&EPA
United States
Environmental Protection
Agency
Office of Drinking
Water
Washington DC 20460
Technology Transfer
Workshops on
Assessment and
Management of
Drinking Water
Contamination
Center for Environmental
Research Information
Cincinnati OH 45268
EPA/600/M-86/026 Oct 198'
-------
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
you, but it is not our intention that this person will lecture. It is expected
that each person take part in the solutions of the problems.
It is hoped that by the closing of this workshop, each participant
will be able to better handle similar problems occurring in that participant's
own Region, State or locality and that the procedures laid out in this work-
shop will improve the quality of performance on the job.
-------
WORKSHOP ON RISK ASSESSMENT AND MANAGEMENT OF DRINKING WATER CONTAMINATION
Table of Contents
I. UNDERSTANDING EPA'S DRINKING WATER HEALTH ADVISORIES
EPA 's Health Advisory Program 1-1 - 1-1 6
Aldicarb Health Advisory I-B-1 - I-B-16
Vinyl Chloride Health Advisory I-C-1 - I-C-1 5
II. RISK ASSESSMENT
Principles of Toxicology .II-A-1 - II-A-1 5
Principles of Absorption, Distribution, Excretion & Metabolism of
Chemicals II-B-1 - II-B-8
Toxicology of Inorganics II-C-1 - II-C-10
Toxicology of Pesticides II-D-1 - ll-D-21
Toxicology of Solvents and Vapors II-E-1 - II-E-7
Principles of Risk Assessment II-F-1 - II-F-56
Principles of Carcinogenicity II-G-1 - II-G-8
III. RISK MANAGEMENT
Overview of Drinking Water Health Advisories: Occurrence,
Chemistry and Treatment Technologies III-A-1 - III-A-42
Inorganics Treatment: Overview & Case Studies . ...III-B-1 - III-B-22
Organics Treatment: Overview s Case Studies III-C-1 - III-C-56
IV. RISK COMMUNICATON
Outline for Videotape IV-1 - IV-1 0
-------
PART I
UNDERSTANDING EPA'S DRINKING WATER HEALTH ADVISORIES
1-1
-------
ACKNOWLEDGMENTS
OFFICE OF DRINKING WATER CRITERIA AND STANDARDS DIVISION STAFF
LARRY ANDERSON
KENNETH BAILEY
AMBIKA BATHIJA
BALDEV BATHIJA
STEVE CLARK
JOSEPH COTRUVO
MARIA GOMEZ-TAYLOR
KRIS HAN KHANNA
PETER LASSOVSKY
WILLIAM MARCUS
JENNIFER ORME
YOGENDRA PATEL
ARTHUR PERLER
PAUL PRICE
FOR FURTHER INFORMATION ON THE HEALTH ADVISORY PROGRAM,
CALL OR WRITE:
MANAGER , HEALTH ADVISORY PROGRAM
OFFICE OF DRINKING WATER (WH-550)
U.S. ENVIRONMENTAL PROTECTION AGENCY
401 M STREET, S.W.
WASHINGTON, D.C. 20460
(202) 382-7571
1-2
-------
EPA'S DRINKING WATER HEALTH ADVISORY PROGRAM*
P.A. Fenner-Crisp and E. V. Ohanian. Office of Drinking Water
U.S. Environmental Protection Agency, Washington, DC, 20460
ABSTRACT
The Office of Drinking Water's non-regulatory Health
Advisory Program provides technical guidance 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.
The Health Advisories are developed from data describing
non-carcinogenic end-points of toxicity. For those chemicals
which are known or probable human carcinogens according to
the proposed Agency classification scheme, non-zero One-day,
Ten-day, Longer-term Advisories may be derived, with attendant
caveats. Advisories for lifetime exposure 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.
* Presented at the 25th Anniversary Meeting of the Society of
Toxicology. The Toxicologist 6(1):280 (Abstract f 1124).
March, 1986.
1-3
-------
ELEMENTS OF THE OFFICE OF
DRINKING WATER'S
HEALTH ADVISORY PROGRAM
• Establish comprehensive Health Advisories Registry
(Computer-based)
• Prepare new and revised Health Advisories for about 50
contaminants (FY85)
• Develop new Health Advisories for about 60 National Pesticide
Survey analytes (FY86)
• Develop new Health Advisories for about 50 unregulated volatile
synthetic organic chemicals under Section 1445 (FY86)
• Institute new procedures to assure timely responses to emergency
situations and requests for information (FY85)
• Establish cooperative program between EPA and the Department
of the Army on (Health Advisory development for) munitions
chemicals in drinking water
• Initiate information-sharing and toxicological support program
between EPA and States
• 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 (Pilot in FY86; Deliver in FY87)
1-4
-------
WHAT ARE HEALTH ADVISORIES?
• Health Advisories are not legally enforceable
Federal standards. They are subject to change
as new and better information becomes available.
• Health Advisories describe concentrations
of contaminants in drinking water
at which adverse non-carcinogenic effects
would not be anticipated to occur
following 1-day, 10-day, longer-term,
or lifetime exposure.
• 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 4 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
1-5
-------
PROPOSED EPA SCHEME
FOR CATEGORIZATION OF EVIDENCE
OF CARCINOGENICITY
Group A: Human Carcinogen
Sufficient evidence in epidemiologic studies to support
causal association between exposure and cancer
Group B: Probable Human Carcinogen
Almost sufficient to inadequate evidence
in epidemiologic studies
Sufficient evidence from animal studies
Group C: Possible Human Carcinogen
Absence of data in humans
Limited evidence from animal studies
Group D: Not Classified
Inadequate animal evidence
Group E: No Evidence of Carcinogenicity for Humans
No evidence in multiple studies
1-6
-------
ODW HEALTH ADVISORY (HA)
CONTENT
I. General Introduction
II. General Information and Properties
• Synonyms
•Uses
• Properties
• Sources of Exposure
• Environmental Fate
III. Pharmacokinetics
• Absorption
• Distribution
• Bbtrartsformation
• Excretion
IV. Health Effects
• Humans
• Animals
- Short-term Exposure
- Longer-term Exposure
• Developmental/Reproductive/Mutagenic/
Carcinogenic Effects
V. Quantification of lexicological Effects
• One-day Health Advisory
•Ten-day Health Advisory
• Longer-term Health Advisory
• Lifetime Health Advisory
• Evaluation of Carcinogenic Potential
VL Other Criteria, Guidances and Standards
1-7
-------
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
1-8
-------
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 (90d)
to one year
Lifetime HA: Chronic
Subchronic (with added
uncertainty factor)
• Route of Administration
Oral: Drinking water, Gavage, Diet
Inhalation
Subcutaneous or intraperitoneal
(on a case-by-case basis)
• Test Species
Human
Appropriate animal model
Most sensitive species
1-9
-------
DERNmON OF ADI/RRf D
ADI = Acceptable Daily Intake
RRfD - Risk Reference Dose
The daily exposure level,
which during the entire lifetime
of a human, appears to be without
appreciable risk on the
basis of all facts known
at the time (modified from
Paynter, et al., 1975)
The ADI/RRfD is expressed in
mg/kg bw/day
-------
THE MATH"
OLD METHOD:
ADI — NOAEL. — Dose in mg/kg bw/day
sRi
NEW METHOD:
RRfD — NOAEL •• Dose in mg/kg bw/day
^
-------
THE "DWEL1
Definition
Drinking Water Equivalent Level: Estimated exposure
(in 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
1-12
-------
SUBSTANCES FOR WHICH HEALTH ADVISORIES ARE BEING DRAFTED IN FY 86
ANALYTES FOR THE
NATIONAL PESTICIDE SURVEY
UNREGULATED VOCs
UNDER SECTION 1445
Actfluorfen
Ametryn
Ammonium SuHamate
Baygon
Bentazon
Bromacll
Butylate
Carbaryl
Carboxin
Chkxamben
Chtorothatonll
Cyanazfne
Cyctoate
Dalapon
DCPA/Oacthal
Diazinon
Dlcamba
Dieldrin
Dimethlpin /Harvade
Dimethrln
Dlnoseb
Diphenamid
Disulfoton
Diuron
Fenamlphos
Fluometuron
Fonofos
Hexazlnone
Maleic Hydrazide
MCPA
Methomyl
Methyl Parathton
Metolachtor
Metribuzln
Nabam
Oxamyl
Paraquat
PCNB
Pictoram
Prometone
Pronamide
Propazine
Propham
Treflan
Trlallate
2, 4, 5-T
Tebuthluron
Terbacil
Chtoromethane
Bromomethane
Bromochloromethane
1, 2, 3-Trtohlofopropane
1, 2, 3-Trlchlorobenzene
n-Propylbenzene
1,1,1, 2-Tetrachloroethane
Chloroethane
1,1, 2-Trichloroethane
Pentachloroethane
bls-2-Chtoroisopropyl ether
sec-Dichtoropropane
Chloroform
Bromodichtoromethane
Chlorodibromomethane
Bromoform
1,2, 4-Trlchlorobenzene
Fluorotrichloromethane
Dichlorodifluoromethasie
1, 2, 4-Trimethylbeni«n«.
n-Butylbenzene
Naphthalene
Hexachlorobutadlene
o-Chlorotoluene
p-Chlorotoluene
1,3, 5-Trimethylbenzcrte
p-Cymene
1,1-Dtehloropropane
Iso-Propylbenzene
tert-Butylbenzene
sec-Butylbenzene
Bromobenzene
Dibromomethane
1,1-Dichkxoethane
1,1,2, 2-Tetrachk>roeMw»n«-
1, 3-Dichtoropropant
-------
FY 85 Draft Health Advisories
(* MA = Not appropriate)
Chemical
Acrylarra.de
Alachlor
Aldicarb
Arsenic
Barium
Benzene
Cadmium
Carbofuran
Carbon let.
Chlordane
Ollorobenzene
Chromium
cyanide
2 ,4-D
DBCP
o-/n»-
Dichlorobenzem
One-day HA
(ug/L)
1500
15000
12
50
_
233
43
50
4000
63
1800
1400
220
1100
200
e 8930
P- 1
Dichlorobenzene 10700
1
1 ,2-Dichloroethane 740
1 ,1-Dichloro-
ethylene
1000
Ten-day HA
(ug/L)
300
15000
12
50
_
233
8
50
160
63
1800
1400
220
300
50
8930
10700
740
1000
longer- term HA
(ug/L)
10 kg
20
NA
12
50
_
NA
5
50
71
_
9000
240
220
-P-
NA
8930
10700
740
1000
70 Kg
70
NA.
42
50
_—
NA
18
180
250
—
30000
840
750
—
NA
31250
37500
2600
3500
Lifetime HA or
DWEL at 100%
(note which)
(ug/L)
DWEL = 7
NA
42
50
1800
NA
18
180
DWEL= 25
DWEL = 30
3150
170
750
350
NA
3125
3750
NA
350
Lifetime HA
with RSC
(ug/L)
NA*
NA
9 (20%)
50
1500 (80%)
NA
5 (25%)
36 (20%)
NA
NA
600 (20%)
120 (71%)
750 (100%)
70 (20%)
NA
620 (20%)
750 (20%)
NA
70 (20%)
Risk at 10"6
(ug/L)
0.01
0.15
NA
200
NA
0.35
NA
NA
0.3
0.0218
NA
NA
NA
NA
0.025
NA
NA .
0.95
0.24
1
EPA
Carcinogen
Group
B
D
E
A
D
A
Bl/D
E
B
B2
C
A/D
D
D
B
D
D
B
C
-------
FY 85 Draft Health Advisories
Revised 3/20/86
Chemical
Cis-1 ,2-
Dichloroethylei
Trans-1 ,2-
Dichloroe thy lei
Dichlorone than*
1,2-
Dichloropropan*
p-Dioxane
Dioxin
EDB
Endrin
Epichlorohydr it
Ethylbenzene
Ethylene glyco.
Heptachlor
Heptachlor epco
Hexachlorobenz<
n-Hexane
Lead
Lindane
Mercury
Methoxychlor
One-day HA
(ug/L)
le 4000
ie 2720
* 13300
k .»
5680
1 x 10"3
8
20
i 140
21000
L 19000
10
cide -
?ne 50
13000
NA
1200
_
6400
Ten-day HA
(ug/L)
1000
2720
1500
90
568
1 x 10 -4
8
5
140
2100
5500
10
—
50
4000
NA
1200
mt
2000
Longer-term HA
(ug/L)
L_ 10 kg^
1000
1000
_
_
-*
1 x 10 "5
NA
4.5
76
_
5500
••
—
50
4000
20 ug/day
33
mf
—
70 kg
3500
3500
w
..
. „
3.5 x 10~
NA
16
76
«•
19250
^
_
175
14000
20 ug/day
120
—
_
Lifetime HA or
DWEL at 100%
(note which)
(ug/L)
350
350
1750
—
«•»
' DWEL - 1 x 10 ~5
NA
1.6
DWEL = 76
3400
_
DWEL = 2.6
DWEL = 1
DWEL = 28
„
20 ug/day
10
5.5
1700
Lifetime HA
with RSC
(ug/L)
70 (20%)
70 (20%)
350 (20%)
-_,_
^
NA
NA
0.32 (20%)
NA
680 (20%)
NA
NA
NA
NA
NA
2 (20%)
3 (55%)
340 (20%)
Risk at 10"6
(ug/L)
NA
NA
50
0.56
?
2.2 x >0'7
0.0005
NA
3.5
NA
NA
0.0104
0.0006
0.02
NA
0.031
0.0263
NA
NA
EPA
Carcinogen
Group
D
D
B
C
ND*
B
B
E
B
D
D
B2
B2
B
D
B2
B2/C
D
D
-------
FY 85 Draft Health Advisories
Chemical
Methyl ethyl k«
Nickel
Nitrate
Nitrite
Oocanyl
PCBs
Pen tachlorophei
Styrene
Tetrachloro-
ethylene
Toluene
Tbxaphene
2,4,5-TP
1 ,1 ,l-Trichlor<
ethane
Trichloro-
ethylene
Vinyl chloride
Xylenes
One-day HA
(ug/L)
stone 75000
_
10 ng/1- 4 kg
111 ng/L-Othei
1 ng/L- 4 kg
11 ng/L-Other
350
_
x>l 1000
27000
_
18000
500
(200)
3-
140000
_
2600
12000
Ten-day HA
(ug/L)
7500
1000
10 ng/L-4 kg
rill ng/L-Othei
1 ng/L- 4 kg
11 ng/LrOtner
350
_
300
20000
34000
6000
80
200
35000
_
2600
7800
Longer-term HA
(ug/L)
10 kg
2500
_
r -
_
_
300
20000
1940
_
_
_
35000
..
13
7800
70 kg
8600
_
—
—
_
1050
70000
6800
..
M
«
125000
_
46
27300
Lifetime HA or
DWEL at 100%
(note which)
(ug/L)
860
350
10 ng/L
1 ng/L
810
—
1050
7000
DWEL = 680
10100
DWEL = 112
260
1000
DWEL = 260
NA
2200
Lifetime HA
with RSC
(ug/L)
172 (20%)
150 (43%)
10 ng/L(100%
Risk at 10"6
(ug/L)
NA
NA
1 NA
1
1 ng/L (100%) NA
160 (20%)
—
220 (20%)
1400 (20%)
NA
2000 (20%)
52 (20%)
200 (20%)
NA
NA
440 (20%)
NA
—
NA
1. 4 xlO~2
0.7
NA
0.031
NA
16.8 (NAS)
22 (GAG)
2.8
0.015
NA
EPA
Carcinogen
Group
D
B/D
D
D
E
B
D
C
B2
D
B2
D
D
B2
A
D
1-16
-------
September 30, 1985
PART I-B-1 HEALTH ADVISORY #1
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 guantitatively 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 from the linearized multistage model which is considered to be
unlikely to underestimate the probable true risk.
[Summary Table-to be added]
I-B-1
-------
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 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 # 86-117751/AS.. The toll free number is (800) 336-4700; in Washington,
D.C. area: (703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
Synonyms: 2-methyl-2-(methylthio)propionaldehyde 0-methylcarbamoyl oxime
Temik®
Use: Pesticide (nematocide, acaracide)
Properties;
CAS #
Chemical formula
Molecular weight
Physical state (room temp.)
Melting point
Boiling point
Vapor pressure
Specific gravity
Water solubility
Taste threshold (water)
Odor threshold (water)
Odor threshold (air)
Structural formula
116-06-3
C7H14°2N2S
190.3
white crystals
100°C
decomposes above 100°C
0.05 torr at 20°C
1.195 at 25°C
6 g/1 (room temp.)
odorless to light sulfur smell
Occurrence
EPA estimated that aldicarb production ranged from 3.0 to 4.7 million
Ibs per year during 1979-1981. Aldicarb is applied both to the soil
and directly to plants.
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
I-B-2
-------
Aldicarb September 30, 1985
its sulfoxide and sulfone degradation products do not bind to soil
or sediments and have been shown to migrate extensively in soil.
Aldicarb does not bioaccumulate to any great extent.
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).
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 ugA--
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.r 1967; Dorough and Ivie, 1968; Dorough,
et al., 1970; Hicks, et al., 1972; Cambon, et al., 1979).
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
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 1:1 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),
I-B-3
-------
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 carbanate
ester and oxidation of the sulfur to sulfoxide and sulfone derivatives
which have been shown to be active cholinesterase 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 C02 has been demonstrated
as a minor route in rats (Knaak, et al., 1966) and in the milk of
cows (Dorough and Ivie, 1968) .
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).
IV. 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.
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 symptoms.
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-
I-B-4
-------
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 value
measured in two subjects dosed at 0.1 mg/kg.
Animals
Short-term Exposure
NAS (1977) stated that the acute toxicity of aldicarb is probably
the greatest of any widely used pesticide.
Reported oral I^>^Q values for aldicarb administered to rats in corn or
peanut oil range from about 0.65 to 1 mg/kg (Weiden, et al., 1965;
Gaines, 1969) . Females appear to be more sensitive than males. The
oral LD5Q in mice is 0.3 to 0.5 mgAg (Black, et al., 1973).
Oral LD5Q values for aldicarb were higher when using a vehicle other
than corn or peanut oil. Weil (1973) reported an oral LDsg of 7.07
mg/kg in rats administered aldicarb as dry granules. Carpenter and
Smyth (1965) reported an LD5Q of 6.2 mgAg in rats administered aldicarb
in drinking water.
Dermal toxicity also is high with 24-hour LD5Q values of 2.5 and 3
mg/kg reported for female and male rats, respectively (Gaines, 1969)
and 5 mg/kg in rabbits (Weiden, et al., 1965).
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).
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
LD5Q in rats) (Nycum and Carpenter, 1970) and at 2.5 mg/kg/day in
chickens (Schlinke, 1970) . The latter dosage also resulted in seme
lethality in test animals.
A NOAEL 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 1:1 ratio in the drinking water
of young rats for 8 to 29 days. Doses ranged up to 1.67 mg/kg/day
for males and 1.94 mg/kg/day for females. Based on statistically
significant reductions in cholinesterase activity in brain, plasma
and RBs at higher dosage levels, a NOAEL of 0.12 mgAg/day was determined.
I-B-5
-------
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 mgAq/day resulted in no significant increases
in adverse effects based on a variety of toxicologic endpoints (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 mg/kg/day for two
years resulted in an increase in the mortality rates of female rats
(Weil, 1975) .
0 Higher dosages of aldicarb sulfoxide (i.e., 0.25 to 1.0 mg/kg/day) or
aldicarb sulfone (1.8 to 16.2 mg/kg/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 histopathology were
noted in any group, however. Data derived from the lower dosage
levels of this study have been used by the World Health Organization
Committee on Pesticide Residues (FAD/WHO, 1980) to derive a NOAEL of
0.125 mg/kg NOEL for aldicarb sulfoxide in the rat.
Teratogenici ty/Reproductive Ef fects
0 No teratogenic or reproductive effects have been demonstrated to
result from the administration of aldicarb to rats (Weil and Carpenter,
1964,1974), rabbits (IRDC, 1983) or chickens (Proctor, et al.,
1976) .
0 No adverse effects on milk production were observed in studies of
lactating cows or rats (Dorough and Ivie, 1968; Dorough, et al.,
1970).
0 Statistically significant inhibition of acetylcholinesterase activity
has been demonstrated in the liver, brain and blood of rat fetuses
when their mothers were administered aldicarb by gastric intubation
on day 18 of gestation (Cambon, et al., 1979). These changes were
seen at doses of 0.001 mgAg and above and were manifested within
five minutes of the administration of 0.1 mg/kg.
Mutagenicity
0 Aldicarb has not been demonstrated to be conclusively mutagenic in
Ames bacterial assays or in a dominant lethal mutagenicity test in
rats (Ercegovich and Hashed, 1973; Weil and Carpenter, 1974; Godek,
et al., 1980) .
I-B-6
-------
Aldicarb September 30, 1985
Carcinogenicity
0 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 B6C3F^ 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
administered 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 mg/kg
bw/day for 2 years.
0 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.
0 Intraperitoneally 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 TCKICOLOGICAL 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:
(NOAEL or LOAEL) (BW) = _ uqA
(UF(s)) (__L/day)
Where: NOAEL or LOAEL = No-Observed-Adverse-Effect-Level
or
Lowest-Observed-Adverse-Effect-Level
(the exposure dose in mg/kg bw)
BW = assumed body weight of protected individual
in kg (10 or 70)
UF(s) = uncertainty factors, based upon
quality and nature of data
I-B-7
-------
Aldicarb September 30, 1985
L/day = assumed daily water consumption (1 or 2) , in liters
The available data suggest that the appearance of cholinergic symptoms
indicative of cholinesterase enzyme inhibition is the most 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 NOAEL 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 NOAEL of 0.125 mg/kg bw/day can be determined from
the Weil and Carpenter (1968b) and Mirro, et al., (1982) studies. From this
NOAEL, all HA values can be determined.
One-day Health Advisory
For the 10 kg child:
One-day H^ - (0.125 mg/kg/day)(10 kg) _ 0_012 mg/L (12 ug/L)
(100H1 L/day)
Where:
0.125 mg/kg/day = NOAEL, 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 NOAEL
1 L/day = assumed volume of water consumed/day by 10 kg
child, in liters
I-B-8
-------
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 mgAg/day) (10 kg) - 0>012 mg/L (12 ug/L)
(100M1 L/day)
Where:
0.125 mgAg/day = NOAEL, 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 NOAEL
1 L/day = assumed volume of water consumed/day by 10 kg
child
For the 70 kg adult:
Longer-term HA = (0.125 mgAg/day)(70 kg) _ 0.042 rogA- (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
=.. (0-125 mg Ag/day) a 0.00125 wg/kg/day
(100)
I-B-9
-------
Aldicarb September 30, 1985
Where:
0.125 mgAg/day = NOAEL
100 = uncertainty factor appropriate for use
with NOAEL from animal study
* 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) = 0 040 ^A = 42 UQA
(2 L/day) " y/
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, guantification of carcinogenic risk for lifetime exposures through
drinking 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 adeguate
animal tests in different species or in both epidemiologic and animal studies.
