. EPA, 1985a).
0 Symptoms of chronic inhalation exposure of workers to vinyl chloride
include hepatotoxicity (Marstellar, et al. 1975), acro-osteolysis
(Lilts, et al., 1975), central nervous system disturbances, pulmonary
insufficiency, cardiovascular toxicity, and gastrointestinal toxicity
(Selikoff and Hammond, 1975).
Animals
Short-tern exposure
0 Inhalation exposure to high levels of vinyl chloride can induce
narcosis and death, and, to lower doses, ataxia, congestion and edema
in lungs and hyperemia in liver in several species (U.S. EPA, 1985a).
Longer-term exposure
° Administration of vinyl chloride monomer to rats by gavage for 13
weeks resulted in hematologic, biochemical and organ weight effects
at doses above 30 mgAg (Feron, et al., 1975).
424
-------
Vinyl Chloride
Setpember 30, 1985
0 Inhalation exposure of rats, guinea pigs, rabbits and dogs to 50 ppm
vinyl chloride, 7 hours/day, 130 exposures in 189 days, did not induce
toxicity. Rats exposed to 100 ppm, 7 hours/day for 6 months, had
increased liver weights (Torkelson, et al., 1961).
Teratogenicity/Reproductive Effects
° Inhalation exposure of rats and rabbits to vinyl chloride concentra-
tions as high as 2,500 ppm on days 6 to 15 (rats) and 6 to 18 (rabbits)
of gestation and mice to vinyl chloride levels as high as 500 ppm on
days 6 to 15 of gestation did not induce teratogenic effects (John,
et al., 1977).
0 Potential effects on reproductive capacity have not been studied.
Mutagenicity
° Chromosomal effects of vinyl chloride exposure in workers is conflicting
in that positive (Ducatmann, et al., 1975; Purchase, et al., 1975) and
negative (Killian, et al., 1975; Picciano, et al., 1977) results have
been reported.
0 Vinyl chloride is mutagenic, presumably through active metabolites in
various systems including metabolically activated systems with S. typhi-
murium (Bartsch, et al., 1975), E. ooli (Greim, et al., 1975), yeast
(Loprfeno, et al., 1977), germ cells of Drosophila (Verburgt and
Vogel, 1977) and Chinese hamster V79 cells (Hubermann, et al., 1975).
Carcinogenicity
0 Increases in the occurrence of liver angiosarcomas as well as in tumors
of the brain, lung, and hematopoietic and lyirphopoietic tissues have
been associated with occupational exposure to vinyl chloride in
humans (IARC, 1979).
° Ingestion of vinyl chloride monomer in the diet by rats at feeding
levels as lew as 1.7 mgAg/day over their lifespan induced liver
angiosarcomas and hepatocellular carcinomas, as well as other adverse
hepatic effects (Feron, et al., 1981). Til, et al. (1983) extended
the Peron, et al. (1981) work to include lower doses and did not find
a significant (p<0.05) increase in carcinogenic effects at feeding
levels as high as 0.13 mgAg/day. Administration of vinyl chloride
monomer by gastric intubation for at least 52 weeks resulted in
carcinogenic effects in liver and other tissue sites in rats (Feron,
et al., 1981; Maltoni, 1981).
° Chronic inhalation of vinyl chloride has induced cancer in liver and
other tissue sites in rats and mice (Lee, et al., 1977, 1978; Maltoni,
1981).
425
-------
Vinyl Chloride September 30, 1985
V. QUANTIFICATION OF TCKIOOLOGICAL EFFECTS
Health Advisories are based upon the identification of adverse health
effects associated with the most sensitive and meaningful non-carcinogenic
end-point of toxicity. The induction of this effect is related to a particular
exposure dose over a specified period of time, most often determined from the
results of an experimental animal study. Traditional risk characterization
methodology for threshold toxicants is applied in HA development. The general
formula is as follows:
Vtoere:
(NOAEL or LOAEL) (BW) 3 t,„A.
"TUFfim L/dayi
NOAEL or LOAEL - No-Observed-Adverse-Effect-Level
or
Lowest-Observed-Adverse-Effect-Level
(the exposure dose in mg/kg bw)
BW 3 assumed body weight of protected individual
in kg (10 or 70)
UF(s) = uncertainty factors, based upon
quality and nature of data
L/day = assumed daily water consumption (1 or 2) in liters
One-day Health Advisory
There are insufficient data for calculation of a One-day Health Advisory.
