Toxicological
Profile
for
p,p -DDT
p,p'-DDE
p,p'-DDD
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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TOXICOLOGICAL PROFILE FOR
DDT, DDE, AND DDD
Prepared by:
Clement Associates
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
In collaboration with:
U.S. Environmental Protection Agency
December 1989
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ii
DISCLAIMER
Mention of company name or product does not constitute endorsement
by the Agency for Toxic Substances and Disease Registry.
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iii
FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental Response,
Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public
law (also known as SARA) directed the Agency for Toxic Substances and Disease
Registry (ATSDR) to prepare toxicological profiles for hazardous substances
which are most commonly found at facilities on the CERCLA National Priorities
List and which pose the most significant potential threat to human health, as
determined by ATSDR find the Environmental Protection Agency (EPA). The lists
of the most significant hazardous substances were published in the Federal
Register on April 17, 1987, and on October 20, 1988.
Section 110 (3) of SARA directs the Administrator of ATSDR to prepare a
toxicological profile for each substance on the list. Each profile must
include the following content:
(A) An examination, summary and interpretation of available
toxicological information and epidemiological evaluations on the
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute, subacute,
and chronic health effects,
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, or chronic
health effects, and
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans.
This toxicological profile is prepared in accordance with guidelines
developed by ATSDR and EPA. The original guidelines were published in the
Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every 3 years, as required
by SARA.
The ATSDR toxicological profile is intended to characterize succinctly
the toxicological and health effects information for the hazardous substance
being described. Each profile identifies and reviews the key literature that
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iv
describes a hazardous substance's toxicological properties. Other literature
is presented but described in less detail than the key studies. The profile
is not intended to be an exhaustive document; however, more comprehensive
sources of specialty information are referenced.
Each toxicological profile begins with a public health statement, which
describes in nontechnical language a substance's relevant toxicological
properties. Following the statement is material that presents levels of
significant human exposure and, where known, significant health effects. The
adequacy of information to determine a substance's health effects is described
in a health effects summary. Data needs that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of the
profiles is on health and toxicological information; therefore, we have
included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested private
sector organizations and groups, and members of the public. We plan to revise
these documents as additional data become available.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been reviewed by
scientists from ATSDR, EPA, the Centers for Disease Control, and the National
Toxicology Program. It has also been reviewed by a panel of nongovernment
peer reviewers and was made available for public review. Final responsibility
for the contents and views expressed in this toxicological profile resides
with ATSDR.
Wi >h.D.
Acting Administrator
Agency for Toxic Substances and
Disease Registry
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V
CONTENTS
FOREWORD iii
LIST OF FIGURES viii
LIST OF TABLES ix
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT ARE DDT, DDE, AND DDD? 1
1.2 HOW MIGHT I BE EXPOSED TO DDT, DDE, AND DDD? 1
1.3 HOW CAN DDT, DDE, AND DDD ENTER AND LEAVE MY BODY? .... 2
1.4 HOW CAN DDT, DDE, AND DDD AFFECT MY HEALTH? 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE
BEEN EXPOSED TO DDT, DDE, OR DDD? 3
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 3
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
TO PROTECT HUMAN HEALTH? 8
1.8 WHERE CAN I GET MORE INFORMATION? 8
2. HEALTH EFFECTS 9
2.1 INTRODUCTION 9
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 9
2.2.1 Inhalation Exposure 10
2.2.1.1 Death 10
2.2.1.2 Systemic Effects 10
2.2.1.3 Immunological Effects 10
2.2.1.4 Neurological Effects 11
2.2.1.5 Developmental Effects 11
2.2.1.6 Reproductive Effects 11
2.2.1.7 Genotoxic Effects 11
2.2.1.8 Cancer H
2.2.2 Oral Exposure H
2.2.2.1 Death 11
2.2.2.2 Systemic Effects 24
2.2.2.3 Immunological Effects 27
2.2.2.4 Neurological Effects 28
2.2.2.5 Developmental Effects 30
2.2.2.6 Reproductive Effects 31
2.2.2.7 Genotoxic Effects 33
2.2.2.8 Cancer 34
2.2.3 Dermal Exposure 36
2.2.3.1 Death 36
2.2.3.2 Systemic Effects 36
2.2.3.3 Immunological Effects 37
2.2.3.4 Neurological Effects 37
2.2.3.5 Developmental Effects 37
2.2.3.6 Reproductive Effects 37
2.2.3.7 Genotoxic Effects 37
2.2.3.8 Cancer 38
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2.3 RELEVANCE TO PUBLIC HEALTH . 38
2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED
WITH HEALTH EFFECTS 48
2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS
IN HUMAN TISSUES AND/OR HEALTH EFFECTS 50
2.6 TOXICOKINETICS . 50
2.6.1 Absorption 50
2.6.1.1 Inhalation Exposure 50
2.6.1.2 Oral Exposure 51
2.6.1.3 Dermal Exposure 51
2.6.2 Distribution 52
2.6.3 Metabolism 52
2.6.4 Excretion 55
2.7 INTERACTIONS OF DDT, DDE, OR DDD WITH OTHER CHEMICALS. . . 56
2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 57
2.9 ADEQUACY OF THE DATABASE 58
2.9.1 Existing Information on Health Effects of
DDT, DDE, and DDD 58
2.9.2 Data Needs 60
2.9.3 On-going Studies 64
3. CHEMICAL AND PHYSICAL INFORMATION 67
3.1 CHEMICAL IDENTITY 67
3.2 PHYSICAL AND CHEMICAL PROPERTIES 67
4. PRODUCTION, IMPORT, USE, AND DISPOSAL 75
4.1 PRODUCTION 75
4.2 IMPORT 75
4.3 USE 75
4.4 DISPOSAL 75
4.5 ADEQUACY OF THE DATABASE 76
4.5.1 Data Needs 76
5. POTENTIAL FOR HUMAN EXPOSURE 79
5.1 OVERVIEW 79
5.2 RELEASES TO THE ENVIRONMENT 79
5.2.1 Air 79
5.2.2 Water 80
5.2.3 Soil 80
5.3 ENVIRONMENTAL FATE 81
5.3.1 Transport and Partitioning 81
5.3.2 Transformation and Degradation 82
5.3.2.1 Air 82
5.3.2.2 Water 82
5.3.2.3 Soil 83
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 83
5.4.1 Air 83
5.4.2 Water 84
5.4.3 Soil 85
5.4.4 Other Media 86
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 86
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 89
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5.7 ADEQUACY OF THE DATABASE 89
5.7.1 Data Needs 90
5.7.2 On-going Studies 90
6. ANALYTICAL METHODS 93
6.1 BIOLOGICAL MATERIALS 93
6.2 ENVIRONMENTAL SAMPLES 101
6.3 ADEQUACY OF THE DATABASE 101
6.3.1 Data Needs 102
6.3.2 On-going Studies 103
7. REGULATIONS AND ADVISORIES 105
8. REFERENCES 109
9. GLOSSARY 139
APPENDIX 143
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LIST OF FIGURES
2-1 Levels of Significant Exposure to DDT, DDE, or DDD - Oral ... 20
2-2 Metabolic Scheme for DDT 53
2-3 Existing Information on the Health Effects of
DDT, DDE, and DDD 59
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LIST OF TABLES
1-1 Human Health Effects from Inhalation of DDT, DDE, or DDD. ... 4
1-2 Animal Health Effects from Inhalation of DDT, DDE, or DDD ... 5
1-3 Human Health Effects from Eating or Drinking
DDT, DDE, or DDD 6
1-4 Animal Health Effects from Eating or Drinking,
DDT, DDE, or DDD 7
2-1 Levels of Significant Exposure to DDT, DDE, or DDD - Oral ... 12
2-2 Genotoxicity of DDT, DDE, and DDD In Vitro 46
2-3 Genotoxicity of DDT, DDE, and DDD In Vivo 47
3-1 Chemical Identity of DDT, DDE, or DDD 68
3-2 Chemical and Physical Properties of DDT, DDE, or DDD 71
5-1 Residues in Adult Total Diet Samples Based on Market
Basket Surveys 87
6-1 Analytical Methods for Determining DDT, DDE, or DDD in
Biological Materials 94
6-2 Analytical Methods for Determining DDT, DDE, or DDD in
Environmental Samples 98
7-1 Regulations and Guidelines Applicable to DDT, DDE, or DDD . . . 106
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT ARE DDT, DDE, AND DDD?
DDT, 1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane, was one of the
most widely used chemicals for controlling insect pests on agricultural
crops and controlling insects that carry such diseases as malaria and
typhus. Technical DDT is primarily a mixture of three forms (p,p'-DDT,
o,p'-DDT, and o,o'-DDT), all of which are white, crystalline, tasteless,
and almost odorless solids, In addition, DDE, 1.l-dichloro-2.2-bisfp-
chlorophenyl)ethylene, and DDD, 1.l-dichloro-2.2-bis(p-
chlorophenyl)ethane, are found in small amounts as contaminants in
technical DDT. DDD was also used to kill pests, and one form of DDD was
used medically to treat cancer of the adrenal gland.
DDT does not occur naturally in the environment. The presence of
DDT in the environment is generally a result of contamination due to
past production and use and subsequent movement from sites of
application to land, water, and air. Several waste sites, including
Superfund sites (National Priority List (NPL) sites], contain these
compounds and might act as additional sources of environmental
contamination. Some DDT may be degraded in air, but the compound may
persist for a long time bound to certain soils. More information on
DDT, DDE, and DDD can be found in Chapter 3--chemical and physical
information, and in Chapter 5--potential for human exposure.
DDT can no longer be used as a pesticide in the United States
except in cases of public health emergency. It is, however, still used
in several other areas of the world. In addition, the use of DDD to
kill pests has also been banned.
1.2 HOW MIGHT I BE EXPOSED TO DDT, DDE, AND DDD?
Humans can be exposed to DDT, DDE, and DDD primarily by eating food
that contains small amounts of these compounds. Even though DDT has not
been used in this country since 1972, small amounts of DDT and DDE are
found in soil and, under certain conditions, may be transferred to crops
grown on this soil. In addition, imported foods may have been directly
exposed to DDT. The amount of DDT in crops has been decreasing and is
expected to continue to decrease with time. In the United States, the
average amount of DDT and DDE eaten daily in food in 1981 was 2.24
micrograms per day (/*g/day) (0.000032 mg/kg/day) with root and leafy
vegetables containing the highest amount. Meat, fish, and poultry also
contain very low levels of these compounds.
DDT or its breakdown products are still found in air, water, and
soil samples. Levels in most air and water samples are low, however,
and exposure by these pathways is of little concern. Air samples in the
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1. Public Health Statement
United States have shown levels of DDT ranging from 0.00001 to 1.56
micrograms per cubic meter of air (/ig/m3) , depending on the location and
year of sampling. Most reported samples were collected in the mid
1970s, and present levels are expected to be much lower. DDT and DDE
have been reported in surface waters at levels of 0.001 micrograms per
liter (fig/L) , while DDD generally is not found in surface water.
National soil testing programs in the early 1970s have reported levels
in soil ranging from 0.18 to 5.86 parts per million (ppm). For more
information on DDT, DDE, and DDD in the environment, see Chapter 5.
DDT has been found at 66, DDE at 33, and DDD at 28 out of 1177
hazardous waste sites. Information on maximum amounts of these
compounds present at these sites can be found in Chapter 5.
1.3 HOW CAN DDT, DDE, AND DDD ENTER AND LEAVE MY BODY?
DDT, DDE, or DDD enter the body mainly when a person eats foods
contaminated with these compounds. Small amounts of DDT, DDE, and DDD
may also be inhaled and pass through the lungs into the body. Because
inhaled DDT, DDE, or DDD particles are generally too large to pass
through the lungs into the body, they are more likely coughed-up and
ingested. These compounds are very poorly absorbed through the skin.
Persons who take part in activities at NPL sites would most likely be
exposed by accidentally taking in soil through the mouth.
Once inside the body, these compounds are stored most readily in
fatty tissue. Stored amounts leave the body very slowly. Levels in
fatty tissues may either remain relatively constant over time or even
increase with continued exposure over time. However, amounts of DDT in
the body will decrease with decreasing exposure. They leave the body
primarily in urine, but breast milk is another way they may leave the
body. More information on how DDT, DDE, and DDD enter and leave the
body can be found in Chapter 2.
1.4 HOW CAN DDT, DDE, AND DDD AFFECT MY HEALTH?
Short-term exposure to high doses of DDT affects primarily the
nervous system. People who either voluntarily or accidentally swallowed
very high amounts of DDT experienced excitability, tremors, and
seizures. These effects on the nervous system appeared to be reversible
once exposure stopped. Some people who came in contact with DDT
complained of rashes or irritation of the eyes, nose, and throat.
People exposed for a long-term at low doses, such as people who made
DDT, had some changes in the levels of liver enzymes, but there was no
indication that DDT caused irreversible harmful (noncancer) effects.
Tests in laboratory animals confirm the effect of DDT on the nervous
system. However, tests in animals suggest that exposure to DDT may have
a harmful effect on reproduction, and long-term exposure may affect the
liver. Studies in animals have shown that oral exposure to DDT can
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1. Public Health Statement
result in an increased occurrence of liver tumors. In the five studies
of DDT exposed workers, results did not indicate increases in the number
of deaths or cancers. However, these studies had limitations so that
possible increases in cancer may not have been detected. Because DDT
caused cancer in laboratory animals, it is assumed that DDT could have
this effect in humans. Therefore, EPA lists DDT, DDE, and DDD as
probable human carcinogens. More information on the health effects
associated with exposure to DDT, DDE, and DDD is presented in Chapter 2.
1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
DDT, DDE, OR DDD?
Specific analytical tests have been developed to detect DDT, DDE,
and DDD in the fat, blood, urine, semen, and breast milk of exposed
individuals. Samples of blood and urine are easy to obtain, and levels
in these samples may help determine the relative amount of exposure of
an individual. Although testing may indicate that an individual has had
low, normal, or excessive exposure to DDT, DDE, or DDD, such tests
cannot indicate the exact amount of exposure or the environmental levels
to which a person was exposed. More information on tests to detect
these compounds in the body can be found in Chapter 6.
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
In several studies, volunteers have eaten measured amounts of DDT
and DDE. A single dose of 6 to 10 milligrams DDT per kilogram of body
weight (mg DDT/kg body weight) may result in sweating, headache, and
nausea, while a dose of 16 mg DDT/kg body weight may lead to
convulsions. Persons who have eaten DDT in these amounts usually
recover within 24 hours. Volunteers ate 0.31 to 0.61 (mg DDT/kg/day)
for up to 21 months without any noticeable effects. These doses may be
compared with the estimated dietary intake in 1981 of 0.000032 mg
DDT/kg/day. A summary of the information on health effects in humans is
presented in Tables 1-1 and 1-3. Minimal Risk Levels (MRLs) are also
included in Table 1-3. These MRLs were derived from animal data for
both short-term and longer-term exposure, as described in Chapter 2 and
in Table 2-1. The MRLs provide a basis for comparison to levels which
people might encounter either in the air or in food or drinking water.
If a person is exposed to DDT at an amount below the MRL, it is not
expected that harmful (noncancer) effects will occur. Since these
levels are based only on information that is currently available, there
is always some uncertainty associated with them. Also, since the method
for deriving MRLs does not use any information about cancer, a MRL does
not imply anything about the presence, absence, or level of risk of
cancer.
Studies done with laboratory animals have tried to associate health
effects with exposure to DDT. A summary of this information is
presented in Tables 1-2 and 1-4. In general, relatively high doses of
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1. Public Health Statement
TABLE 1-1. Human Health Effects from Inhalation of DDT, DDE, or DDD*
Short-term Exposure
(less than or equal to 14 days)
Description n't Effe^.t-s
The health effects
resulting from short-
term human exposure
to air containing
specific levels of DDT,
DDE, or DDD are not
known.
Long-term Exposure
(greater than 14 days)
Levels in Air (com)
Description of Effect?
The health effects
resulting from long-
tern human exposure
to air containing
specific levels of
DDT, DDE, or DDD are
not known.
*See Section 1.2 for a discussion of exposures encountered in daily life.
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1. Public Health Statement
TABLE 1-2. Aninal Health Effects from Inhalation of DDT, DDE, or DDD
Short-term Exposure
(less than or equal to 14 days)
Levels
in Air
(ppm) DescriDtion of Effects
The health effects
resulting from short-
term animal exposure
to air containing
specific levels of
DDT, DDE, or DDD are
not known.
Long-term Exposure
(greater than 14 days)
Levels
in Air
(ppm) Descriotion of Effects
The health effects
resulting from long-
term animal exposure
to air containing
specific levels of
DDT, DDE, or DDD are
not known.
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1. Public Health Statement
TABLE 1-3. Human Health Effects from Eating or Drinking DDT, DDE, or DDD*
Short-term Exposure
(less than or equal to 14 days)
Levels
in Food (ddid)
Duration
of Exoosure
Description of Effect?
214
357
560
571
0.0178
Single
Single
Single
Single
Single
dose
dose
dose
dose
dose
Headache, nausea
Headache, nausea, vomiting
Heart, increased rate
Vomiting, convulsions
Minimal Risk Level
(see Section 1.6 for
discussion)
Levels
in Water (ddih)
The health effects
resulting from short-term
human exposure to water
containing specific
levels of DDT, DDE, or
DDD are not known.
Long-term Exposure
(greater than 14 days)
Levels
in Food fDDm)
Duration
of Rxposure
Description of Effer.ts
22
0.0125
18 months
60 days
No effects
Minimal Risk Level
(see Section 1.6 for
discussion)
Levels
in Water (DDm)
The health effects
resulting from long-term
human exposure to water
containing specific
levels of DDT, DDE, or
DDD are not known.
*See Section 1.2 for a discussion of exposures encountered in daily life.
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1. Public Health Statement
TABLE 1-4. Animal Health Effects from Eating or Drinking DDT, DDE, or DDD
Short-term Exposure
(less than or equal
to 14 days)
Duration
Levels in Food
(m>m)
of Exposure
Description of Effects
20
4 days
Developmental effects in
rabbits (decreased fetal
body weight)
200
1 week
Increases in enzymatic
activity
510
3 days
Developmental effects in
rabbits (increased
resorptions)
2000
Single dose
Death in rats
Levels in Water
fppm)
The health effects
resulting from short-term
animal exposure to water
containing specific levels
of DDT, DDE, or DDD are
not known.
Long-term Exposure
(greater than 14 days)
Duration
Levels in Food
(ppm)
of Exposure
Description of Effects
3.67
8 weeks
Immunological effects
in rabbits
75
36 months
Liver necrosis in rats
200
27 months
Renal necrosis in rats
210
78 weeks
Neurological effects in
rats (tremors)
Levels in Water
fppm)
The health effects
resulting from long-term
exposure to water contain-
ing specific levels of DDT,
DDE, or DDD are not known.
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L. Public Health Statement
these compounds are required to produce serious health e£f«ts in
animals. More information on levels of exposure and harmful health
effects can be found in Chapter 2.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PRDTECT
HUMAN HEALTH?
EPA banned all uses of DDT, except for public health emergencyi in
1972 primarily because amounts were building up in the etiViromnent and
because some cancer tests in laboratory animals showed positive results
Although DDT is no longer used in this country, there are sill federal
regulations concerning the amounts of DDT that are allowed m food (40
CFR 180.147) and water (EPA 440/5-80-038).
The Occupational Safety and Health Administration (OSHA) states
that workers may not be exposed to quantities of DDT greater than ±
milligram per cubic meter (mg/m3) of air for an 8-hour workday. EPA
estimates that at an ambient criteria level of 0.024 nanogram per liter
(ne/L), consuming 2 liters of drinking water and eating 6.5 grams (g) of
fish and shellfish per day would be associated with an increased
lifetime cancer risk of one extra cancer case for every one miUion
persons exposed. In addition, there are tolerance levels set for
virtually all foods. More information on regulations and adviSor^es for
DDT, DDE, and DDD can be found in Chapter 7.
1.8. WHERE CAN I GET MORE INFORMATION?
If you have further questions or concerns, please contact your
State Health or Environmental Department or:
Agency for Toxic Substances and Disease Registry
Division of Toxicology
1600 Clifton Road, E-29
Atlanta, Georgia 30333
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2. HEALTH EFFECTS
2.1 INTRODUCTION
This chapter contains descriptions and evaluations of studies and
interpretation of data on the health effects associated with exposure to
DDT, DDE, or DDD. Its purpose is to present levels of significant
exposure for DDT, DDE, or DDD based on toxicological studies,
epidemiological investigations, and environmental exposure data. This
information is presented to provide public health officials, physicians,
toxicologists, and other interested individuals and groups with (1) an
overall perspective of the toxicology of DDT, DDE, and DDD and (2) a
depiction of significant exposure levels associated with various adverse
health effects.
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the data in this section
are organized first by route of exposure--inhalation, oral, and dermal--
and then by health effect--death, systemic, immunological, neurological,
developmental, reproductive, genotoxic, and carcinogenic effects. These
data are discussed in terms of three exposure periods--acute,
intermediate, and chronic.
Levels of significant exposure for each exposure route and duration
(for which data exist) are presented in tables and illustrated in
figures. The points in the figures showing no-observed-adverse-effect
levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs)
reflect the actual doses (levels of exposure) used in the studies.
LOAELs have been classified into "less serious" or "serious" effects.
These distinctions are intended to help the users of the document
identify the levels of exposure at which adverse health effects start to
appear, determine whether or not the intensity of the effects varies
with dose and/or duration, and place into perspective the possible
significance of these effects to human health.
The significance of the exposure levels shown on the tables and
graphs may differ depending on the user's perspective. For example,
physicians concerned with the interpretation of clinical findings in
exposed persons or with the identification of persons with the potential
to develop such disease may be interested in levels of exposure
associated with "serious effects." Public health officials and project
managers concerned with response actions at Superfund sites may want
information on levels of exposure associated with more subtle effects in
humans or animals (LOAEL) or exposure levels below which no adverse
effects (NOAEL) have been observed. Estimates of levels posing minimal
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2. Health Effeces
risk (Minimal Risk Levels --MRLs) to humans are of interest to health
professionals and citizens alike.
For certain chemicals, levels of exposure associated with
carcinogenic effects may be indicated in the figures. These levels
reflect the actual doses associated with the tumor incidences reported
in the studies cited. Because cancer effects could occur at lower
exposure levels, the figures also show estimated excess risks, ranging
from a risk of one in 10,000 to one in 10,000,000 (10 ** to 10 ), as
developed by EPA.
Estimates of exposure levels posing minimal risk to humans (MRLs)
have been made, where data were believed reliable, for the most
sensitive noncancer end point for each exposure duration. MRLs include
adjustments to reflect human variability and, where appropriate, the
uncertainty of extrapolating from laboratory animal data to humans.
Although methods have been established to derive these levels (Barnes et
al. 1987; EPA 1980a), uncertainties are associated with the techniques.
2.2.1 Inhalation Exposure
2.2.1.1 Death
No studies were located regarding the lethal effects in humans or
experimental animals following inhalation exposure to DDT, DDE, or DDD.
2.2.1.2 Systemic Effects
No studies were located regarding the cardiovascular,
hematological, gastrointestinal, musculoskeletal, hepatic, renal, or
dermal/ocular effects in humans or experimental animals following
inhalation exposure to DDT, DDE, or DD.
Respiratory Effects. Neal al • (1944) exposed human volunteers
by inhalation of aerosols containing DDT at concentrations which left a
white deposit on the nasal hair ° he v°lunteers. Except for moderate
irritation of the nose, throat, an eyes, no significant changes were
reported. The study by Neal et al. (1944) had several limitations. The
study did not provide information concerning conditions of exposure,
dose, or information on persons exposed.
No studies were located regarding the respiratory effects in
experimental animals following innai.ation exposure to DDT, DDE, or DDD.
No studies were located regarc*ing the following effects in humans
or animals following inhalation expoSUre to DDT ^ DDE( or DDD:
2.2.1.3 Immunological Ef^eCts
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2. Health Effects
2.2.1.4
Neurological Effects
2.2.1.5
Developmental Effects
2.2.1.6
Reproductive Effects
2.2.1.7
Genotoxlc Effects
2.2.1.8
Cancer
No studies were located regarding the carcinogenic effects in
humans or animals following inhalation exposure to DDT, DDE, or DDD.
Several studies of workers occupationally exposed to DDT are discussed
under Section 2.3 Relevance to Public Health.
2.2.2 Oral Exposure
Table 2-1 and Figure 2-1 describe the health effects observed in
humans and animals associated with levels of significant exposure (LSE)
for each designated exposure duration. The levels of exposure to
humans, below which the risk of adverse effects (other than cancer) is
presumed to be minimal, are also presented for the oral route of
exposure. Typically individuals are not exposed to DDT, DDE, or DDD
individually, but rather to a mixture of all three, since DDE and DDD
are contaminants, as well as degradation and metabolic products of DDT.
Therefore, the data presented on the LSE graph and LSE table include
toxicity information on all three chemicals.
2.2.2.1 Death
Only one case of fatal poisoning in humans following accidental
oral exposure to DDT has been documented (Hill and Robinson 1945). One
ounce of 5% DDT in kerosene was ingested by a child. Clinical signs
observed included coughing and vomiting followed by tremors and
convulsions. The child then became comatose and death followed;
however, the contribution of the solvent, kerosene, to DDT toxicity is
not clear. Doses as high as 285 mg DDT/kg have been ingested
accidentally by humans with no fatal results (Garrett 1947).
In male and female mice a single oral dose of 237 to 325 mg DDT/kg
caused death (Bathe et al. 1976; Kashyap et al. 1977; Tomatis et al.
1972). The LD50s reported in rats exposed to single oral doses of DDT
ranged from 113 to 800 mg/kg (Cameron and Burgess 1945; Gaines 1969).
The LD50s for guinea pigs and rabbits following oral exposure to DDT and
medicinal paraffin were 400 and 300 mg/kg, respectively (Cameron and
Burgess 1945).