I-B-10
-------
Aldicarb September 30, 1985
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The National Academy of Sciences proposed an ADI of 0.001 rogAg/day
based upon the two-year feeding studies in rats and dogs (NAS, 1977).
NAS reaffirmed this ADI in 1983 (NAS, 1983).
0 In addition, NAS also derived a chronic suggested-no-adverse-effeet-
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 whom 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
mgAq/day based upon the data from the six-month rat feeding study
with aldicarb sulfoxide (U.S. EPA, 1981).
0 The FAO/WHO proposed ADIs for aldicarb residues of 0-0.001 mg/kg/day
in 1979 and 0-0.005 mg/kg/day in 1982.
VI. ANALYSIS
Analysis of aldicarb is by a high performance liquid chromatographic
procedure used for the determination of N-roethyl carbamoyloximes and
N-methylcarbanates in drinking water (Method 531. Measurement of
N-methyl carbamoyloximes and N-methylcarbamates in Drinking Water
by Direct Agueous 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 TfPLC 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.
VIII. TREATMENT
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.
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
I-B-11
-------
Aldicarb September 30, 1985
water softener in which the ion exchange ion was replaced with 38.5
Ib Filtrasorb ® 400 (Calgon GAC). The unit was operated at a flow rate
of 3 gal/rain. 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 rag aldicarb residue
per gram. This value can be compared with an eguilibrium 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 field
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.
Chlorination also appears to offer the potential for aldicarb
removal (Union Carbide, 1979) . The company 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 commonly 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 atm).
I-B-12
-------
Aldicarb September 30, 1985
DC. REFERENCES
Andrawes, N.R., H.W. Dorough and D.A. Lindquist. 1967. Degradation and
elimination of Temik in rats. J. Econ. Entomol. 60(4) :979-987,
Black, A.L., Y.C. Chiu, M.A.H. Fahmy 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. Lindquist and J.R. Coppedge. 1967. Metabolism of 2-
methyl-2- (methyl thio) 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 from 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. 9F0793.
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. Tvie. 1968. Temik-S metabolism in a lactating
cow. 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 for removal of twenty-five synthetic organic chemicals
from drinking water. Prepared for EPA's Office of Drinking Water.
FAOAJHO. 1979 and 1982. References not available.
Gaines, T.B. 1969. The acute toxicity of pesticides. Toxicol, Appl.
PhaDtiacol. 14:515-534.
Godek, E.S., M.C. Dolak, R.W. Naismith and R.J. Matthews. 1980. Ames
Salmonella/Microsome Plate Test. Unpublished report by Pharmakon
Laboratories. Submitted to Union Carbide June 20, 1980.
I-B-13
-------
Aldicarb September 30, 1985
Goes, E.H., E.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. 1933.
Teratology study in rabbits. Union Carbide Corporation.
Knaak, J.B., M.J. Tallant and L.J. Sullivan. 1966. The metabolism of 2-
methy1-2-(methylthio) propionaldehyde 0-(methyl carbamoyl) oxime in
the rat. J. Agr. Food Chem. 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. Worthing, Ed. 1977. Pesticide Manual. British Crop
Protection Council, Worcestershire, England, p. 6.
Mirro, E.J., L.R. DePass and F.R. Frank. 1982. Aldicarb sulfone: aldicarb
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. Public 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. Moscioni and J.E. Casida. 1976. Chicken embryo NAD
levels lowered by teratogenic organophosphorus and methylcarbamate
insecticides. Biochem. Pharmacol. 25:757-762.
I-B-14
-------
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. Union Carbide Agricultural Products Company. Temik ®
aldicarb pesticide. Removal of residues from 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 commodities: 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 agueous injection HPLC with post column derivatization.
Environmental 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.
Weiden, M.H.J., H.H. Moorefield and L.K. Payne. 1965. o-(Methyl carbamoyl)
oximes: A new class of carbamate insecticides-acaracides. J. Econ.
Entcmol. 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.
I-B-15
-------
Aldicarb
September 30, 1985
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 No. 27-158. EPA Pesticide Petition No. 9F0798.
Weil, C.S. and C.P. Carpenter. 1965. Two year feeding of Compound 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.
reference available.
1966b. Skin painting in mice. No
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.
I-B-16
-------
September 30, 1985
PART I-C-1 HEALTH ADVISORY #2
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 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 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 from the linearized multi-
stage model which is considered to be unlikely to underestimate the probable
true risk.
[Summary table-to be added]
I-C-1
-------
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 Sen/ice, 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.
II. GENERAL INFORMATION AND PROPERTIES
Synonyms
0 Monochloroethylene, chloroethene
Uses
0 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, industrial 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).
Properties
CAS # 75-01-4
Chemical Formula H2C=CHC1
Molecular weight 62.5
Physical state gas
Boiling point -13.3°C
Vapor pressure 2,530 mm at 20°C
Specific gravity 0.91
Water solubility 1.1 q/L water at 28°C
Taste Threshold (water) not available
Odor threshold (water) not available
Structural formula H-C=C-C1
H H
Occurrence
0 Vinyl chloride is a synthetic chemical with no natural sources.
I-C-2
-------
Vinyl Chloride September 30, 1985
0 Production of vinyl chloride was approximately 7 billion Ibs in 1983
(U.S. ITC, 1983). Vinyl chloride is used consumptively and little is
released to the environment. Environmental 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 002 ar><3 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 ground water (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/L 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 from 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.
III. PHARMACOKINETICS
Absorption
0 Vinyl chloride is absorbed rapidly in rats following ingestion and
inhalation (Withey, 1976; Duprat, et al.f 1977).
Distribution
0 Upon either inhalation or ingestion of 14ovinvi 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 l^Q-yiny^ chloride showed
the highest 14C activity in liver and kidney, followed by spleen and
brain (Bolt, et al., 1976).
I-C-3
-------
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 ppm 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).
Symptoms of chronic inhalation exposure of workers to vinyl chloride
include hepatotoxicity (Marstellar, et al. 1975), acro-osteolysis
(Lilis, et al., 1975), central nervous system disturbances, pulmonary
insufficiency, cardiovascular toxicity, and gastrointestinal toxicity
(Selikoff and Hammond, 1975).
Animals
Short-term exposure
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 rag/kg (Feron, et al., 1975) .
I-C-4
-------
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
0 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
0 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 J3. typhi-
rnurium (Bartsch, et al., 1975), J3. coli (Greim, et al., 1975), yeast
(Loprieno, 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 lymphopoietic tissues have
been associated with occupational exposure to vinyl chloride in
humans (IARC, 1979).
0 Ingestion of vinyl chloride monomer in the diet by rats at feeding
levels as low as 1.7 mg/kg/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 Feron, 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 mg/kg/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).
0 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) .
I-C-5
-------
Vinyl Chloride September 30, 1985
V. QUANTIFICATION OF TOXICOLOGICAL 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:
(NOAEL or LOAEL) (BW) =
(UF(s)) (_L/day)
Where:
ugA-
NOAEL or LOAEL = No-Observed-Adverse-Effect-Level
or
Lowest-Observed-Adverse-Effect-Level
(the exposure dose in mg/kQ bw)
BW = 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 administered by gavage to
male and female Wistar rats, initially weighing 44 g, at doses of 30, 100 or
300 mgA<3 once daily, 6 days per week for 13 weeks. Several hematological,
biochemical and organ weight values were significantly (P<0.05 or less)
different in both mid- and high-dose animals compared to controls. The 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 = (30 mgAg/day (6/7) (10 kg) = 2.6 roqA (2,600 ug/L)
Y (100) (1 L/day)
I-C-6
-------
Vinyl Chloride September 30, 1985
Where:
30 mg/kg/day = NOAEL for subchronic toxicity from the Feron, et al. (1975)
study
6/7 = expansion of 6 days/week treatment in the Feron, et al. (1975)
study to 7 days/week to represent daily exposure
10 kg = assumed weight of child
1 L/day = assumed amount of water consumed by a child
100 = uncertainty factor for extrapolating results of animal
study with a NOAEL 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 mg/kg/day.
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 mg/kg/day. At dietary levels
of 0.014 and 0.13 mg/kg/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 Tog/kg/day is
identified as the NOAEL for noncarcinogenic effects for the Longer-term HA
calculation.
Using the 0.13 mg/kg/day NOAEL from the Til, et al, (1983) study, the
Longer-term HA is for a child calculated as follows:
Longer-term HA = (0.13 mg/kg/day) (10 kg) - 0.013 mgA or 13 ugA,
(100) (1 L/day)
Where:
0.13 mgAg/day = NOAEL 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 NOAEL was determined.
This HA is equivalent to 13 ug/day or 1.3 ugAg/day.
I-C-7
-------
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 mg/kg/day) (70 kg) _ Q.046 mgA or 46 uq/L
(100) (2 L/day)
This HA is equivalent to 92 ug/day or 1.3 ug/kg/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 recommended.
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 number 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
uq/L, O.I5 ug/L and 0.015 ug/L would increase the risk of one excess cancer
per 10,000 (10~4), 100,000 (10"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.
VI. OTHER CRITERIA, GUIDANCE, AND STANDARDS
0 The National Academy of Sciences (NAS, 1977) estimated a 10~6 risk
from lifetime exposure to 1 ug vinyl chloride/L drinking water with
the 95% upper limit of the multistage model and the lifetime
ingestion study in rats by Maltoni, et al. (1981).
0 In June, 1984, EPA proposed a Recommended Maximum Contaminant Level
(RMCL) of zero for vinyl chloride in drinking water (U.S. EPA, 1984b) .
I-C-8
-------
Vinyl Chloride Sepbember 30, 1985
Ambient water quality critera (U.S. EPA, 1980) are 20, 2 and 0.2 ug/L
for risks of 10~5, io~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).
VII. ANALYSIS
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. This 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 spectronetry (Method 524.1. Volatile organic compounds in water
by purge and trap gas chromatography/mass spectrometry. U.S. EPA,
1985c) . The detection limit for confirmation by mass spectrometry is
0.3 ug/L-
VIII. TREATMENT
0 The value of the Henry's Law Constant for vinyl chloride (6.4
atm-m-Vmole) 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-well 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) .
0 The concentration of vinyl chloride in southern Florida ground water
declined by 25% to 52% following passage through lime softening basins
and filters (Wood and DeMarco, 1980) . Since vinyl chloride is a
highly volatile compound, probably volatilized during treatment
(ESE, 1934).
0 Adsorption techniques have been less successful than aeration in
removing vinyl chloride from water. In a pilot study, water from a
ground water treatment plant was passed through a series of four
30-inch granular activated carbon (Filtrasorb 400) columns (Wood and
DeMarco, 1980; Symons, 1978) ; the empty bed contact time was approxi-
mately six minutes per column. Influent vinyl choride concentrations
I-C-9
-------
Vinyl Chloride September 30, 1985
ranged from below detection to 19 mg/1; erratic removal was reported.
To maintain effluent concentrations below 0.5 mg/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 low. 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 individual 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.
I-C-10
-------
Vinyl Chloride September 30, 1985
DC. REFERENCES
Bartsch, H., C. Malaveille and R. Montesano. 1975. Human, rat and mouse
liver-mediated mutagencity of vinyl chloride in J5. 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
(l,2-14c) 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 chromosome 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. Environmental 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. Cosmet. 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, Z. Radwan, D. Reichert and D. Henschler. 1975.
Mutagenicity _in vitro and potential carcinogenicity of chlorinated
ethylenes as a functTon of metabolic oxirane formation. Biochem.
Pharmacol. 24:2013-2017.
Hawley, G.G., 1981. The Condensed Chemical Dictionary. 10th Edition.
Van Nostrand Reinhold Company.
I-C-11
-------
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 on 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 JLJT. 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. Woods.
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. Daum, 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.
I-C-12
-------
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. Wood 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) :410-411.
Selikoff, I.J., and E.G. 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. Immel 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 Water, food and air. Office of Drinking Water.
U.S. EPA. 1980. U.S. Environmental Protection Agency. Ambient water guality
criteria for vinyl chloride. Office of Water Regulations and Standards.
EPA 440/5-80-078.
I-C-13
-------
Vinyl Chloride September 30, 1985
U.S. EPA. 1981. U.S. Environmental Protection Agency. SNARL document for vinyl
chloride (Draft) . 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. 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
chroma tography. 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 chronatography/mass
spectrcmetry . Environmental Monitoring and Support Laboratory, Cincin-
nati, Ohio 45268. June 1985.
U.S. ITC. 1983. U.S. International Trade Commission. 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. McGowan and P.J. Gehring. 1976a. Fate of (14C) vinyl
chloride after single oral administration in rats. Toxicol. Appl.
Pharmacol . 36 : 339-352 .
Watanabe, P.G., G.R. McGowan, E.O. Madrid and P.J. Gehring. 1976b. Fate of
(14C) 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. Phannacodynamics and uptake of vinyl chloride monomer
administered by various routes to rats. J. Toxicol. Environ. Health.
1:331-394.
I-C-14
-------
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.
Wood, P.R., and J. DeMarco. 1980. Effectiveness of various adsorbents in
removing organic compounds from water. 1: Removing purgeable halogenated
organics. In: Activated Carbon Adsorption of Organics from the Aqueous
Phase. Volume 2. Ann Arbor Science, pp. 85-114.
1-015
-------
PART II
RISK ASSESSMENT
-------
Part HA
Principles of Toxicology
-------
Part HA
General Principles of Toxicology
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. Desc r ip t ive
2 . Mech anistic
3. Regu 1 at ory
II. Specialized Areas of Toxicology
A. Forensic Toxicology: A hybrid of analytical
chemistry and fundamental toxicologic principles.
It is concerned primarily with the medico legal
aspects of the harmful effects of chemicals on man
and an imals.
B. Clinical Toxicology: An area concerned with
diseases caused by, or uniquely associated with
toxic substances. Efforts are directed at treating
patients poisoned with drugs or other chemicals
and at development of new techniques to treat
these intoxications.
C. Environmental Toxicology: Often used to designate
evaluations made in the interest of man but
dealing with compounds in the "environment."
III. Spectrum of Undesired Effects
A. Side effects or undesirable
8. 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 se ns 11 iz a t ion reactions
IIA-1
-------
IV. Classification of Toxic Agents
A. Target organ
E. Source
C. Effects
D. Physical state
E. Labeling requirements
F. Chemistry
G. Toxicity Rat ing
H. Mechanism of action
V. Chemical Exposure
A. Acute: s ingle
B. Subacute: less than 1 month
C. Subchronic: 1-3 months
D. Chronic: more than 3 months
VI. Dose-Response
90-
80-
70-
0) 60-
IsoH
30-
20
10-
i 11111 i i i 1111 H i i r i i n 11 1
5 10 20 50 100 200 400 800 2.000
Dose
hypersuscept ib Le
res istant
IIA-2
-------
r- o
>- o
D D
CB <
1-1
M
>
I
Mortality (Probit Units)
Mortality Frequency (%)
u
H
o
3
03
3
o
O
(0
(I)
I
u>
•o
o
D
to
(9
o
c
(D
0)
t-
iQ
-------
+ 1 SO = 68.3%
+ 2 SO = 95.5%
+ 3 SO = 99.7%
%
0.1
2.3
15.9
50
84.1
97.7
99.9
NED
-3
-2
-1
0
+ 1
+ 2
1-3
Prob
2
3
4
5
6
7
8
it
VIII. 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)
IX. 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)
P arath ion
S t ry chn me
N icot me
d -t ubocura r me
Tetradotoxin
TDDD
Botul inus toxin
7
2
1
0
0
0
0
.05
.01
.001
.00001
extremely toxic (5-50 mg/kg)
super toxic (less 5 mg/kg)
IIA-4
-------
CD
0)
(D
n
o
o>
D
n
at
% Responding (Probit Units)
u
o
J_
Ol
o
O U!
-J 1
H
>
o
in
o>
3" o:
o -
o
-J _
8:
r>>
o
i—i—i i i i i—i—i—r
CD OO^JCDOl-J^GJro —fji
O OOOOOOO O
% Responding (Probit Scale)
to
D
(_..
c
o
o
(A
n
(0
u>
o
D
01
m
o
rr
U)
O
(u
o
O
o
3
CO
g-
Mortality (Probit Units)
(A)
O
c.
o
Ul
o
en
o
JL
O
T3
(D
(V
O
o
CO
ra
i
33
a>
to
T»
o
D
U)
O1-*
O
i i i i i
OO
i
X* CJ1 C> ^1 00
OOOOO
i
UD
C£)C£)
00U3
% Mortality (Probit Scale)
01
rr
-------
XII. Potency versus Efficacy
ft B
§
f
DOSE
DOSE
A is more potent than B: Less ts required to produce
the response
D is more effective than c: A higher percentage
response
XIII. Therapeutic Index and Margin of Safety
LD50
A. Therapeutic index =
B. Margin of safety =
no observed effect level (NOEL)
acceptea daily int ake (AO I)
XIV. Chemical Interactions
A. Addit ive: 2 + 3 =
B. Synergistic:
C. Potentiation:
D. Antagonism:
1 . Functional
2. Chemic a I
3. D i spas i i: lona I
4. Receptor
2 H
0 H
4 H
4 H
- 3
»• 2
K (
h 0
—
-
-4)
=
2G
10
8 =
1
0
IIA-6
-------
XV. 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 high dos.es is a necessary and valid method of
discovering possible hazards in man (for 0.0155
which is 20,000 people in 200 million, it requires
30,000 animals)
XVI. 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 each day -until death -
than give that~dose to next dog
.b. Typical protocol
(1) Often starve animals for 16 hrs
before administration
(2) Usually administer constant concentra-
tion for various doses rather than a
constant volume
(3) Observe the animals at 1,2,4 hrs and
dai ly for 14 day s
(4) Usually calculated as number of
deaths at 14 days after administration
(5) Body weight of animals at 14 days
(6) Minimal or no hlstopathology or
clinical chemistry except in the dog.
Clinical chemistry often performed
before administration and on days 2,
7 and 14
2. Acute dermal toxicity (L050)
a. Typical protocol
IIA-7
-------
(1) Albino rabb its
(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
(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
(2) Hair cl ipped
(3) 0.5 ml liquid or 0.5 g solid
(4) 2 areas with intact skin and 2 with
abraided skin
11 A-8
-------
(5) covered by gauze and then plastic
(6) Chemical in contact with skin for 24
hrs
(7) 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. Buehler occlusive
f. Open epicutaneous
8 . Sub acute
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, h istopatho logy, etc
C . Subchr on ic
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)
d. Route of intended use or exposure (usually diet)
IIA-9
-------
2. Typical observations
a. Mortality
b. Body weight changes
c. Diet consumption
d. Urinalysis (color, specific gravity, pH,
albumin, sugar, leukocytes, erythrocytes,
epithelial cells, casts, bacteria, crystals)
e. Hematology (RBC, WBC, platelets, differential)
f. Clinical chemistry (glucose, creatinine,
BUN, uric acid, sodium, potassium, CO-,
chloride, calcium, phosphorus, cholesterol,
tr igly cendes , bilirubin, SCOT, SGPT,
lactate dehydrogenase, alkaline phosphatase,
iron, total protein, albumin, globulin)
g. Gross and microscopic examination (brain,
heart, liver, kidney, spleen, testes,
thyroid, adrenal [and weigh the 8 afore-
mentioned organs], aorta, bone, bone
marrow-smears, gall bladder, esophagus,
duodenum, jejunum, 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
over average lifetime of species. 60
Animals per sex per dose often started to
assure 30 rats survive. Otherwise similar
to subch ronic.
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
b. In dogs often do opthalmic examination
every 6 months
IIA-10
-------
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 st il Iborn.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
c. Fetuses weighed, measured and examined
grossly
d. Histoiogical and skeletal examination
IIA-11
-------
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. F_ generation given chemical from 40 days
or age until breeding at day 140. F.. thus
exposed in utero and all their life
including breeding and development of F_
generation. F^ are exposed about 160
days, F about 270 days and F« about 60
days.
c. 25 females
d. 3 dose levels and control
• e. Gross necropsy and h is topathology
(1) F • Ten males and 25 females from
each dose
(2) F and F-: 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)
3. Other tests
1 . To x icok me t ics
2 . Ant idotes
3 . Wildlife
IIA-12
-------
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 sens itizat ion
Draize test 6,700
FCAT (Freunds Complete Adjuvant test) 3,900
Guinea pig maximization test 5,500
Split adjuvant test 3,200
Buehler 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
Subchronic mouse study (190 d,ays) 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
XVII. Use of Toxicity Data in Regulations
A. If no carc inogen ic ity, teratogen ic 11y, or muta-
genicity use uncertainty factor
1. If prolonged ingestion studies in man '
\ i
2. If chronic studies in animals
3 . If only scanty results in animals '
3 . R isk vs Safety
1. Risk: The probability that a subtance will
produce harm under specified conditions
2. Safety: The probability that harm will not
occur under specified conditions
IIA-13
-------
3. Estimated risks
a. 1/4000: Automobile accident
b. 1/2,000,000: Lightning
c. 1/5,000,000,000: 'Nuclear reactor accident
4. Acceptable risk
a. People in U.S. = 2.2 x 103
b. Lifespan s 80 years
c. Acceptable risk s 30 tumors per years
= 1 in 100,000
= 0.00001 or 10'
= 0.001S
5. VSD = Virtually safe dose
6. Mathematics used in determining the dose that
should give dose that will produce that
acceptable risk
,-5
:o oo 200 100 coo
IIA-14
-------
a. Various mathematical models used
low-dose risk assessment
for
( 1) Probit
(2) Mantel-Bryan: Uses probit model with
a preassigned slope oF unity,
this being a conservative slope. An
additional conservative feature is
the use of the upper 99* confidence
limit of the response rather than the
observed response for extrapolation.
(3) One-hit: Essentially a straight line
from the bottom data point to the
origin
(4)
( 5)
(6)
Arm 1 1
than
Weibu
one-h
Gamma
age
one
11:
it
Mu
-Doll:
-hit
Sligh
Iti-Hit
Much more liberal
tly more liberal
: Slightly more
than
liberal than Weibull
aosi or SOTULIMM
oca* or
SACOA««
IIA-15
-------
Part IIB
Principles of Absorption, Distribution, Excretion & Metabolism
o£ Chemicals
-------
Part IIB
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.