The Ten-day HA is proposed as a conservative estimate for a One-day HA.
Ten-day Health Advisory
Feron, et al. (1975) reported a subchronic toxicity study in which vinyl
chloride monomer (VCM) dissolved in soybean oil was ackninistered by gavage to
male and female Wistar rats, initially weighing 44 g, at doses of 30, 100 or
300 mgAg once daily, 6 days per week for 13 weeks. Several hematological,
biochemical and organ weight values were significantly (PC0.05 or less)
different in both mid- and high-dose animals compared to controls. Hie NOAEL
in this study was identified as 30 mg/kg.
The Ten-day HA, as well as the One-day HA, for a 10 kg child is calculated
as follows:
Ten-day HA » (3° Tiiff^fl^/dayi (1° ^ " 2,6 (2'600 U9/L)
426
-------
Vinyl Chloride
September 30, 1985
Where:
= NQAEL for subchronic toxicity from the Feron, et al. (1975)
study
¦ expansion of 6 days/week treatment in the Feron, et al. (1975)
study to 7 days/week to represent daily exposure
= assumed weight of child
= assumed amount of water consumed by a child
= uncertainty factor for extrapolating results of animal
study with a NQAEL to humans and for protection of the
most sensitive members of the population.
This HA is equivalent to 2.6 mg/day or 0.26 mgAn/daV.
Longer-term Health Advisory
The Longer-term HA can be calculated from the lifetime feeding study in
rats by Til, et al. (1983). Til, et al. (1983) have extended the earlier work
by Feron, et al. (1981) to include lower doses with basically the same protocol
used in the latter study* Carcinogenic and noncarcinogenic effects were evi-
dent with a vinyl chloride dietary level of 1.3 ng/kg/day. At dietary levels
of 0.014 and 0.13 mgAg/day, increased incidences of basophilic foci of cellu-
lar alteration in the liver of female rats were evident. However, basophilic
foci by themselves are concluded not to represent an adverse effect on the
liver in the absence of additional effects indicative of liver lesions such
as those found in the 1.3 mg/kg/day group; and a dose-related increase in
basophilic foci was not evident. Therefore, the dose of 0.13 wg/kg/day is
identified as the NQAEL for noncarcinogenic effects for the Longer-term HA
calculation.
Using the 0.13 vcq/kg/day NQAEL from the Til, et al. (1983) study# the
Longer-term HA is for a child calculated as follows:
Longer-term HA » (0.13 mgAg/dav) (10 kg) . 0.013 mg/L or 13 ug/L
(100) [l L/day)
Where:
0.13 mgAg/day » NQAEL from the Til, et al. (1983) study
10 kg ¦ assumed weight of child
1 L/day ¦ water consumption per day for a child
100 ¦ uncertainty factor in an animal study where
a NQAEL was determined.
This HA is equivalent to 13 ug/day or 1.3 vg/kg/d&y.
30 mgAg/day
6/7
10 kg
1 L/day
100
427
-------
Vinyl Chloride
September 30, 1985
By assuming 70 kg body weight and 2 L daily water consumption, the
Longer-term HA for an adult is calculated as follows:
Longer-term HA = (0.13 mgAg/day) (70 kg) , q.046 mg/L or 46 ug/L
(100) (2 L/day)
This HA is equivalent to 92 ug/day or 1.3 ugAfl/day.
Lifetime Health Advisory
Because vinyl chloride is classified as a human carcinogen (IARC Group 1
and EPA Group A), a Lifetime Health Advisory is not reccranended.
Evaluation of Carcinogenic Potential
EPA's Carcinogen Assessment Group (CAG) recently has recalculated its
excess carcinogenic risk estimates resulting from lifetime exposure to vinyl
chloride through the drinking water (U.S. EPA, 1984b). CAG based its preliminary
revised estimates on the Feron, et al. (1981) study. The total nuitoer of
tumors, considering tumors of the lung and liver, in rats exposed through the
diet was used to calculate the excess cancer risk. They calculated that
consuming 2 liters of water per day with vinyl chloride concentration of 1.5
ug/Lr 0.15 ug/L and 0.015 ugA would increase the risk of one excess cancer
per 10,000 (10~4), 100,000 (lO"5) or 1,000,000 (10-6) people exposed, respect-
ively, per lifetime. The CAG is presently reassessing the cancer risk estimate
based on the Feron, et al. (1981) study by taking into account the more
recent data by Til, et al. (1983) which, as described previously, is an
extension of the earlier Feron, et al. (1981) work to include lower doses.