Ben-Dyke et al. (1970) reported an LDS0 as a range of single oral
doses (400 to 4000 mg/kg) in which mortality was observed in 50% of rats
-------
TABLE 2-1. Levels of Significant Exposure to DDT, DDE, or ODD - Oral
Exposure
Figure Frequency/ NOAEL
Key Species Route Duration Effect (ng/kg/day)
Less Serious
(mg/kg/day)
LOAEL (Effecti
Serious
(mg/kg/day)
Reference
Chemical
Species
ACUTE EXPOSURE
Death
1 rat
2 mouse
Id
(G) lOd
gn pig (G) Id
rabbit (G) Id
113 (LD50)
237 (LD50)
400 (LD50)
300 (LD50)
Gaines 1969
Tomatis et at.
1972
Cameron and
Burgess 1945
Cameron and
Burgess 1945
DDT
DDT
DDT
DDT
Systemic
5 rat
6
7
6
9
mouse
mouse
(G) 12d
(G) 1wk
(G) 24hr/d
1wk
mouse (F) Iwk
monkey (G) Id
Gastro
Hepatic
Hepatic
Hepatic
Hepatic
Hemato
Hepatic
Renal
Other
40
26
26
150
150
150
150
40 (liver alt)
26 (liver alt)
DeWaziers and
Azais 1987
Pasha 1981
Pasha 1981
Pasha 1981
Agarwal et al.
1978
DDT
DDT
DDE
DDD
DDT
X
(6
P>
*-¦
rr
P*
m
t-tl
<6
0
ft
01
M
franunological
10 rabbit (G) lOd
2.63
Sbiplov et al.
1972
DDT
-------
TABLE 2-1. (Continued)
Exposure
Figure Frequency/ NOAEL
Key Species Route Duration Effect (mg/kg/day)
LOAEL (Effect)
Less Serious
(mg/kg/day)
Serious
(mg/kg/day)
Reference
Chemical
Species
Neurological
11 rat
12 rat
(G) Id
(G) 1d
13
14
15
mouse (G) 1d
mouse (G) 1d
monkey (G) Id
Developmental
16 rat (G) Gd 15-19
17 rabbit (G) Gd 7,8,9
or
21,22,23
18 rabbit (G) Gd 4-7
25 50 (inc 5-HIAA)
0.5 (dec brain recept)
150 (dec brain lipids)
100 (myoclonus)
200 (convulsions)
28 (dec ovary wt)
10 (inc resorp)
1 (dec fet wt)
Hong et al. 1986 DDT
Hwang and Van DDT
Woert 1978
Eriksson and
Nordberg 1986
Matin et al.
1981
Sanyal et al.
1986
Gellert and
Heinrichs 1975
DDT
DDT
DDT
DDT,DDE
Hart et al. 1972 DDT
Fabro et al. DDT
1984
sc
(6
P>
h-1
rt
cr
m
Hi
1-tJ
(t>
O
rt
in
Reproductive
19 rat (G) Id
50 100 (inc dead impl) Palmer et al. DDT
1973
-------
TABLE 2-1. (Continued)
Exposure LOAEL (Effect)
Figure Frequency/ HOAEL Less Serious Serious Chemical
Key Species Route Duration Effect (mg/kg/day) (rag/kg/day) (mg/kg/day) Reference Species
INTERMEDIATE EXPOSURE
Systemic
20 rat
(F) 7d/uk Hepatic
36wk
21 monkey (G) 2,4,or Heraato
6mo
50
3.75 (necrosis)
Jonsson et al.
1981
Cranmer et al.
1972a
DOT
DDT
Immunological
22 human (C) 20d
23
24
25
26
rat IF) 16d
rat
(F) 24hr/d
31d
mouse (F) 3-12uk
rabbit CF) 8wk
0.07 (inc 0,H Ab)
1 (dec mast eel)
6.5 13 (dec Ab titer)
121 (atrophy thymus)
0.18 (atrophy thymus)
Shiplov et al.
1972
Hamid et al.
1974
Gabliks et al.
1975
Banerjee 1987a
Street and
Sharma 1975
DDT
DDD
DDT
DDT
DDT
Neurological
27 monkey (G) 7d/wk
lOOd
10 (dec brain lipids)
Sanyal et al. DDT
1986
Developmental
28 rat (F) 7mo
29
mouse (F) lac
10 (dec growth)
26 (dec learning)
Clement and Okey DDT
1974
Craig and
Ogilvie 1974
DDT
-------
TABLE 2-1. (Continued)
Exposure
Figure Frequency/ NOAEL
Key Species Route Duration Effect (mg/kg/day)
LOAEL (Effect)
Less Serious
(mg/kg/day)
Ser i ous
pj
t—*
rt
rr
pi
Hi
Hi
<0
O
rt
w
-------
TABLE 2-1. (Continued)
Exposure LOftEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious Chemical
Key Species Route Duration Effect (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Species
39
40
41
42
43
44
45
46
rat
rat
24hr/d
27mo
(F) 78wk
rat
(F) 78wk
mouse (F) 78wk
mouse (F) 78wk
hamster (F) 128uk
hamster (F) life
Resp
Hepatic
Renal
Resp
Cardio
Gastro
Hemato
Hepatic
Renal
Derm/Oc
Resp
Cardio
Gastro
Hemato
Hepatic
Renal
Derm/Oc
Resp
Cardio
Gastro
Hemato
Hepatic
Renal
Resp
Cardio
Gastro
Hemato
Hepatic
Renal
Hepatic
Hepatic
dog
(F) 39-40mo Hepatic
10
42
42
42
42
42
42
165
165
165
165
165
165
165
23
23
23
23
23
107
107
107
107
107
107
20
16
10 (hypertrophy)
10 (necrosis)
12 (necrosis)
2.86 (amyloidosis)
41.5 (necrosis)
41.5 (necrosis)
80 (liver alt)
Deichmam et al. DDT
1967
NCI 1978
NCI 1978
NCI 1978
NCI 1978
DDE
DDD
DDT
DDD
Rossi et al. DDE
1983
Cabral et al. DDT
1982a
5C
a>
pj
M
rt
V
pi
t-h
i-h
o
rt
m
Lehman 1965
DDT
-------
TABLE 2-1. (Continued)
Exposure lOftEl (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Key Species Route Duration Effect (mg/kg/day) (mg/kg/day) (mg/kg/day)
Reference
Chemical
Species
47
monkey (F) 3.5-7yr Hepatic
8.0
20 (tremor conv)
Durham et at.
1963
DDT
I nmunological
48 rat
(F) 24hr/d
27mo
10 (hemolysis)
Deichmann et al. DDT
1967
Neurological
49 rat
50
Developmental
51 rat
52 mouse
53
dog
(F) 78wk
hamster (F) life
(F) 2gen
(F) 70wk
(C) 7d/wk
F2gen
40
11 (tremors)
10 (inc rings)
13 (dec survival)
5 (premat pub)
NCI 1978
Cabral et al.
1982a
Ottoboni 1969
Del Pup et al.
1978
Ottoboni et al.
1977
DDT
DDT
DDT
DDT
DDT
5C
(1)
P>
t-1
rt
D*
M
Hi
Ml
m
o
rt
u>
Reproductive
54 rat
55 mous
56
(F) life
(G) 5gen
mouse (F) 15mo
10
2.4
1.3 (abortions)
Ottoboni 1969
Shabad et al.
1973
Wolfe et al.
1979
DOT
DDT
DDT
-------
TABLE 2-1. (Continued)
Exposure
Figure Frequency/ MOAEL
Key Species Route Duration Effect (mg/kg/day)
LOAEL (Effect)
Less Serious
(mg/kg/day)
Serious
(mg/kg/day)
Reference
Chemical
Species
Cancer
57 rat (F) 78wk
58 rat (F) life
59
60
61
«
63
(A
65
mouse (F) 130uk
mouse (G) 80wk
mouse (F) 80wk
mouse (F) life
mouse (F) life
hamster (G) T28wk
mouse (F) 78wk
85 (thyroid tunors)
12.5 (liver tumors)
32.5 (lung tumors)
10 (lung tumors)
13 (lung tumors)
32.5 (liver tunors)
0.26 (liver tumors)
41.5 (liver tunors)
19 (liver tunors)
NCI 1978
DOD
Cabral et al. DDT
1982b
Tomatis et al. DDD
1974a
Kashyap et al. DDT
1977
Kashyap et al. DDT
1977
Terracini et al. DOT
1973
Tomatis et al. DOT
1972
Rossi et al. DDE
1983
NCI 1978
1983
ac
m
(U
'
rf
3"
P3
i-h
Ml
n>
o
rt
w
DDE
^sed to derive acute oral URL of 0.0005; dose divided by an uncertainty factor o-f 1,000 (10 for use of a LOAEL, 10 for extrapolation -from
animals to humans, and 10 for huraan variability). This RRL has been converted to an eqaWaVent concentration in food W.Q178 ppm) -for
presentation in fable 1-3.
'Wrf to derive acute oral MKL of 0.00035; dose divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from
anunals to humans, and 10 for hunan variability). This MRl has been converted to an equivalent concentration in food (0 0125 pan) for
presentation \n Table 1-3. ^ J
header: mg=miIligran; kg=kilogram; NOAEL=no adverse effect level; LOAEL=lowest observable adverse effect level
route: G=gevage; F=food; C=capsule
-------
TMLE 2-1. (Continued)
Exposure
Frequency/
LOftEl (Effect)
Figure
Key
Species Route Duration Effect (ag/kg/day)
HOAEL
Less Serious Serious
(¦g/ks/day) (wg/kg/day>
Reference
Cheaical
Species
Exposure/Frequency/Duration: d=day or dose; wfc=ueek; Gd=gestation day; a»=«onth; hr=hour; yr=year; Gd-lac=gestation through lactation;
gen=generations; F2gert=second generation
Effect: Gastro=gastrointestinal; Hemato=he«atotogical; Other=other changes.
LOAEL(Effects): alt=laterations; inc=increase; 5-HIAA=5-hydroxy indoIacetic acid; dec=decrease; recept=receptors; wt=weight;
resorp=resorptions; fet=fetal, fetus; iMpl=iaplants; 0,H Ab=0,H antibodies; cet=cell; Ab=antibody;
uter=uterine; conv=convulsions; premt pub=prenature puberty.
-------
ACUTE
(< 14 Days)
(mg/kg/day) ^
1,000
/ /
o> /
t
0.1
0.01
0.001
0.0001
n*»1
Key
r
Ftat
¦
LOW
m
UmlMilawMtot
m
Mqum
•
LCMELfaraariouaaMi
icm (antnah) J ^
w» o#>ar «ian eanoar
h
Mb*
Gu*n— Hp
fcin i^i ii i
MOawMy
<3
LCMELtatlmmtou
• aftacM (anbnala)
g
NOAEL (animafc)
vy
k
O
~
UQAEL tor aarioua alfc
Bet (human*)
A
LOAEL tor Im aariou
artact (humaro)
T
DOT
A
NOAEL (human*)
E
006
~
CEL-Canear Elhcl L
Ml
D
DOO
Tha imiitxoMllBMdipotH conaapond« t» *«riai In TaM» 2-1.
X
®
to
l-»
ft N3
3* O
M
H)
Hj
©
o
rt
ia
FIGURE 2'1. Levels of Significant Exposure to DDT, DDE, or DDD - Oral
-------
INTERMEDIATE
(15-364 Days)
(mg/kg/day)
1,000 r-
100 -
10 -
1 -
0.1 -
0.01 -
0.001 -
0.0001 -
//
»23r.
OfNj
®»»T
Oa»T
0»T
0**T
~ *»T
•20r,
Oa»T
T
T
1fT
t
DC
(t>
03
M
rt ho
^ i—1
Pd
Hh
n>
o
rt
w
K*v
r
Rat
¦
LDS0
Mnbnal dik iwH lor
m
Mrnf
•
UOAEL lor aarioua aflaefe |«Mi)
1 aflat* nm
t»
AabM
9
UOAEL lor tarn m*mm aMa (mMi)
•
fc
Mqriwy
o
NO*EL(M*nab)
W
~
LOAEL lor whom aMad (humana)
A
LOAEL tor Ims wrtowi aflac* (twmana)
T
DOT
A
NOAEL (humana)
E
006
~
CEL-CmwONtlj^
D
000
Tha murfcar mil to aach potm uirf—pond< to #na
1
s
1
FIGURE 2-1 (Continued)
-------
CHRONIC
(> 365 Days)
(mg/kg/day)
1,000 r
a?
£
O*
~
/
~
100
O'o
— O43"" 0
O«r0
O43mo
O41'0
043mD
041r
O43m0
R»e
0«»Y T
R»e
o«*9 t
8»
042mT
10
0.1
0.01
I4M,
O«'0
0*3mD
O3* i
0*«T
O^S. T
0»T
04*t '
342mT
>3<*t E
0*1r0
Q43mQ
R»e
o
-------
CHRONIC
(> 365 Days)
(mg/kQ/day)
100 r-'
10
/
/
J*
/
/
0.1
0.01
0.001
0.0001
0.00001
0.000001
0.0000001
0«"T
9«tr
•FT
T W51rT
5»,
OswQfO5;'
~«'o
~s#m04«2n.T
~«5«E a
£6un t W j#,t
T
~63m T
10"*
10~5 -J
10"6 -J
10"7 -J
Estimated Human
Cancer Risk Levels
X
CD
&>
t-1
rt
nr
w
fD
O
rt
t/i
Ktv
t
Am
¦
LOGO
m
Moum
+
LOAEL ler ewtoue (**1*1^
h
FUM
3
LOA£L Ipr t— wrtcnw tWcii Crtniato)
9
QuinM Pl0
Mmfcay
O
NOAEL{v*i»Ib)
ti
A
LOAEL tor — iIoub iMa (iwrnwa)
A
LOAEL lor {human*)
T
DOT
A
NOAHL (human*)
E
OOG
~
CEl-C*wr Efbct tjwat
0
OOO
rwirtMr nan to a*eh point eoriMpond* Id «rtf
FIGURE 2-1 (Continued)
-------
24
2. Health Effects
exposed to DDD. This range was based on numerous studies. Tomatis et
al. (1974a) reported an LD50 in mice following a single oral dose
ranging from 1466 to 1507 mg DDD/kg.
DDE mortality studies also have been conducted. Death occurred in
mice following single oral doses ranging from 810 to 846 mg DDE/kg
(Tomatis et al. 1974a).
The LD50 dose of 113 mg/kg as reported by Gaines (1969) was
converted to an equivalent dose in food of 2260 ppm as presented in
Table 1-4 under short-term exposure.
2.2.2.2 Systemic Effects
No studies were located regarding musculoskeletal or dermal/ocular
effects in humans or experimental animals following oral exposure to
DDT, DDE, or DDD.
Respiratory Effects. No studies were located regarding respiratory
effects in humans following oral exposure to DDT, DDE, or DDD. Rats fed
a diet containing 10 mg DDT/kg body weight/day for 27 months did not
develop adverse respiratory effects with the exception of squamous
bronchial metaplasia in one animal (Deichmann et al. 1967). In the
chronic bioassay conducted by NCI (1978) no adverse effects on the
organs in the respiratory system were observed in male or female mice
and rats treated with either DDT, DDE, or DDD.
Cardiovascular Effects. Cardiovascular performance was one of the
parameters evaluated in human volunteers by Hayes et al. (1956). In
this study, Hayes et al. (1956) exposed volunteers to 3.5 or 35 mg
DDT/man/day, resulting in administered doses of 0.038 to 0.063 or 0.36
to 0.61 mg/kg/day for 12 to 18 months. The background concentration
measured in the food of both controls and test subjects was 0.0021 to
0.0038 mg DDT/kg/day. Although some variation among individuals in
heart rate (resting and with exercise), systolic blood pressure, and
pulse pressure was noted, these variations did not correlate with
increasing dosage of DDT or with duration of exposure. The authors
concluded that DDT at these doses did not result in adverse cardiac
effects. However, following accidental ingestion of 286 to 1716 mg DDT
in food, which corresponds to ^.1 to 24.5 rag/kg body weight, tachycardia
(increased heart rate) was reported in humans (Hsieh 1954). It is not
known if the tachycardia was a direct result of damage to the heart, or
resulted from a neurologically-mediated mechanism.
The cardiovascular system was one of the organ systems evaluated in
the NCI (1978) bioassay. No adverse effects on the organs in the
cardiovascular system were observed £n ma^e OJ: feijiaie mice and rats
treated with either DDT, DDE, or DDD.
-------
25
2. Health Effects
Gastrointestinal Effects. No studies were located regarding the
gastrointestinal effects in humans following oral exposure to DDT, DDE,
or DDD. In rats no adverse effects on the gastrointestinal system were
reported following acute exposure to 40 mg/kg/day by gavage for 12 days
(de Waziers and Azais 1987). No adverse effects were reported in a
chronic bioassay conducted by NCI (1978) in which male and female mice
and rats were maintained on diets containing either DDT, DDE, or DDD for
78 weeks.
Hematological Effects. Hayes et al. (1956) exposed volunteers to
3.5 or 35 nig DDT/man/day, resulting in administered doses of 0.038 to
0.063 or 0.36 to 0.61 mg DDT/kg/day for 12 to 18 months. The background
concentration measured in food of both controls and test subjects was
0.0021 to 0.0038 mg DDT/kg/day. Although some variation among
individuals in hemoglobin levels, red and white blood cell count, and
percentage of polymorphonuclear leukocytes was noted, these variations
did not correlate with increased dosage of DDT or with duration of
exposure.
No adverse hematological effects were observed in male or female
mice and rats treated with either DDT, DDE, or DDD for 78 weeks (NCI
1978). In addition, squirrel monkeys exposed orally to doses of 0.05 to
50 mg DDT/kg body weight/day for up to six months exhibited no
hematological changes; however, all monkeys in the highest dose group
(six animals) died by week 14 (Cranmer et al. 1972a).
Hepatic Effects. Hayes et al. (1956) exposed volunteers to 3.5 or
35 mg DDT/man/day, resulting in administered doses of 0.038 to 0.063, or
0.36 to 0.61 mg/kg/day DDT for 12 to 18 months. The background
concentration measured in food of both controls and test subjects was
0.0021 to 0.0038 mg DDT/kg/day. No signs of illness or adverse hepatic
effects were reported that were considered to be related to DDT exposure
to humans.
There is evidence of mild to severe hepatic effects in experimental
animals as a result of acute, subchronic, or chronic oral administration
of DDT. In addition, DDT has been demonstrated to be an inducer of
microsomal mixed function enzymes of the liver by its ability to promote
the biotransformation of various chemicals (Pasha 1981; Street and
Chadwick 1967).
In experimental animals the liver appears to be one of the primary
targets of DDT toxicity. Acute oral exposure to DDT is associated with
a number of effects in experimental animals including increased liver
weights, increased serum levels of liver enzymes, such as GST and SGPT,
and changes in the appearance of the liver. These effects were observed
in rats following oral doses of 40 mg DDT/kg body weight/day for 12 days
(de Waziers and Azais 1987) or a single dose of 200 mg DDT/kg body
weight/day (Garcia and Mourelle 1984). Mice administered 26 mg
-------
26
2. Health Effects
DDT/kg/day for 1 week (Pasha 1981) and rhesus monkeys exposed to one
oral dose of 150 mg DDT/kg (Agarwal et al. 1978) had increased
microsomal enzyme activity and alterations in levels of other liver
enzymes.
Hepatic cell hypertrophy, histopathologic alterations
(proliferation of the smooth endoplasmic reticulum and concentric
membrane arrays), or increased microsomal enzyme activity are associated
with exposure (15 days to <1 year) of rats to DDT. These effects were
observed in rats following 3 to 6 months of exposure at doses ranging
from 0.25 to 20 mg DDT/kg/day (Hart and Fouts 1965; Laug et al. 1950;
Ortega et al. 1956). In general, as doses increased, hepatic effects in
rats became more severe. Rats exposed continuously to 3.75 mg DDT/kg
body weight/day in the diet for 36 weeks exhibited spotty cellular
necrosis with moderate hepatocyte regeneration (Jonsson et al. 1981).
In contrast, rats exposed to 17.0 mg DDT/kg/day for 33 to 60 weeks
exhibited no histopathologic alterations compared to untreated controls
(Cameron and Cheng 1951). Squirrel monkeys and mice had increased
hepatic enzymes or liver weights following short-term exposure to DDT.
These effects were observed following doses of 1.67 or 8.33 mg
DDT/kg/day for 28 days in mice (Lundberg 1974; Orberg and Lundberg 1974)
and 5 mg DDT/kg/day for up to 6 months in squirrel monkeys (Cranmer et
al. 1972a).
Hepatic effects ranging from increased liver weights to cellular
necrosis have been reported in experimental animals following chronic
exposure to DDT in the diet. Necrosis, centrilobular hypertrophy, and
hyperplasia also have been reported in rats exposed to 10 to 40 mg
DDT/kg/day for 24 to 27 months (Deichmann et al. 1967; Fitzhugh 1948;
Fitzhugh and Nelson 1947). In mice an increased incidence of amyloid in
the liver was reported following 78 weeks of treatment at doses ranging
from 2.86 to 23 mg/kg/day (NCI 1978). Increased liver weights,
increased enzyme activity, and decreased lifespan have been reported in
hamsters following exposure to 20 to 80 mg DDT/kg/day for life (Graillot
et al. 1975). Cabral et al. (1982a) and Rossi et al. (1983) reported a
significant increase in liver necrosis in hamsters exposed to
approximately 40 mg DDT/kg/day in the diet for life, but not at lower
doses. Liver damage was observed in dogs exposed to 80 mg DDT/kg/day
for 39 to 40 months (Lehman 1965). No observed hepatic effects were
reported in rats given up to 32 mg/kg/day for 78 weeks (NCI 1978) or in
rhesus monkeys given up to 8.0 mg DDT/kg body weight/day for 3.5 to 7.5
years (Durham et al. 1963).
Limited information exists on hepatic effects following oral
exposure of experimental animals to DDD or DDE. Mice exposed orally to
26 mg DDD/kg body weight/day in the diet for 1 week exhibited a decrease
in hydroxylation of 2- and 4-biphenyls, but no change in liver weight
(Pasha 1981). However, in the chronic bioassay conducted by NCI (1978),
-------
27
2. Health Effects
no adverse liver effects were reported in mice or rats exposed to DDD
for 78 weeks.
Rats exposed to 2 gavage doses of 350 mg DDE/kg/day exhibited an
increase in enzyme levels (ornithine decarboxylase and cytochrome P-450)
(Kitchin and Brown 1988), while chronic exposure (78 weeks) resulted in
liver necrosis at a dose of 12 mg/kg/day (NCI 1978). Mice exposed to 26
mg DDE/kg body weight/day in the diet for 1 week exhibited increases in
mean liver weights, total protein, and enzyme levels (Pasha 1981).
However, no adverse liver effects were observed in mice chronically
exposed to DDE in the diet at 34 mg/kg/day for 78 weeks (NCI 1978).
Chronic exposure to 40 to 80 mg DDE/kg/day resulted in necrosis of the
liver in hamsters (Cabral et al. 1982b; Rossi et al. 1983).
The highest NOAEL values and all reliable LOAEL values for hepatic
effects in each species and duration category are recorded in Table 2-1
and Figure 2-1. The dose of 26 mg/kg/day from the study by Pasha (1981)
was converted to 200 ppm in food and presented in Table 1-4 under short-
term exposure. In addition, the value of 3.75 mg DDT/kg/day as reported
by Jonsson et al. (1981) was converted to an equivalent value in food of
75 ppm as presented in Table 1-4 under long-term exposure.
Renal Effects. No studies were located regarding renal effects in
humans following oral exposure to DDT, DDE, or DDD. Rats exposed orally
to 10 mg DDT/kg/day for 27 months had tubular polycystic degeneration,
necrosis, and hemorrhaging of the kidney (Deichmann et al. 1967). No
renal effects were observed in male and female mice and rats exposed to
either DDT, DDE, or DDD for 78 weeks (NCI 1978) or in hamsters exposed
to 20 to 80 mg DDE/kg/day for 124 weeks (Rossi et al. 1983).
The dose of 10 mg/kg/day as reported in the Deichmann et al. (1967)
study was converted to 200 ppm in food and presented in Table 1-4 under
long-term exposure.
Other Systemic Effects. The adrenal glands of dogs given 1 to 15
oral doses of DDD ranging from 100 to 200 mg/kg/day had degeneration of
both the zona fasciculata and reticularis (Kirk et al. 1974; Powers et
al, 1974). In one animal there was hemorrhaging, invasion by
lymphocytes, and necrosis of the adrenal cortex (Kirk et al. 1974).
2.2.2.3 Immunological Effects
In a study in which humans were challenged with an injection of
Salmonella tvohimurium. serum antibody levels were higher in three
volunteers given 5 mg DDT (.07 mg/kg) daily for 20 days when compared to
volunteers who received only the bacterial antigen (Shiplov et al.
1972). The volunteers exhibited no other apparent symptoms of DDT
toxicity.
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28
2. Health Effects
Evidence of DDT-induced compromises in immune function has been
obtained from studies conducted in experimental animals. The effects of
DDT on the humoral immune response were studied in mice (Banerjee 1987a;
Banerjee et al. 1986), in rats (Banerjee 1987b; Gabliks et al. 1975) and
in rabbits (Shiplov et al. 1972). Following oral doses of 13 mg
DDT/kg/day for 3 to 12 weeks, mice had decreases in antibody titres,
plaque forming cells, and other immunological responses (Banerjee et al.
1986; Banerjee 1987a). Following exposure to DDT in the diet for 31
days, rats exhibited decreases in mast cells, induced anaphylaxis, and
diphtheria antitoxin titres at doses of 1 mg DDT/kg/day following
administration of diphtheria toxoid (Gabliks et al. 1975). There was no
evidence that DDT adversely affected the humoral response in rabbits;
however, only one dose, 2.63 mg/kg/day, was given (Shiplov et al. 1972).
Rabbits administered an oral dose of 0.18 mg DDT/kg body weight/day in
the diet for 8 weeks exhibited an increase in gamma globulin levels and
atrophy of the thymus (Street and Sharma 1975). In a chronic study,
exposure to DDT at 10 mg/kg/day for 27 months resulted in alterations in
the spleen, which consisted of congestion and hemolysis, that exceeded
that of untreated control rats (Deichmann et al. 1967). Rats exposed to
doses of 121 mg o,p'-DDD/kg body weight/day for 16 days developed plaque
forming cells and rosette forming cells in the spleen and thymus and
atrophy of the thymus and adrenal gland (Hamid et al. 1974). No studies
were located regarding immunological effects in humans or experimental
animals following oral exposure to DDE.