B. Special Transport
1. Active transport: characteristics of
a. Moved against an electrochemical gradient
b. can be saturated
c. Selective - certain basic chemical
structure -competition
d. Requires energy
2. Facilitated diffusion: characteristics of
active transport but does not move against a
concentration gradient
3. Phagocytosis and pinocytosis
II. ABSORPTION OF TOXICANTS
A. Gastrointestinal tract
1. Lipid soluble compounds (nonionized) more
readily absorbed than lipia insoluble
compounds (water soluble, ionized)
2. Specialized transport systems - sugars, amino
acids, pyrimidines, calcium and socfium
3. Almost everything is absorbed at least to a small
IIB-l
-------
extent
4. Effect of digestive fluids on chemicals
a. Snake venon
b. Nitrate to nitrite in newborns
c. Nitrite plus amines to nitrosamines
d. Intestinal flora degrade DDJ to DDE
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. Aerosol deposition
a. Nasopharyngeal - 5 um or larger
b. Tracheobronchiolar - 1 to 5 um
c. Alveolar - 1 um
2. Mucociliary transport
3. 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
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
IIB-2
-------
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
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
IIB-3
-------
3. Active secretion - carrier mediated
a. Two separate carriers
1) Organic acids - P-aminohippurate
2) Organic bases - N-methylnicotinamide
C. Biliary excretion
i
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
a. Liquids
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
F. Milk
1. Importance
a. Toxic material may be passed from mother to
IIB-4
-------
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: conjugation 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 type of oxidation
reactions catalyzed by the cytochrome
P-450-containmg monooxygenases
1) Aromatic hydroxylation
2) Aliphatic hydroxylation RCtt.CH, C \\ — ?
°
IIB-5
-------
J o
II
3) N, 0 and S-dealkylation RClt ,
' ^^
4) Epoxidation R-CH=CHK.'— ^
5) Desulfuration R,R^f x - — > K
p
6) Sulfoxidation R5R, - ^ R-S-
'ff
7) N-hydroxylation RMR-C-CH3 - >
c. Non P-450
1) Amine oxidase - not P-450
2) Epoxide hydrolase (closely associated with
P-450)
3) Esterases and amidases
o
II
0-uCeJoo
4) Alcohol and aldehyde dehydrogenase
^o «
2. Phase II - conjugation
a. Glucuronic acid
b. Glutathione S-transferase
1) Tripeptide (glycine, cysteine and glutamic
0
\\
IIB-6
-------
acid)
2) Enzymatically take off by peptidases
(1) Glutamic acid
(2) Glycine
3) IM-acetyl transferase
4) Then mercapturic acid ,
c. Sulfotransferase - sulfate
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
IIB-7
-------
VII. THE MATHEMATICAL QUANTITATION OF ABSORPTION,
DISTRIBUTION AND EXCRETION IS REFERRED TO AS
1. Pharmacokinetics
2. Toxicokinetics
IIB-8
-------
Part IIC
Toxicology of Inorganics
-------
Part IIC
CURTIS D. KLAASSEN, PH.D.
I. LEAD
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
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
IIC-1
-------
D. Chronic Lead Poisoning (plumbism)
1. Gastrointestinal effects
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
ne I
cases among children
a. Basophilic stippling (RNA in RBC's) --
seen in only 60% of
II * • I M_
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
IIC-2
-------
1. Symptomology
2. History of exposure
3. Blood — lead concentrtion
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
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 inorganic
II. MERCURY
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
IIC-3
-------
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
a. Orally — 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.I.
/
b. More lipid soluble — more evenly dis-
tributed and enters brain and passes
placenta
c. 5-times higher cone in RBC than plasma
d. Half-life is 65 days
IIC-4
-------
C. Acute Mercury Poisoning
1. Local effects
D. Chronic Mercury Poisoning
1. Central neural effects
a. Mercury vapor (elemental mercury):
largely neuropsychiatric: depression
irritability, shyness, insomnia,
emotional instability, forgetfulness,
confusion, excessive perspiration,
uncontrolled blushing (erethism) and
tremors
b. Methylmercury
1) Paresthesia (abnormal spontaneous
sensation, ex. tingling)
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. Hg in urine (normal 25 ug/L; tremors
at chlor-alkali plant at 500 ug/ml)
IIC-5
-------
4. Hair: 300 X blood
III. ARSENIC
A. Exists in Elemental Form and in the Tri-
and Pentavalent Oxidation States
B. Toxicity Rating:
RAs-X < As+s < 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
D. Biochemical Mechanism of Toxicity
1. As+3 reacts with thiols (alpha-lipoic acid)
2. As+5 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
IIC-6
-------
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 ug Cd/g
c. quantitate by B2-microglobulin
2. Lungs
a. After inhalation
IIC-7
-------
b. Emphysema (loss of ventilatory
capacity and increase in lung
volume]
3. Cardiovascular: hypertension
4. Bone
5. Testes — sensitive after acute, not
after chronic
V. 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. Soluble salts (Cl) — G.I. and
cardiovascular
2. Insoluble salts (SO4) — G.I. scans
3. Convert with magnesium sulfate
D. Beryllium:
1. Granuloma
2. Carcinogen in animals
E. Chromium
IIC-8
-------
1. Necessary for glucose metabolism
(trivalentj
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. Essential element
2. Wilson's disease
3. Therapy — penicallamine
H. Fluoride
1. Reduce dental caries at 0.7 - 1.2 mg/l
or ppm
2. Dental fluorosis (discoloration and/or
pitting) in childred above 2 ppm
3. Brittle bones at higher concentrations
4. MCL = 4 ppm
SMCL = 2 ppm
J. Manganese
1. Managanese 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)
IIC-9
-------
L. Phosphorus
1. Used in matches, rat poisons, fireworks
2. G.I. upset — vomitus may be phosphorescent
3. Liver injury — jaundice
4. Chronic — necrosis of bone "phosey jaw"
M. Selenium
1. Essential (glutathione peroxidase)
2. Excess in livestock — "blind staggers
or alkali disease" characterized by lack
of vitality, loss of hair, sterility,
atrophy of hooves, lameness and anemia
3. Excess in man — 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
IIC-10
-------
Part IID
Toxicology of Pesticides
-------
Part IID
PESTICIDES
INTRODUCTION AND HISTORY:
BENEFITS OF PESTICIDES:
1. Control of vector-born disease (malaria, yellow fever, typhus,
plague)
2. Food production, transport and storage
3. Urban Pest Control
RISKS OF PESTICIDES:
1. Occupational injury (formulators, applicators, pickers)
2. Non-occupational poisoning (accidental, intentional)
3. Environmental effects (birds, fish)
k. a. pre-DDT
b. DDT era
c. post-DDT
DEFINITIONS:
1. Pesticide: a) Any substance or mixture of substances intended
for preventing, destroying, repelling or mitigating
any pest (insect, rodent, nemotode, fungus, weed,
other forms of terrestrial or aquatic plant or animal
life, or viruses, bacteria or other microorganisms
except viruses, bacteria, or other microorganisms on
or in living man or other animals) which the adminis-
trator declares to be a pest.
b) Any substance or mixture of substances intended
for use as a plant regulator, defoliant or desiccant.
2. Active ingredient, technical chemical, manufacturing use produce,
formulated product, etc.
IID-1
-------
3. Vehicle, exclplents, solvents, binders, stickers, spreaders,
emulsifiers, inerts, synergiscs, etc.
k. Application methods: granular, wettable powder, ULV spray, IPM.
CLASSIFICATION OF PESTICIDES:
1. I nsect ic ides
2. Herbicides
3. Fungicides
k. Rodenticides
5. Fumigants
6. Repel lants
7. Nematocldcs
8. Mol1uscuc ides
9. Alg ic ides
10. Miscellaneous: defoliants, growth regulators, deslccants, mitlcides,
ster i lants
INSECTICIDES:
I. Organic phosphates (OP's)
2. Cholinergic carbamates (carbaryl, aldicarb, ecc.)
3. Chlorinated hydrocarbons (DDT, linaane, etc.)
A. Botanicals (pyrethrums, nicotine, strychnine)
5. Organic nitrogen derivatives (DNOC, dIn Itrophenol)
6. Organic sulfur derivatives (aramite)
7- Organic thiocyanates (lethane)
8. Petroleum products (fuel oil, kerosene)
9. Stomach poisons (metals, fluorine derivatives, etc.)
10. Sepellants (phthalates, indalones)
IID-2
-------
ORGANIC PHOSPHATE INSECTICIDES:
Classification: see Table
I . Direct ace ing
2. Indirect acting
activation)
Mechanism of Action:
I. Activation to oxon
2. Detoxification by hydrolysis
3. Potentlatlon
A. PhosphorylatIon of receptor site for acetylcholIne
Anlonic
Phosphorylated
enzyme
Symptoms of Poisoning
1. Chollnergic (muscarlnlc, nicotinic)
2. Death due to respiratory failure
3. Residual effects (neuromuscular paralysis)
Treatment of Poisoning:
1. Atrop ine
2. Praladoxlme (2-PAM)
IID-3
-------
ORGANOPHOSPHATE
CHOLINESTERASE-INHIBITING
PESTICIDES
GENERAL CHEMICAL STRUCTURE
C2H5OorCH3O\ ^ S (or O)
C2H5O or CH3Q ^
COMMON COMMERCIAL PESTICIDE PRODUCTS*
— ^ oi> c
Highly toxic: tetraethyl pyrophosphate (TEPP), phorate (Thimet), disulfo- .2? c -^ •§_
tonf (Di-Syston), fensulfothion (Dasanit), demetont (Systox), terbufos ?•££_£
(Counter), mevinphos (Phosdrin), methidathion (Supracide), chlormephos • £ ^ >,
(Dotan, MC2188), sulfotepp (Bladafum, Dithione), chlorthiophos •- — "5 -0
(Celathion), monocrotophos (Azodrin), fonofos (Dyfonate), prothoate (Fac), '* % g » _.
fenamiphos (Nemacur), phosfolan (Cyolane), methyl parathion (Dalf, " ^ x 5 '5
Penncap-M), schradan (OMPA), chlorfenvinphos (Birlane), ethyl parathion •£ 3 £ 2 ti
(Parathion, thiophos), azinphos-methyl (Guthion), phosphamidon 1 "5 £ JJ -5
(Dimecron), methamidophos (Monitor), dicrotophos (Bidrin), isofenphos y ° -^ ^ S
(Amaze, Oftanol), bomyl (Swat), carbophenothion (Trithion), EPN, fam- ~o Q ^, J- •-
phur, (Warbex, Bo-Ana, Famfos), fenophosphon (Agritox, trichloronate), "o — Q : |
dialifor (Torak), cyanofenphos (Surecide). £ g "^ ." ~
Moderately toxic: bromophos-ethyl (Nexagan), leptophos (Phosvel), 1 "8 * •'-"
dichlorvos (DDVP, Vapona), coumaphos (Co-Ral), ethoprop (Mocap), e g •/> | ^
quinalphos (Bayrusil), triazophos (Hostathion), demeton-methylt _x"^ 5 ^ =
(Metasystox), propetamphos (Safrotin), chlorpyrifos (Lorsban, Dursbaji), "5 a « „ v
sulprofos (Bolstar), dioxathion (Delnav), isoxathion (Karphos), phosalone g „, "o « .5
(Zolone), thiometon (Ekatin), heptenophos (Hostaquick), crotoxyphos § 5 S S <2
(Ciodrin), cythioate (Proban), phencapton (G28029), DEF (De-Green, E-Z- a •§. ^ -£ £
off D), ethion, dimethoate (Cygon, De-Fend), fenthion (Baytex, Entex, « J ^ g •-
Tiguvon, Spotton, Lysoff). dichlofenthion (Mobilawn), EPBP (S-Seven). "2 S- b "a ?
^Sl § 8
diazinon (Spectracide), phosmet (Imidan, Prolate), formothion (Anthio), pro- v 2? ,fc S -5
fenofos (Curacron), naled (Dibrom), phenthoate, trichlorfon (Dylox.Dipterex, w .° eo ° 2
Neguvon), pyrazophos (Afugan, Curamil), fenitrothion (Agrothion, g ."y \ g ~
Sumithion), cyanophos (Cyanox), pyridaphenthion (Ofunack), propylthio- H £ g1 H §
pyrophosphate (Aspon), acephate (Orthene), merphos (Folex), malathion
(Cythion), etrimfos (Ekamet), phoxim (Baythion), pirimiphosmethyl (Actellic), * ^
iodofenphos (Nuvanol-N), bromophos (Nexion), tetrachlorvinphos (Gardona,
Rabon), temephos (Abate, Abathion).
TOXICOLOGY
Organophosphates poison insects and mammals primarily by phosphoryla-
tion of the acetylcholinesterase enzyme at nerve endings. The enzyme is critical
to normal transmission of nerve impulses from nerve fibers to innervated
tissues. Some critical proportion of the tissue enzyme mass must be inactivated
by phosphorylation before symptoms and signs of poisoning are manifest. At
sufficient dosage, loss of enzyme function allows accumulation of
acetylcholine (the impulse-transmitter substance) at cholinergic neuroeffector
junctions' (muscarinic effects), and at skeletal myoneural junctions and in
autonomic ganglia (nicotinic effects). Organophosphates also impair nerve im-
pulse transmission in the brain, causing disturbances in sensorium, motor
function, behavior, and respiratory drive. Depression of respiration is the
usual cause of death in organophosphate poisoning. Recovery depends ulti-
mately on generation of new enzyme.
IID-4
-------
Urganophosphates are efficiently absorbed by inhalation, ingestion, and
skin penetration. To a degree, toxicity depends on the rate at which specific
organophosphates are metabolized in the body (principally by hydrolysis in the
liver), thus limiting the amount of pesticide available to attack
acetylcholinesterase enzyme in other tissues.
Many organophosphates readily undergo conversion from -thions to -oxons
(replacement of sulfur by oxygen). In general, -oxons are much more toxic
than -thions. This conversion occurs in the environment under the influence of
sunlight and in the body, mainly by the action of liver microsomes. Ultimate-
ly, both -oxons and -thions are inactivated by hydrolysis at the ester linkage,
yielding alkyl phosphates and phenols which are readily excreted. The
hydrolysis products present little toxic hazard.
One to two days after organophosphate absorption, depending on the
specific organophosphate, some phosphorylated acetylcholinesterase enzyme
can be de-phosphorylated (reactivated) by certain oxime antidotes. After this
interval, the nature of the enzyme-phosphoryl bond changes, rendering the
enzyme inactivation irreversible. New enzyme must then be generated.
Very rarely, organophosphate pesticides have produced a different type of
neurotoxicity, consisting of damage to the myelin substance of peripheral
nerves. This leads to a protracted peripheral neuropathy, characterized by
numbness, pain, and weakness in the extremities, which persists for months or
years. Organophosphates associated with these chronic illnesses have included
some whose acute toxic potential is low; i.e., there appears to be no relation-
ship between acute toxicity and the likelihood of a chronic neuropathic effect.
Particularly suspect as neurotoxic agents of this type are the phenylphospho-
nothioate series, cyanofenphos, EPN, leptophos, and EPBP.
Other unusual properties of specific organophosphates may render them
more hazardous than basic toxicity data suggest. By-products can develop in
long-stored malathion which strongly inhibit the hepatic enzymes operative in
malathion catabolism, thus enhancing its toxicity. Certain organophosphates
are exceptionally prone to storage in fat tissue, prolonging the need for an-
tidote when stored pesticide is released back into the circulation. It is possible
that other unrecognized factors modify the toxicity of organophosphates.
FREQUENT SYMPTOMS AND SIGNS OF POISONING
Symptoms of acute poisoning develop during exposure or within 12 hours
(usually within four hours) of contact. HEADACHE, DIZZINESS, WEAK-
NESS, INCOORDINATION, MUSCLE TWITCHING, TREMOR, NAUSEA,
ABDOMINAL CRAMPS, DIARRHEA, and SWEATING are common early
symptoms. Blurred or dark vision, confusion, tightness in the chest, wheezing,
productive cough, and PULMONARY EDEMA may occur. Incontinence, un-
consciousness and convulsions indicate very severe poisoning. SLOW
HEARTBEAT, salivation, and tearing are common. TOXIC PSYCHOSIS,
with manic or bizarre behavior, has led to misdiagnosis of acute alcoholism.
Slowing of the heartbeat may rarely progress to complete sinus arrest. RESPI-
RATORY DEPRESSION may be fatal. Continuing daily absorption of
organophosphate at intermediate dosage may cause an INFLUENZA-LIKE
ILLNESS characterized by weakness, anorexia, and malaise.
The very few individuals who have suffered peripheral neuropathy follow-
ing organophosphate exposure exhibited diverse clinical courses. Onset of
symptoms was generally slow, sometimes after an asymptomatic interval of
several days following exposure. Principal symptoms have been numbness,
tingling, pain and weakness of the arms and legs. Some recovered fully in a
few weeks; a few others experienced muscle atrophy, leaving a degree of
paresis and sensory loss.
IID-5
-------
TOXICOLOGY OF SOME ORGANOPHOSPHATE INSECTICIDES
COMPOUND
TEPP
Mevinphos
Disulfoton
Azinphos methyl
Parathion
Methyl parathion
Chlorfenvinphos
Dichlorvos
Diazinon
Dimethoatc
Trichlorfon
Chlorothion
Malathion
Ronnel
Abate
STRUCTURE
O O
II II
(CaH.O)a-P-0— P- 2,000
880 1,500-4,500
1,375 > 4,444
1,250 > 5,000
8,000 > 4,000
"NO EFFECT
LEVEL "t
(mglkg/day)
—
—
—
Rat— 0.125
Dog— 0.125
Rat— 0.05
Man— 0.05
—
Rat— 0.05
Dog— 0.05
Rat-0.5
Dog-0.37
Man— O.033
Rat— 0.1
Monkey— 0.05
Dog— 0.02
Man— 0.02
Rat— 0.4
Man— 0.04
Rat— 2.5
Dog— 1.25
Rat— 0.5
Man— 0.2
Rat— 0.5
Dog— 1.0
ADtt
(mglkg)
—
—
—
0.0025
0.005
—
0.002
0.004
0.002
0.02
0.01
0.02
0.01
• Values obtained in standardized tests in the same laboratory (Gaines, 1969). (continued)
t Maximum rate of intake (usually for three-month to two-year feeding studies) that was tested and did not produce
significant toxicologic effects (as listed in the monographs issued jointly by the Food and Agriculture Organization
of the United Nations and the World Health Organization, a* developed by joint meetings of expert panels on
pesticide residues held annually, 1965-1972).
t Acceptable daily intake (ADI) — the daily intake of a chemical that, during a lifetime, appears to provide the
practical certainty that injury will not result (in man) during a lifetime of exposure. Figures taken from World
Health Organization (1973). <.
IID-6
-------
CHOLINERGIC CARBAMATE INSECTICIDES:
Chemistry: see Table 16-6
Toxic AGENTS
Table 16-6. EXAMPLES OF RANGE OF ACUTE TOXICITIES OF SOME CARBAMATE
INSECTICIDES
o
II XH
Baygon (Propoxur) O — C — Nv
1. CH3
VCH3
O
II ^
Carbaryl O— C— NV
^ 1 CH3
LD50 IN MALE RATS*
(mg/kg)
Oral Dermal
83 > 2,400
850 > 4,000
Mobam
Temik (Aldicarb)
Zectran
CH3
CH3
O
CH3— S— C— C=N— O— C—
CH3
150 > 2,000
0.8
3.0
37 1,500-2,500
* Values obtained in standardized tests in the same laboratory (Gaines, 1969).
IID-7
-------
Symptoms of Poisoning:
I. CarbamylatIon of receptor site for acetylchol Ine
2. Chollnerqlc effects (muscarlnic)
Treatment of Poisoning:
1 . Atrop|ne
CARBAMATE
CHOLINESTERASE-INHIBITING
PESTICIDES
GENERAL CHEMICAL STRUCTURE
O
H
H3C
-C—O-
LEAVING
GROUP
COMMON COMMERCIAL PESTICIDE PRODUCTS*
Highly toxic**: aldicarbt (Temik), oxamyl (Vydate), carbofuran
(Furadan), methomyl (Lannate, Nudrin), formetanate HC1 (Carzol, Dicarzol),
aminocarb (Matacil), dimetilan (Snip Fly Bands).
Moderately toxic***: promecarb (Carbamult), methiocarb (Mesurol,
Draza), propoxur (Baygon), pirimicarb (Pirimor, Aphox, Rapid), bufencarb
(Bux), carbaryl (Sevin).
TOXICOLOGY
Insecticides of this class cause reversible carbamylation of acetylcholinester-
ase enzyme, allowing accumulation of acetylcholine at cholinergic neuroeffec-
tor junctions (muscarinic effects), and at skeletal muscle myoneural junctions
and in autonomic ganglia (nicotinic effects). Poison also impairs CNS func-
tion. The carbamyl-cnzyme combination dissociates more readily than the
phosphorylated enzyme produced by organophosphate insecticides. This
lability tends to mitigate the toxicity of carbamates, but also limits the useful-
ness of blood enzyme measurements in diagnosis of poisoning. Carbamates
are absorbed by inhalation, ingestion, and dermal penetration. They are ac-
tively metabolized by the liver, and the degradation products are excreted by
the liver and kidneys.
Listed approximately in order of decreasing toxicity.
Acute oral LD,0 in the rat less than 50 mg/kg.
Acute oral LD,0 in the rat above 50 mg/kg.
This carbamate is a systemic, i.e., it is taken up by the plant and trans-
located into foliage and sometimes into the fruit.
IID-8
-------
CHLORINATED HYDROCARBON INSECTICIDES:
C1 ass I f icatIon:
1. Chlorinated ethanes (DDT, Methoxychlor)
2. Cyclodlenes (aldrln, dleldrln, endrln, chlordane, heptachlor,
endosu1 fan
3- Others: llndane, toxaphene, mlrex, kepone
Chemistry: see Figure 16-?
1. Solubility
2. BlomagnIfIcatIon
Mechanism of Action:
Symptoms of Poisoning:
1. CNS effects (epi1eptI form convulsions)
2. Liver effects
3. Effects on fish and birds
Treatment of Poisoning:
1. AntIconvulsants
2 . Choii styramlne
Tox i cology:
1. DOT and methoxychlor
2. Cyc1od i enes
3. Lindane and BHC
^ . M I rex and kepone
IID-9
-------
SOLID ORGANOCHLORINE PESTICIDES
CHEMICAL STRUCTURES
Cl Ci
HEXACHLOBOBEN7ENE
HEPTACHlOn
METMOKVCMLOR
COMMON COMMERCIAL PESTICIDE PRODUCTS*
Highly toxic: endrin (Hexadrin), a stereoisomer of dieldrin.
Moderately toxic: aldrin (Aldrite, Drinox), endosulfan (Thiodan), dieldrin
(Dieldrite), toxaphene (Toxakil, Strobane-T), lindane (Gammexane), benzene
hexachlori'de (BHC, HCH), DDT (chlorophenothane), heptachlor, kepone,
terpene polychlorinates (Strobane), chlordane (Chlordan), dicofol (Kelthane),
chlorobenzilate (Acaraben), mirex, methoxychlor (Marlate), dienochlor (Pen-
tac), hexachlorobenzene (HCB), ethylan (Perthane). All except HCB are insec-
ticides or acaricides; HCB is a funsicide.
TOXICOLOGY
Most organochlorines are efficiently absorbed from the gut and across the
skin. In adequate dosage, they interfere with axonic transmission of nerve im-
pulses and, therefore, disrupt the function of the nervous system, principally
that of the brain. This results in behavioral changes, sensory and equilibrium
disturbances, involuntary muscle activity, and depression of vital centers, par-
ticularly those controlling respiration. Adequate doses of some organo-
chlorines increase myocardial irritability, and stimulate synthesis of hepatic
drug-metabolizing enzymes.