The IARC (1979) has concluded that the evidence is sufficient to
classify vinyl chloride as a human carcinogen in its Category 1.
Applying the criteria described in EPA's proposed guidelines for
assessment of carcinogenic risk (U.S. EPA, 1984a), vinyl chloride may be
classified in Group A: Human carcinogen. This category is for agents for
which there is sufficient evidence to support the causal association between
exposure to the agents and cancer.
. OTHER CRITERIA, GUIDANCE, AND STANDARDS
° The National Academy of Sciences (NAS, 1977) estimated a 10"6 risk
from lifetime exposure to 1 ug vinyl chloride/t, drinking water with
the 95% upper limit of the multistage model and the lifetime
ingestion study in rats by Maltoni, et al. (1981).
° In June, 1984, EPA proposed a Recommended Maximum Contaminant Level
(RMCL) of zero for vinyl chloride in drinking water (U.S. EPA, 1984b).
428
-------
Vinyl Chloride
Sepbember 30, 1985
0 Ambient water quality critera (U.S. EPA, 1980) are 20, 2 and 0.2 ug/L
for risks of 10"5, 10~6, and 10""7, respectively, assuming consumption
of 2 liters of water and 6.5 grams of contaminated fish per day by a
70 kg adult.
° A workplace standard of 1 ppm (time-weighted average) was set by OSHA
in 1974, as mentioned in U.S. EPA (1980).
V11. ANALYSIS
0 Analysis of vinyl chloride is by a purge and trap gas chromatographic
procedure used for the determination of volatile organohalides in
drinking water (Method 502.1. Volatile halogenated organic compounds
in water by purge and trap gas chromatography. U.S. EPA, 1985b).
This method calls for the bubbling of an inert gas through a sample
of water and trapping the purged vinyl chloride on an adsorbant
material. The adsorbant material is heated to drive off the vinyl
chloride onto a gas chromatographic column. lhis method is applicable
to the measurement of vinyl chloride over a concentration range of
0.06 to 1500 ug/L- Confirmatory analysis for vinyl chloride is by
mass spectrometry (Method 524.1. Volatile organic compounds in water
by purge and trap gas chromatography/nass spectrometry. U.S. EPA,
1985c). The detection limit for confirmation by mass spectrometry is
0.3 ug/L.
VI11. TREATMENT
° The value of the Henry's Law Constant for vinyl chloride (6.4
atm-m^/foole) suggests aeration as a potential removal technique
for vinyl chloride in water (ESE,1984). Removals of up to 99.27%
were achieved at 9°C using a pilot packed tower aerator. In similar
studies, vinyl chloride was removed from ground water using a
spray aeration system with total VOC concentration was 100 to
200 ug/1 (ESE, 1984). Greater than 99.9% VOC removal was obtained
using a four-stage aeration system; each stage employed 20 shower
heads with a pressure drop of approximately 10 pounds per square
inch. In-vrell aeration has also demonstrated up to 97% removal of
vinyl chloride using an air-lift pump. However, practical considera-
tions are likely to limit the application of this (Miltner, 1984).
° The concentration of vinyl chloride in southern Florida ground water-
declined by 25% to 52% following passage through lime softening basins
and filters (Mood and DeMarco, 1980). Since vinyl chloride is a
highly volatile compound, probably volatilized during treatment
(ESE, 1994) .
0 Adsorption techniques have been less successful than aeration in
removing vinyl chloride from water. In a pilot study, water frcm a
ground water treatment plant was passed throuqh a series of four
30-inch granular activated carbon (Filtrasorb 400) columns (Vtood and
DeMarco, 1980; Symons, 1978); the empty bed contact time was approxi-
mately six minutes per column. Influent vinyl choride concentrations
429
-------
Vinyl Chloride
September 30, 1985
ranged from belew detection to 19 rag/1; erratic removal was reported.
To maintain effluent concentrations below 0.5 mq/1, the estimated
column capacity to breakthrough was 810, 1250, 2760 and 2050 bed
volumes for empty bed contact times of 6, 12, 19 and 25 minutes,
respectively. In addition, the estimated service life of the acti-
vated carbon was lew. Similarly, poor removal of vinyl chloride was
achieved using an experimental synthetic resin, Ambersorb XE-340,
(Symons, 1978) .
° Treatment technologies for the removal of vinyl chloride from water
have not been extensively evaluated except on an experimental level.
Available information suggests aeration merits further investigation.