The highest NOAEL values and all reliable LOAEL values for
immunological effects in each species and duration category are recorded
in Table 2-1 and Figure 2-1. In addition, the dose of 0.18 mg
DDT/kg/day as reported in Street and Sharma (1975) was converted to an
equivalent dose in food of 3.67 ppm as presented in Table 1-4 under
long-term exposure.
2.2.2.4 Neurological Effects
The nervous system appears to be one of the primary target systems
for DDT toxicity in humans following acute, high doses and in
experimental animals following acute, subchronic and chronic oral
exposure to DDT. Persons exposed to 6 mg DDT/kg generally exhibit no
illness, but perspiration, headache, and nausea have been reported
(Hayes 1982). Vomiting, which is reported to be of central origin and
not due to gastrointestinal irritation, is reported in humans at doses
of 10 mg DDT/kg (Hayes 1982). Convulsions in humans are reported to
appear at doses of 16 mg DDT/kg or higher (Hsieh 1954). Velbinger
(1947a, 1947b) exposed human volunteers to oral doses of 250, 500, 750,
1000, or 1500 mg DDT (up to 22 mg/kg) suspended in an oil solution.
Variable sensitivity of the mouth (defined by the author as a prickle at
the tip of the tongue, lower lip, and chin area) was reported in
volunteers exposed to 250 and 500 mg DDT per person. Six hours
following exposure to 750 or 1000 mg DDT, disturbance of sensitivity of
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29
2. Health Effects
the lower part of face, uncertain gait, malaise, cold moist skin, and
hypersensitivity to contact were observed. Prickling of the tongue and
around the mouth and nose, disturbance of equilibrium, dizziness,
confusion, tremors, malaise, headache, fatigue, and severe vomiting were
all observed in volunteers within 10 hours following oral exposure to
1500 mg DDT. All volunteers exposed to DDT orally had achieved almost
complete recovery within 24 hours following exposure. Similar symptoms
were reported in persons following accidental or intentional ingestion
of DDT (Francone et al. 1952; Garrett 1947; Hsieh 1954; Mulhens 1946;
Naevested 1947).
Acute oral exposure to high doses of DDT has been associated with
DDT-induced tremors or myoclonus (abrupt, involuntary contractions of
skeletal muscles), hyperexcitability, and convulsions in several
species. Acute oral exposure of experimental animals to DDT is
associated with increases in brain biogenic amine and neurotransmitter
levels, as well as myoclonus. These effects have been observed in rats
following single doses of 75 to 600 mg DDT/kg/day (Herr and Tilson 1987;
Hong et al. 1986; Hwang and Woert 1978). However, mice receiving single
doses of 200 to 600 mg p,pDDT/kg/day had convulsions, but the levels
of neurotransmitters were decreased (Matin et al. 1981). Hong et al.
(1986) reported that alterations in the enzyme 5-HIAA (5-hydroxy-
indoleacetic acid) correlated with DDT-induced tremors and that doses at
50 mg/kg/day or greater resulted in increases in the levels of 5-HIAA in
the brain. Pratt et al. (1986) reported no neurological effects in rats
following oral exposure to a single dose of 50 mg DDT/kg body
weight/day, but doses from 100 mg/kg and up produced dose-dependent
tremor or myoclonus. A single low dose of DDT (0.5 mg/kg/day)
administered orally lowers the binding affinity of muscarinic
cholinergic receptors in mice (Eriksson and Nordberg 1986).
Intermediate and acute exposure to DDT affects total brain lipids
and the relative brain lipid ratios in nonhuman primates. Rhesus
monkeys exhibited a decrease in total brain lipids and the relative
amount of cholesterol to phospholipid following oral exposure to 10 mg
DDT/kg/day for 100 days or a single oral dose of 150 mg/kg/day (Sanyal
et al. 1986).
Chronic exposure of experimental animals to DDT is associated with
tremors and general hyperirritability. Rats exposed orally to doses of
10.5 or 25 mg DDT/kg/day for 78 weeks or life, respectively, exhibited
tremors (NCI 1978; Rossi et al. 1977). Even following a change of diet
or a decrease in dose, the tremors persisted for several weeks. The
persistence of tremors might be attributed to the slow release of stored
tissue levels of DDT. No clinical signs of neurotoxicity were observed
in hamsters given doses up to 41.5 mg/kg/day for life (Cabral et al.
1987a).
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30
2. Health Effects
The highest NOAEL values and all reliable LOAEL values for
neurological effects in each species and duration category are recorded
in Table 2-1 and Figure 2-1. Based on the study by Eriksson and
Nordberg (1986), an acute oral MRL of 5xl0"4 mg/kg/day was calculated,
as described in the footnote in Table 2-2. This MRL considers
neurological effects as the most sensitive end point. This effect is
also seen in intermediate and chronic studies as well. This MRL has
been converted to an equivalent concentration in food (0.0178 ppm) for
presentation in Table 1-3. In addition, the dose of 100 mg/kg/day,
reported to cause myoclonus in rats (Hwang and Woert 1978) , was
converted to an equivalent dose in food of 2000 ppm as presented in
Table 1-4 under short-term exposure. The dose of 10.5 mg DDT/kg/day as
reported by NCI (1978) was converted to an equivalent dose in food of
210 ppm as presented in Table 1-4 under long-term exposure.
2.2.2.5 Developmental Effects
No studies were located regarding developmental effects in humans
following oral exposure to DDT, DDE, or DDD. However, there is evidence
for DDT-induced developmental effects in experimental animals. DDT
produces embryotoxicity and fetotoxicity, but not teratogenicity in
experimental animals.
Developmental effects have been observed in experimental animals
after acute oral exposure to DDT, DDE, or DDD during gestation. Fabro
et al. (1984) reported a decrease in fetal body weights and fetal brain
and kidney weights in the offspring of pregnant rabbits exposed to 1 mg
DDT/kg body weight/day on gestation days 4 through 7. Hart et al.
(1971, 1972) orally exposed rabbit dams on days 7 to 9 of gestation to
10 to 50 mg DDT/kg body weight/day and found an increase in resorptions,
an increase in the incidence of prematurity, a decrease in the length of
gestation, and a decrease in fetal size. Gellert and Heinrichs (1975)
exposed pregnant rats orally to 28 mg DDT, DDE, or DDD/kg body
weight/day on days 15 to 19 of gestation. A significant decrease in
ovary weights was observed in the offspring of the DDT exposed rats.
Exposure to DDD resulted in a delay in vaginal opening, alterations in
adrenal weights, and loss of corpora lutea in the offspring of exposed
rats. No significant developmental effects, other than an increase in
the body weights of neonates, were observed following exposure to DDE.
Intermediate oral exposure to DDT in experimental animals has been
shown to produce developmental effects such as infertility, mortality,
and slow development. Clement and Okey (1974) exposed pregnant rats
during gestation and lactation to 1, 10, or 50 mg o,p'-DDT/kg body
weight/day. Two of the four female offspring of dams treated with 50
mg/kg/day were unable to reproduce when mated to untreated males; the
ovaries of the two sterile offspring contained cystic structures.
Clement and Okey (1974) also exposed groups of pregnant rats to 1, 10,
or 25 mg p,p'-DDT/kg body weight/day during gestation and lactation. An
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31
2. Health Effects
increase in mortality of pups exposed, perinatally via dams receiving 25
mg p,pDDT/kg/day was reported, along with a decrease in growth of the
pups after exposure via nursing from dams receiving 10 or 25 mg p,p'-
DDT/kg/day. Craig and Ogilvie (1974) exposed pregnant mice during
gestation and lactation to 26 mg DDT/kg body weight/day. Preweaning
mortality was observed in 10% of the neonates exposed to DDT prenatally
and nursed on unexposed or "foster" mothers, while 39% of the neonates
exposed perinatally (during gestation and through lactation) died before
weaning. In addition, mice exposed perinatally also showed learning
impairment and decreased memory function in the maze test. Naishtein
and Leibovich (1971) reported slower physical development of neonates
whose mothers were fed 0.02 mg DDT/kg body weight/day during mating.
Developmental effects, including preweaning mortality and premature
puberty, were reported in experimental animals following chronic
exposure to DDT. Turusov et al. (1973) and Tomatis et al. (1972) both
reported an increase in preweaning mortality in the offspring of mice
chronically exposed to 32.5 mg DDT/kg body weight/day. Del Pup et al.
(1978) found a decrease in 30-day survival of neonates after exposing
dams to 13 mg DDT/kg body weight/day in the diet for 70 weeks. However,
Treon et al. (1954) conducted a multigeneration study in which rats were
nursed by dams fed 0.125 to 1.24 mg DDT/kg body weight/day. Changes in
preweaning mortality were reported, but were not considered to be dose-
related. Other developmental aspects evaluated were negative. No
conclusions concerning the developmental effects of DDT could be drawn
from Treon's study.
In a multigeneration study, Ottoboni et al. (1977) reported an
increase in the incidence of premature puberty that increased with dose
and with each consecutive generation among female dogs (4 to 19 dogs per
group) dosed with 1, 5, or 10 mg DDT/kg body weight/day. However, the
Increase was only significant in the two high dose groups when all
generations were combined. A significant increase in constricting rings
of the tail was seen in the offspring of rats fed 10 mg DDT/kg body
weight/day through two generations (Ottoboni 1969).
The highest NOAEL values and all reliable L0AEL values for
developmental effects in each species and duration category are recorded
in Table 2-1 and Figure 2-1, The dose of 1 mg DDT/kg/day as reported by
Fabro et al. (1984) was converted to an equivalent dose in food of 20
ppm and is presented in Table 1-4 under Short-term Exposure. The dose
of 10 mg DDT/kg/day as reported in the study by Hart et al. (1972) was
converted to an equivalent dose in food of 510 ppm and presented in
Table 1-4 under short-term exposure.
2.2.2.6 Reproductive Effects
No studies were located regarding reproductive effects in humans
following oral exposure to DDT, DDE, or DDD, or in experimental animals
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32
2. Health Effects
following oral exposure to DDD or DDE. Evidence in experimental animals
indicates that oral exposure to DDT can result in reproductive toxicity,
the extent and severity of which is based on the administered dose.
Acute exposure to DDT by the oral route has been associated with
reproductive effects in experimental animals which include reduced
fertility. A decrease in male fertility, as demonstrated by adverse
effects on spermatogenesis and decreased testicular weight, was reported
in male rats after exposure to 500 mg DDT/kg/day on days 4 and 5 of
life, then 200 mg DDT/kg/day daily from days 4 to 23 (Krause et al.
1975). Also, an increase in the proportion of untreated females with
one or more dead implants after mating with males exposed to 100 mg
DDT/kg body weight was reported (Palmer et al. 1973). Estrogenic
effects, including increases in uterine wet and dry weights and glycogen
content, were reported by Clement and Okey (1972) in immature rats
exposed to 50 mg DDT/kg body weight for 7 days.
DDT exposures of intermediate duration (15 days to 1 year) produced
several adverse reproductive effects. Effects which were seen include
infertility and a decrease in the frequency of implanted ova and
decreases in ovary and testes weight. A decrease in fertility was seen
in female rats after exposure to 0.35 to 7.5 mg DDT/kg body weight/day
(Green 1969; Jonsson et al. 1976). Green (1969) also reported an
increase in the number of resorptions and that no litters were produced
by second generation animals in a multigeneration study. Although not
significant, an increase in the length of gestation and a decrease in
the number of fetuses was reported by Naishtein and Leibovich (1971)
after exposing mongrel rats to 0.02 mg DDT/kg for 4 months. Duby et al.
(1971) reported a decrease of uterine weights in 14-day, post-
ovariectomized rats exposed to 0.75 mg DDT/kg body weight for 175 days.
Similar effects on fertility were reported in mice after 50 days or
multigenerational exposure to 13 to 39 mg DDT/kg body weight/day
(Bernard and Gaertner 1964; Cannon and Holcomb 1968; Keplinger et al.
1970) . Other effects seen in mice include a significant decrease in the
number of litters per surviving pair of mice exposed to 0.91 mg DDT/kg
body weight/day in the diet for 90 days (Ware and Good 1967). Further
adverse effects, including an increase in the length of estrus and a
decrease in the frequency of implanted ova, were seen after exposing
female mice to 1.67 mg DDT/kg body weight/day (Lundburg 1973). However,
Craig and Ogilvie (1974) and Orberg and Lundburg (1974) reported no
adverse effects on reproduction in mice after exposure to 8.33 to 26.0
mg DDT/kg body weight/day during gestation, lactation, or both.
Developmental effects reported in the study by Craig and Ogilvie (1974)
were discussed in the previous section.
Reproductive effects of DDT were reported following chronic
exposure or exposure for multigenerations. Stillbirths, increased
maternal and fetal mortality, delayed estrus, a reduction in male
libido, and a lack of mammary gland development were observed in dogs
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33
2. Health Effects
following chronic exposure to 12 mg DDT/kg body weight/day for 14 months
(Deichmann et al. 1971). Increases in abortions, stillbirths, and pup
mortality were reported in mice exposed to 1.3 to 6.5 mg DDT/kg body
weight/day in a multigeneration study; however, most of the females in
the 6.5 mg/kg group died before delivery (Shabad et al. 1973). No
adverse effects on reproduction after 15 months exposure were reported
by Wolfe et al. (1979) after exposing field mice to levels up to 2.4 mg
DDT/kg body weight or by Treon et al, (1954), Ottoboni (1969), Duby et
al. (1971) after multigenerational exposing rats to 1.24, 10, or 0.75 mg
DDT/kg body weight/day, respectively.
The highest NOAEL values and all reliable LOAEL values for
reproductive effects in each species and duration category are recorded
in Table 2-1 and Figure 2-1. Based on the value of 0.35 mg DDT/kg/day
from the Green (1969) study, an intermediate oral MRL of 4x10"''
mg/kg/day was calculated as described in the footnote in Table 2-2.
This MRL considers reproduction as the most sensitive end point.
Although the immunological end points are lower, their significance to
the adverse health effects seen are not known. The chronic exposure
data are also supportive of this selection, showing developmental as
well as reproductive health effects. This MRL has been converted to an
equivalent concentration in food (0.0125 ppm) for presentation in
Table 1-3.
2.2.2.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans
following oral exposure to DDT, DDE, or DDD. In animals, the mutagenic
activity of DDT and its metabolites is relatively weak. The results
depend upon the dose, route of administration, and species sensitivity.
In the dominant lethal assay, DDT administered orally to male mice
at 150 mg/kg/day for 2 days (acute), or 100 mg DDT/kg twice weekly for
10 weeks (intermediate) (the final dose given 24 hours before sequential
mating began) produced significant increases in the number of dead
implants per female (Clark 1974). Acute doses resulted in maximum
sensitivity in the induction of dominant lethal effects in week 5 and
chronic doses in week 2, with continued increases above control through
week 6. Chronic, but not acute, dosing caused significant reductions in
testes weight, sperm viability, and a reduction of cell numbers in all
stages of spermatogenesis. Acute treatment produced a significantly
increased frequency of chromosome breakage, univalents, and stickiness
in spermatocytes.
Rats treated orally (by gavage) with DDT in single doses of 50 to
100 mg/kg or daily doses of 20 to 80 mg/kg/day for 5 days did not show a
dose-related increase in percent of chromosomal aberrations over the
solvent control (Legator et al. 1973). DDE when administered in a
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34
2. Health Effects
single dose to male mice orally at the rate of 50 mg/kg, did not induce
inhibition of testicular DNA synthesis (Seiler 1977).
2.2.2.8 Cancer
No case studies or epidemiological investigations concerning the
carcinogenic effects of DDT, DDE, or DDD in humans following oral
exposure were located in the reviewed literature. Epidemiological
studies following occupational exposure are discussed in Section 2.3,
Relevance to Public Health.
DDT is one of the most widely studied pesticides in animals; and
data are available on a number of carcinogenicity studies in several
species. Intermediate exposures (15 days to 1 year), in which
experimental animals were exposed to DDT in food, reportedly caused
increases in cancer in mice, but not in rats or hamsters. Mice
developed liver hepatomas following exposure to 32.5 mg DDT/kg/day for
15 to 30 weeks and observed for 50 to 105 weeks following cessation of
treatment (Tomatis et al. 1974b). DDT did not produce increases in the
tumor incidence in rats exposed to 2.5 to 20 mg/kg/day for up to 45
weeks (Kimbrough et al. 1964; Laug et al. 1950; Numoto et al. 1985), or
in hamsters fed 40 mg DDT/kg/day for 30 weeks (Tanaka et al. 1987).
Chronic exposure (>1 year) to DDT causes cancer in several strains
of mice but not in dogs or nonhuman primates. Some evidence exists to
indicate that DDT may be carcinogenic in the rat and hamster. Chronic
exposure to DDT produced liver neoplasms in several strains of mice fed
DDT at doses as low as 0.26 mg DDT/kg/day or for a minimum of 78 weeks
(Innes et al. 1969; Kashyap et al. 1977; Terracini et al. 1973; Thorpe
and Walker 1973; Tomatis et al. 1972; Turusov et al. 1973; Walker et al.
1972). An increased incidence of pulmonary adenomas was observed in
mice following chronic oral administration of DDT either in the diet
(Kashyap et al. 1977) or by gavage (Kashyap et al. 1977; Shabad et al.
1973). Malignant lymphomas were observed also in mice treated orally
with DDT (Kashyap et al. 1977).
Rats maintained on diets containing DDT for more than 2 years or at
doses higher than 25 mg DDT/kg/day developed liver tumors, primarily in
female rats (Cabral et al. 1982b; Fitzhugh and Nelson 1947; Rossi et al.
1977). Liver tumors occurred in rats at a dose as low as 6.25 mg
DDT/kg/day for 2 years (Rossi et al. 1977). Rossi et al. (1983)
reported increases in adrenal gland tumors in hamsters exposed to 83 mg
DDT/kg/day.
Unlike the positive results found in mice, rats, and hamsters,
several other studies have shown no significant increase in tumor
formation following chronic DDT exposure. No significant increases in
tumor incidence were observed ln mice administered DDT at doses of 3 to
23 mg/kg/day (Del Pup et al- 1978; NCI 1978). DDT was not carcinogenic
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35
2. Health Effects
in rats when administered for up to 27 months or at doses less than 25
mg/kg/day (Cameron and Cheng 1951; Deichmann et al. 1967; NCI 1978;
Radomski et al. 1965; Shivapurkar et al. 1986; Treon and Cleveland
1955). Long-term exposure failed to induce significant increases in
tumors in the hamster at doses up to 83 mg/kg/day for up to 18 months
(Agthe et al. 1970; Cabral et al. 1982a; Graillot et al. 1975); in the
monkey at doses of 8 to 20 mg/kg/day for up to 5 years (Adamson and
Sieber 1979, 1983; Durham et al. 1963); or in the dog at 80 mg/kg/day
for 49 months (Lehman 1965).
Several multigenerational studies have been conducted in mice. In
these studies exposure of the Fx and subsequent generations to DDT was
initially perinatal, followed, post-weaning, by oral exposure to DDT in
the diet. In a study by Tarjan and Kemeny (1969) significant increases
in leukemia and pulmonary carcinomas occurred first in the F3 generation
and occurred with increasing frequency with each subsequent generation
of mice. Liver tumors (Tomatis et al. 1972; Turusov et al. 1973) and
pulmonary tumors (Shabad et al. 1973) in the Fj^ generation had a shorter
latency period than in the parental generation, but the tumor incidence
was comparable and did not increase with consecutive generations.
However, in the study by Terracini et al. (1973) pulmonary adenomas were
significantly increased in the Fx generation, but not the parental
generation.
There are several studies of the potential carcinogenicity of DDE
and DDD in rats, mice, and hamsters. DDE administered chronically in
the diet produced liver tumors in mice at doses of 19 to 34 mg/kg/day
for 30 to 78 weeks (NCI 1978; Tomatis et al. 1974a) and in hamsters
dosed at 40 mg/kg/day for 124 weeks (Rossi et al. 1983). DDE did not
induce significant increases in tumor incidence in rats exposed to DDE
at doses ranging from 12 to 42 mg/kg/day for 78 weeks (NCI 1978). DDD
induced liver tumors and lung adenomas in CF-1 mice (Tomatis et al.
1974a) and thyroid follicular cell tumors in F344 rats (NCI 1978) but
was not tumorigenic in B6C3F! mice (NCI 1978).
EPA (1988a) has estimated an oral potency factor of 3.4xl0_1
(mg/kg/day)"1. This potency factor is derived from the geometric mean
of potency factors based on the incidence of liver tumors in mice and
rats as reported by Cabral et al. (1982b), Rossi et al. (1977),
Terracini et al. (1973), Thorpe and Walker (1973), Tomatis and Turusov
(1975), and Turusov et al. (1973). At this potency factor, the lifetime
average daily dose that would result in risk ranging from lxlO"4 to
lxlO"7 is 2.9x10"'' to 2.9xl0~7 mg/kg/day.
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36
2. Health Effects
2.2.3 Dermal Exposure
2.2.3.1 Death
The dermal LD50 of DDT in rats was reported by Ben-Dyke et al.
(1970), Cameron and Burgess (1945), and Gaines (1969) to be from 2500
to 3000 mg DDT/kg. In guinea pigs, a single dose of 1000 tag DDT/kg
resulted in death of 50% of the animals (Cameron and Burgess 1945). The
LD50 in rabbits was 300 mg DDT/kg (Cameron and Burgess 1945) and 4000 to
5000 mg DDD/kg (Ben-Dyke et al. 1970).
2.2.3.2 Systemic Effects
No studies were located regarding gastrointestinal or
musculoskeletal effects in humans or experimental animals following
dermal exposure to DDT, DDE, or DDD.
All of the information on the systemic and neurological effects of
dermal exposure to DDT in experimental animals is derived from a study
by Cameron and Burgess (1945). In this study rabbits, guinea pigs, and
rats were dermally exposed to various doses of DDT in solvents including
kerosene (1% or 10%), ethyl alcohol, acetone, or ether. It is uncertain
what contribution these solvents made to the toxic effects observed;
the authors stated that kerosene itself may have caused some deaths.
The only information reported on the method of application stated that
the skin area was shaved 24 hours before application of DDT impregnated
on cloth and that precautions were taken to prevent animals from licking
contaminated skin. The duration of exposure was not clearly reported.
In addition, the species and the number of animals exhibiting specific
toxic symptoms was not clearly reported.
Respiratory Effects. No studies were located regarding respiratory
effects in humans following dermal exposure to DDT, DDE, or DDD.
Cameron and Burgess (1945) exposed rats, guinea pigs, and rabbits to
acute dermal doses ranging from 50 to 200 mg DDT/kg and reported
pulmonary edema and respiratory failure.
Cardiovascular Effects. No studies were located regarding
cardiovascular effects in humans following dermal exposure to DDT, DDE,
or DDD. Cameron and Burgess (1945) exposed rats, guinea pigs and
rabbits to acute dermal doses ranging from 50 to 200 mg DDT/kg and
reported fat in the fibers of the heart.
Hematological Effects. No studies were located regarding
hematological effects in humans following dermal exposure to DDT, DDE,
or DDD. Cameron and Burgess (1945) exposed rats, guinea pigs, and
rabbits to acute dermal doses ranging from 50 to 200 mg DDT/kg. A
decrease in hemoglobin and leukocytosis was reported.
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37
2. Health Effects
Hepatic Effects. No studies were located regarding hepatic effects
in humans following dermal exposure to DDT, DDE, or DDD. Cameron and
Burgess (1945) exposed rats, rabbits, and guinea pigs to acute dermal
doses of 10, 50, or 100 mg DDT/kg and reported fatty degeneration,
calcification, and necrosis in the liver.
Renal Effects. No studies were located regarding renal effects in
humans following dermal exposure to DDT, DDE, or DDD. Cameron and
Burgess (1945) exposed rats, rabbits, and guinea pigs to acute dermal
doses ranging from 50 to 100 mg DDT/kg and reported fat deposits,
tubular changes, calcification, and necrosis of the kidneys.
Dermal/Ocular Effects. Cameron (1945) conducted a series of
experiments on volunteers wearing undergarments impregnated with 1% DDT
in order to determine whether this treatment would protect soldiers
against body lice. Several individuals had brief dermatitis, but no
other symptoms were observed. The length of exposure via this route was
not specified. Cameron and Burgess (1945) exposed rats, rabbits, and
guinea pigs to 10, 50, or 100 mg DDT/kg and reported inflammation,
edema, and destruction of the epidermis. Kar and Dikshith (1970) dosed
guinea pigs 5 days a week for 3 weeks with 322 to 400 mg DDT/kg. A
decrease in skin amino acids, disruption and degeneration of the basal
cell layer, and morphologic changes in the cells were reported.
2.2.3.3 Immunological Effects
No studies were located regarding the immunologic effects in humans
or experimental animals following dermal exposure to DDT, DDE, or DDD.
2.2.3.4 Neurological Effects
No studies were located regarding the neurological effects in
humans following dermal exposure to DDT, DDE, or DDD. Cameron and
Burgess (1945) exposed rats, rabbits, and guinea pigs to acute-dermal
doses ranging from 50 to 200 mg/kg DDT and reported tremors and
nervousness.
No studies were located regarding the following effects in humans
or experimental animals following dermal exposure to DDT, DDE, or DDD:
2.2.3.5 Developmental Effects
2.2.3.6 Reproductive Effects
2.2.3.7 Genotoxlc Effects
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38
2. Health Effects
2.2.3.8 Cancer
No case studies or epidemiological investigations concerning the
carcinogenic effects in humans following dermal exposure to DDT, DDE, or
DDD were located. Occupational studies which probably involved both
dermal and inhalation routes of exposure are discussed in Section 2.3,
Relevance to Public Health.
Dermal exposure (skin painting) of mice to DDT did not result in a
significant increase in tumor incidence when applied in a 5% solution in
kerosene once weekly for 52 weeks (Bennison and Mostofi 1950) or at 8
mg/kg twice weekly for 80 weeks (Kashyap et al. 1977). No information
on dermal exposure of rats or hamsters to DDT or dermal exposure to DDE
or DDD was located.
2.3 RELEVANCE TO PUBLIC HEALTH
DDT is probably one of the best known and most widely studied
pesticides. DDT was used extensively during World War II in control of
lice and other insects by application directly to humans. Numerous
studies have been conducted in a variety of species. The human data are
somewhat more limited. The central nervous system (CNS) is a major
target organ in humans and animals, while the liver is a major target
organ in animals (see Section 2.2).