Chlordane has apparently induced a few cases of self-limited megaloblastic
anemia after protracted low-level exposures. The condition has resolved
following termination of exposure.
Kepone has caused nervousness, tremor, incoordination, weakness and in-
fertility in excessively exposed workers. Clinical improvement has occurred as
the pesticide was excreted.
Endrin is more toxic to the liver and kidneys than the other organochlorines
at comparable dosages.
Prolonged ingestion of HCB-treated grain produced porphyria cutanea tar-
da in several thousand Turkish citizens who mistakenly ate the seed grain.
Disease was manifest as excretion of red urine, bullous dermatitis, hyper-
pigmentation, generalized hair growth, muscle wasting and liver enlargement.
Slow improvement occurred when HCB ingestion was stopped.
A series of anecdotal reports of bone marrow injury has tended to indict lin-
dane as a hematotoxic agent in certain predisposed individuals, but no rela-
tionship has been proved.
Lindane, methoxychlor, terpene polychlorinates, chlorobenzilate, dicofol,
and the constituents of chlordane, except heptachlor and oxychlordane, are
excreted rapidly by humans, usually within 3-4 days of ingestion. Dieldrin,
aldrin, endrin, hexachlorobenzene, heptachlor, and oxychlordane are excreted
within weeks to several months of absorption by humans. DDT, kepone,
mirex, and the beta isomcr of benzene hexachloride are excreted very slowly,
requiring months or years for elimination. The excretion kinetics of perthane,
kelthane, and dienochlor are not known. Because of their lipophilicity, all
organochlorines are likely to be excreted in the milk of lactating women.
Listed approximately in order of decreasing toxicity.
IID-10
-------
FREQUENT SYMPTOMS AND SIGNS OF POISONING
APPREHENSION, EXCITABILITY, DIZZINESS, HEADACHE, DIS-
ORIENTATION, WEAKNESS, PARESTHESIAE, muscle twitching,
tremor, tonic and clonic CONVULSIONS (often epileptiform), and uncon-
sciousness are the major manifestations. Soon after ingestion, nausea and
vomiting commonly occur. When chemicals are absorbed dermally, apprehen-
sion, twitching, tremors, confusion, and convulsions may be the first symp-
toms. Respiratory depression is caused by the pesticide and by the petroleum
solvents in which these pesticides are usually dissolved. Pallor occurs in
moderate to severe poisoning. Cyanosis may result as convulsive activity in-
terferes with respiration.
Even though convulsive activity may be severe, the prognosis in poisonings
by these agents is far from hopeless. Although fatalities have occurred follow-
ing absorption of large amounts of some organochlorines, there is a substan-
tial likelihood of complete recovery if convulsions can be controlled, and vital
functions sustained.
Table 16-7. TOXICOLOGY OF SOME ORGANOCHLORINE INSECTICIDES
COMPOUND
Aldrin
Dieldrin
Endrin
Heptachlor
STRUCTURE
"NO EFFECT
LD50 IN MALE RATS DERMAL LEVEL"t
ORAL (mg/kg)' (mg/kg/day) (mg/kg/day)
DDT
DDE§
DDA§
Methoxychlor
See Figure 16-5
See Figure 16-5
See Figure 16-5
See Figure 16-5
217 (technical)
880
740
5,000-7,000
2510
—
Rat— 0.05
Rat— 10
0.005C
0.1
Cl
39
46
18
100
98 Rat—0.025 0.0001
Dog—0.025
90 Rat—0.025 0.0001
Dog—0.025
18 Rat—0.05 0.0002
Dog—0.025
195 Rat—0.25 0.0005
Dog—0.06
ci
IID-ll
-------
Table 16-7. (continued)
COMPOUND
STRUCTURE
"NO EFFECT
LD50 IN MALE RATS DERMAL LEVEt"t ADl{
ORAL (mg/kg)* (mg/kg'day) (mg/kg/day)
Chlordane
Lindane
Mi rex
335
840
88
1,000
Rat—1.0 0.001
Dog—0.06
Rat—1.25 00125
740
> 2,000
* Values obtained in standardized tests in the same laboratory (Games, 1969).
t Maximum rate of intake (usually for three-month to two-year feeding studies) that was tested and did not produce
significant toxicologic effects (as listed in the monographs issued jointly by the Food and Agriculture Organization
of the United Nations and the World Health Organization, as developed by joint meetings of expert panels on
pesticide residues held annually, 1965-1972).
t Acceptable daily intake (ADI) = the daily intake of a chemical that, during a lifetime, appears to provide the
practical certainty that injury will not result (in man) during a lifetime of exposure. Figures taken from World
Health Organization (1973).
5 Metabolites of DDT.
11 Conditional ADI pending further evaluation.
Toxic AGENTS
HCCI2
ecu
ODD
Series of reductive
dechlormation
and oxidation steps
Series of dechlormation
and oxidation steps
-OH
COOH
Figure 16-5. Summary comparison of major metabolic pathways for DDT and methoxychlor.
IID-12
-------
BOTANICAL INSECTICIDES:
1 . N i cot ine
2. Pyrethrums
3. Rotenolds
. Strychnine
5. Res ins
IID-13
-------
HERBICIDES:
C lass i f icat ion:
1. Phenoxy (2,^-0, 2,^,5-T, sllvex, MCPA)
2. Dipyridyls (paraquat, dlquat, morfamquat)
3. Dinitrophenols and analines (DNOC, trlfluralln)
L*. Acetanllldes and acetamldes (propachlor, propanll)
5. Triazlnes and picollnlc acids (amlnotriazole, picloram, atrazine)
6. Urea and uraclle derivatives (dluron, bromocll)
7. Benzole acid and phthalates (amlben, endothal)
8. Carbamates (chloropropham, propham)
9. Inorganics (chlorates, berates)
10. Miscellaneous (fuel oils, arsenaces)
FUMIGANTS:
1 . Methyl brom i de
2. Cyanide
3. Sulfur dioxide
k. Naphthalene
5. p-DIchlorobenzene
6. Carbon tetrachlor!de
7. Chloropicrln
8. Ethylene dibromlde
9- D Ibromochloropropane
10. Miscellaneous (phosphlne)
IID-14
-------
CHLOROPHENOXY COMPOUNDS
GENERAL CHEMICAL STRUCTURE
(or CH3)
Cl
Cl
- O -
(Cl)
H
C
H
O
— C — O — H or
COMMON COMMERCIAL PESTICIDE PRODUCTS
Several hundred commercial products contain chlorophenoxy herbicides in
various concentrations and combinations. Following are names of widely
advertised formulations. In some cases, the same name is used for products
with different ingredients. Exact composition must therefore be determined
from product label.
2,4-D, or 2,4-dichlorophenoxyacetic acid (Weedonef, Agrotec, Amoxone,
Aqua-Kleen, BH 2,4-D, Chipco Turf Herbicide "D", Chloroxone, Crop
Rider, D50, Dacamine 4D, Ded-Weed, Desormone, Dinoxol, DMA4, Dor-
mone, Emulsamine BK, Emulsamine E-3, Envert DT or 171, Esteron 99 Con-
centrate, Esteron Four, Esteron Brush Killer, Estone, Fernoxone, Fernimine,
Ferxone, Fernesta, Formula 40, Hedonal, Herbidal, Lawn-Keep, Macondray,
Miracle, Netagrone 600, Pennamine D, Planotox, Plantgard, Rhodia, Salvo},
Spritz-Hormin/2,4-D, Spritz-Hormit/2,4-D, Superormone Concentre, Super
D Weedone, Transamine, U46, Verton 2D, Visko-Rhap, Weed-B-Gon,
Weedar, Weed-Rhap, Weed Tox, Weedtrol, De broussaillant 600, Lithate,
Dicotox, Field Clean Weed Killer). 2,4-DB is the butyric acid homologue of
2,4-D. Dichlorprop is the propionic acid homologue.
2,4,5-T or 2,4,5-trichlorophenoxyacetic acid (Brush-Rhap, Dacamine 4T,
Debroussaillant Concentre, Ded-Weed Brush Killer, Esteron 245, Fence Rider,
Forron, Inverton 245, Line Rider, Spontox, Super D Weedone, Tormona,
Transamine, Trinoxol, Trioxone, U46, Veon 245, Verton 2T, Weedar,
Weedone Envert T).
Common mixtures of 2,4-D and 2,4,5-T arc: Dacamine 2D/2T, Esteron
Brush Killer, Rhodia Low Volatile Brush Killer No. 2, U46 Special, Tributon,
Visko-Rhap LV2D-2T, and Transamine.
t A product of identical name containing pentachlorophenol (Chapter 4) as
the active ingredient has been discontinued by Amchem Products Co.
t A product of identical name marketed by the Crystal Chemical Company
contains cacodylic acid as the active ingredient (Chapter 10).
IID-15
-------
PARAQUAT AND DIQUAT
CHEMICAL STRUCTURES
CH,
\ /r^j
PARAQUAT
-CH3
2 cr
CH2— CH2 2 Br"
DIQUAT
,CH,
CM,
-CM
CM,
—C —CM —N
CM
" /CM-°X
,— C— N 0
\H_CH/
2 cr
COMMON COMMERCIAL PESTICIDE PRODUCTS
Paraquat products: paraquat dichloride (usually as a 21% concentrate).
Other names: Ortho paraquat-CL, Crisquat, Dextrone X, Esgram. Mix-
tures: Priglone, Preeglone, Weedol—with diquat; Simpar, Terraklene—with
simazine; Gramonol, Mofisal—with monolinuron; Pathclear—with diquat
and simazine; TotaCol, Dexuron—with diuron.
Diquat products: diquat (Reglone, Reglox, Aquacide, Dextrone, Weed-
trine-D). Mixtures: Priglone, Preeglone, Weedol—with paraquat; Pathclear—
with paraquat and simazine.
TOXICOLOGY
These dipyridyls injure the epithelial tissues: skin, nails, cornea, liver, kid-
ney, and the linings of the GI and respiratory tracts. In addition to direct irri-
tant effects, injury may involve peroxidation of intracellular and extracellular
phospholipids and inhibition of surfactant synthesis by lung tissue. These toxic
properties may derive from the capacity of dipyridyls to generate free radicals
in tissues. The injury is usually reversible; however, the pulmonary reaction
which follows ingestion of paraquat is often fatal.
Certain injuries have followed occupational contact with paraquat. Contact
with the concentrate may cause irritation and fissuring of the skin of the
hands, and cracking, discoloration, and sometimes loss of the fingernails.
Splashed in the eye, paraquat concentrate causes conjunctivitis and, if not
promptly removed, may result in protracted opacification of the cornea.
Although nearly all systemic intoxications by paraquat have followed inges-
tion of the chemical, occasional poisonings have resulted from excessive dermal
contact. Absorption of toxic amounts is much more likely to occur if the skin
is abraded. Persons who have experienced extraordinary dermal contact with
paraquat (especially the concentrate) should be examined, and tested for
hazardous concentrations of the agent in the blood and urine (see section on
Confirmation of Diagnosis).
IID-16
-------
NITROPHENOLIC AND
NITROCRESOLIC HERBICIDES
GENERAL CHEMICAL STRUCTURE
N02
O2N <( \O-H (or ESTER)
(ALKYL) (ALKYL)
COMMON COMMERCIAL PESTICIDE PRODUCTS
Dinitrophenol (Chemox PE), dinitrocresol (DNOC, DNC, Sinox, Chemsect
DNOC, Elgetol 30, Nitrador, Selinon, Trifocide), dinoseb (DNBP, Dinitro,
Basanite, Caldon, Chemox General, Chemox PE, Chemsect DNBP,
Dinitro-3, Dinitro General, Dow General Weed Killer, Dow Selective Weed
Killer, Dynamyte, Elgetol 318, Gebutox, Kiloseb, Nitropone C, Premerge 3,
Sinox General, Subitex, Unicrop DNBP, Vertac Dinitro Weed Killer),
dinosam (DNAP), dinoprop, dinoterbon, dinoterb, dinosulfon, bmapacryl
(Morocide, Endosan, Ambox, Dapacryl), dinobuton (Acrex, Dessin, Dinofen,
Drawinol, Talan), dinopenton, dinocap (Crotothane, Karathane). Several
combinations are widely used: Dyanap and Klean Krop = dinoseb + nap-
talam; Ancrack = sodium salts of dinoseb + naptalam; Naptro =
dinitrophenol + naptalam.
TOXICOLOGY
These materials should be regarded as highly toxic to humans and animals.
Most nitrophenols and nitrocresols are well absorbed from the gastrointestinal
tract, across the skin, and by the lung when fine droplets are inhaled. Except in
a few sensitive individuals, aromatic nitro-compounds are only moderately
irritating to the skin. Like other phenols, they are toxic to the liver, kidney,
and nervous system. The basic mechanism of toxicity is a stimulation of oxida-
tive metabolism in cell mitochondria, by interference with the normal coupling
of carbohydrate oxidation to phosphorylation (ADP to ATP). Increased oxi-
dative metabolism leads to pyrexia, tachycardia, and dehydration, and ulti-
mately depletes carbohydrate and fat stores. Most severe poisonings from
absorption of these compounds have occurred in workers who were concur-
rently exposed to hot environments. Pyrexia and direct action on the brain
cause cerebral edema, manifest clinically as a toxic psychosis and sometimes
convulsions. Liver parenchyma and renal tubules show degenerative changes.
Albuminuria, pyuria, hematuria, and increased BUN are often prominent
signs of renal injury.
Agranulocytosis has occurred in humans following large doses of
dinitrophenol. Cataracts have occurred in some chronically poisoned
laboratory species, but this effect has not been observed in humans.
Nitrophenols and nitrocresols are efficiently excreted by the kidneys, and
there is some hepatic excretion into the bile. Unless the absorbed dose was ex-
tremely high, or kidney function is impaired, nearly complete elimination
from the body can be expected within 3-4 days.
Death in nitrophenol poisoning is followed promptly by intense rigor mortis.
IID-17
-------
ORGANONITROGEN HERBICIDES
MS OK OR(;ANONITKO<;KN m-Riiiai>KS AND
COMMON COMMERCIAL I'KODUCTS
ACETANILIDE OERIVITIVES
K = AI.KVI
— H
/
I
\
liopropyl or
C —C-CI
II H
0
pi.ip.uliliir (H.inuud).
prop.iml lOI'V I'rup.inci. Si.nn I--3-4I
ACETAMIOt COMPOUNDS
,AIIVI
Ally! — H
\
H
C —C-CI
II H
0
(K.inJtii. I DAA)
I TRIA2INE COMPOUNDS
on
x 01 I sn
N N
H| || II
N—C C —N
1^/1
R N fl
.III .1/1111- I A.HUM All.iMCX (iCMplllll I'f"
Ml.ll.ll Al
^Itflll/IMt* ll*IIIUt'|l t'lllll llt*l N Suit tilt \.
prup.if.inc iMilupJiJ. Cicv.nnil. rnin.iiui
priMiicloii^ (1'r.uitiiiil, (icv.U'.ini ^riimt
Ion I
.III .Iliill (All .IIIIIH I
amcir> n'{ h. vik. /vntcfftt. (Jcsap.xju
IID-18
-------
UREA OERIVITIVES
0-C
H
or R
nionuiun (\Kinurc\ Idvur)
Uuiron (Di-on. Jitircx. karmex. Von-
diiron)
(CD liniiron (HOK-2KIU /Vf.ilon. I nru\. .Yirc-
RorOR
URACIL DERIVITIVES
H
H,C — C
X_C
\
00
| CH3
N-C —H
I!
0
PICOUNIC ACID DEfllVITIVES
rniii.uil 111.in-.i. ll\v.ir X. Myvur X-l .
llurtx.il l\'. Uro\ MX or H. Uucil)
C,
NH,
CAR8AMATE COMPOUNDS
piclorani (! ordon, borolji)
— N_C —Q — CH chlorprophAtn (Chloro 1PC, C1PC. Fur-
i loe)
Cl
II
0
CH.
Benzole acid i Phchalace Derivatives
EmJolt-.all
7-0/aLicyclc (^,2,1) hcptanc-2,3 'li
lie acid
Chlorar.ben
j-^"—r.r.-2 , 3-rlichlorccen:- vc ac id
.COjH
IID-19
-------
PENTACHLOROPHENOL OR SODIUM
PENTACHLOROPHENATE
CHLMICAL STRUCTURE
Cl C!
-0-H
(or Na)
CI
COMMON COMMERCIAL PLSTIC3DE PRODUCTS
PCP. Dowicidc-7, Pcnchlorol, Pcntncon. Pcnwar, Wccdonc. Vcp-!-Kill,
Wood Preserver. Wood Ton 140. Purinn Insect Oil Concentrate, Gordon
Termi To\. Usol Cjbin Oil, Ccrtilicd Riltrol-74 Weed Kilter, Ciba-Gcicy
Onirnck OS 3, 4 or .S. Orilio Trio.\ Liquid Vegetation Killer, Block Leaf
Grass Weed ;nul Vcj:clalinn Killer Spray.
1'eniai.hloroplienol lu* ni.iny lives as a weed killer. dcfoli;mt. wood pre-
servative, jicrmicidc. fungicide, .ind molluscicidc. It is an ingredient of many
other formulated mixture* sold for one or more of these purposes.
ANTICOAGULANT RODENTICIDES
STRUCTURKS OK PRINCIPAL CLASSES
ALKYL, PHENYL
DIPHENYLACETYL or
CHLORODIPHENYLACETYL
WARFARIN
1,3 INDANDIONE
COMMON COMMERCIAL PICSTICIDli PRODUCTS
Cnimiann type: warfarin (Kypf.irm, W,irf-42, D-Con, Warfictdc. Prc.!in\
coinn.iltiryl (lriiin.inn), Oellimor, U.ix
l,3-iiul.iiidiunc lypc: ilipli.icinnuL'. or iliplicn;ulionc (Kainik). clilnropli.iL'i-
none (Dr.it, C.nd, Liph.idionc, Micro/ul, Raniucide, Ratonict, Ravine, Topi-
(o\), pnulone (Piv;tl\ n. Piv.ian, Tri-lian, Pival), valonc, (PMP).
1 liL'sc niateriaN are coinnmnly ailileil in bails or dissolved in sm.ill nninimls
of water for pesl roilenis lo dunk One luuulrcd grains of (lie prepared com-
mercial bails mubl be meesieil I'1 yield 25 iii(;in oi .inlicn.iLul.int Kinlcnli-
Lide "dnnks" aic made hy .iddine dry eoin.enir.ile (054 em of nclne in-
eredient per 100 ^iiu oi powder) 10 specilied volumes of water. The poison m
(lie coneelilrale is ^.o.iied on suear or sand lo laeihlaic measuremenl and
handling.
IID-20
-------
RODENTICIDES:
1. WarfarIn
2. Red squ i 1 1
3. Sodium f louroacetate (1080)
k. Phosphorus and phosphides
5. ANTU
6. Thai 1ium
7. Vacor
FUNGICIDES:
1. Metals
a. copper derivatives
b. mercury derivatives
2. Halogens
a . chlorine g roup
b. Iodine group
c. bromine group
3. D I thiocarbamates
1». Phthalimldes (captan, folpet)
5. Miscellaneous (borax, sa1 Icy 1 an 11 I de , carbolIneum)
DIMETHYLDITHIOCARBAMATE
COMPOUNDS"
t.M.MKKAl. CM KM If A I. SIKUCHJUr.
COMMON COMMI Ufl \l. I'lSltCU)!. I'UODUCTS
rcir.iiiu'ihx I tlnur.ini tl
Thir.im (Ar.is.in. 1hir.ini.nl. Thir.is.in. Tliyl.uc. Tir.imp.i. Ponuisol forte,
TMFDS Thio(i:\. r\rn.i\.in. Nomcrs.m. TI.TN.UI. TUADS)
Mei-illndinicllu Id ilh inc.irh.nn.il CN
Zir.mi. I'om.isol /. foru- I/UK). IVrtum (iron). V.ip.ini (smliunil
IID-21
-------
Part HE
Toxicology of Solvents and Vapors
-------
Part HE
Toxicology of Solvents and Vapors
SOLVENTS AND VAPORS
CURTIS D. KLAASSEN, PH.D.