Selection of indivicfcjal or combinations of technologies to achieve
vinyl chloride removal must be based on a case-by-case technical
evaluation, and an assessment of the economics involved.
430
-------
Vinyl Chloride
September 30, 1985
• REFERENCES
Bartsch, H., C. Malaveille and R. Montesano. 1975. Human, rat and mouse
liver-mediated mutagencity of vinyl chloride in S. typhimurium strains.
Int. J. Cancer. 15:429-437.
Bartsch, H., and R. Montesano. 1975. Mutagenic and carcinogenic effects of
vinyl chloride. Mutat. Res. 32:93-114.
Bolt, H.M., H. Kappus, A. Buchter and W. Bolt. 1976. Disposition of
(1,2-1*C) vinyl chloride in the rat. Arch. Toxicol. 35:153-162.
Bolt, H.M., R.J. Laih, H. Kappus and A. Buchter. 1977. Pharmacokinetics of
vinyl chloride in the rat. Toxicol. 7:179-188.
Brodzinsky, R., and H.B. Singh. 1982. Volatile organic chemicals in the*
atmosphere: an assessment of available data. Prepared by SRI Interna-
tional for Office of Research and Development, USEPA, Research Triangle
Park, N.C. Contract No. 68-02-3452.
Ducatman, A., K, Hirschhorn and I.J. Selikoff. 1975. Vinyl chloride expo-
sure and human chromoscme aberrations. Mutat. Res. 31:163-168.
Duprat, P., J.P. Fabry, D. Gradiski and J.L. Magadur. 1977. Metabolic
approach to industrial poisoning: blood kinetics and distribution of
l*c-vinyl chloride monomer (V.C.M.). Acta. Pharmacol. Toxicol. Suppl.
(Kbh) 41(1):142-143.
ESE. 1984. Envirormental Science and Engineering. Technologies and costs for
the removal of volatile organic chemicals from potable water supplies.
(Draft) ESE No. 84-912-0300. Prepared for U.S. EPA, Science and Technology
Branch, CSD, ODW, Washington, DC.
Feron, V.J., A.J. Speek, M.I. Williams, D. van Battum and A.F. de Groot.
1975. Observations on the oral administration and toxicity of vinyl
chloride in rats. Fd. Cosnet. Toxicol. 13:633-638.
Feron, V.J., C.F.M. Hendrikson, A.J. Speek, H.P. Til and B.J. Spit. 1981.
Lifespan oral toxicity study of vinyl chloride in rats. Fd. Cosmet.
Toxicol. 19:317-331.
Gay, B.W., P.L. Hanst, J.J. Bufalini and R.C. Noonan. 1976. Atmospheric
oxidation of chlorinated ethylenes. Environ. Science Technol. 10:58-67.
Greim, H., G. Bonse, 2. kadwan, D. Reichert and D. Henschler. 1975.
Mutagenicity in vitro and potential carcinogenicity of chlorinated
ethylenes as a function of metabolic oxirane formation. Biochem.
Pharroaool. 24:2013-2017.
Hawley, G.G., 1981. The Condensed Chemical Dictionary. 10th Edition.
Van Nostrand Reinhold Corpany.
431
-------
Vinyl Chloride
September 30, 1985
Hefner, R.E., Jr, P.G. Watanabe and P.J. Gehring. 1975. Preliminary studies
on the fate of inhaled vinyl chloride monomer in rats. Ann. NY. Acad.
Sci. 246:135-148.
Hill, J., H.P. Kollig, D.F. Parris, N.L. Wolfe and R.G. Zepp. 1976. Dynamic
behavior of vinyl chloride in aquatic ecosystems. EPA 600/3-76-001.
(PB-249 302). 63 pp.
Huberman, E., H. Bartsch and L. Sachs. 1975. Mutation induction in Chinese
hamster V79 cells by two vinyl chloride metabolites, chloroethylene
oxide and 2-chloro-acetaldehyde. Int. J. Cancer. 16:639-644.
IARC. 1979. International Agency for Research cm Cancer. IARC monographs
on the evaluation of carcinogenic risk of chemicals to man. Vol. 19.
Lyon, France.
John, J.A., F.A. Smith, B.K.J. Leong and B.A. Schwetz. 1979. The effects
of maternally inhaled viny chloride on embryonal and fetal development
in mice, rats and rabbits. Toxicol. Appl. Pharmacol. 39;497-513.