In experimental animals, liver effects, ranging from increased
enzyme levels to necrosis and tumors, and neurological effects,
including myoclonus, appear to be the primary effects associated with
DDT and DDE exposure. Reproductive effects have also been reported.
Adrenal toxicity, advancing to necrosis, appears to be the primary
effect associated with DDD exposure in animals.
Clinical and Epidemiological Studies. Studies in workers in DDT
manufacturing plants or spray applicators who had occupational exposure
to DDT over an extended period provide information on the possible
adverse effects on human health. Occupational exposure to DDT involved
multiple routes of exposure. The primary contact was probably
inhalation and dermal; however, absorption of DDT from the lungs may not
have been significant, and ingestion due to the mucociliary apparatus of
the upper respiratory tract is most likely. Therefore, occupational
exposures cannot be assigned a single route. In addition, there are no
experimental studies in animals by the inhalation route with which to
compare observed human effects. Some of the CNS effects observed in
animals by the oral route have also been identified in humans exposed
occupationally or through voluntary or accidental ingestion of DDT.
These effects include cold moist skin, hypersensitivity to contact,
tremor, and convulsion.
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39
2. Health Effects
The most extensive of these studies measured organochlorine
pesticide concentrations in blood of 2600 pesticide-exposed individuals
(Morgan and Lin 1978). One thousand controls, with minimal exposure to
pesticides, were recruited and monitored. However, controls were not
matched for age, sex, or race to pesticide-exposed individuals. Various
clinical tests were performed during 1967 to 1973. Extensive
hematologic and biochemical analyses were performed, including
determination of p,p'-DDT and p,p'-DDE levels in blood and adipose
tissue. Although several of the parameters measured correlated
positively with DDT and/or DDE blood levels, the results did not
demonstrate impaired health among pesticide handlers. Positive
correlations were reported between serum DDE and total white blood
count, and between serum DDT and DDE and activity of several enzymes
including alkaline phosphatase, SGOT, SGPT, and LDH. The correlation of
DDT and DDE levels with these indices of liver damage was said to
indicate that liver metabolism is slightly modified by tissue
organochlorine concentrations or by closely related factors.
In a follow-up study, Morgan et al. (1980) analyzed morbidity and
mortality in the same group of pesticide-exposed persons. The follow-up
included 73% of the original cohort. Disease incidence rates were
studied in relation to occupational subclasses and to serum levels of
organochlorine pesticides measured in the original study. There were no
significant differences in mortality patterns between pesticide-exposed
workers and controls except for an excess of deaths by accidental trauma
in workers engaged in pesticide application. When all pesticide-exposed
subjects were considered collectively, incidence of internal cancer and
leukemia was not significantly different from controls. A suggestive
relationship was observed between high serum levels of DDT and DDE and
subsequent development of vascular disease, especially hypertension.
However, exposure to multiple pesticides is a significant confounding
factor in this study.
Wong et al. (1984) conducted an historical prospective mortality
study of 3600 white male workers employed between 1935 and 1976 in
occupations which involved exposures to various brominated compounds,
organic and inorganic bromides, and DDT. Among those individuals
exposed to DDT, overall mortality, expressed as the standard mortality
ratio, was not elevated over expected values. However, there was an
excess of deaths from respiratory cancer. Several factors confound
these results: those individuals exposed to DDT also were potentially
exposed to other chemicals, and smoking history was not included in the
analysis.
Ortelee (1958) performed clinical and laboratory examinations on 40
workers exposed to DDT, some of whom had also been exposed to other
pesticides. Exposure was reported to occur primarily via dermal and
inhalation routes. No protective equipment was used and the workers
were often coated with concentrated DDT dust. Clinical examinations
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40
2. Health Effects
included a complete medical history, physical and neurological
examination, and hematological and blood chemistry analyses. In
addition, plasma and erythrocyte cholinesterase levels were determined
as well as urinary excretion of bis(p-chlorophenyl) acetic acid (DDA).
On the basis of DDA excretion, it was estimated that these workers
received absorbed doses equivalent to oral doses of 14 to 42 mg/man/day
(approximately 0.2 to 0.6 mg/kg/day). Despite this relatively high
exposure, no correlation was found between DDT exposure and the
frequency and distribution of abnormalities, except for a few cases of
minor skin and eye irritation.
Laws et al. (1967) studied 35 workers who had been involved in the
manufacture and formulation of DDT for an average of 15 years.
Extensive medical examinations and blood, urine, and fat analyses were
performed in an attempt to find any correlation between any health
problems and exposure to DDT. The authors concluded that the clinical
findings for this group of men were not significantly different from
those expected in an appropriate control group with no occupational
exposure to DDT. However, this study did not include a control group
and comparisons of data were made by using information derived from the
"general population."
In a follow-up study, Laws et al. (1973) reexamined 31 of the 35
men involved in the original study. These men completed detailed
questionnaires concerning their daily contact with DDT. In addition,
liver function tests and DDT serum sample tests were performed. Despite
the fact that these workers had an average exposure to DDT for 21 years
at levels estimated to correspond to 3.6 to 18 mg daily (0.05 to 0.26
ng/kg/day), the authors found no evidence of hepatotoxicity, hepatic
enlargement, or dysfunction.
Although epidemiological studies of DDT-exposed workers show no
evidence of overt hepatotoxicity, workers often exhibit increased
activity of hepatic microsomal enzymes. Kolmodin et al. (1969) studied
drug metabolism in 26 workers with occupational exposure to several
pesticides; primarily DDT, chlordane and lindane. An appropriate
control was included. Drug metabolism was analyzed by administering
antipyrine in a single dose of 10 to 15 mg/kg after which blood levels
were monitored. Antipyrine was chosen because it is metabolized in the
liver and appreciably not bound to plasma proteins. The half-life of
antipyrine (both mean and median) was shorter in workers exposed to
insecticides than in control subjects. In addition, the range of the
half-life was much smaller in the exposed group. These results indicate
that exposure to these insecticides does induce hepatic enzyme
activities. However, analysis of blood samples of exposed individuals
indicated that exposure to lindane exceeded that to DDT. Therefore, the
relative contribution of DDT to the observed enzyme induction is
unknown.
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41
2. Health Effects
Poland et al. (1970) investigated the effect of high DDT exposure
on phenylbutazone and endogenous Cortisol metabolism in exposed workers.
Both of these compounds are metabolized via hepatic microsomal enzymes.
Nineteen workers with an average of 14 years of employment in a plant
producing only DDT were selected for study and matched controls were
obtained. Both groups were screened for medical history, and given a
physical examination, and venous blood samples were drawn. Following a
single dose of 400 mg phenylbutazone, serum was obtained at regular
intervals beginning at 24 and ending at 120 hours after drug
administration. The serum half-life of phenylbutazone was significantly
shorter in DDT exposed workers than in the control population. However,
the serum half-life of phenylbutazone did not correlate with the total
concentration of DDT and related compounds in the serum of either group.
In addition, the urinary excretion of Cortisol was increased by 57% in
DDT exposed individuals when compared to controls. These results
suggest that high-level, prolonged exposure to DDT stimulates hepatic
enzyme activities.
Lethality. There seems to be no documented, unequivocal report of
a fatal human poisoning that occurred exclusively from ingestion of pure
DDT. In one fatal case, DDT dissolved in kerosene was ingested by a
child. The patient exhibited typical neurotoxic symptoms of DDT
intoxication observed in animals (tremors and convulsions). Since
kerosene is not known to cause neurotoxic symptoms (tremors and
convulsions) the occurrence of these symptoms indicates some effects of
DDT in this patient. Signs and symptoms of poisoning in humans and
animals resulting from exposure to relatively high doses of DDT include
paresthesia of the tongue, lips and face; apprehension;
hyperexcitability to stimuli; irritability; dizziness; disturbed
equilibrium; tremor; and tonic and clonic convulsions. Symptoms appear
several hours after exposure, and in animals exposed to lethal doses,
death occurs within 24 to 72 hours.
Lethality (LD50s) for several experimental animal species has been
reported following exposure to DDT by injection. The LD50 for rats
following intraperitoneal and subcutaneous injections of DDT was
reported to be 9.1 and 1500 mg/kg/day, respectively (Bathe et al. 1976;
Cameron and Burgess 1945). The LDS0 following a subcutaneous injection
of DDT was much higher than the values reported following oral exposure
(153 to 800 mg/kg) and lower than the value reported following dermal
exposure (2500 to 3000 mg/kg). However, the LD30 through
intraperitoneal exposure was lower than the Values reported through oral
or dermal exposure.
Several studies reported the LDS0 in mice through intraperitoneal
exposure to DDT. These studies reported LDsos ranging from 32 to 333 mg
p,p'-DDT/kg (Bathe et al. 1976; Okey and Page 1974). These lethal doses
span a much smaller range of doses than those reported in mice following
oral exposure to DDT (237 mg technical DDT/kg to 810 mg p,p'-DDT/kg).
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42
2. Health Effects
Following subcutaneous injection of DDT, the LD50 was reported to
be 900 and 250 mg/kg for guinea pigs and rabbits, respectively (Cameron
1945). The LD50 for subcutaneous injection in rabbits is comparable to
the LD50 reported following oral and dermal exposure (300 mg/kg/day).
The LD50 for guinea pigs following subcutaneous exposure is much higher
than the value reported following oral exposure (400 mg/kg/day), and
slightly lower than the value reported following dermal exposure (1000
mg/kg/day). No studies were located regarding lethality to experimental
animals following exposure to DDD or DDE by injection.
Liver. While there is a reported correlation between DDT serum
levels and the activity of some liver enzymes, there is no conclusive
evidence of irreversible liver damage in humans following oral exposure
to DDT. DDT does stimulate production of liver enzymes, in particular
the mixed function oxidase (MF0) enzymes. The consequences of induction
of MF0 enzymes include altered metabolism of drugs, xenobiotics, and
steroid hormones. The implications of induction of MF0 enzymes are
uncertain and, in the absence of other hepatic effects, such induction
is not considered an adverse effect. Furthermore, the implications of
MFO enzyme induction for the alteration of chemicals present in the body
to ultimate carcinogens are unknown.
In animals the liver appears to be one of the primary targets of
DDT toxicity. The severity of the injury to the liver increases
progressively with dose. With acute oral exposure adverse liver effects
can include increased liver weight and elevated serum levels of liver
enzymes (Agarwal et al. 1978; de Waziers and Azais 1987; Pasha 1981).
Subchronic and chronic exposure to DDT results in hepatic cell
hypertrophy, histopathologic alterations, necrosis, and hyperplasia
(Cranmer et al. 1972a; Fitzhugh and Nelson 1947; Graillot et al. 1975;
Jonsson et al. 1981; Orberg and Lundberg 1974).
Acute studies in which experimental animals were exposed to DDT by
injection demonstrated many of the same effects seen in animals exposed
by the oral and dermal routes. Rats and mice exposed to DDT
intraperitoneally at doses ranging from 100 to 200 mg DDT/kg body
weight/day exhibited an increase in hepatic enzyme levels or a decrease
in liver weights (Chhabra and Fouts 1973; Nigg et al. 1974; Parkki et
al. 1977). An increase of hepatic enzyme activities was also observed
in rats exposed intratracheally to 50 mg DDT/kg body weight/day for 3
days (Narayan et al. 1985a, 1985b).
Respiratory. Moderate irritation to the upper respiratory tract
has been reported in humans (Neal et al. 1944). Oral exposure of rats
to DDT resulted in limited adverse effects on the respiratory system.
However, following intraperitoneal exposure to 12.5 mg DDT/kg body
weight/day for up to 72 hours, guinea pigs exhibited a decrease in lung
mast cells and histamine levels (Askari and Gabliks 1973). Rats exposed
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43
2. Health Effects
intratracheally to 50 mg DDT/kg body weight/day for 3 days, resulted in
decreased pulmonary lipid peroxidation and ratio of reduced:oxidized
glutathione (Narayan et al. 1985a, 1985b).
Cardiac. Tachycardia occurred in an individual following
accidental ingestion of an estimated dose of 16.3 mg DDT/kg body weight
(Hsieh 1954). Cardiovascular effects, which were not observed in any
oral or dermal animal studies, were reported in several species
following intravenous exposure. Ventricular fibrillation, which
resulted in respiratory failure and death, was reported to have occurred
in some cats, rabbits, monkeys, and dogs exposed intravenously to DDT at
doses ranging from 25 to 75 mg/kg/day (Philips and Gilman 1946).
Immunological. Evidence of immunotoxicity in humans is
inconclusive and is limited to a single study with only three
volunteers. While increases in antibody titre specific for certain
bacterial antigens were elevated when DDT was given intraperitoneally
along with the antigen, the levels may not be outside of the normal
range of values for exposure to the antigen alone. Immunological
effects have been reported in animals and include increases in gamma
globulin, serum immunoglobulin, and thymus weight. Guinea pigs
immunized with diphtheria toxoid followed by intraperitoneal injections
of 20 mg DDT/kg body weight/day exhibited a decrease in anaphylactic
shock upon challenge with DDT compared to untreated controls (Gabliks et
al. 1973). According to the authors, this effect may be related to
alterations in the histamine-mediated mechanism of anaphylaxis. While
effects on immune competence in humans have not been fully
characterized, immune responses observed in animals may be indicative of
effects in humans subjected to long-term low-level exposure to DDT.
Neurological. Human case studies indicate that the central nervous
system is the primary target organ system for DDT toxicity in humans
following oral exposure (Hayes 1982). Clinical symptoms include
hyperexcitability, tremors, and convulsions. Experimental data in
animals confirm the effects of DDT on the nervous system. Clinical
signs in experimental animals are similar to those observed in humans.
Alterations in levels of neurotransmitters and biogenic amines in
animals indicate that subclinical neurological changes could also occur
in humans exposed to DDT. Rats had an increase in neurotransmitter
levels in the brain and a decrease in learning and retrieval of memory
following 15 days treatment of intraperitoneal injections of 47.5 mg
DDT/kg body weight/day (Uppal et al. 1983). Rats given intramuscular
injections of 5 mg DDT/kg/day for up to 45 days had a decrease in
neurotransmitter levels (Hrdina et al. 1972). Tremors and convulsions
were reported in mice given 8.33 mg DDT/kg body weight/day
subcutaneously for 80 weeks (Kashyap et al. 1977). Chronic oral doses
that produced the same neurological response (tremors and convulsions)
in mice were higher (10.5 to 65 mg/kg/day).
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44
2. Health Effects
No studies were located regarding neurological effects following
oral exposure to DDD. However, neurological responses following
intraperitoneal injections of DDD have been reported. Guinea pigs
exposed intraperitoneally to 300 mg DDD/kg body weight/day for 14 days
exhibited tremors (Jensen et al. 1957).
In general, the data on both animals and humans indicate that
although the prime target for functional injury produced by high acute
doses of DDT is the peripheral and the central nervous system, little
pathological change occurs and effects appear to be reversible once
exposure ceases. It is believed that the sites of primary neurotoxic
action of DDT are the sensory and motor nerve fibers and the central
nervous system. Studies indicate that DDT affects the flow of sodium
ions into the nerve axon (Murphy 1986). By keeping the sodium channel
in the cell membrane open, excess ions enter the nerve cells. The
membrane slowly returns to its normal resting potential. The result is
an elevated sensitivity to a continual neuronal discharge of impulses,
which leads to such neurological symptoms as tremor and more severe
effects such as convulsion.
Reproductive and Developmental. There is no indication that DDT
has an adverse effect on human reproduction. Wilcox (1967) found no
impairment in reproductive capability in heavily exposed DDT factory
workers, the same worker population studied by Laws et al. (1967). No
studies were located regarding developmental toxicity following DDT
exposure in humans. The available information from animal studies
indicates that DDT is not a structural teratogen. However,
embryotoxicity and fetotoxicity including infertility have been reported
in experimental animals in the absence of maternal toxicity.
Results from studies in which experimental animals were exposed to
DDT by injection further confirm the reproductive and developmental
toxicity of DDT in experimental animals exposed by the oral route (Fahim
et al. 1970; Gellert et al. 1974, 1972; Kihlstrom et al. 1975; Nigam et
al. 1977). Although parenteral exposure to DDT and its metabolites in
humans is unlikely, reproductive and developmental effects have been
seen in animals when exposed by this route.
DDT (o,p'- and p,pisomers) has also been shown to be estrogenic
following oral and intraperitoneal administration. This estrogenic
activity is evidenced by a uterotrophic effect; increases in uterine wet
weight and increases in concentrations of RNA or DNA and/or
carbohydrates in uterine tissue. Doses ranging from 50 to 100 mg DDT/kg
body weight/day have been reported to elicit estrogenic activity in rats
(Bitman and Cecil 1970; Clement and Okey 1972; Singhal et al. 1970).
Welch et al. (1969) reported the estrogenic activity of o.p'-DDT >
technical DDT > p,p'-DDT. No studies regarding the estrogenic effects
of DDT in mice following exposure to DDT were located.
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4 5
2. Health Effects
Genotoxic Effects. DDT, DDE and DDD have been tested in several
genotoxicity studies. Tables 2-2 and 2-3 report the results of in vitro
and in vivo studies, respectively.
Humans. Results following in vitro and in vivo exposure to DDT are
similar (Table 2-2). Human lymphocytes exposed in vitro to
concentrations of technical DDT ranging from 0.06 to 0.20 and 1 to 15
H/mL (0.0017 to 0.0057 and 0.28 to 0.43 mg/kg/day) exhibited a
significant increase of chromosomal aberrations at 0.20, 4.05, and 8.72
fi/mL (0.0057, 0.116, 0.25 mg/kg/day; however, no correlation could be
established between DDT concentration and cells with chromosomal
aberrations (Lessa et al. 1976). Chromosomal aberrations have been
reported in irj vivo studies. Blood cultures of men occupationally
exposed to several pesticides, including DDT, exhibited an increase in
chromatid lesions (Yoder et al. 1973). Rabello et al. (1975) reported
chromosomal aberrations in workers occupationally exposed to DDT. When
all workers were considered, regardless of direct or indirect exposure,
a significant increase in the incidence of chromosomal damage was
reported. These studies suggest that DDT may cause chromosomal damage
in humans.
Nonhtiman. Chromosomal damage was observed in nonhuman test systems
following iii vitro and irj vivo exposure to DDT, DDE, or DDD (Table 2-3).
Mahr and Miltenburger (1976) reported chromosomal damage in the B14F28
Chinese hamster cell line following exposure to DDT, DDE, or DDD.
Palmer also observed these same results in kangaroo rat cells (Potorus
tridactvlis) in vitro following exposute to DDT, DDE, or DDD. Kelly-
Garvert and Legator (1973) reported a significant increase in
chromosomal aberrations in Chinese hamster V79 cells following exposure
to DDE, but not DDT. BALB/C mice exposed in vivo to DDT exhibited
chromosomal aberrations of the bone marrow (Johnson and Jalal 1973;
Larsen and Jalal 1974). Overall, DDT and its metabolites appear to
produce chromosomal aberrations in nonhuman and humans systems.
la vivo studies also have reported other genotoxic effects of DDT.
Clark (1974) reported an increase in dominant lethality in early
spermatid and spermatocyte stages in the mouse exposed to DDT at high
doses. Based on these results in mice, it may be possible to conclude
that DDT causes an effect on spermatogenesis or fertility in humans, but
this effect may not occur at exposure levels encountered in the
environment.
Cancer. Studies of workers exposed to DDT do not indicate
conclusively an association between exposure to DDT and the development
of cancer (Blair et al. 1983; Laws et al. 1967; Morgan and Lin 1978;
Morgan et al. 1980; Ortelee 1958; Wong et al. 1984). These studies were
not conclusive because the duration of exposure and observation may have
been inadequate; the exposure concentration was not known with certainty
(although some estimates of "expected" exposure were computed by
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46
2. Health Effects
TABLE 2-2. Genotoxicity of DDT, DDE, and ODD In Vitro
End point
PROKARYOTIC ORG AMI SMS
Gene mutation
DNA damage
FUNGAL AND PLAUT CELLS
Gene mutation
Recessive
Lethal
Mitotic gene
conversion
MAWAT.IAH CELLS
Chromosomal
aberrations
Gene mutation
DNA damage
Species/Test System
Result
Salmonella tvphlraurimn/
TA1535, TA1537, TA98, TA100
Escherichia coll/Pol-A
Escherichia coli/Back mutation
Escherichia marcescens/glucose
prototrophy
Bacillus subtllis/rec-assay
Haiirosmora crassa
Naurospora crassa
Saccharomvces carevisiae
Human/lymphocytes
Human/lymphocytes (structural)
Chinese hamster V79 cells
Chinese hamster/B14F28 cells
(cytogenetic)
Chinese hamster/B14F28 cells
(chromosotnaL damage)
Kangaroo rat/cells
Human/Hepatocyte-mediated cell
Chinese hamster/V79 cells
(6-thioguanine rssistent mutation)
Mouse/L51784 Lymphoma calls
Rat/liver epithelial cell
Human SV-40/unscheduled DMA
synthesis (UDS)
Mouse/hepatocytes-UDS
Rat/hepatocytes-UDS
Hamster/hepatocytes-UDS
+ (DDE)
- (DDT)
Reference
McCann et al. 1975
Fluck et al. 1976
Fahrig 1974
Fahrig 1974
Shirasu et al. 1976
Clark 1974
Clark 1974
Fahrig 1974
Lessa et al. 1976
Lessa et al. 1976
Kelly-Garvert and
Legator 1973
Mahr and Miltenburger
1976
Mahr and Miltenburger
1976
Palmer et al. 1972
Tong et al. 1981
Tsushimoto et al.
1983
Amacher and Zelljadt
1984
Telang et al. 19B1
Ahmed et al. 1977
Probst et al. 1981
Probst and Hill 1980
Maslansky and Williams
1981
- - negative results
+ - positive results
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47
2. Health Effects
TABLE 2-3. Ganotoxicity of DOT, DDE, and ODD Vivo
End point
Species/Test System
Result
Reference
1WMALIAN SYSTEMS
Chromosomal
aberrations
Dominant
lethal
DNA synthesis
Mitotic
response
HOST-MEDIATED ASSAYS
Gene mutation
THVERTEBRATE SYSTEMS
Dominant lethal
+~
Human/plasma
Human/plasma
Mouse
Rat
Mouse/bone marrow
Mouse
Rat/testes
Rat
Mouse/inhibition of testicular
synthesis
Rat/adrenal cortex
Salmonella typhlmurium/
mouse host-mediated assay
Serratla marcescens/
mouse host-mediated assay
Drosophila roelanonaster
- (DDT,DDE)
+ (DDD)
- (DDT,DDE)
+ (DDD)
Rabello et al. 197S
Yoder et al. 1973
Clark 1974
Legator et al. 1973;
Palmer et al. 1973
Johnson and Jalal
1973; Larsen and Jalal
1974
Clark 1974
Krause et al. 1975
Palmer et al. 1973
Seiler 1977
Danz and Urban 1980
Buselmaier et al. 1973
Buselmaier et al. 1973
Clark 1974
positive results
negative results
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48
2. Health Effects
comparing excretion of the DDT metabolite, DDA, in workers with those of
volunteers who had ingested known amounts of DDT); exposures to
chemicals may have occurred; and the follow-up of these groups may not
have been adequate.
Evidence exists from animal studies to consider DDT, DDE, and ddd
probable human carcinogens (based on EPA's B2 classification). Chronic
exposure (81 weeks to life) at doses as low as 0.26 mg DDT/kg/day
produced liver tumors, primarily hepatomas, in several strains of mice
(Innes et al. 1969; Thorpe and Walker 1973; Tomatis et al. 1972). jn
mice pulmonary adenomas occurred at doses ranging from 1.3 to 32.5 mg
DDT/kg/day (Kashyap et al. 1977; Shabad et al. 1973) and malignant
lymphomas occurred after exposure to 10 mg DDT/kg/day for 80 weeks
(Kashyap et al. 1977). Liver-cell tumors in rats dosed with 6.25 to 42
mg DDT/kg/day for 120 weeks to life (Gabral et al. 1982b; Rossi et ai.
1977) and adrenal gland tumors in hamsters given 83 mg DDT/kg/day for
120 weeks (Rossi et al. 1983) also have been reported.
2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS
Statistically significant associations between levels of stored DDT
or DDT metabolites and certain types of chronic disease in humans have
been reported. However, causal relationships have not been establish^
and other reports indicate that there is no association between DDT
levels and chronic disease.
Saxena et al. (1987) reported that the concentration of DDT in
normal human uterine tissue (0.103 ppm) differed from that in
leiomyomatous tissue (0.845 ppm). The authors proposed that these
significantly higher levels of DDT in leiomyomatous tissue indicated an
involvement of DDT in uterine leiomyomas. In a case control study (51
case and 63 control subjects), Unger et al. (1982) reported a
correlation between DDE levels in adipose tissue of deceased cancer and
non-cancer patients. The authors reported a significant association
between DDE concentrations in adipose tissue and occurrence of cancer
after allowing for confounding factors such as weight, height,
occupation, and place of residence.
Morgan et al. (1980) reported a suggestive relationship between
serum organochlorine pesticide levels (p,p'-DDT, p,p'-DDE, Dieldrin, and
J5-HCH) and the subsequent appearance of hypertension, arteriosclerotic
cardiovascular disease, and an unusually high prevalence of skin cancer
in fumigators.
DDT and its metabolites have been found in human blood, placental
tissue, and umbilical cord blood. These levels are often increased in
women who have delivered prematurely or had spontaneous abortions.
However, the concentrations in blood or placental tissues have riot been
correlated with reproductive toxicity in humans. Saxena et al. (1980,
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49
2. Health Effects
1981, 1983), Wassermann et al. (1982), and Procianoy and Schvartsman
(1981) reported increased DDT levels in maternal blood ranging from 7.42
to 393.8 ppb and levels in placental tissue ranging from 19.8 to 162.2
ppb in mothers who gave birth to premature infants or who spontaneously
aborted fetuses. Mothers who gave birth to full term infants had lower
blood DDT levels ranging from 3.0 to 26.5 ppb and placental tissue
levels ranging from 3.66 to 39.8 ppb.