I. CrC4 ALIPHATIC HYDROCARBONS
A. Methane — natural gas — asphyxia
B. Ethane — natural gas — asphyxia
C. Propane — bottled gas — CNS.depression
D. Butane — bottled gas — CNS depression
II. C5-C8 ALIPHATIC HYDROCARBONS
A. Produce CNS depression
B. n-Hexane
1. CNS depression
2. Polyneuropathy
a. Muscular weakness and sensory
impairment of extremities
b. Demyelination and axonal
degeneration
c. Also produced by methyl n-butyl ketone
CH3-CH2-CH2-CH2-CH2-CH3 CH3-C-CH2-CH2-CH2-CH3
n-hexane methyl n-butyl ketone
CH3-C-CH2-CH2-CH-CH3
5-hydroxy-2-hexanone
CH3-C-CH2-CH2-C-CH3
2,5-hexanedione
IIE-1
-------
III. GASOLINE AND KEROSENE
A. CNS depression — death from respiratory
failure
B. Sensitize myocardium to epinephrine —
ventricular fibrillation
C. Aspiration — chemical pneumonitis
IV. 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 by P-450 to trichloro-
methyl free radical
b) Attacks membrane lipids and
produces lipid peroxidation
2) Alcohol potentiation
a) Ethanol
b) Isopropanol
e. Carcinogenic
IIE-2
-------
C. Other halogenated hydrocarbons
CNS
Depression
Sensitize
Heart
Lhcr Kidney
Injury Injury Cancer
Methanes Carbon tctrachloride
Chloroform
Dichloromcthanc
(mcthylcnc chloride)
-H- +
Ethanes
1,1-Dichlorocthane
1,2-Dichloroethanc
1,1,1-Trichloroc thane
1,1,2-Trichloroc thane
1,1,2,2-Tctrachlorocthanc
Hcxachloroethanc
+-
-n-
Ethylcncs
Chlorocthylcne
(vinly chloride)
1,1-DJchlorocthylcnc
(vinylidine chloride)
1,2-Trans-dichlorocthylenc
Trichlorocthylcnc
Tctrachlorocthylcnc
(pcrchlorocthylcne)
+-
IIE-3
-------
V. ALIPHATIC ALCOHOLS. Ethanol effects
1. Acute effects
a. CNS depression
b. Diuresis — volume and inhibition
of ADH release
c. Liver — fatty infiltration
d. G.I. tract — increase flow of saliva
and gastric juices — at high concen-
trations causes Gl irritation
e. CV system — peripheral vasodiiitation
f. Hypoglycemia
g. Pancreas
h. Sexual
2. Blood levels
a. Legal limit for operation of motor vehicle =
O.f0% (w/v)
1) 100 Ib person, 3 beers
2) 200 Ib person, 6 beers
b. 0.3-0.4% stupor or coma
c. 0.5% often fatal
3. Distribution — body water
a. Air/blood, 0.05% (2000 ml air = 1 ml blood)
4. Biotransformation (90-98%)
a. Pathway
alcohol acetaldehyde
Ethanol \ acetaldehyde v acetate —^
dehydrogenase dehydrogenase
acetyl CoA > Citric Acid Cycle
IIE-4
-------
b. Blood level decrease 0.016%/hr
5. Chronic effects
a. Liver
1. Fatty liver
2. Alcoholic hepatitis — 30% of alcoholics
3. Cirrhosis
a) 50% of cirrhosis is associated
with alcoholism
b) 7 times more frequent among
ill"
alcoholics
b. "Fetal Alcohol Syndrome"
B. Methanol
1. Used in canned fuels, some paints,
paint removers, antifreeze fluids
2. Distribution and biotransformation
like ethanol
3. Toxicology
a. CIMS depression — but less inebriating
than ethanol ^
b. Acidosis — due to oxidation to formic acid
c. Blindness
C. Isopropanol
1. Use— rubbing alcohol, hand lotions,
deicing and antifreeze
2. Toxicity
a. CMS depression — longer lasting
(biotransformed slower)
b. Prominent gastritis
IIE-5
-------
VI. GLYCOLS
A. Ethylene glycol (OHCH2CH2OHH)
1. Toxicity
a. CNS depression
b. Kidney injury - oxalate
B. Diethylene glycol (HOCH2CH2OCH2CH2OH)
1. Used in sulfanilamide preparation
2. Toxicity similar to ethylene glycol
C. Propylene glycol (CH3-CHOH-CH2OH)
1. CNS depression
2. Low toxicity
VII. GLYCOL ETHERS
A. Ethylene glycol monomethyl ether
CH3OCH2CH2OH
B. Ethylene glycol monoethyl ether
CH3CH2OCH2CH2OH
1. Both produce degeneration of testicular
germinal epithelium
2. Teratogenic
C. Propylene glycol monomethyl ether
1. Not a reproductive toxin
VIII. AROMATIC HYDROCARBON SOLVENTS
A. Benzene
1. Acute toxicity — CNS depression
2. Chronic toxicity
IIE-6
-------
a. Bone marrow depression — aplastic
anemia
b. Leukemia — humans but not in labora-
tory animals
c. Toxicity due to a metabolite
B. Toluene (C6H5CH3)
1. CNS depression
2. Industrial monitoring — hippuric acid in
urine
3. Relatively safe solvent
C. Styrene (C6H5CH2=CH2)
1. Used in production of plastics
2. Dermatitis
3. Mutagenic in some studies but noncarcino-
genic
IX. OTHERS
A. Acrylonitrile (CH2=CHCN)
1. Cyanide released
2. Depletes glutathione
3. CNS is major target organ but also affects
liver and kidney
4. Mutagen and carcinogen
B. Carbon disulfide
1. Chronic - neuropsychiatric
C. Dioxane (C4H8O2)
1. Respiratory irritant
2. Kidney and liver injury
3. Tumors—liver and nasal cavity
IIE-7
-------
Part IIP
Principles of Risk Assessment
-------
OF RIIK AOagaSHINT
A Nontechnical Review
WORKSHOP ON RISK ASSESSMENT
United States Environmental Protection Agency
IIF-l
-------
The materials presented here have been reviewed by personnel from the
United States Environmental Protection Agency. They do not, however, necessarily
reflect United States Environmental Protection Agency policy. The materials
were prepared primarily by:
ENVIRON CORPORATION
Washington, D.C.
IIF-2
-------
CONTENTS
Page
I. INTRODUCTION 1-1
II. RISK AND RISK ASSESSMENT II-l
Basic Concepts and Definitions II-3
The Components of Risk Assessment II-3
Dose II-4
III. HAZARD IDENTIFICATION III-l
Introduction III-l
Toxicity Information from Animal Studies III-l
The Use of Animal Toxicity Data III-l
General Nature of Animal Toxicity Studies III-2
Manifestations of Toxicity III-4
Design and Cpnduct of Toxicity Tests III-6
Design of Tests for Carcinogenicity III-8
Conduct and Interpretation of Toxicity Tests 111-10
Categorization of Toxic Effects III-ll
Uncertainties in Evaluation of Animal
Carcinogenicity Test Results 111-12
Short-Term Tests for Carcinogens 111-13
Data from Human Studies 111-13
Hazard Identification: A Summary 111-16
IV. DOSE-RESPONSE EVALUATION IV-1
Introduction IV-1
Threshold Effects IV-1
Effects that May Not Exhibit Thresholds IV-3
The Carcinogenic Process IV-3
Potency and High-to-Low Dose Extrapolation IV-4
Interspecies Extrapolation IV-7
Dose-Response Evaluation: A Summary IV-7
IIF-3
-------
CONTENTS (con't)
Page
V. HUMAN EXPOSURE EVALUATION V-l
VI. RISK CHARACTERIZATION VI-1
APPENDIX: Toxic Effects on Organs or Other Target Systems
Introduction A-l
Liver A-l
Kidney A-2
Reproductive System A-3
Lungs A-5
Skin A-6
Central Nervous System A-6
Blood A-8
Immune System A-9
Genetic Toxicology A-9
IIF-4
-------
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 of 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. Others (e.g., 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 a specific chemical may
reveal aspects of its behavior in biological systems that suggest
a general principle (e.g., that data obtained in rodent studies
are generally applicable to humans) may not hold. In such in-
stances, the usual approach is to modify the risk assessment
process to conform to the scientific finding.
IIF-5
-------
II. RISK AND RISK ASSESSMENT
BASIC CONCEPTS AND DEFINITIONS
RisJc is the probability of injury, disease/ or death under
specific circumstances. It may be expressed in quantitative
terms, taking values from zero (certainty that harm will not
occur) to one (certainty that it will). In 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.
ANNUAL
Coal Mining
Accident
Black lung
Motor Vehicle
Truck Driving
Falls
Home Accidents
1 Selected from
^Estimated base
Table 1
RISK OT DEATH FROM SELECTED
Number of Deaths
in Representative
Year
180
disease 1,135
46,000
400
16,339
25,000
COMMON HUMAN
Individual
1.30 x 1CT3
8 x 10-3
2.2 x 10-*
10-*
7.7 x 10-5
1.2 x 10-5
Hutt (1978) Foodj^Drug, Cosmetic Law J.
d upon 70-year lifetime and
45-year work
ACTIVITIES1
Risk/Year
or 1/770
or 1/125
or 1/4,500
or 1/10,000
or 1/13,000
or 1/83,000
33:558-589.
exposure.
Lifetime
Risk2
1/17
1/3
1/65
1/222
1/186
1/130
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
single, 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
IIF-6
-------
not cause immediately observable forms of 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.1
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
Assessment in the Federal Government: Managing the Process
(Washington, D.C.:National Academy Press, 1983).
IIF-7
-------
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. In 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 realized 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.^
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 characterization of the behavior of a chem-
ical within the body and the interactions it undergoes
with organs, cells, 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 group 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 (e.g., are sub-
stances found to be carcinogenic or teratogenic in ex-
perimental animals likelv to have the same result in
humans?).
B. Dose-Response Evaluation—Involves describing the quan-
titative relationship between the amount of exposure to
a substance and the extent of toxic injury or disease.
Data derive from animal studies or, less frequently,
from studies in exposed human populations. There may be
many different dose-response relationships for a sub-
stance if it produces different toxic effects under
2Some scientists will claim that carcinogens display their toxic
properties under all conditions of exposure, and that there is
no "safe" level of exposure to such agents. This special prob-
lem receives extensive treatment in later sections.
IIF-8
-------
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 risk 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 concept of "dose," which under-
lies all the discussions to follow of both experimental 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 routes of administration:
injection under the skin (subcutaneous), into the 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
administered.
2. Measurement of the amount received by the subject,
whether human or animal.
IIF-9
-------
It 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. It may be substituted or supple-
mented, however, in cases where environmental modeling 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 (pgt one-
millionth of a gram * 1/28,571,429 ounce) range. The analyst
will usually report the number of mg or ug of the substance
present in one liter of water, i.e., mg/1 or ng/1. These two
units are sometimes expressed as parts per million (ppm) or parts
per 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 id of interest. In 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
at 10 ppm in water, the average daily individual intake of the
substance is obtained as follows:
10 rag/liter x 2 liter/day = 20 mg/day
For toxicity comparisons among different species, it is necessary
to take into account size differences, usually by dividing daily
intake by the weight of the individual. Thus, for a man of aver-
age weight (usually assumed to be 70 kilograms (kg) or 154
pounds), the daily dose of our hypothetical substance is:
20 mg/day r 70 kg = 0.29 mg/kg/day
A liter of water weighs 1,000 g. One mg is thus one-millionth
the weight of a liter of water; and one ,ug is one-billionth the
weight of a liter.
IIF-10
-------
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 rag/day r 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 * 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.
IIF-11
-------
Table 2
DATA AND ASSUMPTIONS NECESSARY TO ESTIMATE
HUMAN DOSE OF A WATER CONTAMINANT FROM KNOWLEDGE OF ITS CONCENTRATION
Total Dose is Equal to the Sun of Doses fro* Five Routes
1. Direct Ingeation Through Drinking
Amount of water consumed each day (generally assumed to be 2 liters for
adults and 1 liter for 10 kg child).
Fraction of contaminant absorbed through wall of gastrointestinal tract.
Average human body weight.
2. Inhalation of Contaminants
Air concentrations resulting from showering, bathing, and other uses of
water.
Variation in air concentration over time.
Amount of contaminated air breathed during those activities that may lead
to volatilization.
Fraction of inhaled contaminant absorbed through lungs.
Average human body weight.
3. Skin Absorption from Mater
Period of time spent washing and bathing.
Fraction of contaminant absorbed through the skin during washing and
bathing.
Average human body weight.
4. Ingeation of Contaminated Food
Concentrations of contaminant in edible portions of various plants and
animals exposed to contaminated groundwater.
Amount of contaminated food ingested each day.
Fraction of contaminant absorbed through wall of gastrointestinal tract.
Average human body weight.
5. Skin Absorption for Contaminated Soil
Concentrations of contaminant in soil exposed to contaminated
groundwater.
Amount of daily skin contact with soil.
Amount of soil Ingested per day (by children).
Absorption rates.
Average human body weight.
IIF-12
-------
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).
In 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 systemically rather
than only at the point of initial contact), it is usually con-
sidered appropriate to add doses received front 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 least 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 excreted. (However, some chemical types—usually
substances with high solubility in fat, such as DDT—are stored
for long periods of time, usually in fat.)
IIF-13
-------
Figure 1
KEY ROUTES OF CHEMICAL ABSORPTION, DISTRIBUTION, AND EXCRETION
Some chemicals undergo chemical change (metabolism) within the cells of the body before excretion.
Toxicity may be produced by the chemical as introduced, or by one or more metabolites.
Ingestion
Inhalation
Gastrointestinal
Tract
I
c
V)
5
Dermal
Contact
Lung
*- Absorption- •
Liver
Bile
Blood and Lymph
Kidneys
Lung
Bladder
Feces
Urine
Expired
Air
EXCRETION
Extracellular
Fluids
Secretion
Glands
Fat
Organs of
the Body
Soft Tissues
or Bones
o
3D
>
O
m
Secretions
IIF-14
-------
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 100% 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 (in 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. For 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
IIF-15
-------
substance (e.g., we say that animals are exposed to air contain-
ing 10 mg/m3, 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).
IIF-16
-------
III. 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 Use 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. In 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. In addition, the acutely toxic
doses 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
basic anatomical, physiological, and biochemical parameters are
similar across species.
IIF-17
-------
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
an increase in the number of tissue sites affected by the agent,
there is an increase in the strength of the evidence. Similarly,
an 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 substance* 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 substance to refer to a pure chemical, to a
chemical containing impurities, or to a mixture of chemicals.
It is clearly important to know the identity and composition of
a tested substance before drawing inferences about the toxicity
of other samples of the same substance that might have a some-
what different composition.
IIF-18
-------
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 LD5Q
(lethal dose, on average, for 50% of an exposed population). In
a group of chemicals, those exhibiting lower LDsgs are more
acutely toxic than those with higher values. A group of well-
known substances and their LD5Q values are listed in Table 3.
Table 3
APPROXIMATE ORAL LDjQS IN RATS FOR A
GROUP OF WELL-KNOWN CHEMICALS1'2
Chemical
Sucrose (table sugar)
Ethyl alcohol
Sodium chloride (common salt)
Vitamin A
Vanillin
Aspirin
Chloroform
Copper sulfate
Caffeine
Phenobarbital, sodium salt
DDT
Sodium nitrite
Nicotine
Aflatoxin 81
Sodium cyanide
Strychnine
LDc;n(iiig/kg)
29,700
14,000
3,000
2,000
1,580
1,000
800
300
192
162
113
85
53
7
6.4
2.5
1 Selected from NIOSH, Registry of Toxic Effects of Chemical
Substances, 1979. Results reported elsewhere may differ.
^Compounds are listed in order of increasing toxicity—i.e.,
sucrose is the least toxic and strychnine is the most toxic.
IIF-19
-------
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 some 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.
Each 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. In
general, the reasons to conduct toxicity studies can be summar-
ized as follows:
• Identify the specific organs or systems of the body
that may be damaged by a substance.
• Identify specific abnormalities or diseases that a
substance may produce, such as cancer, birth defects,
nervous disorders, or behavioral problems.
• Establish the conditions of exposure and dose that give
rise to specific forms of damage or disease.
• 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
still 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
IIF-20
-------
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 is seen; 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
cases, 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
cassation 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 are 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
IIF-21
-------
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
section, 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 LD5Q using high doses of the substance is frequently the
first toxicity experiment performed. After completing these
experiments, investigators study the effects of lower doses
IIF-22
-------
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 is not always
sought or achieved). A toxicity experiment is of limited value
unless a dose of sufficient magnitude to cause some type of
adverse effect within the duration of the experiment is achieved.
If no effects are seen at all doses administered, the toxic
properties of the substances will 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 duration (e.g., 8 hours of inhala-
tion). Chronic studies involve exposures for near the full life-
times of the experimental animals. Experiments of varying dura-
tion between these extremes are referred to as subchronic stud-
ies.
Number of Dose Levels
Although it is desirable that many different dose levels be
used to develop a well characterized dose-response relationship,
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,
strain, 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.
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
adverse 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.
IIF-23
-------
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 some 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.
Specialized 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 specialized 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 specialized tests is the
carcinoqenesis bioassay. 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. We shall
then discuss, in turn, controversial issues in the design of
animal tests and interpretation of test results.
Design of Tests for Carcinogenicity
In 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 design previously dis-
cussed apply to carcinogenicity testing, but one critical design
issue that has been highly controversial requires extensive dis-
cussion. The issue is the concept of maximum tolerated dose
(MTD), which is defined 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
IIF-24
-------
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 are 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 size, assuming none of the
control animals develop tumors, the lowest incidence of cancer
that is detectable with statistical reliability is in the range
of 5%, 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 5% 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. By
using the MTD, the toxicologist 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 summarized: (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 an 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 work 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.
IIF-25
-------
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 was 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.
In 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. Was 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. Was the dose of test compound correctly determined by
chemical analysis?
4. Was the test compound adequately characterized with
regard to the nature and extent of impurities?
5. Did the animals actually receive the test compound?
6. Were animals that died during the test adequately exam-
ined?
7. How carefully were test animals observed during the
conduct of the test?
IIF-26
-------
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 results in areas where answers were missing or
unsatisfactory.
Categorization of Toxic Effects
Toxicity tests may 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. Some 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-
rized according to the organs or systems they affect (e.g., liv-
er, kidney, nervous system) or the diseases they cause (e.g.,
cancer, birth defects). The most commonly used categorizations
of toxicity are briefly described in Appendix I.
Although there are uncertainties associated with most evalu-
ations of animal 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.
IIF-27
-------
Uncertainties in Evaluation
of Animal Carcinogenicity
Test Results
One area of uncertainty and controversy concerns the occur-
rence of certain types of tumors in control animals. In 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. In 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 35% 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 significant 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 35% 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 the lifetime of the 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 total tumor incidence. Many path-
ologists disagree with such combining, and there appears to be no
end to the controversy in this area. The issue has been espe-
cially controversial in connection with tumors found in rodent
livers.
IIF-28
-------
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 DtfA 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 HUMAN 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
IIF-29
-------
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. In case-control studies, a group of individuals
with a specific disease is identified 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. In 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. Benzene 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 under actual conditions of exposure to a
specific 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
size 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
differences exist, several points must be considered when their
results are interpreted:
• Appropriately matched control groups are difficult to
identify, because the factors 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).
• It is difficult to control for related risk factors
(e.g., cigarette smoking) that have strong effects
on health.
IIF-30
-------
• Few 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.
• 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.
• 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-
tion.6
is important to recognize the limitations of negative epide-
miological findings. A simple example reveals why this is so.
Suppose 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 15 years, an
epidemiologist decides to study its effects. He 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. Is it correct to conclude that the drug is not
carcinogenic?
IIF-31
-------
HAZARD IDENTIFICATION; A SUMMARY
For some 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
for 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.,
smoking, 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
is, exposure to chemicals A and B produces less than 3 units of
disease. Hazard evaluation of mixtures of chemicals is complex
and not standardized.
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
IIF-32
-------
about toxicity in human populations who might be exposed. At
this stage of risk assessment, however, there is no attempt to
project human risJc. For the latter, at least two additional sets
of analyses must be conducted.
IIF-33
-------
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. Hence, 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-
ityr 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
effects that involve alteration of genetic material (including
the initiation of cancer), there are theoretical reasons to be-
lieve that effects may take place at very low dose levels; sever-
al specific mathematical models of dose-reponse relationships
have been proposed. For most other biological effects, it is
usually assumed that "threshold" levels exist. However, it is
very 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
the 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
setting public health standards, that the human population is
likely to have much more variable responses to toxic agents than
are the small groups of well-controlled, genetically homogeneous
IIF-34
-------
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., 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
(ADI) 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 EPA, 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
IIF-35
-------
risk to humans. The "NOEL-safety factor" approach includes no
attempt to ascertain how risk changes below the range of experi-
mentally-observed dose-response relat.ions.
The assessment of low dose "risks" from threshold agents are
discussed in Section VI on Risk Characterization.
EFFECTS THAT MAY NOT EXHIBIT THRESHOLDS
At present, only agents displaying carcinogenic properties
are 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 zero dose; as the dose increases above zero, the risk
immediately becomes finite and thereafter increases as a function
of dose. Risk is the probability of cancer, and at very low
doses 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 cell 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
tha 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 cancer-
ous cells at one or more of the various stages, and that a great-
er amount of the carcinogen merely increases the probability that
a given transition would occur. Under these circumstances there
is little likelihood of an absolute threshold below which there
is no effect on the process (even though the effect may be ex-
ceedingly small).
IIF-36
-------
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 High-to-Low Dose Extrapolation
The following example, drawn from Rodricks and Taylor,^
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 20%; 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 Food Safety Decision-Making,
Regulatory Toxicology & Pharmacology (1983), 3:275-307.
IIF-37
-------
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
are usually based on results of the one-hit or multistage models.
They also use multihit, Weibull, and logit models for risk
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:
8A11 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 Rodricks and Taylor, 1983).
IIF-38
-------
Model Applied Lifetime Risk at 1.0 mg/kg/day
One-hit 6.0 x 10"5 (one in 17,000)
Multistage 6.0 x 10~6 (one in 167,000)
Multihit 4.4 x 10~7 (one in 230,000)
Weibull 1.7 x 10~8 (one in 59 million)
Probit 1.9 x 10~10(one in 5.2 billion)
There may be no experimental basis for deciding which esti-
mate is closest to the truth. Nevertheless, it is possible to
show that the true risk, at least to animals, is very unlikely to
be higher than the highest risk predicted by the various models.
In cases where relevant data exist on biological mechanisms
of action, the selection of a model should be consistent with
the data. In many cases, however, such data are very limited,
resulting in great uncertainty in the selection of a model for
low dose extrapolation. At present, understanding of the mecha-
nism of the process of carcinogenesis is still quite limited.
Biological evidence, however, does indicate the linearity of
tumor initiation, and consequently linear models are frequently
used by regulatory agencies.
The one-hit model always yields the highest estimate of low
dose risk. This model is 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 that eventually lead to a tumor.
The multistage model, which yields risk estimates either
equal to or less than the one-hit model, is based on the same
theory of cancer initiation. However, this model can be more
flexible, allowing consideration of the data in the observable
range to influence the extrapolated risk at low dose. It is also
based on the multistage theory of the carcinogenic process and
thus has a plausible scientific basis. EPA generally uses the
linearized multistage model for low dose extrapolation because
its scientific basis, although limited, is considered the strong-
est of the currently available extrapolation models. This model
yields estimates of risk that are conservative, representing a
plausible upper limit for the risk. In other words, it is un-
likely that the "actual" risk is higher than the risk predicted
under this model.
The probit model incorporates the assumption that each indi-
vidual in a population has a "tolerance" dose and that these
doses are distributed in the population in a specified certain
way. The other models have more complex bases; because none is
IIF-39
-------
widely used we shall not discuss them. None of the models, as
currently used, incorporates a threshold dose for an exposed
population.
Interspecies Extrapolation
For 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 size 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.
DOSE-RESPONSE EVALUATION; A SUMMARY
For substances that do not display carcinogenic properties,
or for the noncarcinogenic effects of carcinogens, dose-response
evaluation consists of describing observed dose-response rela-
tions and identifying experimental NOELs. NOELs can be used to
establish ADIs, or can be used for the type of risk character-
ization described in Section VI.
For carcinogens, various models are applied to project the
dose-response curve from the range of observed dose-responses to
IIF-40
-------
the 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 will 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.
IIF-41
-------
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 cases, 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 assessment:
• Information on the factors controlling the production
of the hazardous agent and its release into the envi-
ronment .
• Information on the quantities of the agent that are
released, and the location and timing of release.
• 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.)
• Information on factors controlling human contact with
the agent, including the size and distribution of vul-
nerable human populations, and activities that facili-
tate or prevent contact.
• Information on human intakes.
The amount of information of these types that is available
varies greatly from case to case and is difficult to discuss in
general terms. For some 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 common 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.
IIF-42
-------
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 risJc characterization.
IIF-43
-------
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 MOS 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 jeopardized. The
magnitude of the MOS needed to achieve this condition will vary
among different substances, but its selection would be based on
factors similar to those used to select safety factors to estab-
lish ADIs.
IIF-44
-------
Appendix
TOXIC EFFECTS ON ORGANS AND OTHER TARGET SYSTEMS
IIF-45
-------
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
multiple 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 cast 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
IIF-46
-------
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 P-450
systems) or attaching polar groups to the compound (e.g., gluta-
thione, glycuronyl, or sulfo-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. If !a nonmetabolized compound is toxic, exposure
to an inducer may decrease the toxic effect by increasing the
rate at which the compound is metabolized. If the compound needs
to be metabolized to be toxic, however, exposure to an inducer
may increase the toxic effect by increasing the rate of its meta-
bolism.