Killian, D.J., D,J. Picciano and C.B. Jacobson. 1975. Industrial monitoring:
A cytogenetic approach. Ann. N.Y. Acad. Sci. 269:4-11.
Laib, R.J., and H.M. Bolt. 1977. Alkylation of RNA by vinyl chloride metabo-
lites in vitro and in vivo; Formation of l-N'-etheno-adenosine.
Toxicology. 8:185-195.
Lee, C.C., J.C. Bhandari, J.M. Winston, W.B. House, R.L. Dixon and J.S. Wbods.
1977. Inhalation toxicity of vinyl chloride and vinylidene chloride.
Environ. Health Perspect. 21:25-32.
Lee, C.C., J.C. Bhandari, J.M. Winston, W.B. House, R.L. Dixon and J.S. Woods.
1978. Carcinogenicity of vinyl chloride and vinylidene chloride.
J. Toxicol. Environ. Health. 4:15-30.
Lilis, R., H. Anderson, W.J. Nicolson, S. naum, A.S. Fischbein and I.J. Seli-
koff. 1975. Prevalence of disease among vinyl chloride and polyvinyl
chloride workers. Ann. N.Y- Acad. Sci, 246:22-41.
Lillian, D., H.B. Singh, A. Appleby, L. Lobban, R. Arnts, R. Bumpert, R. Hague,
J. Toomey, J. Kazazis, M. Antell, D. Hansen and B. Scott. 1975. Atmos-
pheric fates of halogenated compounds. Environ, Sci. Technol. 9:1042-1048.
Loprieno, N., R. Barale, S. Baroncelli, H. Bartsch, G. Bronzetti, A. Cammellini,
C. Corsi, D. Frezza, R. Nieri, C. Leporini, D. Rosellini and A.M. Rossi.
1977. Induction of gene mutations and gene conversions by vinyl chloride
metabolites in yeast. Cancer Res. 253-257.
Maltoni, C., G. Lefemine, A. Ciliberti, G. Cotti and D. Carretti. 1981.
Carcinogenicity bioassays of vinyl chloride monomer: a model of risk
assessment on an experimental basis. Environ. Health Perspec. 41:3-31.
432
-------
Vinyl Chloride
Setpember 30, 1985
Marsteller, H.J., W.K. Lelbach, R. Muller and P. Gedigk. 1975. Unusual
splenomegalic liver disease as evidence by peritoneoscopy and guided
liver biopsy among polyvinyl chloride production workers. Ann. N.Y.
Acad. Sci. 246:95-134.
Miltner, R., 1984. Personal communication, U.S. EPA Technical Support
Division, ODW, Cincinnati, OH. Cited in Technologies and Costs for the
Removal of Volatile Organic Chemicals from Potable Water Supplies by
Environmental Science and Engineering.
NAS. 1977. National Academy of Sciences. Drinking Water and Health.
Volume 1, National Academy Press. Washington", DC. pp. 783-787.
Parsons, F., P.R. Vtood and J. DeMarco. 1984. Transformation of Tertrac-
hloroethene and Trichloroethene in Microcosms and Groundwater, J.A.W.W.A.,
Vol. 26 No. 2, pg 56f.
Picciano, D.J., R.E. Flake, P.C. Gay and D.J. Killian. 1977. Vinyl chloride
cytogenetics. J. Occup. Med. 19:527-530.
Purchase, I.F.H., C.R. Richardson and D. Anderson. 1975. Chromosomal and
dominant lethal effects of vinyl chloride. Lancet. 2(7931)i410—411.
Selikoff, I.J., and E.C. Hammond, eds. 1975. Toxicity of vinyl chloride-
polyvinyl chloride. Ann. N.Y. Acad. Sci., Vol. 246.
Symons, J.M. 1978. Interim Treatment Guide for Controlling Organic
Contaminants in Drinking Water Using Granular Activated Carbon. U.S.
EPA Office of Research and Development, MERL, DWRD, Cincinnati, OH.
Cited in U.S. EPA SNARL Document for Vinyl Chloride (Draft) and in U.S.
EPA May, 1983. Treatment of Volatile Organic Compounds in Drinking
Water. Report No. EPA-600/8-83-019, Office of Research and Development,
MERL, DWRD, Cincinnati, OH.
Til, H.P., H.R. Inmel and V.J. Feron. 1983. Lifespan oral carcinogenicity
study of vinyl chloride in rats. Final report. Civo Institutes TNO.
Report No. V 83.285/291099.