O'Leary et al. (1970a) reported a difference in DDE blood levels
between full-term and premature infants. Women who delivered early had
infants with mean DDE blood levels of 19 to 22.1 ppb, while women who
delivered at full-term had infants with mean DDE blood levels of 4.9 to
6.1 ppb. Saxena et al. (1980, 1981), Wassermann et al. (1982), and
Procianoy and Schvartsman (1981) reported increased DDE levels in
maternal blood ranging from 10.1 to 163.8 ppb and levels in placental
tissue ranging from 31.2 to 83.6 ppb in mothers with premature infants
or who spontaneously aborted. Mothers with infants born at full term
had 1.2 to 12.6 ppb DDE in their blood and 11.8 ppb in the placental
tissue.
Saxena et al. (1980, 1981) and Wassermann et al. (1982) reported
the levels of DDD in the maternal blood of women with premature infants
or spontaneously aborted fetuses ranged from 10.1 to 65.5 ppb and
placental tissue levels from 10.7 to 20.6 ppb. Mothers with full-term
infants had blood DDD levels ranging from 3.3 to 6.9 ppb and placental
tissue concentrations of 4.9 ppb. However, Wassermann et al. (1982),
Saxena et al. (1983), and O'Leary et al. (1970b) stated that although
results suggest an association, they found no significant causal
relationship between DDT, DDE, and DDD levels in infants and premature
birth or spontaneously aborted fetuses.
Grasso et al. (1973) also reported an increase in chlorinated
pesticide concentrations in the blood of premature and underweight full
term newborns. Trebicka-Kwiatkowska et al. (1971) reported a case of
intrauterine fetal death in a woman who had been occupationally exposed
to DDT and DDE. The concentrations of DDT and DDE in her placenta and
blood were higher than in women who gave birth to healthy children.
Rogan et al. (1987) reported a decrease in the length of lactation
in women with concentrations of DDT in breast milk greater than 4.0 ppm.
Rogan et al. (1986) did not find any correlation between DDE levels in
maternal milk fat and birth weights, head circumference, or jaundice in
neonates. However, the authors indicated that higher levels of DDE (>4
ppm) in maternal milk fat were associated with hyporeflexia in infants.
Levels in maternal milk fat were used as an indicator of maternal body
burden and possible placental transfer. Actual levels in infants were
not monitored. Nishimura et al. (1977) determined the levels of p,p'-
DDE in embryo, fetal, and neonatal organs. The levels in the embryos
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50
2. Health Effects
and neonates did not exceed the corresponding values in normal adult
organs.
2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN TISSUES
AND/OR HEALTH EFFECTS
Concentrations of DDT, DDE, or DDD can be measured Ln the blood,
serum, adipose tissue, breast milk, and semen of exposed individuals
using several analytical techniques. However, there are no quantitative
data available that allow correlation of levels of the compounds in
human tissue or fluids and environmental levels. Studies in pesticide
production workers reported that blood levels of these compounds are
higher in persons exposed to greater amounts of DDT and its metabolites
in the workplace. The biological half-lives for elimination of these
compounds are ranked as follows: DDE > DDT > DDD. Therefore, detection
of higher ratios of DDD or DDT to DDE is believed to indicate more
recent exposure while lower ratios are believed to correlate with long-
term exposure and storage capacity (Morgan and Roan 1971). There is a
direct correlation between DDE and DDT levels in blood and adipose
tissue (Hayes et al. 1971; Morgan and Roan 1971). Concentrations of DDT
in adipose tissue are approximately 280 times higher than those of blood
(Anderson 1985). However, because DDT and DDE are extensively stored in
fatty tissue and are slowly released from storage sites, there is no
correlation between levels in tissues and the time course of exposure.
No quantitative data are available to correlate environmental
levels of DDT, DDE, or DDD with health effects. Environmental exposure
levels are far below doses which cause any noticeable health effects.
Even in studies with volunteers who consumed 0.61 mg/kg of DDT per day
for an extended period of time, no adverse effects were noted despite
extensive testing to determine such effects (Hayes et al. 1956),
2.6 TOXICOKINETICS
2.6.1 Absorption
2.6.1.1 Inhalation Exposure
Absorption of DDT by the lung is considered to be a minor route of
entry. It is assumed that inspired DDT (crystalline), due to the large
particle size, does not enter the deeper, smaller spaces of the lung,
but rather is deposited in the upper respiratory tract and, due to the
action of the mucociliary apparatus, is eventually swallowed (Hayes
1982). However, some crystalline DDT could be small enough to readily
pass through the tracheal system. In occupational settings, human
exposure has occurred by a mixture of routes, including inhalation with
subsequent oral ingestion and dermal absorption. Evidence of DDT
absorption was indicated by the appearance of DDA (a DDT metabolite) in
the urine (Laws et al. 1967; Ortelee 1958) and the presence of DDT in
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51
2. Health Effects
adipose tissue (Laws et al. 1967) and plasma or serum (Morgan et al.
1980; Rabello et al. 1975). However, no studies were located that
quantify the rate or extent of absorption of DDT, DDE, or DDD in humans
following inhalation exposure. No studies were located regarding the
absorption of DDT, DDE, or DDD following inhalation exposure in
experimental animals.
2.6.1.2 Oral Exposure
Absorption following ingestion of DDT, DDE, and DDD is evident in
humans both directly from measurements of serum and adipose tissue
concentrations of these chemicals or by measuring DDA in the urine
(Hayes et al. 1971; Morgan and Roan 1971, 1977) and indirectly by the
development of toxicity following accidental or intentional (suicide)
ingestion of DDT (Hsieh 1954). In subjects chronically exposed to oral
doses of DDT up to 20 mg/man/day (approximately 0.3 mg/kg/day), DDT
appeared in the serum and reached peak serum concentrations 3 hours
after ingestion (Morgan and Roan 1971). Serum levels remained elevated,
but returned to normal values 24 hours after dosing.
Gastrointestinal absorption can be inferred in experimental
animals. The production of urinary metabolites in mice, rats, and
hamsters (Fawcett et al. 1987; Gold and Brunk 1982, 1983, 1984), the
presence of DDT and metabolites in bile collections (Jensen et al.
1957), and the induction of tumors in experimental animals following
oral administration of DDT, DDE, or DDD provides evidence of
gastrointestinal absorption. In animals, absorption of orally
administered DDT is enhanced when DDT ie dissolved in digestible oils
(Keller and Yeary 1980). Approximately 70% to 90% of the administered
dose is absorbed following oral exposure to DDT in vegetable oils
(Keller and Yeary 1980). DDT is absorbed 1.5 to 10 times more
effectively when given in digestible oils than when dissolved in
nonabsorbable solvents (Hayes 1982) .
Portal blood absorption has been demonstrated indirectly by Sieber
(1976) who showed that 20% of the administered dose appeared in the
lymph of thoracic duct-cannulated rats. Gastrointestinal absorption by
way of the intestinal lymphatic system may play a major role in the
uptake of DDT in animals (Noguchi et al. 1985; Pocock and Vost 1974;
Sieber 1976; Turner and Shanks 1980).
2.6.1.3 Dermal Exposure
Dermal absorption of DDT in humans and animals is considered to be
limited, but can be inferred by observation of toxicity following dermal
application of DDT. Acute toxicity studies in several species
demonstrate that toxicity, expressed as an 1D50, is less when DDT is
applied dermally than when given by gavage or by injection. The data
indicate that DDT is four times more toxic when given by intraperitoneal
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52
2. Health Effects
injection than when administered orally and forty times more potent when
given by intraperitoneal injection than when administered by the dermal
route (Hayes 1982).
2.6.2 Distribution
The distribution and storage of DDT in humans and animals has been
extensively studied. DDT and its metabolites, DDE and DDD, are lipid
soluble compounds, and once absorbed readily distribute to all body
tissues in proportion to respective tissue lipid content (Morgan and
Roan 1971) .
Hayes et al. (1971) and Morgan and Roan (1971, 1977) evaluated the
distribution of orally administered DDT, DDE, or DDD in human
volunteers. Morgan and Roan (1971, 1977) and Roan et al. (1971)
measured the concentration of DDT, DDE, DDD, and DDA in blood, fat, and
urine following oral dosing. The administered doses ranged from 5 to 20
mg DDT/man/day for up to 6 months; the ratio of concentration of DDT
stored in adipose tissue to that present in blood was estimated to be
280:1.
2.6.3 Metabolism
The metabolism of DDT, DDE, and DDD has been studied in humans and
a variety of mammalian species. The metabolism in rats, mice, and
hamsters is similar to that in humans; however, not all of the
intermediary metabolites identified in animals have been identified in
humans. It has been proposed by a number of investigators that the
major urinary metabolite of DDT, 2,2-bis(p-chlorophenyl) acetic acid
(DDA), in mammals (Gingell 1976) is produced by a sequential combination
of reductive dechlorination, dehydrochlorination, reduction,
hydroxylation, and oxidation (Peterson and Robinson 1964). It has been
proposed that DDT is initially metabolized to two intermediary
metabolites, DDE (Mattson et al. 1953; Pearce et al. 1952) and DDD
(Klein et al. 1964). In rats, DDE is slowly converted in the liver to
l-chloro-2,2-bis(p-chlorophenyl)ethene (DDMU) and then to DDA by way of
1,1-bis(p-chlorophenyl)ethane (DDNU) (Datta 1970; Datta and Nelson
1970). DDD is rapidly detoxified by way of DDMU to l-chloro-2,2-bis(p-
chlorophenyl)ethane (DDMS) and then to DDNU (Datta 1970); DDNU is then
further metabolized, primarily in the kidney, to 2,2-bis(p-
chlorophenyl)ethanol (DDOH) then to 2,2-bis(p-chlorophenyl)ethanal
(DDCHO) (Suggs et al. 1970) or to DDA (Peterson and Robinson 1964). A
scheme for DDT metabolism adapted from Gold and Brunk (1982) is
presented in Figure 2-2.
Recent evidence in mice and hamsters suggests an alternative
metabolic scheme (Gold and Brunk 1982, 1983). In these studies, [3H]-
DDT or [14C]-DDT and [14CJ-DDD, dissolved in olive oil, was administered
by gavage in a single dose of 500 mg/kg. After 72 hours the principal
-------
-HCL
R2CH-CCL3.
DDT
-CL1+H
-O
CL
r2c-ccl2
DDE
-CL,+H
R2C-CHCL
-CL +H
»ini
i
R2C - CH2
DDNU
Hj,0
H2CH-"CH/)H
DDOH
1 2H
R2CH-CHCL2
DDD
I
-HCL
RjjC.CHjCL
DDMU
R-CH - CH-CL
DDMS
[0]
[R2CH - CHO]
DDCHO
FIGURE 2-2. Metabolic Scheme for DDT
RzCH-COOH
DDA
sc
a>
n>
i—•
rt
zr
w
Ml
(D
O
rt
CO
l_n
OJ
f8n 193-4
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54
2. Health Effects
urinary metabolite was DDA, which accounted for 86 to 95% and 95 to 99%
of the urinary radioactivity in hamsters and mice, respectively.
Unmetabolized DDD (< 1%, hamsters; 4%, mice), DDMU (< 1%), DDE (< 1%),
2-hydroxy-2,2-bis(p-chlorophenyl)acetic acid (ct-OH-DDA, 1%) and DDQH (<
1%) were excreted in the urine. Based on the DDA to DDOH ratio and
levels of DDCHO or DDNU-diol excreted in the urine of mice treated with
DDT or DDD versus DDMU (Gold et al. 1981), it was hypothesized that DDD
is hydroxylated at the chlorinated 1-ethane side chain carbon to yield
2,2-bis(p-chlorophenyl)acetyl chloride (DDA-C1), which in turn can be
hydrolyzed to the major urinary metabolite, DDA. Epoxidation of DDMU, a
minor metabolite of DDD, yields DDMU-epoxide (Gold et al. 1981). This
epoxide is then believed to be rearranged to DDA-C1 and then hydrolyzed
to OH-DDA. Gold and Brunk (1982, 1983, 1984) suggested that the urinary
metabolite DDA-C1, which is an agent capable of acylating nucleophilic
cellular molecules, and DDMU-epoxide, which is an agent found to be
mutagenic in Salmonella tvphimurium assay (Gold et al. 1981), could, via
the formation of covalent adducts of DNA, contribute to the known
tumorigenicity of DDT and DDD in the mouse. Urinary metabolites were
similar in both species. The authors suggested that the metabolic
disposition of DDT, DDD, and DDMU in the hamster is similar to that of
the mouse and proceeds by the same oxidative metabolic pathways in both
species. Therefore, it is unlikely that the observed differences in
species sensitivity to the DDT-induced tumorigenicity in the mouse and
the relative resistance to tumor production from DDT exposure in the
hamster is due to differences in the production of the DDMU-epoxide or
DDA-C1. However, there was a species difference in the metabolic
conversion of DDT to DDE. DDE was detected in much higher levels in the
urine of mice following both acute and chronic studies than in hamsters
(Gingell 1976; Gold and Brunk 1983). The data indicate that the hamster
was less efficient than the mouse in the conversion of DDT to DDE. DDE
has been shown to cause liver tumors in hamsters (Cabral et al. 1982a).
According to Gingell (1976), the metabolism in the rat follows
essentially the same pathway as the mouse. In a more recent study,
Fawcett et al. (1987) evaluated the metabolism of DDT, DDE, DDD, and
DDMU in rats. This study confirmed the similarity in metabolism between
mice and rats. Each compound was administered in a single 200 mg/kg
dose by intraperitoneal injection. The major fecal metabolite was DDA;
other fecal metabolites included a trace of DDE, 4,4-dichloro-
benzophenone (DBP), DDD, and unmetabolized DDT. Based on the relative
amounts of these fecal metabolites, the authors postulated that the
metabolism of DDD to DDA proceeds via the acid chloride (DDA-C1), as has
been previously suggested for DDD in the mouse and hamster (Gold and
Brunk 1982, 1983, 1984). It was hypothesized that DDD could form DDA-C1
via C-2 hydroxylation. The formation of the metabolite DBP from DDD was
hypothesized to arise by means of hydroxylation of the C-l carbon of the
ethane group. According to Reif and Sinsheimer (1975) the urinary
metabolites in rats and humans following exposure to o,p'-DDD are
similar, indicating a similar metabolic pathway.
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55
2. Health Effects
Several investigators have studied the metabolism of DDT in humans
and have inferred a metabolic pathway from urinary metabolites and
metabolites found in serum and adipose tissue. The DDT metabolites in
humans are the same as some of those produced in animals and it can be
inferred that the metabolic pathways in humans and animals have some
similarity. In humans, ingested DDT undergoes reductive dechlorination
to DDD which is further degraded and readily excreted as DDA (Roan et
al. 1971). DDT is also converted by dehydro-chlorination to DDE,
although at a slower rate than the DDT to DDD pathway (Morgan and Roan
1971). Morgan and Roan (1971) concluded that the conversion of DDT to
DDE occurs with considerable latency and that the extent of the
conversion was estimated to be less than 20% over the course of the 3
year study. Further metabolism of DDE is apparently slow and DDE is
retained in adipose tissue (Hayes et al. 1971; Morgan and Roan 1971).
According to Roan et al. (1971) and Morgan and Roan (1971), oral
administration of DDT or DDD to human volunteers resulted in an
increased urinary excretion of DDA, but no increase in excretion of DDA
above predose values was noted following oral ingestion of DDE.
According to the authors the data indicate that DDD, not DDE, is the
precursor for DDA in humans and that little DDE is further converted to
DDA.
2.6.4 Excretion
Excretion of DDT has been studied in humans and a variety of
experimental animals. The major route of excretion of DDT in humans
appears to be in the urine, but some excretion also occurs by way of
feces, semen, and breast milk.
The excretion of DDT was investigated in human volunteers (Hayes et
al. 1971; Roan et al. 1971). Hayes et al. (1971) reported that in
subjects receiving 35 mg/man/day (approximately 0.5 mg/kg), urinary
excretion of DDA increased rapidly for the first few days to a steady
state level of approximately 13 to 16% of the daily dose. Urinary
excretion of DDA fell rapidly following cessation of dosing. It would
appear that a steady state was reached within 12 to 18 months of daily
dosing, after which humans were apparently able to eliminate the entire
daily dose of 35 mg/man/day. Since only 5.7 mg/day of all DDT isomers
were found in the urine at steady state, it was postulated that other
routes of excretion are involved. Roan et al. (1971) reported that
increased urinary excretion of DDA is detectible within 24 hours of
ingestion of DDT (5, 50, or 20 mg/day), DDD (5 mg/day) or DDA (5
mg/day). DDA excretion levels return to predose levels within 2 to 3
days of dose termination for DDA, but continue significantly above
predose levels for over 4 months following termination of DDD or DDT
doses. Ingestion of DDE (5 mg/day) failed to produce any increase in
DDA excretion.
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56
2. Health Effects
DDT excretion in the feces may be a major route of excretion at
high doses of DDT. DDT and DDT-related metabolites have been identified
in the feces of human volunteers receiving 35 mg/man/day (Hayes et al.
1956); however, this result has not been confirmed by later
investigations (Hayes 1982).
Analysis of urine from humans occupationally exposed to DDT showed
the presence of DDA (Laws et al. 1967; Ortelee 1958; Ramachandran et al.
1984). By comparing the urinary excretion of DDA with that of
volunteers given known doses of DDT, the average occupational exposure
can be estimated (TOO 1979). The observations by Laws et al. (1967) and
Ortelee (1958) indicate that the urinary excretion of DDA is correlated
with the level of exposure to DDT. The concentration of DDA in the
urine in occupationally exposed workers was reported to be greater than
that observed in the general population, while DDE excretion was
reported to be only slightly higher than in the general population. The
presence of DDT in human milk has been identified by a number of
investigators. Takei et al. (1983) reported concentrations from the
1969-70 U.S. national human milk study. The p,p'-isomer of DDT and DDE
were found in 100% of the samples tested, with ranges of non-detected to
1.7 ppm, and 0.24 to 11.0 ppm (lipid-basis), respectively. However,
variance in levels of DDT and its metabolites may be influenced by such
factors as number of children nursed, diet, and cigarette smoking (Bradt
and Herrenkohl 1976). A steady decrease in the levels of DDT and its
metabolites in human milk has been reported as a result of decreased
intake. In Finland, samples taken between 1973-1982 indicate a greater
than 50% reduction in total DDT concentration in human milk (Wickstrom
et al. 1983) .
Results of studies with mice, rats, and hamsters indicate that the
metabolites of DDT and small amounts of unmetabolized DDT are excreted
primarily in the urine and feces (Fawcett et al. 1987; Gold and Brunk
1982, 1983, 1984). In rats given a single intraperitoneal injection of
200 mg radiolabeled DDT, DDE, or DDD/kg, the time required to excrete
50% of the administered radioactivity in both the urine and feces was 12
days for DDT, 24 days for DDE, and 3 days for DDD (Fawcett et al. 1987).
2.7 INTERACTIONS OF DDT, DDE, OR DDD WITH OTHER CHEMICALS
One of the major concerns about pesticide residues is the
possibility that they may act synergistically and/or antagonistically
with other chemicals over a long period of time to produce cancer. DDT
induces microsomal mixed function oxidase enzymes of the liver. These
enzymes are involved in the metabolic conversion or biotransformation of
xenobiotics. In most cases this biotransformation results in compounds
that are less toxic than the parent and are more readily excreted from
the body. For some chemicals this metabolism results in the production
of metabolites that are more toxic than the parent and may be
carcinogenic. One interaction of concern is the enhanced conversion of
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57
2. Health Effects
other chemicals to the active, carcinogenic form through the action of
DDT. Several investigations indicate that DDT administered to
experimental animals along with a known carcinogen results in greater or
lesser tumor production than when that carcinogen is tested without DDT.
DDT is reported to promote the tumorigenic effects of several known
carcinogens, such as 3-methyl(4-dimethylamine)-azobenzene (Kitagawa et
al. 1984), 2-acetylaminofluorene (2-AAF) (Peraino et al. 1975), diethyl-
nitrosamine (DEN) (Nishizumi 1979), and carbon tetrachloride (CC14)
(Preat et al. 1986). The promoting effect of DDT in rats is reported to
act in a dose-dependent fashion, with DDT decreasing the latency period
of tumor development and increasing the incidence and yield of hepatic
tumors, mainly hepatocellular carcinomas.
Pretreatment of experimental animals with DDT is reported to
decrease the tumorigenic effects of some previously determined
carcinogens. Pretreatment of rats with DDT significantly lowered the
incidence of mammary tumors per rat following treatment with 7,12-
dimethylbenz[a]anthracene (DMBA), versus DMBA-treated controls
(Silinskas and Okey 1975). It was suggested by the authors that DDT may
inhibit DMBA-induced mammary tumors by stimulating hepatic metabolism
and accelerating the excretion of DMBA, so that less carcinogen is
available to peripheral tissues. Other studies also have reported the
induction of microsomal enzymes of the liver by DDT, which reduced the
carcinogenicity of azo dyes and similar carcinogens (Williams and
Weisburger 1986) . Rodents pretreated with DDE have also exhibited the
induction of hepatic enzymes, which may reduce the tumorigenic effects
of carcinogens (Coney 1971).
The effects of DDT on the nervous system are altered when DDT is
given in combination with certain neuronally active pharmacological
agents. Some pharmacological agents (hydantoin, phenobarbital,
mephenesin) prevent some or all of the neurological effects seen in
experimental animals treated with DDT (see Section 2.2.2.4 on
neurological effects of DDT), while other agents (trihexyphenidyl,
haloperidol, propranolol) enhance DDT-induced neurotoxicity (Herr et al.
1985; Hong et al. 1986; Matin et al. 1981). One of the effects of DDT
is to hold sodium channels open, which contributes to the mechanism of
DDT-induced neurological effects (tremors and hyperexcitability).
Chemicals which reduce the neurotoxic effects of DDT may block
repetitive firing of nerves by binding to and interfering with the
alteration of sodium channels caused by DDT or by interfering with
neurotransmitter systems associated with DDT-induced neurotoxicity.
2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
Children who are breast-fed receive greater amounts of DDT than
children who are not breast-fed, because DDT is ubiquitous and is found
in higher concentrations in human milk than in cows milk or other foods
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58
2. Health Effects
(Bevenue 1976; Rogan et al. 1986; Strassman and Kutz 1977). According
to Wassermann et al. (1982), breast-fed children are a group susceptible
to the greatest exposure (excluding occupational exposure) of
organochlorine compounds, including DDT-related residues.
Groups who are particularly susceptible to the toxic effects of DDT
are individuals with diseases of the nervous system, liver, or blood
(International Labor Office 1983).
2.9 ADEQUACY OF THE DATABASE
Section 104 (i)(5) of CERCLA directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of DDT, DDE, and DDD is available. Where adequate
information is not available, ATSDR, in cooperation with the National
Toxicology Program (NTP), is required to assure the initiation of a
program of research designed to determine these health effects (and
techniques for developing methods to determine such health effects).
The following discussion highlights the availability, or absence, of
exposure and toxicity information applicable to human health assessment.
A statement of the relevance of the identified data needs is also
included. In a separate effort, ATSDR, in collaboration with NTP and
EPA, will prioritize data needs across chemicals that have been
profiled.
2.9.1 Existing Information on Health Effects of DDT, DDE, and DDD
Figure 2-3 graphically describes whether a particular health effect
end point has been studied for a specific route and duration of
exposure. There is little information concerning the health effects of
DDT in humans and no information in animals following inhalation
exposure. Most of the information concerning the health effects in
humans is reported in occupational studies in which exposure levels were
usually not described; the route of exposure was probably by a
combination of routes including oral, dermal, and inhalation.
Therefore, the effects seen cannot easily be assigned to a specific
route of exposure. In some cases, exposure to a variety of chemicals
including DDT occurred. The information on the health effects
associated with oral exposure to DDT in humans is limited. In animals
these health effects have been well-documented in a variety of species
following acute, intermediate, and chronic exposure duration. The
studies describing adverse health effects for DDT by the dermal route
are also limited. In animals limited information exists for the dermal
route; with the exception of the data on cancer, the information for
other health effects is derived primarily from one study.
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59
2 . Health Effects
SYSTEMIC
iS>
Inhalation
Oral
Dermal
HUMAN
SYSTEMIC
iS>
Inhalation
Oral
Dermal
ANIMAL
• Existing Studies
FIGURE 2-3. Existing Information on Health
Effects of DDT, DDE, and DDD
F9O091-1
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60
2. Health Effects
2.9.2 Data Needs
Single-Dose Exposure. With acute exposure to high doses, the
nervous system appears to be the major target in both humans and
experimental animals. Information regarding single oral or injection
exposures of rats, guinea pigs, and mice have provided information on
lethal and non-lethal levels of DDT. Further single dose exposure
studies may not add significantly to the existing information.
Repeated-Dose Exposure. Repeated-dose exposures in both humans
(inhalation/dermal and oral) and experimental animals (oral only) have
been reported. In most studies, the exact duration and level of
exposure in humans cannot be quantitated because the information is
derived from case reports or epidemiological studies that do not
adequately characterize exposure. The animal studies describe
predominantly neurological, hepatic, immunological and
reproductive/developmental end points. Little or no information on
respiratory, cardiovascular, gastrointestinal, hematological,
musculoskeletal or dermal/ocular effects in animals exists. The data
indicate that the liver is the major target organ following subchronic
or chronic oral exposure. There is no evidence that liver function in
humans occupationally exposed has been impaired. However, the data are
limited. As with the nervous system, the significance of more subtle
biochemical changes in humans, such as the induction of microsomal
enzymes, is not known with certainty.
Chronic Exposure and Carcinogenicity. The epidemiological evidence
is inconclusive to establish with reasonable certainty if DDT is a human
carcinogen. In addition, data on experimental animals provide
conflicting results. For example, DDT is carcinogenic in most strains
of mice tested and in a few studies was carcinogenic in rats. However,
several other rat studies were negative, as were most of those in
hamsters, and the one study in monkeys. One area of uncertainty is the
significance of liver tumors in certain strains of mice and the
appropriateness of extrapolating this information to humans. There is
little Information on the mechanism of action of DDT in these
susceptible species and whether or not species-specific biomarkers
exist. Another uncertainty results from more recent studies in which a
higher concentration is required to produce adverse health effects than
previously thought.