KIDNEY
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 metabolize and detoxify some of the
same compounds as the liver, although the fate of metabolism is
usually slower. Compounds that injure the kidney are called
renal toxicants. Some renal toxicants may cause cell death
(necrosis) or cancer. In addition, the kidney produces chemicals
necessary for homeostasis (maintenance of the body's balance of
functions) and responds to the sympathetic nervous system. To
efficiently remove the body's waste, the kidneys must process
IIF-47
-------
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 metabolize 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 endpoints: 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 or egg. The formation of sperm (sperrnatogene-
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 fertilize. 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 fertilization.
IIF-48
-------
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 mother, 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 affecft 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 metabolizing 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 severe.
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
IIF-49
-------
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 fibres is, to
cancer.
The air not only contains a variety of gases but also small
suspended particulates and liquid aerosols. The fate and, there-
fore, potential to cause damage, for each physical state depends
on the size 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
smaller appendages. Given the size of the passage and the fact
that large particles fall out of suspension faster, larger in-
haled 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 the 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 metabolize some chemicals. These
changes may alter the chemical properties and, therefore, the
transport of the chemical.
IIF-50
-------
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. How-
ever, the skin is a route of entry for some toxicants. Dermal
toxicants can cause irritation, sensitization, 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
may 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 major function of the central nervous system (CNS) is
communication. Control of reflexes, movement, sensory informa-
tion, autonomic functions (e.g., breathing), and intelligence are
IIF-51
-------
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 brain 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. In 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
released 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 some 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.
IIF-52
-------
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.
In the human being and other mammals, blood cells are formed
in bone marrow; the three major types of blood cells 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 for 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
affect 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 oxidizing the heme group (causing methemoglobin) or by
denaturing the hemoglobin (which may lead to the formation of
Heinz bodies).
Two other hematopoietic organs that may be affected are the
spleen and heart. The former removes old or damaged red blood
cells from circulationj The rate and efficiency of the heart's
pumping action can be altered by many causes. Chemicals that
IIF-53
-------
constrict or dilate the blood vesicles can also affect circu-
latory function.
IMMUNE 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-
mune 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 some
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 (DNA) in all cells is crit-
ical to cell function and may be affected by some toxic agents.
Damage may take several forms: alteration in 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 mechanisms; the results are
generally classified in three groups: mutations, clastogenic
events, and aneuploidy. Mutagens are substances that change the
IIF-54
-------
chemical structure of 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 Ames mutagenicity assay) and use cells grown in
liquids; some are performed i^n 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.
IIF-55
-------
III. "Project Evaluation: Benefit-Cost Analysis"
Reproduced from A Primer for Policy Analysis by
Edith Stokey and Richard Zeckhauser,(pp.TT4-158)
by permission of W.W. Norton and Company, Inc.
copyright « 1978 by W. W. Norton & Company, Inc.
IIF-56
-------
Part IIG
Principles of Carcinogenicity
-------
Part IIG
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
IIG-l
-------
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(Ch!oromethyl)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 Nucleophiles 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
IIG-2
-------
a. Benzo(a)pyrene, 3-methylcholanthrene,
7,12-dimethylbenz(a)antnracene
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
d. in vivo formation of N-nitroso compounds
a) Small amounts of nitrite and
larger amount of nitrate are
consumed in foods and water
b) Nitrate is absorbed in upper
small intestine, excreted in
saliva and reduced to nitrite by
mouth bacteria
c) Nitrite is then swallowed with
saliva. Therefore, nitrite may
be available in stomach for
IIG-3
-------
N-nitrpsations (acid-catalyzed;
bacterial?)
d) NH4 may be converted to nitrite
and nitrite by microorganisms in
lower intestinal tract
2) Amides and amines
a) May be taken in foods and
medicines
b) May be formed in tissues and Gl
tract from normal intermediates
such as choline, amino acids,
etc.
5. Symmetric dialkylhydrazines
a. Cycad nut—methylazodymethanol—glucoside
(CYASIN)
6. Dioxane
7. Benzene - leukemia
8. Thioamides
a. Thioacetamide
b. Thiouracil
9. Urethane
10. Ethionine
11. Carbon tetrachloride, chloroform, DDT,
Tris(2,3-dibromopropyI)-phosphate, vinyl
chloride (CH2=CrtCir
12. Microbiologic carcinogens
a. Mycotoxins
Aflatoxin Bl (B2, Glf G2)
13. Plant carcinogens
a. Tobacco - some carcinogens, some pyrolysis
products, promoter
b. Safrole
IIG-4
-------
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
4. Depletion of competing nucleophiles
IIG-5
-------
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 look for increase in
number of preneoplastic nodules
XIII. PHARMACOLOGICAL AND TOXICOLOGICAL IMPLICATIONS
A. Dose response
1. Number of tumors increases
2. Time to onset decreases
B. Inducers
1. Often increase detox and decrease tumors
C. Species and strain
1. Species - benzidene in man affects bladder:
in rat the liver
IIG-6
-------
2. Age - younger more susceptible, DES transplacenta
D. Sex
1. May be promoter
E. Immunologic factors
F. Biotransformation
G. Repair
1. Lacks it
2. More susceptible
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 [n 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,
glucuronosyltransferase) — 12 weeks, last
2 weeks plus iron
D. Chronic bioassay
IIG-7
-------
XV. EPA PROPOSED CLASSIFICATION OF CARCINOGENS
A. Human carcinogen
B. Probable human carcinogen
Bl. Limited human data, sufficient animal
data
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
IIG-8
-------
PART III
RISK MANAGEMENT
-------
Part IIIA
Overview of Drinking Water Health Advisories
Occurrence, Chemistry, and Treatment Technologies
-------
Overview of Drinking Water Health Advisories
Occurrence, Chemistry, and Treatment Technologies
I. Occurrence
A. Contaminants regulated under Safe Drinking Water Act (SDWA)1 [Figure 1]
1. Classes of contaminants not yet covered in
Health Advisories
a. Microbials — filtration and disinfection
treatment required
b. Radionuclides
(1) Most are naturally-occurring alpha emitters
(2) Radon-222 (gas) [Figures 2 & 3] radionuclide
found in some ground waters^
c. Disinfection by-products [Figure 4]
(1) Most of these will not be the subject of
the same kinds of "spill" situations as
synthetic organic chemicals (SOCs) and some metals
(2) Subject of long-term research
2, Corrosion by-products [Figure 5]
a. Generally are associated with the corrosion of
metal pipes by low alkalinity, low pH (acidic) waters3
b. Other factors can be important — temperature,
electrical currents, galvanic corrosion
c. Metals — (Cd, Pb, Zn, Cu, Sb, Sn, plus asbestos)
d. Corrected with a corrosion control program
(1) Addition of lime or other base to increase
pH and alkalinity
(2) Other chemicals like phosphates and silicates
may help
IIIA-1
-------
FIGURE 1: REGULATORY AGENDA
FOR DRINKING WATER
USEPA Agenda
Phase I
Trichloroethylene
Carbon tetrachloride
1,1,1-Trichloroethane
1,2-Dichloroethane
Vinyl chloride
Benzene
Dichlorobenzene
1,1 -Dichloroethylene
Fluoride
Phase IA
Tetrachloroethylene
USEPA Target Congressional Congressional
Dates Deadlines Requirements
June 1987
June 1987
9 standards
June 1988
June 1988
40 standards
(December 1987)
Mandatory
filtration
Phase II
Total conforms
Giardia lamblia
Turbidity
Viruses
Required filtration
for surface water systems
Inorganics
Arsenic
Asbestos
Barium
Cadmium
Chromium
Copper
Lead
Mercury
Nitrate
Selenium
Nitrite*
'Contaminants substituted for seven listed in the congressional conference report
IIIA-2
-------
FIGURE 1 (Continued): REGULATORY
AGENDA FOR DRINKING WATER
USEPA Target Congressional Congressional
USEPA Agenda Dates Deadlines Requirements
Organics
Lindane
Methoxychlor
Toxaphene
2,4-D
2,4,5-TP
Aldicarb
Chlordane
Carbofuran
Alachlor
Epichlorohydrin
Toluene
Ethyl benzene*
Heptachlor*
PCBs
Acrylamide
Dibromochloropropane (DBCP)
1,2-Dichloropropane
Pentachlorophenol
Ethylene dibromide
Xylene
frans-1,2-Dichloroethylene
c/s-1,2-Dichloroethylene
o/t/7o-Dichlorobenzene
Chlorobenzene
Heptachlor epoxide*
Styrene*
"Contaminants substituted for seven listed in the congressional conference report
IIIA-3
-------
FIGURE 1 (Continued): REGULATORY
AGENDA FOR DRINKING WATER
USEPA Target Congressional Congressional
USEPA Agenda Dates Deadlines Requirements
Phase III October 1988 June 1989 35 standards
Radium 226 and 228
Beta particle and
photon radioactivity
Uranium
Gross alpha particle activity
Radon
Phase IV September 1990
Required disinfection Mandatory
Chlorine and by-products disinfection
Chlorine dioxide and by-products
Chlorinated acids, haloalcohols
and haloaldehydes
Iodine and by-products
Ozone
High pH
Silver
Ferrate
Chloramines and ammonia
Chlorophenols
Trihalomethanes
Acetonitriles
Bromine and by-products
Potassium permanganate
Ionizing radiation
UV light
"Contaminants substituted for seven listed in the congressional conference report
IIIA-4
-------
FIGURE 1 (Continued): REGULATORY
AGENDA FOR DRINKING WATER
USEPA Target Congressional Congressional
USEPA Agenda Dates Deadlines Requirements
Phase V June 1989
Inorganics
Molybdenum
Sulfate
Antimony
Vanadium
Nickel
Thallium
Cyanide
Organics
Dalapon
Diquat
Endothall
Glyphosate
Adi pates
2,3,7,8-TCDD (Dioxin)"
Dibromomethane
Hexachlorocyclopentadiene
Methylene chloride*
1,1,2-Trichloroethane
Vydate
Simazine
PAHs
Atrazine
Phthalates
Pichloram
Dinoseb
'Contaminants substituted for seven listed in the congressional conference report
IIIA-5
-------
FIGURE 2:226Ra DECAY CHAIN CHARACTERISTICS
tadionuclide
226
88Ra
222
86Rn
218
84 Po
9.98% 0.02%
| I
14 I
32Pb 218
85At
i
1
214
83Bi
9.98% 0.02%
t I
14 t
J4Po 210
I 81"
I I
*
210
82Pb
210
83Bi
00% 0.0001%
'10 I
J4Po 206
81"
I
t
206
Historical
name
Radium
Emanation
Radon (Rn)
Ractium A
Radium B
Astatine
Radium C
Radium C'
Radium C"
Radium D
Radium E
Rarlinm F
i IQVJ i u 1 1 1 i
Radium E"
Radium G
Half-life
1.6 103a
3.823 d
3.05 min
26.8 min
~2s
19.7 min
164 s
1.3 min
22.3 a
5.01 d
nft 4 H
1 OO.H U
4.2 min
Stable
IIIA-6
-------
l-t
H
y
-------
FIGURE 4: SOME DISINFECTION BY-PRODUCTS
UNDER CONSIDERATION
•—Health Advisories—.
IrKMIZKIA UUL/UIVItP
COMPOUND
• 1 / Longer
11 -day 10-day term
HALOACIDS, HALOALCOHOLS, HALOALDEHYDES
monochloroacetic acid
dichloroacetic acid
trichloroacetic acid
trichloroethanol
chloroacetaldehyde
dichloroacetaldehyde
trichloroacetaldehyde
1,1,dichloropropanone
1 ,3-dichloropropanone
1,1,1-trichloropropanone
1 ,1 ,1 ,3-tetrachloropropanone
X
X
X
X
X
X
CHLORINE DIOXIDE, CHLORITE, and
chlorine dioxide
chlorite
chlorate
CHLOROPHENOLS
2-monochlorophenol
2,4-dichlorophenol
2,6-dichlorophenol
2,4,6-trichlorophenol
HALOACETONITRILES,
bromochloroacetonitrile
dichloroacetonitrile
dibromoacetonitrile
chloropicrin
cyanogen chloride
TRIHALOMETHANES
chloroform
bromoform
bromodichloromethane
dibromochloromethane
X
X
X
X
X
X
X
X
X
X
NE
NE
NE
NE
NE
NE
NE
NE
NE
NE
NE
Life
time)
cancer
risk
10-cities
survey
90-day
requested
and HALOKETONES
X
. x
X
- X
X
X
X
X
X
X
c
c
X
X
X
X
X
X
X
X
P
P
P
P
P
X
X
X
X
X
CHLORATE
X
X
X
X
CHLOROPICRIN and
X
X
X
X
X
X
NE
NE
NE
NE
NE
NE
NE
X
X
CYANOGEN
NE
NE
NE
NE
NE
NE
NE
NE
NE
X
X
X
X
X
X
X
c
X
X
CHLORIDE
X
X
I
I
I
P
P
P
P
P
P
P
P
P
X
CHLORAMINES and AMMONIA
chloramine NE IPX
I = study in progress C = data suggest possible carcinogemcity
X = data not available to determine P = present
NE = not evaluated
IIIA-8
-------
FIGURE 5: CORROSION
>
Fe" + 2H20 ^
Fe(OH)2 + 2H+
Galvanic series —
Order of activity
of common metals used
in water distribution systems
Metal
Activity
Zinc
Mild steel
Cast iron
Lead
Brass
Copper
Stainless steel
More active
t
Less active
-------
(3) Materials —
a) Lead ban
b) Coatings
c) Cathodic protection
3. Volatile Synthetic Organic Chemicals (VOCs)
a. Industrial solvent [Figure 6] production scheme^
b. Used for paint stripping metal degreasing
c. Vinyl chloride or "How do we spill a gas into
ground water?" [Figure 7] — biodegradation 5
d. Rank order of occurrence [figure 8] — CERCLA (Superfund)
and RCRA Sites
4. Synthetic Organic Chemicals (SOCs)
a. Additives
(1) Direct — acrylamide and epichlorohydrin
monomers (contaminants in polymer coagulants)
(2) Indirect — coatings
a) Coal tar — polyaromatic hydrocarbons (PAHs)
b) Paint solvents — tetrachloroethylene,
toluene, xylenes, etc.
c) Pentachlorophenol — wood preservative
b. Pesticides
(1) Generally found in agricultural areas
(2) Ground water — aldicarb plus breakdown
products sulfoxide and sulfone from Long
Island potato fields
IIIA-10
-------
FIGURE 6: SIMPLIFIED MANUFACTURING
SCHEME FOR INDUSTRIAL SOLVENTS
CH CH
Ethylene
F<
1
CI2.
3^/lp ""
_ /TM
1
v^riovy 1 viio v>
1,2-Dichloroethane
(ethylene dichloride)
OriOl — v^v^ip
Trichloroethylene
(TCE)
i
Excess
+ heat
CCI2 = CCI2
Tetrachloroethylene
(perchloroethlene)
CI2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
HCI
Fed,
CH, = CHCI
Vinyl chloride
CH3CHCI,
1,1-Dichloroetnane
Cl,
Cl,
CH-CICHCI,
,1,2-Tnchloroetnane
CH3CCI3
1,1,1-Trichloroethane
(methyl chloroform)
NaOHor lime
Heat +
catalyst
CCI4
Carbon tetrachloride
CH, = CCI2
1,1-Dichforoethylene
(vinylidene chloride)
CH2CI2
Methylene
chloride
Cl,
T
CHCI = CHCI
1,2-Dichloroethylene
-------
FIGURE 7: DEGRADATION OF UNSATURATED
CHLORINATED ETHANES
M
>
M
K)
1,1 Dichloroethylene
Cl.
ci-
Perchlorothylene
C=C:
I
Cl
Cl
Cl
Cl
Trichloroethylene
:C=C
-CI
H
trans 1,2 Dichloroethylene
I
H
H
Vinyl Chloride
•C=C
H
cis 1,2 Dichloroethylene
-------
FIGURE 8: RANK ORDER OF CHEMICALS DETECTED IN
GROUND WATER AT RCRA AND CERCLA SITES
(EMSL, 1985)
NUMBER % OF
OF SITES SITES
RANK POSITIVE POSITIVE
i
M
OJ
1
2
3
4
5
6
. 7
8
9
10
11
12
13
14
15
16
17
18
19
20
63
57
57
57
52
52
50
50
49
46
46
39
37
35
30
30
28
23
23
22
43.2
39.0
39.0
39.0
35.6
40.0
34.2
34.2
33.6
31.5
21.5
26.7
25.3
27.1
20.0
20.5
21.5
18.7
15.8
CHEMICAL NAME
f RICHLOROETHENE (-ETHYLENE), TCE
METHYLENE CHLORIDE
TETRACHLOROETHENE (PCE) (-YLENE)
TOLUENE
1,1-DICHLOROETHANE
BIS(2-ETHYLHEXYL) PHTHALATE
BENZENE
1,2-TRANS-DICHLOROETHENE
1,1,1-TRICHLOROETHANE
CHLOROFORM (TRICHLOROMETHANE)
ETHYL BENZENE
1,2-DICHLOROETHANE
1,1-DICHLOROETHENE
PHENOL
VINYL CHLORIDE
CHLOROBENZENE
DI-N-BUTYL PHTHALATE
NAPHTHALENE
CHLOROETHANE
ACETONE
CHEMICAL
TYPE*
v
v
V
V
V
B
V
V
V
V
V
V
V
A
V
V
B
B
V
V
* V = volatile organic chemical
B = base neutral compound
A = acid extractable compound
P = pesticides
-------
FIGURE 8 (Continued): RANK ORDER OF CHEMICALS
DETECTED IN GROUND WATER AT RCRA
AND CERCi-A SITES (EMSL, 1985)
NUMBER % OF
OF SITES SITES
RANK POSITIVE POSITIVE
CHEMICAL NAME
CHEMICAL
TYPE*
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
20
20
17
17
16
16
15
14
14
14
13
13
12
12
11
10
10
10
10
15.5 PENTACHLOROPHENOL A
14.2 BH.C-GAMMA (LINDANE) P
11.6 CARBON TETRACHLORIDE V
(TETRACHLOROMETHANE)
11.6 1,1,2,2-TETRACHLOROETHANE V
11.0 1,1,2-TRICHLOROETHANE V
11.0 FLUOROTRICHLOROMETHANE V
11.5 DIETHYL PHTHALATE B
10.8 BUTYL BENZYL PHTHALATE B
10.8 1,2-DICHLOROBENZENE B
10.9 2,4-DIMETHYLPHENOL A
8.9 1,2-DICHLOROPROPANE V
8.9 CHLOROMETHANE (METHYL CHLORIDE) V
9.2 DI-N-OCTYL PHTHALATE B
8.5 BHC-ALPHA P
7.8 HEPTACHLOR P
7.1 DIELDRIN P
7.1 ENDRIN P
7.1 BHC-BETA P
7.1 BHC-DELTA P
* V = volatile organic chemical
B = base neutral compound
A = acid extractable compound
P= pesticides
-------
(3) Surface water — alachlor from corn
fields in Tiffin, Ohio water
(4) More difficult to measure than VOCs, so less
data are available
c. Industrial chemicals
(1) Polychlorinated biphenyls (PCBs)
a) Transformers and capacitors
b) llOv submersible well pump capacitors
in Region V found to contain PCS oil
(Figure 9)
(2) Combustion products
a) Polyaromatic hydrocarbons (PAHs)
b) Dioxins
d. Inorganic Chemicals (lOCs)
(1) Generally found in well water
(2) Generally due to mineral formations
(3) Concentrations do not vary as much as SOCs
(4) Some surface waters may contain asbestos
— mine tailings or natural erosion
(5) Nitrates
a) Wastewater (septic tanks)
b) Fertilizer
B. Other contaminants for which Health Advisories exist
or are contemplated
1. Pesticide survey [Figure 10]
a. Ground water
b. Tend to be more water soluble compounds
IIIA-15
-------
FIGURE 9: VIEW OF SUBMERSIBLE PUMP
Power Cable
Drop Pipe
Connection
Check Valve
Pump Casing
Inlet Screen
Diffusers
& Impellers
Inlet Body
Power Leads
Motor Shaft
Motor
Section
Lubricant Seal
til ii
IIIA-16
-------
FIGURE 10: TENTATIVE LIST OF ANALYTES
FOR THE NATIONAL PESTICIDES SURVEY
Acifluorfen
Alachlor
Aldicarb
Ametryn
Ammonium Sulfamate
Atrazine
Baygon
Bentazon
Bromacil
Butylate
Carbaryl
Carbofuran
Carboxin
Chloramben
Chlordane
Chlorothalonil
Cyanazine
Cycloate
Dalapon
DBCP
DCPA/Dacthal
Diazinon
Dicamba
2,4-D
1,2-Dichloropropane
Dieldrin
Dimethrin
Dinoseb
Diphenamid
Disulfoton
Diuron
EDB
ETU/EDBCs
Endothall
Fenamiphos
Fluometuron
Fonofos
Glyphosate
Hexazinone
Maleic Hydrazide
MCPA
Methomyl
Methyl Parathion
Metolachlor
Metribuzin
Oxamyl
Paraquat
PGP
Picloram
Promeione
Pronamide
Propachlor
Propazine
Propham
Simazine
Trifluralin
2,4,5-T
2,4,5-TP
Tebuthiuron
Terbacil
Terbufos
IIIA-17
-------
c. A number of methods are under development
to cover these compounds
2. 1445 monitoring
a. VOCs [Figure 11]
b. Plus pesticide survey list [Figure 10]
II. Analytical Methods
A. Sampling procedures
1. Bottles and instruction should be provided by labs
2. Problems
a. Adsorption to container
(1) Acids for metals
(2) Solvents for some SOCs
b. Volatile Organic Chemicals (VOCs)
(1) Carefully fill bottle
(2) No air space (as indicated by lab)
(3) Seal container tightly
c. Sunlight can break down a number of VOCs and SOCs
— ultraviolet light attacks double bonds
d. Reducing agents are used to stop TTHM reaction —
may interfere with other DBP's
e. Corrosion by-products — time function
B. Analytical Procedures
1. Inorganic Chemicals (lOCs)
a. Wet chemistry — colorimetric
b. Atomic adsorption metals
c. Specific ion probes — nitrate, fluoride, etc.