Torkelson, R.R., F. Oyen and V.K. Rowe. 1961. The toxicity of vinyl chloride
as determined by repeated exposure of laboratory animals. Amer. Ind.
Hyg. Assoc. J. 22:354-361.
U.S. EPA. 1979. U.S. Environmental Protection Agency, water related
environmental fate of 129 priority pollutants. Office of Water Planning
and Standards. EPA-440/4-79-029.
U.S. EPA. 1980. U.S. Environmental Protection Agency. Vinyl chloride
Occurrence in drinking Wlater, food and air. Office of Drinking Water.
U.S. EPA. 1980. U.S. Environmental protection Agency. Ambient water quality
criteria for vinyl chloride. Office of Water Regulations and Standards.
EPA 440/5-80-078.
433
-------
Vinyl Chloride
September 30, 1985
U.S. EPA. 1931. U.S. Environmental Protection Agency. SNARL document for vinyl
chloride (Draft). Office of Drinking Mater.
U.S. EPA. 1984a. U.S. Environmental Protection Agency. Proposed guidelines
for carcinogenic risk assessment; Request for comments, Federal Register
49(227):46294-46301. November 23.
U.S. EPA. 1984b. U.S. Environmental Protection Agency. National primary
drinking water regulations; Volatile synthetic organic chemicals;
Proposed rulemaking. Federal Register 49(114):24330-24355. June 12.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Final draft for
the drinking water criteria document on vinyl chloride (Office of
Drinking Water). TR-540-162.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. Method 502.1.
Volatile halogenated organic compounds in water by purge and trap gas
chromatography. Environmental Monitoring and Support Laboratory, Cincin-
nati, Ohio 45268. June 1985.
U.S. EPA. 1985c. U.S. Environmental Protection Agency. Method 524.1.
Volatile organic compounds in water by gas chromatography/mass
spectrometry. Environmental Monitoring and Support Laboratory, Cincin-
nati, Ohio 45268. June 1985.
U.S. ITC. 1983. U.S. International Trade Ccrmission. Synthetic organic
chemicals United States production, 1982. USTIC Publication 1422.
Washington, D.C. 20436. 1983.
Verburgt, F.G., and E. Vogel. 1977. Vinyl chloride mutagenesis in Drosophila
melanogaster. Mutat. Res. 48:327-333.
Vogel, T., and P. McCarty. 1985. Biotransformation of Tetrachloroethylene
to Trichloroethylene, Dichloroethylene, Vinyl Chloride, and Carbon
Dioxide Under Methanogenic Conditions, Applied and Environmental
Microbiology, Vol 49 No.5.
Watanabe, P.G., G.R. McGcwan and P.J. Gehring. 1976a. Fate of (l^C) vinyl
chloride after single oral adninistration in rats. Toxicol. Appl,
Pharmacol. 36:339-352.
Watanabe, P.G., G.R. McGcwan, E.O. Madrid and P.J. Gehring. 1976b. Fate of
(l^c) vinyl chloride following inhalation exposure in rats. Toxicol.
Appl. Pharmacol. 37:49-59.
Winholz, M. 1983. The Merck Index. 10 Edition. Merck and Co., Inc.,
-Rahway, N.J.
Withey, J.R. 1976. Pharmacodynamics and uptake of vinyl chloride monomer
administered by various routes to rats. J. Toxicol. Environ. Health.
1:331-394.
434
-------
Vinyl Chloride September 30, 1985
Withey, J.R., and B.T. Collins. 1976. A statistical assessment of the
quantitative uptake of vinyl chloride monomer from aqueous solution.
J. Toxicol. Environ. Health. 2:311-321.
Wbod, p.R., and J. DeMarco. 1980. Effectiveness of various adsorbents in
removing organic compounds from water. 1: Removing purgeable halogenated
organics. In: Activated Carton Adsorption of Organics from the Aqueous
Phase. Volume 2. Ann Arbor Science, pp. 85-114.