Genotoxicity. Experimental data indicate that DDT, DDE, and DDD
are carcinogenic in some species tested. However, the mechanism by
which DDT causes cancer in these animals, especially of mouse liver
tumors, is not known with certainty. The mechanism of carcinogenic
action may or may not be a genotoxic mechanism. Information on the
genotoxic effects of DDT may help elucidate this mechanism. Evidence
Indicates that DDT is nonmutagenic in bacterial systems i]i vitro. The
evidence in mammalian systems, including humans, both An vivo and in
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2. Health Effects
vitro is equivocal. More information would be useful to assess the
potential for genotoxic effects in humans.
Reproductive Toxicity. The information on reproductive toxicity in
humans exposed to DDT, DDE, or DDD is limited. However, information
exists in animals which provides evidence that DDT produces adverse
effects on reproductive capability in several species of experimental
animals.
Developmental Toxicity. Information concerning the developmental
effects of DDT, DDE, or DDD in humans was not located. Animal data
indicate that DDT is not a structural teratogen but is embryotoxic and
fetotoxic following high levels of oral exposure. There are limited
data in animals and none in humans that address the possibility of
subtle impairment to the developing fetus that may not be manifested by
overt clinical symptoms but rather as impaired functional ability, such
as learning or cognitive dysfunction.
Immunotoxicity. No usable information was located on the
immunotoxic effects in humans resulting from exposure to DDT. Some
information on DDT-induced immunotoxic effects in animals has been
reported, but these effects in animals are not well characterized. In
view of the complexity of the immune system, a multiple assay battery
would be helpful in order to evaluate the effects of DDT on major
components of the immune system.
Neurotoxicity. There is evidence to indicate that DDT is
neurotoxic in both humans and animals. While there are several studies
that indicate overt clinical signs of neurotoxicity to humans exposed at
relatively high doses, there are no data to evaluate the existence of
more subtle neurological effects and the significance of these effects
in humans. For example, one study in animals indicated that DDT may
affect the level of neurotransmitters and the amount of lipids in the
brain. Clinical observations of overt neurotoxicity such as tremors or
convulsions, have been reported, but data presenting the results of
histological examinations of organs and tissues of the neurological
system have not been reported. A battery of neurotoxicity tests would
provide further information of the neurotoxicity in animals, which then
might be related to possible neurotoxic effects in humans.
Epidemiological and Human Dosimetry Studies. Known health effects
in humans at high exposure levels of DDT, DDE, or DDD are irritation of
the eyes, nose, and throat, sweating, nausea, headache, tremors, and
convulsions. This information comes from studies where volunteers
ingested measured amounts of DDT and DDE and from clinical studies.
However, effects in experimental animals include liver alterations,
developmental and reproductive effects, and neurological effects. DDT
and its degradation products are found in virtually all air, water, and
soil samples. However, levels in most air and water samples are low and
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2. Health Effects
exposure through these pathways is minimal. A more important exposure
pathway is from the DDT and DDE which remain in the soil and which may
be transferred to crops grown in this soil. More information on the
effects of DDT, DDE, or DDD could be obtained from epidemiological
studies of people who live in areas where high concentrations have been
found. Information on exposure could be obtained from more frequent and
detailed market basket surveys and monitoring of the residues in
imported foods. Also, more insight could be gained through monitoring
and publishing data from NPL sites.
Studies have been located which monitor human tissues for DDT and
its metabolites. However, no correlation has been made between the
levels found in these tissues and specific disease states.
Biomarkers of Disease. Limited information exists concerning the
biological effects associated with specific concentrations of DDT, DDE,
or DDD in human blood and tissues. The available data suggest that the
presence of these chemicals at certain concentrations may be associated
with clinical symptoms, including leiomyomas, arteriosclerotic disease,
hypertension, diabetes, and possibly premature delivery and spontaneous
abortions in women. However, no information is available to establish a
causal relationship between DDT, DDE, or DDD concentrations in the blood
or other tissues and a specific disease state nor is there information
to correlate these blood levels with NOAELs and LOAELs for these
effects.
Disease Registries. Known health effects from ingestion of large
amounts of DDT include incoordination, numbness, weakness, and in severe
cases, seizure. However, there has been no correlation between normally
incurred exposure to DDT and any disease states. Epidemiological
studies may help identify the number of people affected and the factors
associated with identifying the adverse health effects in certain
populations, such as those people exposed to DDT from living or working
near hazardous waste sites.
Bioavailability from Environmental Media. No studies were located
regarding the bioavailability of DDT, DDE, and DDD from environmental
media. Although it is known that one can incur exposure to these
compounds in the environment, there is a lack of data to quantify the
bioavailability. In particular, it is known that fish bioaccumulate
these compounds and that those who consume these fish will incur some
exposure to these compounds. However, due to universal body burdens of
these compounds, the contribution of any particular media is not clearly
understood.
Food Chain Bioaccumulation. Little information was located
regarding food chain bioaccumulation of DDT, DDE, and DDD, although
fairly extensive monitoring of fish populations has been performed. A
clearer understanding of the potential for bioaccumulation would aid in
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63
2. Health Effects
determining how levels in the environment affect the food chain and
potentially impact human exposure levels. This type of information
could be obtained by studying accumulation of these compounds in
organisms from several trophic levels.
Absorption, Distribution, Metabolism, and Excretion. Qualitative
information from occupational and ingestion studies indicate that humans
absorb DDT via inhalation, dermal, and oral routes of administration.
No quantitative information exists concerning the rate or extent of
absorption following inhalation exposure, although some information
exists that quantifies the extent of absorption following oral
administration.
Information exists on the distribution of DDT, DDE, and DDD and on
the storage and release from storage of these compounds. However, there
is limited information on the long-term release rates from these storage
depots.
The metabolism of DDT in experimental animals appears to be well
described and there is some information on the metabolites found in
humans. Some species-specific metabolic differences, especially in the
area of efficiency of the conversion of DDT to DDE, have been
identified. However, the role of these metabolic differences in
species-specific sensitivity to toxicity, especially carcinogenicity, is
not well characterized. The presence of both an epoxide and an
acylating agent as DDD metabolites has been hypothesized in animals.
The significance of these compounds for cancer production or the
presence of these compounds in animals or humans has not been
identified.
Comparative Toxicokinetics. The metabolism studies by Gold and
Brunk (1982, 1983, 1984) indicate that the metabolism of DDT is
qualitatively similar among several species, but that the efficiency of
formation of certain metabolites and the proportion of metabolites
excreted may be quantitatively different. Differences in the
toxicokinetics of DDT among species may account for differences in toxic
responses, especially cancer. The potential for DDT to produce toxic
effects has been investigated in rats, dogs, mice, guinea pigs, and non-
human primates, but the animal species that serves as the best model for
extrapolating results to humans is not known. Ethical considerations
limit the amount of information that can be obtained in humans, but
analysis of urine of persons with known exposure to DDT to determine
levels of parent compound and metabolites could provide more information
on the metabolic pathways in humans. This information could help
identify an animal model to study toxic effects and mechanisms of
action.
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64
2. Health Effects
2.9.3 On-going Studies
A number of studies concerning health effects associated with DDT,
DDE, and DDD have been identified in the Federal Research in Progress
database.
Linda L. Uphouse (Texas Woman's University) is examining DDT and
other chlorinated pesticides to evaluate the neurotoxicity and
reproductive toxicity of these chemicals. Her studies will investigate
estrogen-mediated changes in central nervous system progesterone
receptors, pituitary luteinizing hormone release, and sexual behavior in
rats. The pesticides' antiestrogenic action at the CNS estrogen
receptor and disruption of neurotransmitter function will be studied.
If these pesticides decrease sexual behavior, sexual receptivity in
female rodents may be an effective tool for evaluating other potential
neuro/reproductive toxicants.
The neuropharmacological basis for tremor and hyperexcitability
produced by DDT and other compounds is being further studied by H.A.
Tilson (NIH). For example, in his previous work he found that phenytoin
blocked tremors induced by DDT and other compounds (Tilson et al. 1987).
Subsequent experiments found that systemic administration of
phenoxybenzamine attenuated the tremor and hyperexcitability produced by
chlordecone and DDT. Further study proposed by Tilson will emphasize
the neural substrate responsible for the modification of tremor and
startle reflexes mediated at the level of the brainstem.
F. Matsumura (NIH) is studying the toxic effect of DDT and other
pesticides in the liver and nervous system by identifying specific
enzyme systems that are sensitive and that are active in important
physiological functions. DDT has been found to bind to calmodulin, a
universal calcium binding protein, and thereby causes inhibition of
calmodulin-modulated enzyme functions. DDT apparently attaches to the
hydrophobic end of calmodulin and interferes with the ability to carry
calcium ions.
Donald Johnson (University of Kansas Medical Center) is examining
the hypothesis that the mode of action for DDT reproductive toxicity is
an altered embryo-uterine interaction at the time of implantation in
rats.
No on-going studies concerning environmental levels of DDT and its
metabolites associated with concentrations of these chemicals in the
body or human health effects were identified.
Timothy L. MacDonald (University of Virginia, Charlottesville) is
examining the chemical processes involved in the metabolism of
halocarbon compounds such as DDT which are catalyzed by cytochrome P-
450.
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65
2. Health Effects
W.J. Rogan (National Institute of Environmental Health Sciences,
NIH) is conducting a cohort follow-up epidemiological study of children
who were born to mothers exposed to different levels of chlorinated
chemicals. In this study he is examining the potential genotoxicity of
DDE and other chlorinated compounds in children exposed to these
compounds transplacentally and through breast milk.
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67
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
The chemical formulas, structures, and identification numbers for
DDT, DDE, and DDD are listed in Tables 3-la, 3-lb, and 3-lc,
respectively.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Important physical and chemical properties of DDT, DDE, and DDD are
listed in Tables 3-2a, 3-2b, and 3-2c, respectively.
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68
3. Chemical and Physical Information
TABLE 3~la. Chemical Identity of DDT
Property
Value
Reference
Chemical Name
Synonyms
Trade Name
Chemical Formula
Wiswesser notation
DDT
p,p'-DDT; 1,1,l-trichloro-2,2-bis(p-chlorophenyl)«thane;
Dichlorodiphenyl trichloroethane; i,4'DDT
Genitox, Anofex, Detoxan, P*ntachlorin, Dicophant,
Chlorophenothane
CuHgCls
GXGGYR DG&R DG
NIOSH 1905
NIOSH 1985;
CIS 1986
Epstein at al. 1972;
HSDB 1988
HSDB 1988
HSDB 1968
Chemical. Structure
Identification
Numbers:
CAS Registry
NIOSH RTECS
KQ>°
CCIa
50-29-3
KJ3325000
EPA Hazardous Waste U061;DDT
OHM-TAD
DOT/UN/NA/IMCO
SHIPPING
HSDB NO.
NCI NO.
STCC NO.
7216510
2761-55
NA2761
IMCO 6.1;DDT
UN2761
200
ND
k9 411 29
Klaassen et al.
1986
NIOSH 1985
NIOSH 1985
HSDB 1988
HSDB 1988
NIOSH 198 5
HSDB 1988
HSDB 1988
HSDB 1968
HSDB 1988
HSDB 1988
ND - No data
CAS - Chemical Abstracts Service
NIOSH - National Institute for Occupational Safety and Health
OHM-TADS - Oil and Hazardous Materials/Technical Assistance Data System
DOT/UN/NA/IMCO - Department of Transportation/United Nations/North America/International Maritime
Dangerous Goods Code
HSDB - Hazardous Substances Data Base
NCI - National Cancer Institute
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69
3. Chemical and Physical Information
TABLE 3-lb. Chemical Identity of DDE
Property
Value
Reference
Chomical Name
Synonyms
Trade Name
Chemical Formula
Wlswesser notation
DDE
DDT dihydrochloride; p,p'-DDE;
Dichlorodiphenyldichloroethylene;
1,l-Dichloro-2,2-bis(p-chlorophenyl)ethylene
ND
cuh8cia
GYGUYR DG7R DG
HSDB 1988
RSDB 1988
HSDB 1988
HSDB 1988
Chemical Structure
Identification
Numbers
CAS REG. NO.
NIOSH RTECS NO.
EPA HAZ. WASTE NO.
OHM-TADS NO.
DOT/UN/NA/IMCO
SHIPPING NO.
HSDB NO.
NCI NO.
STCC NO.
C,<0>5<0>CI
CCIj
72-55-9
KV9«50000
ND
ND
ND
1625
ND
ND
Klaassen et al.
1986
HSDB 1988
HSDB 1988
HSDB 1988
ND - No data
CAS - Chemical Abstracts Service
NIOSH - National Institute for Occupational Safety and Health
OHM-TADS - Oil and Hazardous Materials/Technical Assistance Data System
DOT/UN/NA/IMCO - Department of Transportation/United Nations/North America/International Maritime
Dangerous Goods Code
HSDB - Hazardous Substances Data Base
NCI - National Cancer Institute
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70
3. Chemical and Physical Information
TABLE 3-lc. Chemical Identity of DDD
Property
Value
Reference
Chemical Name
Synonyms
Trade Name
Chemical Formula
VJiswesser notation
DDD
1,1-bia (4 -chlorophenyl)-2,2-dichloroethane •
4,4'-DDD; 1,l-dichloro-2,2-bia(p-chlorophenyl)ethane
(German); 1,l-dichloro-2,2-bi«(p-chlorophenyl)ethane
(French); TDE
DDD; ftothane; Dilene
cuh10ci4
GYGYR DG4R DG
HSDB 1968
HSDB 1988
HSDB 1988
HSDB 1988
HSDB 1988
H
Chemical Structure
Identi fication
Numbers
CAS Reg. No.
NIOSH RTECS NO.
EPA HAZ. WASTE NO.
OHM-IADS NO.
DOT/UN/NA/IMCO
SHIPPING NO.
HSDB NO.
NCI NO.
STCC NO.
CI?CI
HCClj
72-54-8
KI0700000
U060; DDD
7215098
NA 2761;
28S
ND
IMCO;TDE
TDE
Klaassen et al.
1986
HSDB 1988
HSDB 1988
HSDB 1988
HSDB 1988
HSDB 1988
HSDB 1988
HSDB 1988
ND - No data
CAS - Chemical Abstracts Service
NIOSH - National Institute for Occupational Safety and Health
OHM-TADS - Oil and Hazardous Materials/Technical Assistance Data System
DOT/UN/HA/IMCO ~ Department of Transportation/United Nations/North America/International Maritime
Dangerous Goods Code
HSDB - Hazardous Substances Date Base
NCI - National Cancer Institute
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71
3. Chemical and Physical Information
TABLE 3-2*. Chamical and Fhyaieal Proparttaa of DDT
Property
Value
Refarenca
Molacular weight
Color
Fhyaieal state
Odor
Malting point, °C
Boiling point, °C
Solubility
watar, mg/L 825°C
organic aolventa
Danaity, g/em3
Odor thraahold
watar, mg/kg
air
Partition coefficient
?ow
Koc
Vajjor pranura I 20°C, torr
Henry's law eonatant,
atm-nr/mol
Autoignition temperature, °C
Flaah point, °C
Flaomability limita
Convaraion factors
ppre(v/v) to mg/m3 in air 6 20°C
mg//m3 to ppm(v/v) in air 0 20°C
354.49
Colorlaaa cryatala, whita powder
Solid
Odorlaaa or weak aromatic odor
108-109
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72
3. Chemical and Physical Information
TABLZ 3-2b. Chemical and Physical Proptrti»« of DDE
Property
Value
Reference
Molecular weight
Color
Physical itata
Odor
Malting point, °C
Boiling point, °C
Solubility
water, mg/L 025°C
organic tolvanta
Density (g/cm3)
Odor thraihold
water
air
Partition coefficient
log *<*,
*00
Vapor pressure at 20°C, torr
Hanry'i law constant,
atm-ar/mol
Autoignitlon temperature, °C
Flash point, °C
Flanmability limiti
Conversion factors
Ppn(Y/v) to B(/n3 in air • 20°C
mg/rn3 to ppm(v/v) in air • 20°C
316.03
White
Crystalline solid
HD
88.4-90
ND
0.12
Lipids and nott organic solvants
ND
ND
ND
7.00
*.* X 10®
6.5x10"® (p'p'J
6.2x10 (o'p')
6.8 X 10"3
ND
ND
ND
Pta(y/v> x 13.28 ¦ mg/sr
fog/io x 0.08 " pjm(v/v)
NIOSH 1977a
BSDB 1988
BSDB 1888
BSDB 1988
IAKC 1973
EPA 1986a
EPA 1986a
BSDB 1988
BSDB 1988
EPA 1986a
ND - no data
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73
3. Chemical and Physical Information
TABLE 3-2c. Chaalcal and Phyaical Propartias of DOD
Property
Valua
Rafaranea
Molaculac waight
320.03
HSDB 1986
Color
Colarlaaa crystals
, whita powdsr
BSDB 198S
Physical atata
Solid
HSDB 1988
Odor
Odorlaas
HSDB 1988
Malting point, °C
100-110
HSDB 1988
Boiling point, °C
193 • lad
ic
BSDB 1988
Solubility
watar, mg/L C23°C
organic aolvanta
Insolubls
ND
(maximum 0.160)
IARC 1973
Oanalty (g/m^>
1.3B3
BSDB 1988
Odor thraahold
watar
air
ND
ND
Partition coafflclant
lo» Ko,
*oe
8.20 .
7.7*10®
EPA 1988a
EPA 1988a
Vapor praaaura • 30°C, torr
10.2xl0~7
HSDB 1988
Httory'a law constant,
itarwr/mol
ND
Autoignltion taoparaturi, °C
ND
Flaah point
m
Flaomability limits
m
Convaraion factor*
ppo(y/v) to mg/or In air 1 20°C
mg/m3 to ppn(v/v) In air • 20°C
ppn(y/v) x
mt/ms x 0.
13.34 - ag/a3
07 ¦ ppa(v/v)
ND - no data
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75
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.1 PRODUCTION
Technical DDT is made by condensing chloral hydrate with chloro-
benzene in the presence of sulfuric acid. It was first synthesized in
1874, but it was not until 1939 that Mueller and his coworkers
discovered its insecticidal properties. Production of DDT in 1971 in
the United States was estimated to be 2 million kilograms (kg). This
represented a sharp decline from the 82 million kg produced in 1962, and
from the 56 million kg produced in 1960. In 1972, EPA announced that
DDT could no longer be used except in the case of a public health
emergency. In the U.S. in 1985, producers exported approximately
303,000 kg of DDT (HSDB 1988). Currently, there are three U.S.
companies which report manufacture of DDT (CSCORP 1989); however, no
data were located on the present levels of DDT production in the U.S.
There are still major producers of DDT in India and some Central and
South American countries. Information on the production of DDE and DDD
was not located.
4.2 IMPORT
DDT was last imported into the United States in 1972, when imports
amounted to 200,000 kg. Since 1972, no DDT has been imported.
4.3 USE
DDT was extensively used for the control of malaria, typhus, and
other insect-transmitted diseases during World War II. It has been used
worldwide in agriculture in the control of insects. In 1972, 4.5 to 6.4
million kg of DDT were utilized in the United States. Use on cotton
crops was estimated to account for 67% to 90% of the total use of DDT in
the U.S in 1972. The remainder was primarily used on peanut and soybean
crops. Since 1973, utilization of DDT has been limited to control
public health problems. It was estimated in 1973, that more than 2
billion kg of DDT had been used for insect control since 1940, about 80%
of that in agriculture. DDT was once registered for use on 334
agricultural commodities. Peak usage occurred in 1963, when 80 million
kg of DDT were used. DDD was also used as a pesticide and one form was
used medically in the treatment of cancer of the adrenal gland.
4.4 DISPOSAL
Under current federal guidelines, DDT and DDD are potential
candidates for incineration in a rotary kiln at a temperature of 820 to
1600°C. DDT formulated in 5% oil solution and other solutions are
mainly disposed of by using liquid injection incineration at a
temperature of 878°C to 1260°C, along with a residence time of 0.16 to
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76
4. Production, Import, Use, and Disposal
1.30 seconds and 26% to 70% excess air. Destruction efficiency was
reported to be >99.99%. Multiple-chamber incineration is also used for
10% DDT dust and 90% inert ingredients at a temperature range of 930 to
1210°C, along with a residence time of 1.2 to 2.5 seconds and 58% to
164% excess air. DDT powder may be disposed of by molten salt
combustion at a temperature of 900°C (no residence time or excess air
conditions specified). Landfill disposal methods are rarely used at the
present time.
4.5 ADEQUACY OF THE DATABASE
Section 104 (i)(5) of CERCLA directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of DDT, DDE, and DDD is available. Where adequate
information is not available, ATSDR, in cooperation with the National
Toxicology Program (NTP), is required to assure the initiation of a
program of research designed to determine these health effects (and
techniques for developing methods to determine such health effects).
The following discussion highlights the availability, or absence, of
exposure and toxicity information applicable to human health assessment.
A statement of the relevance of the identified data needs is also
included. In a separate effort, ATSDR, in collaboration with NTP and
EPA, will prioritize data needs across chemicals that have been
profiled.
4.5.1 Data Needs
According to the Emergency Planning and Community Right to Know Act
of 1986 (EPCRTKA), (§313). (Pub. L. 99-499, Title III, §313), industries
are required to submit release information to EPA. The Toxic Release
Inventory (TRI), which contains release information for 1987, became
available in May of 1989. This database will be updated yearly and
should provide a more reliable estimate of industrial production and
emission.
Production, Use, Release, and Disposal. Since the banning of DDT
in the early 1970's in the United States there has been little
information published on the production of DDT and DDD. No current data
were located on the domestic and world-wide production of these
compounds. This type of information is important for estimating the
potential for environmental releases from various uses, as well as
estimating the potential environmental burden. In turn, this would
provide a basis for estimating public health risk. The domestic or
world-wide uses of DDT, DDE, or DDD are not well documented despite the
use of DDT in some developing countries for vector control. Release
information might be used to estimate environmental burden and
potentially exposed populations.
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77
4. Production, Import, Use, and Disposal
Disposal information is equally important for determining
environmental burden and areas where environmental exposure may be hi
Although disposal methods of DDT and its metabolites are reported to
limited extent, no current information on disposal sites and quantity
disposed was located. Information on how the current users wash DDT
equipment and dispose of the remaining waste would be helpful for
estimating potential environmental and human exposure.
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79
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
Historically, DDT was released to the environment during its
formulation and extensive use as a pesticide in agricultural and vector
control applications. Although it was banned for use in this country in
1972, it is still being used in several areas of the world. DDT, DDE,
and DDD in the atmosphere are subject to photodegradation or
redeposition by rain or dry deposition. DDT and its environmental
degradation products preferentially bind to soil and sediment, where
they may be subject to photodegradation on the surface and
biodegradation in the subsurface. However, under certain conditions,
DDT may persist for long periods of time or may be converted to DDE,
which persists even longer. DDT, DDE, and DDD in water are subject to
sedimentation, volatilization, photodegradation, and uptake into the
food chain. Both DDT and DDE bioaccumulate in organisms, and levels are
subject to increase as they advance up the food chain. DDT and its
metabolites have been detected in virtually all media. Human exposure
in this country results primarily from ingestion of meat, fish, poultry,
and root and leafy vegetables.
5.2 RELEASES TO THE ENVIRONMENT
DDT and its primary metabolites, DDE and DDD, are not known to
occur naturally in the environment (WHO 1979). All releases of these
chemicals are related to their formulation and use as insecticides in
agriculture and vector control. Use of DDT, except in a public health
emergency, was banned in the United States in 1972. DDT has been found
at 66, DDE at 33, and DDD at 28 of 1177 NPL hazardous waste sites (VIEW
1989) . The EPA Contract Laboratory Program has collected data on the
occurrence, distribution, and concentration of chemicals found at sites
listed on the NPL and at other contaminated but non-listed sites. The
data are composed of samples from 45 sites. There is the potential for
release of DDT, DDE, and DDD from these sites to the environment. DDT
is still used in agriculture and for vector control in some tropical
countries (Coulston 1985), and direct release to the environment and
movement of residues through the environment and in imported goods may
result in potential low-level exposure to the population of the United
States. In addition, due to the extensive past use of DDT worldwide and
the persistence of DDT and its metabolites, these materials are
virtually ubiquitous and are continually being transformed and
redistributed in the environment.
5.2.1 Air
During the period when DDT was extensively used, a large source of
DDT release to air occurred during agricultural or vector control
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80
5. Potential for Human Exposure
applications. Because use of DDT was banned in the United States in
1972, release of DDT in recent years should be negligible in this
country. In 1985, there were two producers of DDT in the United States,
and in that year 303,000 kg of DDT were exported (HSDB 1988).
Production at these two facilities could have resulted in a small amount
of release of DDT via fugitive or noncontrolled emissions. However,
monitoring data for the areas surrounding these facilities were not
located.
Rapaport et al. (1985) measured DDT residues in peat lands across
the mid-latitudes of North America. These areas are unique in that they
receive all pollutant input from the atmosphere; therefore, they are
important indicators of global levels of certain chemicals. The
results, based on peat cores, snow, and rain samples, indicate that
there are continuing sources of direct input of DDT into the
environment, although levels are still relatively low (10% to 20% of
concentrations detected during the 1960s). They hypothesize that
atmospheric transport is occurring from areas where current use is
substantial.
Atmospheric release of DDT and its metabolites from disposal sites
or hazardous waste sites has not been documented but is likely
considering the physical and chemical properties of DDT.
5.2.2 Water
Historically, DDT was released to surface water when it was applied
primarily for vector control. This source of release may still be
occurring in countries which rely on DDT in the control of mosquitos as
vectors of malaria. In addition, the remaining producers of DDT may
discharge small amounts of DDT into wastewater through plant effluents.
5.2.3 Soil
In the United States, large amounts of DDT were released to the
soil via direct application of the pesticide or by direct or indirect
releases during manufacturing, formulation, storage or disposal. During
the peak of DDT production and use (1963), approximately 81,000 metric
tons were produced and 27,000 metric tons were utilized in the United
States alone (WHO 1979) . With the banning of DDT use in the United
States, large stores of these products were relocated to hazardous waste
sites where they are potential sources of release to soil. Information
to quantify such releases was not located.