IIIA-18
-------
FIGURE 11: TENTATIVE LIST OF HEALTH
ADVISORIES FOR UNREGULATED VOCs
UNDER SECTION 1445
Chloroform
Bromodichloromethane
Chlorodibromomethane
Bromoform
trans-1,2-Dichloroethylene
Chlorobenzene
m-Dichlorobenzene
Dichloromethane
cis-1,2-Dichloroethylene
o-Dich!orobenzene
1,2,4-Trichlorobenzene
Fluorotrichloromethane
Dichlorodifluoromethane
Dibromomethane
1,2-Dibromo-3-chloropropane
Toluene
p-Xylene
o-Xylene
m-Xylene
1,1-Dichloroethane
1,2-Dichloropropane
1,1,2,2-Tetrachloroethane
Ethyl benzene
1,3-Dichloropropane
Styrene
Chloromethane
Bromomethane
Bromochloromethane
1,2,3-Trichloropropane
1,2,3-Trichlorobenzene
n-Propy I benzene
1,1,1,2-Tetrachloroethane
Chloroethane
.1,1,2-Trichloroethane
Pentachloroethane
bis-2-Chloroisopropyl ether
sec-Dichloropropane
1,2,4-Tri methyl benzene
n-Buty I benzene
Naphthalene
hexachlorobutadiene
o-Chlorotoluene
p-Chlorotoluene
1,3,5-Trimethylbenzene
p-Cymene
1,1-Dichloropropane
iso-Propylbenzene
tert-Buty I benzene
sec-Butyl benzene
Bromobenzene
IIIA-19
-------
2. Organics (gas chromatography) [Figures 12 & 13]
a. VOCs — purge and trap
(!) Carrier is gas (nitrogen or helium)
(2) Solid surface for adsorption or solid
support partitioning
b. SOCs
(1) LLE (liquid-liquid extraction)
(2) CLS (closed loop stripping)
3. Organics [HPLC — high performance (pressure)
liquid chromatography]
a. Carrier is solvent under high pressure
b. Solid surfaces are also used for adsorption or
partitioning
c. Used for carbamate and chlorophenoxy herbicides
that breakdown when heated
C. Numbers — goals, detection, quantification, etc.
1. Maximum contaminant level goals are zero for
Class A S B carcinogens
2. Zero can not be measured
3. Detection — blip on the chart
4. Quantification — a number obtained via relative
response ratio (for GC) to an internal standard
a. Generally 5 to 10 times the method detection
limit (MDL)
b. Subject to measurement error
(1) Same sample, same lab
(2) Same sample, different labs
c) Cannot quantitate sampling error
d) Example, vinyl chloride
IIIA-20
-------
FIGURE 12: FLOWCHART OF
PURGE-ANDTRAP PROCEDURE
SAMPLE
t
PURGE
SORB
>
DESORB
- ISOLATION
SPLITLESS
INJECTION
CAPILLARY
RESOLUTION
PACKED
COLUMN
SPLIT
INJECTION
CAPILLARY
IDENTIFICATION AND QUANTIFICATION
MCD
ELCD
MS
ECD
FID
OUTPUT
-------
ZZ-VIII
o
CO
°
0
_L<°
o - *^-*— Acetone
Tetrahydrofuran
o f-v*—•cisortrans-1,2-Dichloroethylene
o
Chloroform
1,1,1-Trichlorethane
CJl
Bromodichloromethane m^
i ~ —
ro
o ^" Benzene, Trichloroethylene
Dibromochioromethane OO
Dichloroiodomethane 55^
-oo
c/>i
Tetrachloroethylene IT] *
co I J Toluene ^
01 - )
° Chlorobenzene
Js.
o
o
OD
Xylenes —,
>
-------
(1) i40% at 1 .5ug/L (multi-lab variation)
(2) 10~6 cancer risk number is 0.15ug/L.
5. Resampling positive findings
a. The VOCs have shown a wide range of variability^
in concentration over time [Figure 14]
b. VOCs more often occur in mixtures** than alone
[Figure 15]
c. Naturally occurring minerals tend to be more
constant in concentration over time
III. Treatment Technologies
A. Non-treatment alternatives
1. Regional water supply extension
a. Dependent on geography
b. Also politics and cost
2. Alternate source — drill a new well
3. Pump well to waste
4. Bottled water — interim solution to reduce risk
B. Inorganic Chemical (IOC) treatment
1. Conventional treatment — (schematics)^
a. Coagulation/filtration (Figure 16J
b. Lime softening [Figure 17]
c. Ion exchange softening [Figure 18]
d. Iron removal [Figure 19]
2. Removal rates vary10 [Figures 20-21] and may depend
on pH, coagulant chemical, and many other factors
3. Advanced treatment
a. Activated alumina or bone char adsorption for
fluoride11 [Figure 22]
IIIA-23
-------
FIGURE 14: VARIATKjNOFVgJ CONCENTRATION
M
>
I
ro
NEW JERSEY GROUND WATER
10
20 30 40
TIME (WEEKS)
50
60
-------
I
to
FIGURE 15: CO-OCCURRENCE OF VOCs FOR THE
GROUND WATER SUPPLY SURVEY (1980-1)
vinyl chloride
0
T"i
\J
O
_c
o
•^
c
>
7
1,2-dichloroethane
0
c
CO
JC
0
o
.c
o
•9
CM
T~
1
10
1,2-dichloropropane
0
co
Q.
O
Q.
2
O
2f
0
•9
CM
T-
0
1
13
1,1-dichloroethylene
0
C
0
>,
f~
0
P
O
JC
o
•9
"*"
4
3
1
24
carbon tetrachloride
0
f
O
}— .
0
•i— •
CO
O
1
5
0
3
30
1,1 -dichloroethane
0)
c
CO
jC
0
P
o
0
"*"
5
1
2
17
2
41
cis/trans-1 ,2-dichloroethylene
0
c
_0
r~
b
"p:
Q
9
CO
c
CO
CO
o
7
2
3
11
4
21
54
1,1,1-trichloroethane
0
c
/*<
Cu
(—
•+_ •
CD
O
O
jC
0
}~.
T—
1 —
3
2
3
16
4
28
23
78
tetrachloroethylene
0
c
Cl)
^^
•*— •
rt^
UJ
0
/^
Q
CO
•i— •
1
3
1
7
7
16
23
35
79
trichloroethylene
0
c
0
JC
0
2
o
jC
.S2
*J
6
3
3
17
6
26
45
45
39
91
O
^
0
JC
0
o
c
0
2
8
0
17
3
5
19
27
12
-------
FIGURE 16: SCHEMATIC OF
COAGULATION/FILTRATION PROCESSES
M
H
M
I
CTi
— u
1-ltMIOM
/
^
UQ
/
/ /
^
^
/
D
ISINFECTANT -,
/ .
RAPID MIX
FLOCCULATION
SEDIMENTATION
FILTRATION
-------
FIGURE 17: SCHEMATIC OF
LIME SOFTENING PROCESSES
to
I
— o
1-ltMIO^
/
^
.!_£>
/
/ /
^
<*
/
•^ ^
D
ISINFECTANT— ,
• * • •'•^* ••&••* •* •
••••:.-.£ »>*-:v?:::
c.'-.s': :.•:••:•:-..•.
RAPID MIX
FLOCCULATION \X^ RECARBONATION
SEDIMENTATION FILTRATION
-------
FIGURE 18: SCHEMATIC OF
ION EXCHANGE SOFTENING PROCESS
DISINFECTANT
H
M
M
I
OO
RAW
WATER
I I
PRETREATMENT
ION EXCHANGER
-------
CHEMICALS
FIGURE 19: SCHEMATIC OF
IRON REMOVAL PROCESS
i
N>
VO
RAPID MIX
AERATION
OXIDATION
SEDIMENTATION/
DETENTION
FILTRATION
-------
PERCENT REMOVED
O) —
o
O)
\
•a
n:
O
-n
3J
m
5
m
o
H oo-^
m
I w
i ;
i i\
CO
+
o>
o
o
s
• •
com
>0
O3J
CO
r>
31
o°
-------
Te-vin
PERCENT REMOVED
00
0)0
m"n
mP
-------
FIGURE 22: SCHEMATIC OF ACTIVATED
ALUMINA PROCESS
CONTACTOR
i
U)
WELL(S)
\ACTIVATEDvN
O ALUMINA \
WASH WATER-
ACID STORAGE
AND FEED
CAUSTIC STORAGE
AND FEED
^REGENERANT WASTE/RINSE
WATER TO SEWER
RINSE TO WASTE
TREATED WATER TO
DISTRIBUTION SYSTEM
REGENERATION CHEMICALS
STORAGE AND
FEED FACILITIES
-------
b. Anion exchange for nitratesl2 [Figure 23]
c. Reverse osmosis — desalting using pressure
and membranes [Figure 24]
d. Electrodialysis — desalting using direct
current electricity and membranes [Figure 25]
C. SOC treatment
1. Aeration
a. Transfer to air phase by intimate mixing of
air and water
b. VOCs — low solubility plus high vapor pressure
c. Henry's Constant:
H =
[Atm-m3]
S mole
where, Pv = vapor pressure, (atm)
S = solubility, (moles/m 3)
d. Packed tower^^ ±s the most efficient (cost-
effective) system [Figure 26]
2. Adsorption (Granular Activated Carbon, GAG)
a. Transfer to solid phase due to relatively
low water solubility and higher affinity of
solute for the carbon
b. Occurs in a fixed bed 15 [Figure 27]
c. Suitable for most VOCs (except vinyl chloride)
(1) Adsorption capacity measured by isotherms
(2) Design based on bench or pilot studies
(3) Trade-offs between GAC absorption versus
aeration
a) Aeration and air pollution
b) GAC — reactivation, control of
microbes
IIIA-33
-------
FIGURE 23: SCHEMATIC OF
ION EXCHANGE PROCESS
CONTACTOR
7
RAW
WELL(S)
u>
WATER
BYPASS
WATER
r
ANIONIC
EXCHANGE
RESIN
REGENERANT WASTBRINSE
WATER TO SEWER
TREATED WATER TO
DISTRIBUTION SYSTEM
RINSE/WASH
WATER
SALT STORAGE
AND FEED
REGENERATION STORAGE
AND FEED FACILITIES
-------
FIGURE 24: TYPICAL REVERSE OSMOSIS
TREATMENT FACILITY
FEED WATER-
i
U)
Ul
MEMBRANE
PRE-FILTER
HIGH PRESSURE
PUMP
REVERSE
^ PH ADJUSTMENT
OSMOSIS
DEMINE
WA
3ALIZED
ER
CONCENTRATED
WASTE WATER
-------
FIGURE 25: CROSS-SECTION OF
ELECTRODIALYSIS PROCESS
SALINE FEED
^-
C
1
A
C
i
i
A
1
1
I
C
A
ELECTRODE
BRINE
/*
/r,
NOTES:
C = CATION PERMEABLE MEMBRANE
A = ANION PERMEABLE MEMBRANE
I I I I I I I I I I I I
ELECTRODE
PRODUCT.
•WATER
-------
FIGURE 26: SCHEMATIC OF
PACKED COLUMN AERATION
U)
DEMISTERMAT
PACKING MATERIAL
EXIT AIR
n n n
ORIFICE PLATE DISTRIBUTOR
PACKING MATERIAL
SUPPORT PLATE
INCOMING AIR
BLOWER
EFFLUENT
PACKED COLUMN
-------
FIGURE 27: SCHEMATICS OF
CARBON CONTACTORS
RAW WATER INLET
TOP BAFFLE
APPROX. 50%
FREEBOARD
FILTERED
WATER
OUTLET
LATERALS
SURFACE WASHER
SUPPORT LAYERS
CONCRETE
SUB-FILL
SUPPORTS
PRESSURE CONTACTOR
SURFACE WASHERS
SUPPORT LAYERS
NORMAL WORKING LEVEL_ OPERATING FLOOR
WASH
TROUGH — 7
BED
^
INLET
BACKWASH OUTLET
•^-
GRAVITY CONTACTOR
IIIA-38
-------
c) Processes as a function of molecular
weight and solubility" [Figure 28]
d) Aeration is generally more cost-
effective-^
D. Decentralized treatment
1. Most technologies are available in sizes to treat
single buildings (point-or-entry) and single taps
(point-of-use)H [Figure 29]
2. Point-of-use is only acceptable for short term
emergency use since it only treats one tap
3. Point-of-entry devices treat all the water in a
single building — maintenance by service contract.
References
1. Cook, M. B. and D. W. Schnare. 1986. Journal American
Water Works Association. Vol 78. No. 8. p. 66.
2. USEPA. 1985. "Draft for the Criteria Document on Radon".
Health Effects Branch, Office of Drinking Water.
Washington, D.C.
3. Environmental Science and Engineering, Inc, 1984.
"Corrosion Manual for Internal Corrosion of Water
Distribution Systems". EPA 57019-84-001. Office of
Drinking Water. Washington, D.C.
4. 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.
5. Parsons, F., P. R. Wood, and J. DeMarco. 1984. "Trans-
formations of Tetrachloroethlylene and Trichloroethylene
Microcosyms and Groundwater". Journal American Water Works
Association. Vol. J_6_. No. 2. p. 56.
6. James M. Montgomery, Consulting Engineers, Inc. 1985.
Water Treatment Principles and Design. John Wiley and
Sons. New York.
7. 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.
IIIA-39
-------
FIGURE 28: TREATMENT PROCESSES
FOR ORGANICS REMOVAL
1 kg/L
i
£>•
O
O
CO
1 mg/L
• 20
Oxidation and/or coagulation
• 21
1 ng/L
102
103 104
MW, g/mole
105
106
KEY TO NUMBERED COMPOUNDS
1 Resorcinol
2 Phenol
3 Hexanoic acid
4 Chloroform
5 Benzene
6 Bromoform
7 Carbon
tetrachloride
8 Chlorobenzene
9 Perchloroethylene
10 Hexane
11 Decane
12 Lindane
13 Arochlor 1232
(PCB)
14 Pyrene
15 Arochlor 1254
(PCB)
16 Benzo(a)pyrene
17 Dieldrin
18 Aldrin
19 Amylose
20 Fulvic acid
21 Humic acid
-------
FIGURE 29: POINT-OF-USE-DEVICES
(2)
LEGEND
1. ION EXCHANGE
2. DRINKING WATER FAUCET
ION EXCHANGE TREATMENT UNIT
(4)
LEGEND
1. BOOSTER PUMP
2. REVERSE OSMOSIS MODULE
3. WATER STORAGE TANK
4. DRINKING WATER FAUCET
REVERSE OSMOSIS TREATMENT UNIT
IIIA-41
-------
8. Westrick, J. J., J. W. Mellow, and R. F. Thomas. 1984
"The Ground Water Supply Survey". Journal American Water Works
Association. Vol. 76. No. 5. p. 52.
9. 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.
10. 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.
11. USEPA. 1985. "Technologies and Costs for the Removal of
Fluoride from Potable Water Supplies". Office of
Drinking Water. Washington, D.C.
12. USEPA. 1985. "Technologies and Costs for the Removal of
Nitrates from Potable Water Supplies". Office of Drinking
Water. Washington, D.C.
13. USEPA. 1985. Revised Draft "Technologies and Costs
for the Removal of Synthetic Organic Chemicals from
Potables Water Supplies". Office of Drinking Water. Washington,
D.C.
14. Dobbs, R. A. and J. M. Cohen. 1985. "Isotherms for Toxic
Organics". EPA 600/880-023. Office of Research and
Development, Wastewater Treatment Division. Cincinnati,
Ohio.
15. AWWA Research Foundation. "Occurrence and Removal of
Volatile Organic Chemicals from Drinking Water",
Cooperative Research Report with KIWA. AWWA Research
Foundation. Denver, Colorado.
IIIA-42
-------
Part IIIB
Inorganics Treatment
Overview and Case Studies
-------
Part IIIB
WORKSHOP ON
RISK ASSESSMENT AND MANAGEMENT
OF
DRINKING WATER CONTAMINATION
INORGANICS TREATMENT
OVERVIEW AND CASE STUDIES
I. CONVENTIONAL TREATMENT
LIME SOFTENING
REVERSE OSMOSIS
II. ION EXCHANGE
III. ACTIVATED ALUMINA
IV. PROCESS SELECTION
IIIB-1
-------
I. CONVENTIONAL TREATMENT, LIME SOFTENING AND REVERSE OSMOSIS
Scope; 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.
A. 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.
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. This process is generally effective for the treatment of the
following 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
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.
IIIB-2
-------
CHEMICALS
DISINFECTANT.
RAPID MIX
FLOCCULATION
SEDIMENTATION
FILTRATION
FIGURE - SCHEMATIC OF
COAGULATION/FILTRATION PROCESSES
CHEMICALS
RAPID MIX
DISINFECTANT-
V
^^
V
^V}
V
^s
i'.' -'.-:'. ••'••••:•
RECARBONATION
FLOCCULATION SEDIMENTATION FILTRATION
FIGURE - SCHEMATIC OF
LIME SOFTENING PROCESSES
IIIB-3
-------
B. 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
following 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
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.
C. Reverse Osmosis
1. Process used for the desalting of sea water or brackish
groundwaters. 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 1-1. A process
schematic is presented as Figure 1-2.
2. Typical unit processes include:
- raw water pumpage
- pretreatment
- membrane desalination
- disinfection
- storage and distribution
IIIB-4
-------
FIGURE I- 1
TYPES OF REVERSE OSMOSIS MEMBRANES
xAnti-tPlescopinq
irine '' device
Product tube
Product
Brine
i
Feed-channel
spacer"
Tricot
product-
water
collection
channel
^Fiberglass
' outerwrap
Membrane
surface
Membrane
support-backing
Product \ \
flow •
Membrane
surface
^Brme seal
Feed
SPIRAL WOUND
Epoxy
nub
Flow
Sample
xShell
End plate'' > \ 'Permeator sleeve
End-plate \Feed tube
sleeve
Fiber 0-ring Support 0-ring
seal
*>• Product
End plate
Distributor' Epox'y 1 Porous ^-Segmented
tube-sheet support-block rln9
HOLLOW FIBER
IIIB-5
-------
REVERSE OSMOSIS
M
M
03
RAW WATER
PRETREATMENT
DISINFECTION
REVERSE OSMOSIS
ELECTRODIALYSIS
BRINE
o
c
3
m
T
to
-------
3. Process design considerations
- influent suspend solids
- competing ions
- ionic size
- membrane pore size
- membrane type
4. This process is generally effective for the treatment of the
following inorganic species:
Good to Excellent for:
As (III) Cd F Nitrate
As(V) Cr(III) Pb Se(IV),(VI)
Ba Cr(VI) Hg Ag
5. Limitations - the process is generally effective in removing
all inorganic chemicals.
IIIB-7
-------
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
IIIB-8
-------
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
2. 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 rate: 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
3. 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); 5 feet (maximum)
- Treatment flow rate: 250 gpm
- Fjnpty Bed Contact Time: 2.54 minutes
- Service loading rate: 9.03 gpm/ft
4. Regeneration
a. Regeneration material
- 6% sodium chloride brine (2.6 Ibs/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
IIIB-9
-------
McFARLAND, CA.
TREATMENT PLANT FLOW DIAGRAM
SALT
LOADING
OVERFLOwT
BRINE
I
BRINE
-e
OTABLE WATER TO BRINE SYSTEM
PRESSURE
TANK
r—BLENDING
\ VALVES
\ TREATED WATER
M
| |
i_j
|. -IT
(TRIBUTION
(VftTPM
\ — — i-i— »-r-
6
T
J.
T - - -». i 1
I
Lr t
S ^
jr<
p i
i
i
— i i
CONDUCTIVn
RAW WATER
VESSEL
2
7 VESSEL
.3
I
r
BACKWASH
NITRATE
WASTE TO
DISPOSAL
ALARM AND
SHUTDOWN
WELL SUPPLY
O
c
30
m
-------
c. Slow Rinse procedure
- Slow rinse rate: 64 gpm
- Slow rinse duration: 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
5. Waste Handling
- Brine discharge to municipal wastewater treatment plant
- Brine treated by aerated lagoons with spray irrigation for
animal feed crops and cotton.
6. 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 Ibs. 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
7. 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: 12.8C per 1000 gallons
which includes:
- Operator: 1.3* per 1000 gallons
- Power: 2.2C per 1000 gallons
IIIB-11
-------
Resin replacement: 3.2C per 1000 gallons
Salt: 3.4C per 1000 gallons
Normal O & M: 1.9C per 1000 gallons
Miscellaneous 0.8C per 1000 gallons
IIIB-12
-------
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
IIIB-13
-------
ACTIVATED ALUMINA
M
03
I
RAW WATER
PRETREATMENT
DISINFECTION
ACTIVATED ALUMINA
ION EXCHANGE
o
c
3)
m
-------
b. Water Quality
Fluoride: 4 to 6 mg/L
2. 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
3. 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
- Desert Center, California - 1,000 + grains/ft with
7.5 ppm fluoride
- Alcoa Laboratory - 700 grains/ft with 22 ppm fluor-
ide
- 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 = 2 feet -
6 inches
Tank free board - 6 inches
- Superficial residence time of raw water flowing
through bed - 5 minutes (min.)
Treatment unit flow rate - 7 gpm/ft (max)
2
- Treatment unit backwash flow rate - 11 gpm/ft (max)
IIIB-15
-------
BASIC OPERATING MODE
FLOW SCHEMATICS
03
I
RAW WATER
ACID
.TREATED WATER
TREATMENT
UNIT
RAW WATER
TREATMENT
UNIT
TREATMENT AND
DOWNFLOW RINSE
RAW WATER
TREATMENT
UNIT
WASTE
BACKWASH AND
UPFLOW RINSE
RAW WATER
.CAUSTIC
T
ASTE
CAUSTIC
WASTE
UPFLOW
REGENERATION
TREATMENT
UNIT
WASTE
DOWNFLOW
REGENERATION
0
c
30
m
-------
4. 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 gpm/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 H SO
- Blend of 93 percent H SO and raw water in "mixing T"
at treatment unit
- Ninety-three percent H?SO4 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
5. 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)
6. Operating Data
a. Regenerate every 3.5 to 4 mg of water treated
b. Ten hours to regenerate
IIIB-17
-------
c. Activated alumina media lost: 10-12 percent per year
d. Water temperature: 107 F
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
IIIB-18
-------
TYPICAL OPERATING RUN
AT GILA BEND, AZ.
M
M
CD
I
12
10
X
a
6
Treated Water pH
-18
Treated Water F Content
I
2 4 6 8 10
Water Flow Through Treatment Bed - 100m3
9
O
4
u
O
O
12
14
o
c
3D
m
-------
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 producesludges
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
technologies.
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
conventional 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
Secondary Drinking Water parameters.
6. Other Considerations
a. Availability of local supply of process chemicals
b. Power costs
IIIB-20
-------
7. The most probable application for each treatment process is
summarized in Table IV-1.
IIIB-21
-------
TABLE IV- 1
MOST PROBABLE APPLICATION
PROCESS
CONVENTIONAL
LIME SOFTENING
CATION EXCHANGE
ANION EXCHANGE
ACTIVATED ALUMINA
POWERED ACTIVATED
CARBON
GRANULAR ACTIVATED
CARBON
REVERSE OSMOSIS
AND ELECTRODIALYSIS
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
IIIB-22
-------
Part III C
ORGANICS TREATMENT
OVERVIEW AND CASE STUDIES
-------
WORKSHOP ON
RISK ASSESSMENT AND MANAGEMENT
OF
DRINKING WATER CONTAMINATION
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
III-C-1
-------
I. GRANULAR ACTIVATED CARBON - TREATMENT OVERVIEW
Scope; 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.