435
-------
PART V
RISK COMMUNICATION
Outline for Videotape
436
-------
Part IV - Risk Communication
A- Wed la Basics
Media Coverage - Kdvantages
o Quick dissemination of Information to public
o Allays unfounded fears
o Inspires confidence
Modia Coverage - Disadvantages
o Shallowness
¦ Tight deadlines
• Stories must be brief
- Reporters are generallsts
o Sensationalism
- News stories required daily but true sensational stories don't
happen daily
-• Public interest in what went wrong not what went right
o Subjectivity
Coping With the Disadvantages of Media Coverage
o Shallowness
o Sensationalism
o Subjectivity
o Educate reporter
o Know and present facts
o Appeal to values
437
-------
®• Rules For Dealing With the Media
No such thing as "off the record"
Assume microphones always on
Plan ahead
o Primary and backup spokesperson
o Infotm media and government who spokesperson is how to contact
o Telephone operators Informed how to reach spokesperson
o Establish Information gathering teams to report information to
spokesperson
o Establish contingency press area with telephones and backup
communications equipment
Develop ability to take control of interview
438
-------
C. Controlling the Interview
winning at confrontation
o Rules of the game
o Crisis comnunlcations exercise I
You have been thrown Into the middle of a hot controversy about contamination
of drinking water supplies. During a public meeting, which was attended by
organized protesters and the media, a woman runs up to you, pokes her finger into
your chest, and calls you "not human, robot."
Evaluate the pros and cons of these various ways of dealing with her outburst
h) Walk out with as much dignity as you posses and issue a statement latet
refuting her charges.
PRO: CON:
B) fcsk the police to remove her and other hecklers from the hall
PRO: CON:
C) Remain silent until she calms down and then try to avoid saytng
anything that might agitate the audience.
PRO: CON:
439
-------
U) Grab the microphone, ask for a chance to respond and emphatically dlsagroc
with her.
PRO: CON:
o Guidelines for success
Dealing with fear
o The problem
o Crisis Communication Exercise II
After the train derailed and spilled a large quantity of chemicals, you are
In charge of the cleanup. The residents don't trust the railroad and believe it is
understating the potential long-term danger to drinking water supplies. Evaluate
each of the following as a possible first action on your part:
A) Hold a joint news conference with the railroad spokesman to refute the
charges.
PRO: COW:
B) Issue a statement announcing a study to ascertain the facts.
CRO: CON:
440
-------
C) Meet with residents at City Hall to hear their complaints and fill tctr,
In on the cleanup.
PRO:
CON:
l>) Accelerate efforts to contain the spill and pump the liquid into tanks.
PKO; CON:
o Guidelines for success
441
-------
D. Disclosing Information
Oner a 1
Ground Rules
Crisis Communications Exercise III
You «re an official of a water district experiencing a prolonged drought. A
newspaper reporter calls and asks If It Is true that a major Industrial plant It.
using water at the same rate as before the drought, despite official requests for
conservation. His Information Is correct. Analyze the pros and cons of each of the
following ways of answering his question.
A) Tell him to call the manufacturer. Giving out such information about
users violates privacy rights.
PRO: CON:
ID Acknowledge It's true but warn that If water usage by this industry Is
cut, the budget will go In the red and the rates will go up for everyone.
PRO: 00N:
C) Tell him you will seek an audit and get back to hln (and give him the
results after the drought is over).
PRO: CON:
442
-------
D) acknowledge it's true but explain that the manufacturing process It such
that there can be little variation In water consumed in the process as long as tht-
plant is operating.
PRO: CON:
Guidelines for success
443
-------
t£. Conclusions and Checklist
General Risk Peiception
o The problem of Involuntary risks
o Communication Exercise IV
Assume that a volatile chemical is detected in the drinking water that yout
scientific expeits say has about the same chance of causing cancer as saccharin.
After the story is leaked to the press you appear at a town meeting. Analyze the^<-
v
-------
Crisis Communication Checklist
I. BE PREPARED. REVIEW THE FACT'S.
BE HONEST. TELL THE TRUTH.
3. ANTICIPATE LIKELY QUESTIONS.
4. CONSIDER WHAT THE AUDIENCE IS INTERESTED IN KNOWING.
¦>. DECIDE WHAT YOU WANT TO SAX.
6 CONSIDER IF THERE ARE THINGS YOU DON'T WANT TO DISCUSS.
COMPOSE CONCISE. ACCURATE ANSWERS.
8. AVOID JARGON.
9. DON'T FLY BY THE SEAT OF YOUR PANTS, YOU MIGHT CRASH.
10. IF YOU DON'T KNOW THE ANSWER TO A QUESTION. DON'T GUESS.
II. STAY CALM, DO NOT LOSE YOUR COOL.
12. SPEAK UP, DO NOT MUMBLE.
13. BE ASSERTIVE. NOT ARROGANT.
14. DO NOT FIGHT WITH REPORTERS, BYSTANDERS, ACTIVISTS.
15. DO NOT FUDGE.
16. DO NOT SHOW FRIGHT. RELAX. BREATHE DEEPLY.
H. AVOID FLIGHT. DON'T TRY TO RUN AWAY.
18. COUNTER FALSE ASSUMPTIONS IN QUESTIONS.
19. WHEN FINISHED, STOP. IT IS HARDER TO PUT ONE'S FOOT IN ONE'S MOUTH WtlKhi IT
IS SHUT.