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81
5. Potential for Human Exposure
5.3 ENVIRONMENTAL FATE
5.3.1 Transport and Partitioning
DDT and its metabolites may be transported from one medium to
another by the processes of solubilization, adsorption, bioaccumulation,
or volatilization. Each of these processes will be discussed in the
following paragraphs. Studies of DDT transformations in soils indicate
prolonged persistence. During these extended periods of time, these
compounds undergo extensive adsorption to soil particles, as predicted
by their organic carbon partition coefficients (Koc) of 2.4xl05, 4.4xl06,
and 7.7xl05, for DDT, DDE and DDD, respectively (EPA 1986a). DDT, DDE
and DDD are only slightly soluble in water (with solubilities of 0.0034,
0.12, and 0.160 mg/L at 25°C, respectively) (Verschueren 1983).
Therefore, loss of these compounds in runoff is primarily due to
transport of particulates to which these compounds are bound. Since
they are bound strongly to soil, they are not easily displaced from
their site of application, nor do they tend to leach to groundwater, and
appreciable amounts may remain in the soil for extended periods of time.
Volatilization of DDT and DDE is known to account for considerable
losses of these compounds from soil surfaces and water. Their tendency
to volatilize from water can be predicted by their Henry's law
constants, 5.13x10"* and 6.8xl0"5 atm-m3/mol, respectively, and from soil
surface by their vapor pressures, 5.5xl0"6 and 6.5xl0~6 Torr
respectively, and the organic content of the soil (EPA 1986a). The
tendency of DDD to volatilize is approximately three-fold less than that
of DDT or DDE. Estimates of the rate of loss from volatization of DDT
from water range from several hours to 50 hours (HSDB 1988). Laboratory
studies of the air/water partition coefficient of DDE indicate that it
will volatilize from seawater 10 to 20 times faster than from freshwater
(Atlas et al. 1982). The authors suggest that this process may be
related to interaction at the bubble-water surface.
Small particles which carry DDT or its degradation products may
also be distributed through the atmosphere. Once volatilized or
airborne, transport of these compounds into the ambient atmosphere of
North America is facilitated by a circulation pattern which brings
moisture from the Gulf of Mexico into the Midwest and airflow patterns
across the eastern seaboard (Rapaport et al. 1985). Residues are
removed from the atmosphere by precipitation, diffusion into large
bodies of water, and chemical transformation. Precipitation is believed
to account for the greatest rate of removal from the atmosphere
(Woodwell et al. 1971). Vhen DDT is released to water, it quickly
adsorbs to particles and is subject to sedimentation, or may
bioconcentrate in microorganisms and can become part of the food chain.
DDT, DDE, and DDD are highly lipid soluble, as reflected by their
log octanol-water partition coefficients (log Kow) of 6.19, 7.00, and
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82
5. Potential for Human Exposure
6.20, respectively (EPA 1986a). This lipophilic property, combined with
an extremely long half-life, has resulted in bioaccumulation (levels in
organisms exceed those levels occurring in the surrounding environment).
When they are present in ambient water, DDT and its metabolites are
concentrated in freshwater and marine plankton, insects, mollusks, other
invertebrates, and fish. As these organisms become part of the food
chain, a progressive accumulation of residues may result in high levels
of residues in organisms at the top of the food chain. In some cases,
humans may be the ultimate consumer of these contaminated organisms.
The bioconcentration factor (BCF) is defined as the ratio at equilibrium
between the concentration of the chemical in the organism or tissue of
the organism, and the concentration of the chemical in the surrounding
media. There are numerous measurements and estimates of BCFs in fish.
Oliver and Niimi (1985) estimated the steady-state BCF in rainbow trout
as 12,000. Geyer et al. (1986) reported a BCF of total DDT in humans to
be 1646 (on lipid basis, mg/kg).
5.3.2 Transformation and Degradation
Environmental processes contribute to the degradation arid
transformation of DDT to different extents. These mechanisms may
account for the fact that levels of DDT worldwide have more or less
remained constant and not accumulated (Coulston 1985).
5.3.2.1 Air
Under simulated atmospheric conditions, both DDT and DDE decompose
to form carbon dioxide and hydrochloric acid (WHO 1979). In air and
sunlight, DDT is subject to direct photooxidation and reaction with
photochemically produced hydroxyl radicals. The latter process has an
estimated half-life of 2 days. Since DDT residues are ubiquitous in the
atmosphere, it seems likely that photodegradation must occur at a slow
rate. DDT which reaches the photochemically active ionosphere may be
rapidly destroyed by solar irradiation as indicated under laboratory
conditions (Coulston 1985).
5.3.2.2 Water
DDT present in water may be partitioned, transported, or converted
in several ways: adsorption to sediments, bioconcentration in aquatic
organisms, volatilization, photodegradation, and biodegradation. DDT in
water is photodegradable by wavelengths of light which are present in
the troposphere (Coulston 1985). DDT in excess of water solubility
limits is adsorbed onto sediments which act as the primary reservoir for
excess quantities of DDT. There it is available for ingestion by
organisms. Biodegradation by aquatic microorganisms is reported to be a
minor source of transformation (Johnsen 1976).
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83
5. Potential for Human Exposure
5.3.2.3 Soil
Four mechanisms have been suggested to account for most losses of
DDT residues from soils: 1) volatilization, 2) removal by harvest of
organic matter, 3) water runoff and 4) chemical transformation (Fishbein
1973). DDT is subject to volatilization, with an estimated half-life of
100 days (Sleicher and Hopcraft 1984). Photooxidation of DDT is known
to occur on soil surfaces; however, DDT is not known to hydrolyze
(Lichtenstein and Schultz 1959). Biodegradation may occur under both
aerobic and anaerobic conditions in the presence of certain soil
microorganisms (HSDB 1988). Under aerobic conditions, slow conversion
to DDE normally occurs, whereas, under anaerobic conditions, conversion
to DDD results and is much more rapid than the aerobic conversion to
DDE. Under aerobic conditions, dehydrochlorination is the dominant
reaction, while under anaerobic conditions, reductive dechlorination
occurs. Both metabolites are very resistant to further transformation.
Due to the prolonged half-life of DDE, average levels of DDT are
expected to decline slowly while the ratio of DDE to DDT is expected to
increase. Estimates of the half-life for DDT biodegraded in soil range
from 2 to >15 years (Lichtenstein et al. 1959; Stewart and Chisholm
1971).
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
5.4.1 Air
Stanley et al. (1971) measured atmospheric levels of pesticides
during a time of high DDT usage. Nine localities were sampled
representing both urban and agricultural areas. Of 12 pesticides
evaluated, only DDT was detected at all localities. Maximum levels of
DDT ranged from 1.4 to 1560 ng/m3, while those for DDE ranged from 1.9
to 131 ng/m3. DDD was found at a maximum concentration of 33.3 ng/m3.
Highest levels were found in the agricultural areas of the south. The
authors reported that their samples indicated that most pesticides were
present in the particulate phase.
Some agricultural areas in which DDT was extensively used have been
monitored periodically since usage was halted. Atmospheric conditions
in the Mississippi Delta were monitored intermittently from 1972 through
1975 (Arthur et al. 1977). Air samples taken in 1975 were from an area
with extensive cotton acreage. The arithmetic mean for those samples
was 7.5 ng/m3, compared to similar sampling in 1974 with an arithmetic
mean of 11.9 ng/m3. The authors reported that by 1975, the arithmetic
mean of DDT and its metabolites combined had decreased 92% in the area
sampled since the ban of DDT use.
Ten samples taken in the Gulf of Mexico in 1977 contained an
average of 0.034 ng/m3 of DDT, with a range of 0.010 to 0.078 ng/m3
(Bidleman et al. 1981).
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84
5. Potential for Human Exposure
Ligocki et al. (1985) conducted concurrent rain and air sampling
for rain events in Portland, Oregon in 1984. In rain samples, no p,p'-
DDT, p,p'-DDE, or p,p'-DDD were detected. However, in the gas phase
associated with this rainfall, p,p'-DDE was detected in 5 of 7 samples.
Levels detected ranged from non-detected to 0.42 ng/m3, in the samples.
Rapaport et al. (1985) measured DDT residues in peatlands across
the mid-latitudes of North America. These areas are unique in that they
receive all pollutant input from the atmosphere; therefore, they are
important indicators of global levels of certain chemicals. Samples of
snow taken during 1981 and 1982 contained an average of 0.32 ng/L of
p,p'-DDT while those taken during 1982 and 1983 contained an average of
0.60 ng/L. Samples taken during 1983 and 1984 contained levels of 0.18
ng/L of DDT. Rain samples at these same locations in 1983 contained an
average of 0.3 ng/L DDT. Although the sample numbers in this study were
low (total of 11 samples), the results indicate that there is still
measurable global contamination with DDT.
5.4.2 Water
Although there are numerous reports in the literature of DDT levels
in specific bodies of water throughout the United States, there is
little information which allows one to observe trends in the DDT levels
over time. EPA operates STORET (STOrage and RETrieval), a computerized
water quality database; however, little of that information has been
made available to the public. Staples et al. (1985) reported limited
data on priority pollutants from STORET. Information from data
collected from 1980 to 1983 indicated that from 3500 to 5700 ambient
water samples were analyzed for DDT, DDE, and DDD with approximately 45%
of the samples containing one of these compounds. The median level
reported for both DDT and DDE was 1 part per trillion (ppt), while the
median level reported for DDD was 0 ppt. Approximately 50 samples of
industrial effluents had been sampled and showed median levels of 10 ppt
for all three compounds.
During the same time period approximately 1100 samples of sediments
from water bodies were analyzed. The median levels for DDT, DDE, and
DDD were 0.1, 0.1, and 0.2 ppb, respectively. Biota from selected sites
were found to contain all three compounds, with DDT, DDE, and DDD
detected at median levels of 14, 26, and 15 ppm (Staples et al. 1985).
A summary of pesticide levels in surface waters of the United
States during 1967 and 1968 was reported by Lichtenberg et al. (1970).
During these 2 years (which were prior to the ban of DDT use), a total
of 224 samples were analyzed from various sites in all regions of the
country. The results of samples analyzed in the 2 year period indicated
that DDT was found in 27 samples at levels ranging from 0.005 to 0.316
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85
5. Potential for Human Exposure
^g/L; DDE was found in three samples at levels of 0.02 to 0.05 /ig/L; DDD
was found in six samples at levels of 0.015 to 0.840 Mg/L-
The U.S. Geological Survey and EPA cooperatively monitored levels
of selected pesticides in the water and bed material at more than 150
river sites between 1975 and 1980. Gilliom (1984) reported the number
of samples taken and percent positive found. For DDT, DDE, and DDD in
water, 177 stations were monitored and 2.8%, 0.6%, and 4.0% were
positive for the three compounds, respectively. Sediments from 171
stations were tested and 26%, 42%, and 31% were positive for DDT, DDE,
and DDD contamination, respectively. However, levels detected in these
various media were not reported.
Other reports of DDT and related metabolites in particular bodies
of water are numerous. Drinking water in Oahu, Hawaii was found to
contain p,p'-DDT at an average level of 1 ppt in 1971 (Bevenue et al.
1972). Sampling at three drinking water plants in New Orleans resulted
in 67% of samples testing positive for DDE; levels were not quantified
(Keith et al. 1976). Kraybill (1977) cites a 1976 EPA list of suspected
carcinogens in drinking water which reports DDT was present in
nondetectable quantities while DDE was present at levels of 0.05 ppb.
The specific isomers detected were not reported.
Johnson et al. (1988) report DDT and metabolite levels in the
Yakima River basin in Washington State. Use of DDT was halted in this
area when the 1972 ban was initiated; however, considerable residues are
present in the river and sediments. Water samples, primarily in the
tributaries, were reported to contain between non-detectable to 0.06
tig/h of total DDT compounds, while river bed sediment samples contained
from 0.1 to 234 /ig/kg of total DDT compounds (DDT+DDE+DDD).
Concentrations of p,p'-DDT in water equaled or exceeded those of p,p'-
DDE: an unexpected finding in light of what is believed concerning
biological half-lives of DDT and its normal environmental degradation.
The authors indicated that these findings suggest an unusually long
half-life for DDT in Yakima basin soils.
5.4.3 Soil
The United States National Soils Monitoring Program has provided
valuable information on the overall pattern of DDT residues in soil
during the years following the DDT ban. Each year since the ban of DDT,
approximately 1500 samples were taken. In 1970, samples contained an
average of 0.18 ppm p,p'-DDT (Crockett et al. 1974), while in 1972,
samples contained an average of 0.02 ppm (Carey et al. 1979). In 1973,
levels of the p,p'- and o,p'- isomers averaged 0.13 ppm (HSDB 1988).
DDT was extensively used in Arizona for 18 years, after which
agricultural residues were closely monitored following a statewide
moratorium on DDT use in January, 1969. Levels of DDT plus metabolites
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5. Potential for Human Exposure
in green alfalfa fell steadily from an average level of 0.22 ppm at the
time of the ban, to a level of 0.057 ppm 18 months later, and a level of
0.027 ppm after almost 7 years (Ware et al. 1978). After 3 years,
residues in agricultural soils had decreased 23%. Furthermore, the
ratio of DDE:DDT was increasing, indicating a transformation of DDT to
DDE. Buck et al. (1983) reported similar results from monitoring these
same sites over 12 years following the ban on DDT use. After 12 years,
residues in green alfalfa averaged 0.020 ppm. At the end of the same
period, combined DDT and DDE residues in agricultural soils had fallen
from 1.2 ppm to 0.39 ppm, while those in surrounding desert soil had
fallen from 0.40 to 0.09 ppm.
5.4.4 Other Media
Market basket surveys indicate that there have been continual
decreases in the overall levels of DDT and DDE in all classes of food
tested from 1965 to 1975 (EPA 1980b). Between 1970 and 1973, DDE
residues decreased only 27% compared to a decrease of 86% and 89% for
DDT and DDD, respectively (EPA 1980b). A study by Duggan et al. (1983)
reported the following average residues in grocery items from 1969 to
1976: domestic cheese, 3 ppb; ready-to-eat meat, fish and poultry, 5
ppb; eggs, 4 ppb; domestic fruits, 13 ppb; domestic leaf and stem
vegetables, 24 ppb; domestic grains, 7 ppb; corn and corn products, 0.7
ppb; peanuts and peanut products, 11 ppb.
Current market basket surveys have been reported by Gartrell et al.
(1985, 1986). Results of these surveys are summarized in Table 5-1.
Overall, these surveys indicate that DDT and DDE levels are very low in
food commodities and are decreasing. However, with continued use of DDT
in other countries, imported foods may continue to contribute small
amounts of DDT and DDE to the daily diet of consumers.
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
The general population is exposed to DDT and its metabolites
primarily as a result of ingestion of small amounts in the diet. As
indicated in the previous section, although residue levels in food
continue to slowly decline, there are measurable quantities in many
commodities. Because of the extreme persistence of DDT and DDE, it is
anticipated that low levels of residues will be present in commodities
for decades to come. In fact, depending on use and export patterns in
other countries, levels in the diet may even increase (Coulston 1985).
Even in domestic commodities, the potential for low-levels of dietary
exposure to consumers may result from residues bioaccumulated in some
food items.
The estimated dietary intake of DDT and metabolites in the United
States in 1970 was 420 /ig/day, and in 1974, 8 /ig/day (Coulston 1985).
Current market basket surveys indicate that dietary intake of DDT and
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87
5. Potential for Human Exposure
TABLE 3-1. Residue* in Adult Total Diat Samples
Baaed on Market Baakat Survey*
Octobar 1978 - September 1880s October 1980 - March 1982b
DDE DDT DDE DDT
(ppb) (ppb) (ppb) Cppb)
Dairy product*
0.9
0
1.5
0
Meat, flah and poultry
4.8
0.8
3.0
0
Sraina and caraal
0
0
0
0
Potatoes
0.5
<0.1
0.5
0
Leafy vegetable!
1.7
0.2
2.4
0.4
Legume*
0
0
<0.1
0
Root vegetable*
1.0
0
4.6
0.6
Garden vegetable*
0.2
0
0.1
0
Frulta
0
0
<0.1
0
Oils and fata
<0.1
0
<0.1
0
Sugar
<0.1
0
<0.1
0
Beverages
0
0
0
0
'Adapted from Gartrell et al.(1985)
bAdapted from Gartrell at al. (1986)
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88
5. Potential for Human Exposure
DDE in 1980 was 2.4 /ig/day (Gartrell et al. 1985), and in 1981 was 2.2
Hg/day (Gartrell et al. 1986). The acceptable daily intake of DDT from
food established by WHO/FAO is 5 ^g/kg/day or 350 ,wg/day (WHO 1979).
DDT and DDE selectively partition into fatty tissue, and human
breast milk has a higher fat content than cow's milk. Therefore, these
compounds are found in human breast milk in concentrations higher than
in cow's milk or other infant foods. As a result, breast-fed infants
may receive higher dietary exposure than children who are not breast
fed.
Due to the extremely low solubility of DDT and DDE in water and to
standard water treatment methods, intake of these compounds via drinking
water is believed to be negligible. The criteria cited in the EPA
Ambient Water Quality Criteria document is 0.0024 ng/L and is based on
ingestion of 2 liters of drinking water per day plus 6,5 grams of fish
and shellfish (EPA 1980b). This criteria corresponds to an increased
cancer risk level of lxlO"7 or one cancer per 10 million persons
exposed.
Data indicate that, even with relatively high doses, there is
minimal absorption of DDT through skin (Gaines 1969; Wolfe and Armstrong
1971). Therefore, exposure via dermal absorption is considered to be
negligible. DDT and its metabolites are ubiquitous in the atmosphere
but in such low concentrations that exposure via inhalation is
negligible. Potential inhalation of relatively high levels of DDT
should be possible only in areas of production or formulation. Wolfe
and Armstrong (1971) estimated a respiratory exposure potential of 14.1
mg/person/hr for formulating plant workers; however, no current data
were located on exposure to workers utilizing modern technology in the
production and formulation of these compounds.
DDT and DDE elimination from the body is not an efficient process,
therefore, tissue levels will probably increase with repeated exposure.
For this reason, body burdens of DDT and DDE tend to correspond with
exposure levels, as indicated in long-term studies. From July 1969 to
1975, residues of DDT and its metabolites were measured in human adipose
tissue collected through an annual national survey-the National Human
Monitoring Program for Pesticides (Kutz et al. 1977). During that time
levels of DDT and DDE in tissue samples declined. However, the
frequency of occurrence in lipid samples did not decline, indicating
both a long biological half-life and the ubiquitous occurrence of these
compounds in the population. For fiscal years 1970 through 1974 all
samples were positive for DDT and metabolites (a total of 1412 samples).
Using all age groups sampled, the geometric mean lipid DDT and
metabolite (combined) levels reported for years 1970 through 1974 were
7.88, 7.95, 6.88, 5.89, and 5.02 ppm, respectively. Notable trends
reported in Kutz et al. (1977) included increasing body burden with
increasing age as well as a significant increase in residues in Blacks
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89
5. Potential for Human Exposure
when compared to Whites. Results published for 1975 showed little
change from 1974 (Kutz et al. 1979).
The Second National Health and Nutrition Examination Survey (NHANES
II) has served as a continuation of the National Human Monitoring
Program; however, published results have been few. Murphy and Harvey
(1985) published selected results from the NHANES II survey for 1976 to
1980 based on data from the northeast, midwest, and south. These
results are based, not on lipid samples, but on serum samples. For the
years covered, 3300 serum specimens were analyzed for DDT and DDE. In
31% of those samples p,p'-DDT was detected, with a median quantifiable
level of 3.3 ppb (0.0033 ppm). However, in 99% of those tested p,p'-DDE
was detected, with a median quantifiable level of 11.8 ppb (0.0118 ppm).
These results offered further proof of the extensive biological half-
life of DDE as compared to DDT. Again, for both compounds, serum levels
increased with increasing age. These data were not reported for each
year, but a decreasing trend could certainly be expected based on the
data of Murphy and Harvey (1985).
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
Because of the ban on DDT use, few persons should be exposed to
high levels of these compounds. Workers involved with formulation of
DDT would be exposed to levels higher than those encountered in the
environment. As previously mentioned, because of the partitioning of
DDT and DDE into fatty tissue, breast-fed infants are likely to receive
doses in excess of those occurring from ingestion of cow's milk or other
infant foods. Monitoring of exposure to infants via breast milk has
been extensive and provides evidence of the persistence of DDT and DDE
in fatty tissues.
5.7 ADEQUACY OF THE DATABASE
Section 104 (i)(5) of CERCLA directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of DDT, DDE, and DDD is available. Where adequate
information is not available, ATSDR, in cooperation with the National
Toxicology Program (NTP), is required to assure the initiation of a
program of research designed to determine these health effects (and
techniques for developing methods to determine such health effects).
The following discussion highlights the availability, or absence, of
exposure and toxicity information applicable to human health assessment.
A statement of the relevance of the identified data needs is also
included. In a separate effort, ATSDR, in collaboration with NTP and
EPA, will prioritize data needs across chemicals that have been
profiled.
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5. Potential for Human Exposure
5.7.1 Data Needs
Physical and Chemical Properties. Physical and chemical properties
are well described in the literature.
Environmental Fate. Data on the environmental fate of DDT and its
metabolites are abundant for the late 1970s. More studies on global
redistribution would contribute to the knowledge of the environmental
fate of DDT.
Exposure Levels in Environmental Media. Information on
environmental levels of DDT, DDE, and DDD are abundant for the late
1970s. New information on environmental levels would contribute to the
understanding of current worldwide concentrations and trends.
Exposure Levels in Humans. There are two major sources of
information on pesticide exposure of the general population of the
United States, the NHANES II, which utilized analysis of blood, serum,
and urine, and the National Human Adipose Tissue Survey. However,
comprehensive results of these surveys have not been published in
accessible journals. Improved accessibility of these data would enable
us to monitor current levels in humans and determine if the levels have
decreased as expected.
Exposure Registries. An exposure registry, even for occupationally
exposed groups, currently is not available. The development of a
registry of exposures would provide a useful reference tool in assessing
exposure levels and frequencies. In addition, a registry developed on
the basis of exposure sources would allow an assessment of the
variations In exposure levels from one source to another and the effect
of geographical, seasonal, and regulatory actions on the level of
exposure within a certain source. These assessments, in turn, would
provide a better understanding of the needs for research or data
acquisition based on the current exposure levels.
5.7.2 On-going Studies
L.E. Chase (Cornell University) is examining the variation in
nutrient composition in specific types of by-product feeds. Lactating
dairy cows were fed diets containing 50% of the total ration dry matter
as apple pomace for nine days. The apple pomace contained 88 ppb of DDE
residue. The milk from these cows contained 1.88 ppb DDE.
D.J. Lisk (Cornell University) is examining the metabolism and fate
of DDT and other pesticides and their residues in or on agricultural
commodities being fed to livestock by commercial animal or milk
producers. Small amounts of DDT were found In the milk of cows fed
commercial apple pomace on both a short- and long-term basis.
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5. Potential for Human Exposure
L.F. Ohraann is the principal investigator in a study to analyze
atmospheric deposition samples worldwide through analysis of
precipitation and peatcores. Current results indicate that present
input of DDT from the atmosphere is about 10% to 20% of that during peak
use around 1960. This study will continue through 1989.
The U.S. Department of Agriculture is conducting a study of
watershed processes for hydrologic modeling. Studies are being carried
out on specific components of the hydrolytic cycle. The focus of this
work is to develop and improve models of these components and to improve
their representation of physical processes. A study of an intensively
cultivated watershed showed that seven years after spraying had ceased
DDT was still available to surface water in streams and lakes by way of
eroded soil materials.
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93
6. ANALYTICAL METHODS
The purpose of this section is to briefly describe the analytical
methods for detecting and/or measuring, and to some extent monitoring
DDT, DDE, and DDD in environmental media and in biological samples. Our
intent here is not to provide an exhaustive list of analytical methods
that could be employed to detect and quantify DDT, DDE, and DDD.
Rather, we intend to identify well-established methods that are used as
the standard methods of analysis by various federal agencies. Many of
the analytical methods used to detect DDT, DDE, and DDD in environmental
samples are methods approved by federal agencies such as the
Environmental Protection Agency (EPA) and the National Institute for
Occupational Safety and Health (NIOSH). Other methods presented in this
section are those that are approved by a trade association, such as the
Association of Official Analytical Chemists (AOAC) and the American
Public Health Association (APHA). A third category of analytical
methods emphasizes research and development activities in which efforts
are underway to refine previously used methods, to obtain better
resolution, and to increase accuracy and precision.
The analytical methods used to quantify DDT, DDE, and DDD in
biological and environmental samples are summarized below. Tables 6-la,
6-lb, and 6-lc list the applicable analytical methods used for
determining DDT and its metabolites found in biological fluids and
tissue, and Tables 6-2a, 6-2b, and 6-2c list the methods for measuring
DDT and its metabolites (DDE and DDD) in environmental samples.
6.1 BIOLOGICAL MATERIALS
Blood, serum, semen, urine, breast milk, and adipose tissue are
most frequently examined to detect exposure to DDT and its metabolites,
DDE and DDD, because of ease of sample collection and the availability
of a variety of analytical methods.
DDT, DDE, and DDD residues have been primarily measured in
biological samples such as adipose tissue, blood serum, urine, milk and
other samples by gas chromatographic (GC) methods. The GC methodology
proposed by Cranmer et al. (1972b) has detected DDT, DDE, and DDD in
human urine at levels as low as 50 pg. Various authors cited in Tables
6-la, 6-lb, and 6-lc used GC methods to monitor the residues of these
compounds in blood, serum, semen, liver, human milk, and adipose tissue,
which were detectable at the part per million and part per billion
level.