A. 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.
- branched-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
III-C-2
-------
FIGURE 1-1
Solvent
Adsorbate
Adsorbent
^^tZ.^ptt^yr^**'?*-'!'!. "'w=--"/^ M» -«n.'*•=•.. • !.-.-•• *K . •ji«rT«-i'v*\.~v :.:'--^A>s» r.w.»-'*1>S.
>^!>«^^^'j--^ry,"^^3 - *^tf', • £r,w£r-.^~»v*. «r ^vJ^fs^f^^^tciL^^VV^^^^-Hr^Xi " **-ji—V-J^ .-^T-1
Attached
Adsorbate
THE ADSORPTION SYSTEM
III-C-3
-------
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 ethers
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 Aliphatics
III-C-4
-------
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 organics
d. Radon - 100 to 200 minutes
3. Carbon Usage Rate
a. Rate of carbon adsorption
b. Affects O&M cost
c. 100 to 300 Ib/mg for most organics
4. Carbon Usage Rates for Several Organics:
a. Volatile Organics
Ib/MG
TCE - 200
PCE - 70
Vinyl Chloride - NA
Cis-l,2-Dichloroethylene - 250
b. Pesticides
Aldicarb - 25
Chlordane - 5
DBCP - 15
III-C-5
-------
Ib/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:
/ L.
x/m = kc
x/m = equilibrium capacity (mg SOC/gm carbon)
k = capacity at 1 mg/L SOC concentration
c = SOC 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. Downflow
- Pressure - see diagram on Figure 1-6
Gravity - see diagram on Figure 1-7
III-C-6
-------
FIGURE 1-2
100.0
10.0
o
CD
DC
O
E
O)
Q
LU
CD
DC
O
CO
Q
O)
E
5 0.0001 0.001 0.01 O.I 1.0
x RESIDUAL CONCENTRATION oig/l
NOTE: NUMBER IN PARENTHESIS (166) INDICATES
THE MOLECULAR WEIGHT OF THE COMPOUND
ADSORPTION ISOTHERMS FOR SEVERAL ORGANIC
COMPOUNDS FOUND IN GROUND WATER SUPPLIES
PENTACHLOROPHENOL (866)
III-C-7
-------
I
n
I
oo
i * a ronoot Fina
„ truuu irm COIUIM
•v*
D • fl IHMB OO
rm.ON TIBIHO l.lilM D I I.On* OO
M OlAU IAHPU COUf CnOM ITMHOC
WITH/uurno umjH HW
- PYWX WOOL
I • rruMXtt mo. FMT
DMCAT COLUMN
DIAGRAM OF DYNAMIC MINI-COLUMN ADSORPTION
TECHNIQUE SYSTEM
a
c
3)
m
co
-------
FIGURE 1-4
200
111
U.
g IOO
CD
CC
O
TRICHLOROETHYLENE
10 MINUTE EBCT
EFFLUENT CONCENTRATION
50 jug/I
10jug/l
1 jug/I
I I
j I
IOO 200 300 400 500 600 700 800 900 IOOO
INFLUENT CONCENTRATION, jug/I
EFFECT OF CONTAMINANT LEVELS
ON CARBON LIFE
III-C-9
-------
FIGURE 1-5
400
(0
>
o 300
uT
u.
o 200
CO
cc
u
100
0
EFFLUENT CONCENTRATION 10ug/l
EBCT-10 MINUTES
TETRACHLOROETHYLENE
TRICHLOROETHYLENE
1,1,1,-TRICHLOROETHANE
0 IOO 200 300 400 500600 700 800 900 IOOO
INFLUENT CONCENTRATION/ug/l
EFFECT OF TYPE OF COMPOUND ON CARBON LIFE
III-C-10
-------
FIGURE 1-6
INFLUENT
20,000 LB EA.
GRANULAR
ACTIVATED CARBON
COLLECTOR
SYSTEM
TREATED WATER
GAG CONTACTORS
SCHEMATIC OF TREATMENT PROCESSES
III-C-ll
-------
-------
3. Transfer System
a. Hydraulics
b. Velocities
c. Materials of construction
d. GAG loss
4. GAG 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. GAG TREATMENT ECONOMICS
1. Capital cost components include:
Basic Site Specific
contactors special sitework
activated carbon raw water holding tank
piping new/restaged well pump
GAG contactor building
chemical facility
clearwell
finished water pump(s)
backwash storage
2. Capital costs are shown on Figure 1-9 at end of this section.
III-C-13
-------
FIGURE 1-8
INFLUENT
WAVEFRONT
EFFLUENT
GAC CONTACTOR
III-C-14
-------
o
I—>
tn
o
o
o
400
350-
300
250
I— 200
g 150 +
100
50 +
0
0.5
CAPITAL COSTS FOR
GAC SYSTEMS
0
+
1.0 1.5 2.0
SYSTEM SIZE
(MGD)
3.0
o
c
3)
m
7
-------
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 - 1
VOCs - most costly
III-C-16
-------
O & M COSTS FOR GAC SYSTEM
o
o
CD
**
i — i ^*^
t-H
^ (/>
O
O
60r
55
50
45
40
35
30
25
20
15
10
5
0
w w
m
•
-.
-
•
_
• i • ••!
0.5 1.0 1.5 2.0 2.5 3.0
SYSTEM SIZE (MGD)
o
c
3
m
-------
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. PCE: 50-500 ug/L
b. TCE: 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.
f.
g.
h.
Hydraulic
Loading:
(gpm/ft2)
EBCT (min) :
Washwater:
See Figure
7.1
10.5
sand-filtered and
II-2 for schematic
recycled
of Vannatta Street Station
III-C-1'?
-------
CONCENTRATION OF
CONTAMINANTS IN THE RAW WATER
o
I
10
20 30
HOURS OF OPERATION
50
60
o
c
3)
m
-------
GAC TREATMENT PLANT SCHEMATIC
V ANN ATT A STREET STATION
o
i
ro
O
CARBON
WASTEWATER RECYCLE
FILTERED WATER TO
DISTRIBUTION SYSTEM
0
c
3)
m
to
-------
5. Carbon Usage Rates
Ibs GAC/mg
PCE
Breakthrough 102
5 ug/L 91
1,1,1-TCEA
Breakthrough 271
10 ug/L 209
6. Costs
a. Capital: $508,500 (1981)
b. Operating: $80,000/year
B. GAG 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 II-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 II-5 for schematic of Cincinnati treatment train
III-C-21
-------
FIGURE 11-3
CINCINNATI TREATMENT TRAIN
1
r
*\
PRESETTLING
BASIN
1
I
/" >
PRESETTLING
BASIN
j
k
V *
VX
LAMELLA
SETTLER
PUMPING
STATION
FLOCCULATION/
EAST SEDIMENTATION
CHEMICAL BASINS FILTERS
BUILDING
CLEARWELL DISTRIBUTION
SYSTEM
III-C-22
-------
TYPICAL TOC REDUCTION CURVE
DURING PILOT STUDY
O
I
ro
CO
4000
3500
a 3000
g 2500
CONTACTOR EFFLUENT
O
60
TIME, DAYS
100
O
c
01
7
-------
FIGURE 11-5
CINCINNATI TREATMENT TRAIN
1
r
PRESETTLING
BASIN
5
t
PRESETTLING
BASIN
4
>
\\\
\ ,\
*b
i
\
LAMELLA —- \\ ^
SETTLER PUMPING \ ^
STATION ^
FLOCCULATION/
EAST SEDIMENTATION
CHEMICAL BASINS FILTERS
BUILDING
CLEARWELL DISTRIBUTION
SYSTEM
PROPOSED
PUMPING
STATION
PROPOSED
GAC
FACILITIES
III-C-2 4
-------
6. GAC design criteria:
Plant Flowrate (mgd):
Annual Average 124
Maximum Day 175
Empty Bed Contact Time (min) 15
GAC Bed Depth (feet) 11
Maximum Loading Rate (gpm/sf) 5.5
Carbon Usage Rate (Ib/day):
Annual Average 54,000
Peak Period 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. blends
3" pipe - 24" radius
4" pipe - 36" radius
8" pipe = 48" radius
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
e. Modification of Existing Facilities
Capital Cost = $40 Million
13. O&M Costs
a. Labor
b. Power
c. Natural Gas
III-C-25
-------
•INLET CHAMBER
f>
en
CARBON
CONTACTED
WATER
EXISTING FILTER BUILDING
WEIR CHAMBER
FILTERED WATER
VWASTEWATER
DRAIN
CARBON
CONTACTOR
BUILDING
WASTEWATER
RECOVERY TANK
-OVERFLOW
TO RIVER
CARBON CONTACTOR BUILDING LAYOUT
o
c
3J
m
7
o>
-------
SEAL WELL
(TYR)-
CARBON
CONTACTED
WATER
EFFLUENT
inn
o
I
ro
CARBON
CONTACTORS
REGENERATION
AREA
n n
CARBON STORAGE
CARBON
CONTACTORS
CARBON
CONTACTORS
FILTERED
WATER
INFLUENT
CARBON
CONTACTORS
\
J
I
CARBON CONTACTOR BUILDING
FLOOR PLAN
o
c
2J
m
-------
FIGURE 11-8
f-
o
LU
(/)
cc
o
h-
o
o
o
o
<
o
III-C-28
-------
OUTLINE OF
EXPANDED
BED
DURING
BACKWASH^
CCARBON CONTACTOR
BACKWASH
TROUGH
ITYP.)
WALKWAY
(TYP.)
EL. 124.00
CARBON
FILL
PIPES
TOP OF CARBON EL. 110.00
-S.S. UNDERDRAIN
HEADER (TYP.)
SPENT CARBON
DISCHARGE SUMP
S.S. WEDGE WIRE
UNDERDRAIN •
LATERAL (TYP.)
lO'-O"
GAG CONTACTOR
CROSS SECTION
T|
5
c
30
m
i
-------
REGENERATION SYSTEM SCHEMATIC
o
I
CO
o
DEWATERED
SPENT CARBON
REGENERATION
FURNACE
\
RECYCLE
DRIED SPENT
CARBON
DRYER
OFF-GAS
FURNACE
OFF-GAS
TO SCRUBBERS
AND STACK
RECUPERATOR
AFTERBURNER
o
c
3)
m
-------
d. Make-up GAC
O&M Cost = $3 to 4 Million/yr
14. Cost Impact of GAC
a. Average Bills Before Installation of GAC
Quarterly: $ 8.10 for first 1,200 ft
10.80 for next 1,800 ft
$18.90 3,000 ft
Annual: $80.00
b. Projected Annual Bills After Installation of GAC
- If 30 percent increase, $80 + 30 percent = $105
- If 40 percent increase, $80 + 40 percent = $115
III-C-31
-------
III. 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 AP
L
Where: M = mass of substance transferred per unit time and
volume (Ib/hr/cf)
K = coefficient of mass transfer (Ib/hr/sf)
a = effective area (sf/cf)
A P = 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.
III-C-32
-------
-------
5. Henry's Constants for several organic chemicals:
a. VOCs
Dimensionless Units
- Vinyl chloride: 285
- TCE: 0.44
- PCE: 0.88
- Cis-l,2-Dichloroethylene: 0.18
b. Pesticides
- Aldicarb: 1 x 10~7
- Chlordane: 0.015
- DBCP: 0.011
c. Chlorinated Aromatics
- PCB: 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 nozzles
Packed column
2. Diffused air system - Figure II-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 III-4.
c. Catenary grid unit - diagram shown on Figure III-5.
d. Higee System - diagram shown on Figure II1-6.
III-C-34
-------
FIGURE 111-2
AIR SUPPLY
X
INFLUE21T
DCFFUSE3 Gnl
— ^M.
j
it
t
LaD — — .
7
<-.
. „
—
™
T>
• _ *
• .
•
.
-— • —
J-!
•-'• |
•J
Z"
•9 &
P
EFFLUENT
• %UJ*3i.^-*' -—^
DIFFUSED AIR BASIN
III-C-35
-------
FIGURE 111-3
INLET
CHAMBER
DISTRIBUTOR
NIPPLES
STAGGERED
SLAT TRAYS
AIR INLET
BLOWER
WATER
INLET
AIR SEAL
WATER
OUTLET
BAFFLES
AIR STACKS
"^F3
=3 cib cib r±±i ctb c±=i
,bci^ci=, '
cifcj dij riia cia niti ciii ciia cSa £±=a eia ci±3 <±zi t±ti ij
-
i i< v •?, ': -r -i. -!t -!• ^ -'i -]
1:1 1 i* r-^-'V- H V i1 •* I) .
DIAGRAM OF A REDWOOD SLAT
TRAY AERATOR
III-C-36
-------
FIGURE MI-4
INFLUENT
EFFLUENT
LIQUID DISTRIBUTOR
PACKING MATERIAL
PACKING SUPPORT
u
AIR IN
DIAGRAM OF PACKED COLUMN
III-C-37
-------
FIGURE 111-5
DEMISTER
FLUIDIZED
ZONE
CATENARY
GRID (TYP.)
TREATED WATER
SAMPLE COLLECTOR
MANOMETER FOR
AIR FLOW RATE
MEASUREMENT-
BLOWER
WATER INLET
(TYP.)
AIR FLOW
DAMPER
/-RAW WATER
" ROTAMETER
RAW WATER
SAMPLE TAP
TREATED WATER
SAMPLE TRAP
WATER FLOW
METERING VAL
RAW WATER
FROM WELL
TREATED WATER
TO DRAIN
MAUOCXM
PIRNIE
III-C-38
DIAGRAM OF PILOT-SCALE
CATENARY GRID UNIT
-------
GO
l-D
EXHAUST AIR
AIR IN
BLOWER
GROUNDWATER
FILTER
NIGEE
PUMP
HIGEE SYSTEM
PRODUCT
WATER
o
o
c
3)
m
o>
-------
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. Restaging well pumps
b. Flow and system pressure
c. Repumping to distribution system
III-C-40
-------
100
^ 80
•
h-
LL
o
h-
CL
LJJ
Q
O
60
O
<
0.
40
20
EFFECT OF COMPOUND
ON PACKED COLUMN DESIGN
CHLOROFORM
TCE
20/1
1,2 DICHLOROETHANE
95% REMOVAL
55°F
40/1
60/1
80/1
100/1
120/1
O
c
3J
m
A/W RATIO
-------
0)
0)
H
g
LJJ
X
o
z
*
o
LIQUID LOADING RATE-3Qgpm/sf
AIR : WATER RATIO = 30: I
-SITE Q
(32 ug/L)
SITE S
(IO,500ug/L)
75
90 95 J7.5 99
REMOVAL EFFICIENCY (%)
99.5
99.8
PACKING HEIGHT VS REMOVAL EFFICIENCY
TCE
o
c
3J
m
I
a
-------
PACKED
COLUMN
i
o
i
-P>
00
H
vrvru1
i I i
TO ATMOSPHERE
- SPRAY
HEADER
^- PLASTIC
MEDIA
HIGH SERVICE
VERTICAL
AIR TURBINE PUMPS
BLOWER
ASSEMBLY
FINISHED WATER
TO SYSTEM
CLEAR WELL
WELL
PACKED COLUMN SYSTEM COMPONENTS
o
c
3
m
i
(0
-------
4. Housing
a. Freezing potential (see Figure 111-10 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 111-12)
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
III-C-44
-------
FIGURE III- 10
TEMPERATURE EFFECTS
ON AERATION SYSTEM - JANUARY 1983
51°F
WATER OUT
49°F
1
1
r>
j
i
'
i
f
r
A
i
k
1
i
L_
k
)
\
IR OUT
AmmmkiT AID
MmDIElI>l 1 Mlrf
•1 OO C
1 Of"
AIR IN
III-C-45
-------
FIGURE Ill-i
Orifice-type distributor
III-C-46
-------
/ v v v
-------
e. Vapor phase carbon (see Figure 111-13)
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 Special sitework
Internals Raw water holding tank
Packing New/restaged well pump
Blower(s) Blower building
Clearwell Booster pump building
Booster pump(s) Chemical facility
Piping Noise control installation
Air emissions control
2. Capital costs of packed columns - see Figure 111-14.
3. O&M costs of packed columns - see Figure 111-15.
4. Relative costs for removal:
Vinyl Chloride - least costly to remove
PCE
TCE
Carbon Tetrachloride
1,2-Dichloroethane
DBCP - most costly to remove
III-C-48
-------
UD
CONTAMINATED
AIR
RAW WATER
CLEAN
AIR
PACKED
COLUMN
BLOWER
TREATED
WATER
TREATED AIR
A
GAC
HEATING BLOWER
ELEMENT
VAPOR PHASE CARBON
O
c
3D
(Tl
-------
ANNUAL O&M COSTS
FOR PACKED COLUMN SYSTEMS
I
en
O
W 100
O
O
O
rT 80
60
40
20
O
O
<*
O
z
1.0 2.0 3.0 4.0
SYSTEM SIZE (MGD)
5.0
O
c
33
m
-------
ANNUAL O&M COSTS
FOR PACKED COLUMN SYSTEMS
o
I
en
W 100
O
O
O
T-" 80
60
40
20
o
o
<*
o
<
z
2
1.0 2.0 3.0 4.0
SYSTEM SIZE (MGD)
5.0
O
c
30
m
-------
IV. AERATION - CASE STUDY
Scope; Describes experience of a water supplier in dealing with organic
contamination of its supply using packed column aeration.
A. 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 gpm
b. Packing Height: 12 feet
c. A:W 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
III-C-52
-------
EXHAUST
AIR
INFLUENT
WATER
TREATED WATER
TO RESERVOIR
i
en
CO
SCHEMATIC DIAGRAM
SCOTTSDALE PACKED COLUMN
WELL NO.6
BOOSTER
PUMP
Tl
O
c
m
<
-------
SCOTTSDALE FACILITY LAYOUT
'0:
PUMP ROOM
BLOWER
ROOM
O
'•f. •."•:.•;*•
PACKED
COLUMN
o
c
XI
m
i
ro
-------
c. establish background TCE levels
d. monitor air quality during operation
e. recommend long-term monitoring program
10. Proposed Packed Column Operating Schedule (see Figure IV-3).
11. Air Quality Monitoring
Weather Distance
Date Conditions Downwind (m)
2/20/85 Sunny, breezy
3/6/85 Overcast, calm
20
48
16
48
61
95
TCE
Concentration (ug/m )
<0.01
<0.01
0.05
0.04
<0.01
<0.01
12. Full-scale Operating Results
TCE Concentration (ug/L) Percent
Date
2/20/85
3/6/85
3/17/85
3/19/85
Influent
67.3
89.1
190
200
Effluent
0.5
1.1
1.1
1.2
Removed
99.3
98.7
99.4
99.4
1. 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
e. 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
III-C-55
-------
en
o
z
h-
<
cc
LLJ
Q.
O
CO
DC
D
O
I
CITY OF SCOTTSDALE
PROPOSED PACKED COLUMN
OPERATING SCHEDULE
MONTH
JAN FEB MAR APR MAY JUN JUL AUQ SEP OCT NOV DEC
o
c
3}
m
i
CO
-------
PART IV
RISK COMMUNICATION
-------
Part IV - Risk Communication
A-
Media Cove rjfje_ -___ Advantages
o Quick dissemination of information to public
o Allays unfounded fears
o Inspires confidence
Media _Qoye_ra<]e_ .i_Di^a_dyan^a£es
o Shallowness
- Tight deadlines
- Stories must be brief
- Reporters are generalists
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 WitJL the pisad vantages of Media Coverage
o Shal lowness
o Sensationalism
o Subjectivity
o Educate reporter
o Know and present facts
o Appeal to values
IV - 1
-------
B. Rules For Dealing With the Media
No such thing as "Off the record"
Assume microphones aIways on
Plan ahead
o Primary and backup spokesperson
o Inform 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 back up
communications equipment
Develop ability to take control of interview
IV-2
-------
C. Controlling tjhe^ TntervJew
Winning at confrontation
o Rules of the game
o Crisis communications exercise 1
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:
A) Walk out with as much dignity as you posses and issue a statement later
refuting her charges.
PRO: CON:
B) Ask 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 saying
anything that might agitate the audience.
PRO: CON:
-------
D) Grab the microphone, ask for a chance to respond and emphatically disagree
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: CON:
B) Issue a statement announcing a study to ascertain the facts.
PRO: CON:
IV-4
-------
C) Meet with residents at City Hall to hear their complaints and fill tern
in on the cleanup.
PRO: CON:
D) Accelerate efforts to contain the spill and pump the liquid into tanks.
PRO: CON:
o Guidelines for success
IV-5
-------
D. Disclosing InFormation
General
Ground Rules
Crisis Communications Exercise III
You are 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 is
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:
B) 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: CON:
C) Tell him you will seek an audit and get back to him (and give him the
results after the drought is over).
PRO: CON:
IV-6
-------
D) Acknowledge it's true but explain that the manufacturing process is such
that there can be little variation in water consumed in the process as long as the
plant is operating.
PRO: CON:
Guidelines for success
IV-7
-------
E. Conclusions and Checklist
General Risk Perception
o The problem of involuntary risks
o Communication Exercise IV
Assume that a volatile chemical is detected in the drinking water that your
scientific experts 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 these
various responses:
A) Asked "Is the water safe to drink?" you pick up a glass and chug-a lug
it, saying, "Safe enough for me."
PRO: CON:
B) Tell them that it is unlikely that anyone could drink enough water
every day over his/her lifetime for exposure to be a significant risk for cancer.
PRO CON:
C) Cite scientific data that someone who drank one glass of town water per
day for 70 years would face a cancer risk of 6.4 in 10,000.
PRO: CON:
o Guidelines for success
IV-i
-------
Crisis Communication Checklist
1. BE PREPARED. REVIEW THE FACTS.
2. BE HONEST. TELL THE TRUTH.
3. ANTICIPATE LIKELY QUESTIONS.
4. CONSIDER WHAT THE AUDIENCE IS INTERESTED IN KNOWING.
5. DECIDE WHAT YOU WANT TO SAY.
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.
11. 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.
17. 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 WHEN IT
IS SHUT.
FOR OUR MANUAL ON CRISIS COMMUNICATIONS (100 pages, paperback)
CALL FORD ROWAN AT (202) 296-9710
OR WRITE: FORD ROWAN, 1899 L. STREET, N.W., SUITE 105, WASHINGTON, D.C. 20036
(price per copy: $14)
IV-9
-------
THE DOZEN MOST COMMON MISTAKES IN CRISIS COMMUNICATIONS
By Ford Rowan
The first mistake most managers make is failing 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 importance
of the media at the onset of a 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 minicams.
Palling 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 fail 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 fail to anticipate likely questions. The old
standards what, when, where, who, why and how can bo 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 and candor that you will cooperate with courteous journalists. Keep
cool .
The twelfth mistake is to fail to learn from mistakes. Life Is full of
trial and error. Put the hard earned knowledge to work to prevent future crises.
as. Environment^ Protection Agency.
U.S. GOVERNMENT PRINTING OFFICE:1986-6 4 foniiK^/VO t-ibfafV ^
South Dearborn Street .
Illinois
------- |