FOR OUR MANUAL ON CRISIS COMMUNICATIONS (100 pages, paperback)
CALL PORD ROWAN AT (202) 296-9710
OR WRITE: FORD ROWAN, 1899 L. STREET, N.W., SUITE 405, WASHINGTON, D.C. 2003C
(price per copy: $14)
445
-------
THE DOZEN MOST COMMON MISTMCES IN CKVJ1S COMMUNICATIONS
By Ford Rowan
The first mistake most managers make Is Falling to prepare for a worst
case scenario. Perhaps it's human nature to avoid the unthinkable. But the single
most Important thing that can be done to prevent a catastrophe Is to prepare for it.
The second mistake most managers make is to underestimate the Impoitar.ee
of the media at the onset of 0 crisis. The dissemination of information is crucial
and the presence of reporters and photographers is automatic at most serious
emergencies. If the press is an unwelcome guest, it returns the cool reception by
heating up the rhetoric.
The third mistake Is to fall to understand the needs of the press for
regular updates. Deadlines come often In this day of instant-eyes and mlnlcams.
Falling to provide concise factual updates can result in wild speculation.
The fourth mistake is the failure to establish a communications command
center where Information can be coordinated. Reporters will be wandering all over
the place, talking with uninformed bystanders. Communications must be coordinated to
assure accurate information.
The fifth mistake is to fall to take charge. The spokesperson must be a
leader. His role Is not just to answer questions but to disseminate information.
The sixth mistake is to fall to anticipate likely questions. The old
standards what, when, where, who, why and how can be expected. Remember,
people want to know, "Is it safe now?"
The seventh mistake is to be lured into answering hypothetical
questions. Avoid "What ifs," they can be scary. When asked to predict, stick to the
facts and make projections if any ¦ based on what is known.
The eighth mistake occurs when a spokesperson inadvertently uses an
emotionally charged word or sensational phrase in response to a question. Don't
contribute to hype.
The ninth mistake is to assign blame for an accident. It's likely that
litigation will last for years anyway, so keep your opinions in check.
The tenth mistake Is to try to stonewall if things get worse, to fudge
the facts if the situation begins to deteriorate, or to compound the confusion as
fatigue sets in. Credibility Is at stake; preserve it with candor.
The eleventh mistake is to let questions get under your skin. Show by
your demeanor end candor that you will cooperate with courteous journalists. Keep
cool.
The twelfth mistake is to fail to learn from mistakes, i.lfe ts full of
trial and error. Put the hard earned knowledge to work to prevent future crises.
446
-------
Seminar Evaluation
ASSESSMENT AND MANAGEMENT OF DRINKING WATER CONTAMINATION
Please fill in Name of City where eeainar is being held:_^
Attendee's Profile - Organization You Represent (Please Mark with an "X*)
Municipal/Local Agency Consulting Engineer
or Scientist
State Agency _____ Federal Wacy
___________ Other
Presentations
Please evaluate each presentation using the following scale as applicable:
1 - Excellent 2 * Good 3 * satisfactory A * Marginal S « unsatisfactory
Speaker Audio/Visual Question and
Topic Content Effectiveness Material Answer Period
Regional update ___
(if applicable)
Introduction to ^ _ _
Risk Assessment
and Management
Problems
principles of
Toxicology
Absorption#
Distribution,
Secretion and
Netabolism
Tox approaches to
developing Natl.
DH Standards
ON Health
Advisory Program
"toxicology of
Inorganics,
Pesticides,
Solvents and
Vapors
-2-
Speaker Audio/Visual Question and
Topic Content Effectiveness Material Answer period
Principles of
Carcinogenicity
Risk Assessment _
Principles
Risk Assessment _____ _________
Case Study
Radionuclides
Lecture
Overview of Treatment
a# applied to Risk
Management
Inorganics Treatment
Organica Treatment
Risk Communication
Risk Management
Case Stud/
Please list any topics which should have been given more emphasis in the
presentations:
Please list any topics which should have been given less emphasis in the
presentations:
------- |