There are methods for measuring DDT in blood, serum, urine, semen,
liver, and adipose tissue; however, examination of blood, urine, and
semen is most frequently conducted to determine exposure because of ease
of sample collection. Although these methods can detect and quantify
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94
6. Analytical Methods
TABLE 6-la. Analytical Methods far Determining DDT In Biological Materials
Sample Matrix
Sample
Preparation
Analytical
Method
Sample
Detection
Limit
Blood/plasma/
a arum
Semen
Urine
Nanograde hexane EC/GC 2 ppb
extraction
Mixed in acetic acid, EC/GC ND
1:1 ratio, then
petroleum ether and
acetone extraction,
Florisil-column cleanup
Mix with acetic acid EC/GC 0.50 pg
in hexane followed HPLC/NAA 0.01 mg/ml
by methylation
Accuracy
> 90S
ND
97.61 (p,p')
96.61 (o,p' )
References
Nachman et al. 1972
EPA 1980c
Waliszewski and
Syzmczneki 1983
95-96X (p,p') Cranmer et al. 1972b
ND HSDB 1968
Hair
ND
ND
HD
ND
Liver and
kidney
Muscles
Human milk
Sample macerated with EC/GC
acetonitrile, aqueous
sodium sulfate solution
added, residues par-
titioned into hexane,
clean-up/separation with
Florisil column and
hexane, methanol elution
ND
ND
ND
ND
Hexane extraction, GC/MS
Florisil column cleanup
Sample macerated with EC/GC
acetonitrile, aqueous
¦odium sulfate solution
added, residues par-
titioned into hexane,
clean-up/separation with
Florisil column and
hexane, methanol elution
EPA 1980c
ND
2.0 ppb
ND
ND
ND
ND
Krauthacker et al
1980
EPA 1980c
Adipose tissue Co-extracted with EC/GC 0.25 ppm (o,p') 1051 Barquet et al. 1961
(1:1) acetonitrile, 0.31 ppm (p,p') 103Z
and acetone (v/v),
followed by addition of
sodium sulfate, final
extraction with hsxane,
separated on chromaflex
column
Sample macerated with EC/GC ND 85-100* EPA 1980c
sand and anhydrous
sodium sulfate and
extracted with petroleum
ether, residues extracted
with acetonitrile then
back extracted into pet-
roleum ether, clean-up/
separation with Florisil
column
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95
6. Analytical Methods
TABLE 6-l«, (Continued)
Sample
SampLa Matrix Preparation
Sampl*
Analytical Detection
Mathod Limit
Accuracy
Rafarancaa
Lymph
Co-extracted with HFLC
ether, than centri-
fuged, final axtrac-
tion with 0.1 ml of
cyclopentanone
KD
96.*:
Nojuchi at al. 19SS
HD - no data
EC * alactron captura detector
OC - gae-liquid chromatography
HFLC " high performance liquid chromatography
HAA " neutron activation analyaii
MS " maai ipectroscopy
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96
6. Analytical Hethods
TABLE 6-lb. Analytical Method* for Determining DDE in Biological Materials
Sample Matrix
Sample
Preparation
Analytical
Method
SarapLe
Detection
Limit
Accuracy
References
Blood/plesrea/
serum
Semen
Urine
Hair
Liver and
kidney
Muscles
(skeletal)
Human milk
Extracted with EC/GC
methanol and hexane-
ethyl ethers, Florlsil
column clean-up
Nanograde hexane EC/GC
extraction
Mixed in acetic acid EC/GC
in 1:1 ratio, then in
petroleum ether and
acetone extraction
Mixed in acetic acid EC/GC
in hexana followed
by methylatlon
Extracted with hexana EC/GC
ND ND
Hexane, sulfuric acid
oil extraction
GC
Extracted by n-hexana EC/GC
Sample macerated with EC/GC
acetonitrile, aqueous
sodium sulfate solution
added, residues par-
titioned into hexane,
clean-up/separation
with Florlsil column
and hexane, methanol
elution
Homogenized and
extracted with hexane
Triple solvent
extraction using
ethanol, hexane, then
hexane-ethyl ether,
Florlsil column clean-
up
Adipose tissue Digested by
perchloric-acetic
acid mixture,
extracted by n-hexane
Feces
Skin
Homogenized and
extracted with hexane
Homogenized and
extracted with hexane
EC/GC
EC/GC
EC/GC
EC/GC
EC/GC
0.8 ppb
1 ppb
1 ppb
ND
ND
2 pg
ND
ND
2 PS
ND
2 pg
2 ppb
2 pg
2 Pg
2 pg
90-1001
100-1101
ND
91.4!
McKinney at al. 1984
Nachman at el. 1972
EPA 1980c
Wslisxewski and
Syzmcznski 1983
94-961
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97
6. Analytical Methods
TABLE 6-lc, Analytical Hatboda Car Datamini ng ODD in Biological Matariala
Sampla Matrix
Sampla
Preparation
Analytical
Mathod
Sampla
Dataction
Limit
Accuracy
References
Blood/plasma/
a arum
Nanograda haxana
axtraction
EC/GC
2 ppb
ND
EFA 1980c
Sanan
Mixad in aeatie acid,
1:1 ratio, than
patrolaun athar and
acatona axtraction
EC/GC
HD
91.«X
Waliszawski and
Syzmcznski 1983
Urina
Mix with aeatie aeid
in haxana followed
by mathylation
OC
HD
94-97X
ND
Livar and
kidnay
Formic acid and
n-haxana axtraction
EC/GC
WD
81. 51
Ando 1979
EPA 1980c
Muse las
ND
ND
ND
HD
Human milk
Haxana axtraction
EC/GC
GC/MS
1.5
80-1001
Krauthacker at al.
1980
NO-no data
EC - alactron eaptura datactor
OC - gas-liquid chromatography
MS - mass spectroscopy
-------
98
6.
Analytical Mechods
TABLE 6-2a. Analytical Method* for Datarminin£ DDT in bvltonMntil Saatplea
SMipl® Matrix
Air
Watar
Soil
Food
Sample
Preparation
Mixed in petroleum
ether and hexane,
separated with silicic
•cid column
Filter collection
and iso-octane
extraction
Extraction of mam-
bran* with haxana
and than acetonitrile
Extraction with
methylene chloride,
c lean-up/separation
with a Florisil column
Mixed and shaken
in 0.2M ammonium
chloride solution,
then add hexane-
acetone, clean-up/
separation with
Florisil column
Medium-dependent,
aolvent extraction
than solvent-haxana
exchange with a K-D
apparatus, claan-up/
separation with a
Florisil column
Sample dependent
preparation, extracted
with acetonitrile into
petroleum ether,
clesnup/seperetion
with Florisil column
Analytical-
Method
EC/GC
Sample
Detection
Limit
Accuracy
GC
GC; Metric*}-
filter circl*
104-106*
0. *9-2.60 mg/m3
(CVT>
ND 8 SI
EC/GC
EC/GC
0.012 mil
ND
921
ND
GC with
EC or USD
EC/GC
0.012 (ig/L
931
ND
801
ND - no data
EC - slectron capture dector
GC - gaa-liquid chromatography
BSD - halogen-specific detector
R*t«rances
Bidleman «t al. 1978
HSDB 1866
NIOSH 1877b
Kurt* 1877
EPA 1982
Williams 1984
EPA 1986b
Williams 1984
McMahon and Burke
1978
-------
99
6. Analytical Methods
TABLE 6-2b. Analytical Methods for Determining DOE In Envirooaental Samples
Sample Matrix
Sample
Preparation
Analytical
Method
Sample
Detection
Limit
Accuracy
References
Air
Water
Soil
Food
Mixed in petroleum
ether and hexane,
separated with
silicic acid column
ND
Extraction with
methylene chloride
clean-up/separation
with a Florisil column
Mix and shaka in
0.2M amnonium chloride
solution and then add
hexana acetone, clean-
up/separation with a
Florisil colunn
Had iunrdependent
solvent extraction
than aolvent-hexane
exchange with a K-D
apparatus, clean-up/
separation with a
Floriail colunn
Sample dependent
preparation, extrected
with acetonitrila into
petroleum ether, clean-
up/separation with
Florisil column
EC/GC
ND
EC/GC
EC/GC
ND
HD
0.004 pg/L
HD
100%
74X
89X
ND
Bidleman et al. 1976
Kurtz 1977
EPA 1982
Williams 1984
GC with
EC or BSD
EC/GC
0.004 nt/L
85X
EPA 1986b
> BOX
Williams 1984
McMahon and Burke
1978
ND - no data
EC - electron capture detector
GC - gas-liquid chromatography
HSD - halogen-specific detector
-------
100
6. Analytical Methods
TABLE 6~2c. Analytical Methods for Determining DDD in Environmental Samples
Sample Matrix
Sample
Preparation
Analytical
Method
Sample
Detection
Limit
Accuracy
References
Air
Mater
Soil
Food
Mixed in petroleum
ether and hexane
separated with
silicic acid column,
then mix in ethylene
glycol solution
In starch cellulosic
material
Extraction with
methylene chloride,
clean-up/separation
with a Florisil column
Mix and shake in
0.1M ammonium chloride
solution and then add
hexane acetone, clean-
up/separation with a
Florisil column
Medium-dependent
solvent extraction
then solvent-hexane
exchange with a K-D
apparatus, clean-up/
separation with a
Florisil column
Sample dependent
preparation, extracted
with acetonitrile into
petroleum ether, clean-
up/separation with
Florisil column
EC/GC
Impinger
Sampler
0.8 ng/m^
Metricel ND
filter. GC
EC/GC
EC/GC
GC with
EC or HSD
EC/GC
0.011 (ig/L
ND
0.011 Mg/L
8BZ
ND
ND
92Z
ND
84 Z
Bidleman »t al. 1978
Lewis and Lee 1976
Kurtz 1977
EPA 1982
Williams 1984
EPA 1986b
ND
> 80Z
Williams 1984
McMahon and Burke
1978
ND - no data
EC - electron capture detector
GC - gas-liquid chromatography
HSD - halogen-specific detector
-------
101
6. Analytical Methods
levels of DDT, there is no information available to quantitatively
correlate levels in these fluids with environmental levels or toxic
effects.
There are methods for detecting metabolites of DDT (DDE and DDD) in
urine, blood, semen, liver, adipose tissue, and breast milk. However,
no information is available to quantitatively correlate the presence of
these metabolites with environmental exposure to DDT.
6.2 ENVIRONMENTAL SAMPLES
DDT residues are detected in the environment because of its use as
an insecticide until the early 1970s, and its slow transformation in the
environment. Well established analytical test procedures to analyze
environmental samples use gas chromatography and mass spectrometry. EPA
methods 608 and 625 are recommended to detect DDT, DDE, and DDD in
surface water and municipal and industrial discharges (EPA 1984). These
are required procedures under the Clean Water Act. EPA method 8080
describes analysis of solid waste (soil) for detection of DDT, DDE, and
DDD in compliance with RCRA regulations (EPA 1986b) . Detection limits
for these methods are reported in the ^g/L (ppb) range. Gas
chromatography is also used for the analysis of DDT in foods with a
detection limit of 0.5 ppm (Williams 1984). Bidleman et al. (1978) used
silica acid column chromatography for the analysis of DDT and its
metabolites in air samples. The detection limit for DDT in air was
reported to be 0.03 to 0.08 ng/m3. Even though analytical methods exist
for detection of DDT in almost all samples, many references did not
state detection limits or accuracy of the method.
6.3 ADEQUACY OF THE DATABASE
Section 104 (i)(5) of CERCLA directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of
the Public Health Service) to assess whether adequate information on the
health effects of DDT, DDE, and DDD is available. Where adequate
information is not available, ATSDR, in cooperation with the National
Toxicology Program (NTP), is required to assure the initiation of a
program of research designed to determine these health effects (and
techniques for developing methods to determine such health effects).
The following discussion highlights the availability, or absence, of
exposure and toxicity information applicable to human health assessment.
A statement of the relevance of the identified data needs is also
included. In a separate effort, ATSDR, in collaboration with NTP and
EPA, will prioritize data needs across chemicals that have been
profiled.
-------
102
6. Analytical Methods
6.3.1 Data Needs
Methods for Determining Parent Compound and Metabolites in
Biological Materials. Methods for the analysis of DDT, DDE, and DDD in
blood/plasma, semen, urine, liver and kidney, adipose tissue, human
milk, and lymph are described in the literature. These methods are
helpful in estimating the potential health risk of exposed populations.
In certain cases, spike recoveries were performed in a variety of
biological samples to determine the recovery efficiency and analytical
sensitivity of the method. In only a very few cases information was
unavailable on the detection limit and accuracy of a method. Obtaining
detection limits and information on the accuracy of a method is
important to effectively and precisely quantify the parent and
metabolites in biological system.
Methods for Biomarkers of Exposure. Although methodology for
measuring amounts of DDT, DDE, and DDD in various biological tissues is
described in the literature, there is no acceptable methodology for
extrapolating from those tissue levels to the amount of exposure which
would result in those levels. Even in those studies in which human
volunteers were fed measured doses of DDT, such a relationship could not
be determined because of bioaccumulation of DDT and its metabolites in
adipose tissues and by individual variability. Further research would
help in understanding the relationship between exposure and the
resulting level found in biological materials.
Methods for Determining Parent Compound and Degradation Products in
Environmental Media. Methods for the analysis of DDT and its
metabolites (DDE and DDD) in air, water, soil, and food are described in
the literature. However, in a few cases complete information is not
supplied for the above-mentioned environmental media. No data were
located for the detection limit of DDT in water and soil; and on the
accuracy of methods for soil and food sampling. Development of
detection limits and information on the accuracy or recovery efficiency
of methods would be helpful for quality control (e.g., food and water),
clean-up procedures, and estimating exposure to both humans and the
environment. No specific description of methods for analysis of DDE and
DDD in food samples was located. However, since the analytical method
described for DDT is a multi-residue method that encompasses a wide
range of chlorinated pesticides, it also could be used for the analysis
of DDE and DDD. In the case of air, water, and soil samples, general
information such as sample preparation and analytical methods for DDE
and DDD were given, but in almost all cases, information on detection
limits and accuracy of methods was lacking. The development of
detection limits and information on the accuracy or recovery efficiency
of methods would be helpful in environmental fate studies that identify
the degradation products.
-------
103
6. Analytical Methods
6.3.2 On-going Studies
No on-going studies concerning techniques for measuring and
determining DDT in environmental samples were identified.
-------
105
7. REGULATIONS AND ADVISORIES
DDT, DDE, and DDD are on the list of chemicals appearing in "Toxic
Chemicals in Section 313 of the Emergency Planning and Community Right-
to-Know Act of 1986" (EPA 1987a).
The international, national, and state regulations and guidelines
pertaining to DDT in air, water, and food are listed and referenced in
Table 7-1.
-------
106
7. Regulations and Advisories
TABLE 7-1. Regulations and Guideline* Applicable to DDT, DDE. or DDD
Agency
WHO
WHO
OSHA
EPA-ODW
EPA OERR
EPA OSW
EPA OTS
EPA
EPA
Description
Value
Conditional Acceptable
Daily Intake in Food
No Evidence of Human
Carcinogenicity
TWA
Meets Criteria for Proposed
Medical Records Rule
Maximum Contaminant Level
in Drinking Water
Reportable Quantity
Listing as a Hazardous
Waste Substance
Listing as Toxic Pollutant
Listed in RCRA Appendix IX
for Groundwater Monitoring
TSCA Chemical Substance Inv.
Recommended Action Levels
for sum of residues
Range
Most fruits and vegetables
Eggs
Grains
Milk
Meat
Reference Dose (oral)
Potency Factor (oral,
inhalation)
Xnternetional
0.003 mg/kg
ND
National
1 mg/m3
ND
ND
1 lb (proposed)
ND
ND
ND
ND
0.05 (grapes, tomatoes)
-3.0 (carrots) ppm
0.1 ppro - 0.5 ppm
0.5 ppm
0.5 ppm
0.05 ppm
5 ppm
5.0x10"* mg/kg/day
3.4X10"1 mg/kg/day
(DDT, DDE)
2.4X10"1 mg/kg/day (DDD)
References
WHO 1979
WHO 1979
OSHA 1988
OSHA 1982
EPA 1986a
EPA 1987b
EPA 1985a
EPA 1985b
EPA 1987c
EPA 1966c
EPA 1988a
EPA 1988a
FIFRA
guidelines
NIOSH
ACGIH
EPA ODW
Most Uses Cancelled (1972)
IDLH
TWA (air and skin)
TWA
Maximum Contamination
Level Goal
Health Advisories
1-dey
10-day
Longer term
Adult
Child
Lifetime
ND
ND
1 ng/m3
1 mg/m3
ND
ND
ND
ND
ND
ND
EPA 1972
NIOSH 1985
NIOSH 1977a
ACGIH 1S87
EPA 1986a
EPA 1980b
-------
107
7. Regulations and Advisories
TABLE 7-1. (Continued)
Agency
Description
Value
References
NAS
Suggested No-Adverse-
Response-Level (SNARL)
7-day
24 -hour
NO
ND
ND
EPA OWRS
Ambient Water Quality
Criteria to Protect
Human Health
2.85 (ig/L (DDT)
ND (DDD)
ND (DDE)
EPA 1980b
EPA
Carcinogenic Classification
Water and Fish and
Shellfish Ingestion
B2
0.0024 ng/L (DDT)
(risk level corresponding
to 10"7)
6.9xl0~6 jig/L for con-
centrations < lxlO3 lit,It
(DDD)
EPA 1986a
EPA 1980b
Fish and Shellfish
Consumption Only
0.0024 ng/L (DDT)
(risk level corresponding
to 10-7)
EPA 1980b
State Regulations and Guidelines
Stats
Environmental
Agencies
Drinking water quality standards
and guidelines for DDT for several
states
Alabama
No
special
or
state
rule
Alaska
No
special
or
state
rule
Arizona
No
special
or
state
rule
California
No
special
or
state
rule
Colorado
No
special
or
state
rule
Connecticut
Ho
special
or
state
rule
Delaware
No
special
or
state
rule
Florida
No
special
or
state
rule
Georgia
No
special
or
state
rule
Hawaii
No
special
or
state
rule
Idaho
No
special
or
state
rule
Illinois
SO
Mg/L
Indiana
No
spscial
or
state
rule
Iowa
No
special
or
state
rule
Kansas
0.42 (tg/L (DDT)
2.4x10"= pg/L
(DDE)
2.4x10"' «/L
(DDD)
Kentucky
No special
or
state
rule
Maine
0.83 (ig/L
Maryland
No special
or
state
rule
Massachusetts
No special
or
state
rule
Minnesota
1.0 jig/L
Mississippi
No
special
or
state
rule
Missouri
No
special
or
state
rule
Montana
No
special
or
state
rule
Nebraska
No
special
or
state
rule
Nevada
No
special
or
state
rule
New Hampshire
No
special
or
state
rule
New Mexico
No
special
or
state
rule
New York
No
special
or
state
rule
North CaroLina
No
special
or
state
rule
Ohio
No
special
or
state
rule
Oklahoma
No
special
or
state
rule
Oregon
No
special
or
state
rule
Rhode Island
No
special
or
state
rule
South Carolina
No
special
or
state
rule
South Dakota
No
special
or
state
rule
Tennessee
No
special
or
state
rule
EPA 1988b
EPA 1988b
EPA 1988b
EPA 1988b
EPA 1988b
EPA 1988b
-------
108
7. Regulations and Advisories
TABLE 7-1. (Continued)
Agency
State
Environmental
Agencies
Description
Texas
Utah
Vermont
Virginia
West Virginia
Wisconsin
Acceptable ambient air
concentrations standards
and guidelines for DDT f°r
several states
Connecticut
Kansas
Nevada
Pennsylvania
Philadelphia
Virginia
Value
References
No special or
No special or
No special or
No special or
No special or
No special or
state rule
state rule
state rule
state rule
state rule
state rule
5 /ig/m3 ( 8 hr)
2.381 /jg/nr (DDT)
(annual)
2.4x10 US/k (DDE)
< guideline)
2.4xl(T5 /ig/L (ODD)
(guideline)
0.024 lig/tn (8 hr)
1.8 pg/mj? (DDT) <1 yr)
1.8 tig/ffl (DDE)
16 Mg/m <24 hr)
EPA 1987d
EPA 1987d
EPA 1988b
EPA 1988b
EPA 1987d
EPA 1987d
EPA 1987d
EPA 1987d
ND - no data
-------
109
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-------
Ill
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112
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113
8. References
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Cueto C. 1970. Cardiovascular effects of o,p'-DDD. Ind Med 39:55-56.
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and DDE values among Michigan dairy farmers. Environ Health Perspect
23:315-319.
Wolff M, Anderson H, Selikoff I. 1982. Human tissue burdens of
halogenated aromatic chemicals in Michigan. JAMA 247:2112-2116.
*Wong 0, Brocker W, Davis H, et al. 1984. Mortality of workers
potentially exposed to organic and inorganic brominated chemicals, DBCP,
TRIS, PBB, and DDT. Br J Ind Med 41:15-24.
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8. References
*Woodwell G, Craig, P, Johnson H. 1971. DDT in the biosphere: Where
does it go? Science 174:1101-7.
Woolley D. 1973. Studies on 1,1,1-trichloro-2,2-bis(p-
chlorophenyl)ethane (DDT)- induced hyperthermia: Effects of cold
exposure and aminopyrine injections. J Pharmacol Exp Ther 184:261-268.
Woolley D, Talens G. 1971. Distribution of DDT, DDD, and DDE in
tissues of neonatal rats and in milk and other tissues of mother rats
chronically exposed to DDT. Toxicol Appl Pharmacol 18:907-916.
Wrenn T, Weyant J, Fries G, et al. 1971. Effect of several dietary
levels of o,p'-DDT on reproduction and lactation in the rat. Bull
Environ Contam Toxicol 6:471-480.
Yau E, Mennear J. 1977. The inhibitory effect of DDT on insulin
secretion in mice. Toxicol Appl Pharmacol 39:81-88.
*Yoder J, Watson M, Benson W. 1973. Lymphocyte chromosome analysis of
agricultural workers during extensive occupational exposure. Mutat Res
21:335-340.
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9. GLOSSARY
Acute Exposure - - Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical
adsorbed per unit weight of organic carbon in the soil or sediment to
the concentration of the chemical in solution at equilibrium.
Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment
or soil (i.e., the solid phse) divided by the amount of chemical in the
solution phase, which is in equilibrium with the solid phse, at a fixed
soild/solution ratio. It is generally expressed in micrograms of
chemical sorbed per gram of soil or sediment.
Bioconcentration Factor (BCF) -- The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or
group of studies which produces significant increase in incidence of
cancer (or tumors) between the exposed population and its appropriate
control.
Carcinogen -- A chemical capable of inducing cancer.
Ceiling Value (CL) -- A concentration of a sbustance that should not be
exceeded, even instantaneously.
Chronic Exposure -- Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity -- The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as
a result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
EPA Health Advisory --An estimate of acceptable drinking water levels
for a chemical substance based on health effects information. A health
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9. Glossary
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH) -- The maximum
environmental concentration of a contaminant from which one could escape
within 30 minutes without any escape - impairing symptoms or irreversible
health effects.
Intermediate Exposure -- Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immumologic Toxicity -- The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro -- Isolated from the living organism and artifically
maintained, as in a test tube.
In vivo -- Occurring within the living organism.
Lethal ConcentrationlLO) (LC^) -- The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration{50) (LC50) -- A calculated concentration of chemical
in air to which exposure for a specific length of time is expected to
cause death in 50% of a defined experimental animal population.
Lethal Dose(L0) (LD^) -- The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose(50) (LD50) -- The dose of a chemical which has been
calculated to cause death in 50% of a defined experimental animal
population.
Lethal Time (LT50) -- A calculated period of time within which a
specific concentration of a chemical is expected to cause death in 50%
of a defined experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed populatoin and its appropriate control.
Malformations -- Permanent structural changes that may adversely affect
suriwal, development, or function.
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9. Glossary
Minimal Risk Level - - An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen -- A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
Neurotoxicity -- The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOEAL) -- That dose of chemical at
which there are no statistically or biologically significant increases
in frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of
the concentrations of a chemical in n-octanol and water, in dilute
solution.
Permissible Exposure Limit (PEL) --An allowable exposure level in
workplace air averaged over an 8-hour shift.
qx* -- The upper-bound estimate of the low-dose slope of the dose-
response curve as determined by the multistage procedure. The qx* can
be used to calculate an estimate of carcinogenic potency, the
incremental excess cancer risk per unit of exposure (usually pg/L for
water, mg/kg/day for food, and ng/n? for air).
Reference Dose (RfD) --An estimate (with uncertainty spanning perhaps
an order of magnitude) of the daily exposure of the human population to
a potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ) -- The quantity of a hazardous substance that
is considered reportable under CERCLA. Reportable quantities are: (1) 1
lb or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantitites are measured over a 24-hour period.
Short-Term Exposure Limit (STEL) -- The maximum concentration to which
workers can be exposed for up to 15 minutes continually. No more than
four excursions are allowed per day, and there must be at least 60
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9. Glossary
minutes between exposure periods. The daily TLV-TWA may not be
exceeded.
Target Organ Toxicity -- This term covers a broad range of adverse
effects on target organs or physiological systems (e.g., renal
cardiovascular) extending from those arising through a single limited
exposure to those assumed over a lifetime of exposure to a chemical.
Teratogen -- A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV) -- A concentration of a sbustance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL or as a CL.
Time-Weighted Average (TWA) -- An allowable exposure concentration
averaged over a normal 8-hour workday or 40-hour workweek.
Toxic Dose TD50 -- A calculated dose of a chemical, introduced by a
route other than inhalation, which is expected to cause a specific toxic
effect in 50% of a defined experimental animal population.
Uncertainty Factor (UF) -- A factor used in operationally deriving the
RfD from experimental data. UFs are intended to account for (1) the
variation in sensitivity among the members of the human population, (2)
the uncertainty in extrapolating animal data to the case of humans, (3)
the uncertainty in extrapolating from data obtained in a study that is
of less than lifetime exposure, and (4) the uncertainty in using LOAEL
data rather than NOAEL data. Usually each of these factors is set equal
to 10.
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APPENDIX
PEER REVIEW
A peer review panel was assembled for DDT, DDE, and DDD. The panel
consisted of the following members: Dr. James R. Harr, Private
Consultant, Rochester, New York; Dr. Rolf Hartung, Professor of
Environmental Sciences, University of Michigan; and Dr. Fumio Matsumura,
University of California. These experts collectively have knowledge of
DDT's, DDE's, and DDD's physical and chemical properties,
toxicokinetics, key health endpoints, mechanisms of action, human and
animal exposure, and quantification of risk to humans. All reviewers
were selected in conformity with the conditions for peer review
specified in the Superfund Amendments and Reauthorization Act of 1986,
Section 110.
A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
of the content of this profile lies with the Agency for Toxic Substances
and Disease Registry.
O US GOVERNMENT PRINTING OFFICE:1 950 .7 1 2 .5 3 2/
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