"Current Awarenessl' Program
Vol.,
Halogenated Cycloalkanes, Cycloalkenes
and Aromatics: Carcinogenic!ty and
Structure-Activity Relationships. Other
Biological Properties. Metabolism. Environmental
Significance.
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
\ 1 1983
OFFICE OF
PESTICIDES AND TOXIC SUBSTANCES
MEMORANDUM
TO: Prank D. Kover, Chief
CHIB/AD
SUBJECT: Transmittal of "Current Awareness" assessment-support
review on "Halogenated Cycloalkanes, Cycloalkenes and
Aromatics: Carcinogenicity and Structure-Activity
Relationships. Other Biological Properties.
Metabolism. Environmental Significance"
This is to inform you that Vol. VI of the series, containing
a 287-page review on the above topic, has been completed and has
been distributed, as usual, to CHIB, HERD ana 4th floor
Library. This monumental, support-document represents the most
exhaustive and up-to-date review on this subject available at
present in the world literature.
Joseph C. Arcos
Senior Environmental Health
Scientist
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HALOGENATED CYCLOALKANES, CYCLOALKENES AND AROMATICS
CARCINOGENICITY AND STRUCTURE-ACTIVITY
RELATIONSHIPS. OTHER BIOLOGICAL PROPERTIES.
METABOLISM. ENVIRONMENTAL SIGNIFICANCE.
David Y. Lai, Ph.D.
Yin-Tak Woo, Ph.D.
Joseph C. Arcos, D.Sc., and
Mary F. Argus, Ph.D.
Preparation for the Chemical Hazard
Identification Branch "Current
Awareness" Program
883
-------
TABLE OF CONTENTS
5.2.2.2 Halogenated Cycloalkanes, Cycloalkenes and Aroma tics: Organochlorine
Pesticides, Polyhalogenated Biphenyls and Related Compounds
5.2.2.2.1 Introduction
5.2.2.2.2 Physicocheraical Properties and Biological Effects
5.2.2.2.2.1 Physical and Chemical Properties
5.2.2.2.2.2 Biological Effects Other Than Carcinogenic!ty
5.2.2.2.3 Carcinogenic!ty and Structure-Activity Relationships
5.2.2.2.3.1 Overview
5.2.2.2.3.2 Halogenated Cycloalkane Pesticides
5.2.2.2.3.3 Halogenated Cycloalkenes: Cyclodiene pesticides
5.2.2.2.3.4 Halogenated Benzenes and Naphthalenes
5.2.2.2.3.5 Halogenated Aromatics with Intercyclic Bond:
Polyhalogenated Biphenyls and Terphenyls
5.2.2.2.3.6 Halogenated Bridged Aromatics: DDT and Related Compounds
5.2.2.2.3.7 Modification of Carcinogenesis ;
5.2.2.2.4 Metabolism and Mechanism of Action
5.2.2.2.4.1 Metabolism
5.2.2.2.4.1.1 Metabolism of Halogenated Cycloalkanes
5.2.2.2.4.1.2 Metabolism of Halogenated Cycloalkenes
5.2.2.2.4.1.3 Metabolism of Halogenated Benzenes and Naphthalenes
5.2.2.2.4.1.4 Metabolism of Polyhalogenated Biphenyls
and Terphenyls
5.2.2.2.4.1.5 Metabolism of DDT and Methoxychlor
5.2.2.2.4.2 Mechanism of Action
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TABLE OF CONTENTS
(continued)
5.2.2.2.5 Environmental Significance
5.2-.2.2.5.1 Epidemiological Evidence
5.2.2.2.5.2 Environmental Sources, Occurrence and Exposure
5.2.2.2.5.2.1 Soil
5.2.2.2.5.2.2 Water
5.2.2.2.5.2.3 Air
5.2.2.2.5.2.4 Food
References to Section 5.2.2.2
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5.2.2.2 Halogenated Cycloalkanes, Cycloalkenes and Aromatics; Organochlorine
Pesticides, Polyhalogenated Biphenyls and Related Compounds.
5.2.2.2.1 'Introduction.
Halogenated cycloalkanes, cycloalkenes and aromatics are halogenated
derivatives of saturated or unsaturated cyclic hydrocarbons which include such
controversial compounds as DDT, aldrin, dieldrin, chlordane, heptachlor,
kepone, mirex, hexachlorobenzene, polychlorinated biphenyls and polybrominated
biphenyls. The advent of these agricultural and industrial chemicals had
economic and health effects perhaps unmatched by any other chemical agent ever
synthesized. For example, it has been estimated that during its first decade
of use, DDT saved about 50 million human lives and averted more than 1 billion
cases of human illness by eradicating malaria, typhus and other vector-borne
diseases (cited in ref. 1). In countries around the world, the yield of crops
during the 1950's and 1960's was found to be proportional to the quantity of
organochlorine insecticides used. On the other hand, because of their
environmental stability and tendency to bioaccumulate, few chemicals in
history have had the tremendous ecological impact as many of these com-
pounds. They have polluted the entire biosphere and are now detectable in the
tissues of wildlife and humans worldwide. The widespread contamination of the
environment by these compounds and their potential hazard to human health
raised considerable public concern. As the title of Rachel Carson's book
"Silent Spring," published in 1962 implies: "Unless the use of these persis-
tent pesticides was curtailed, someday a spring would arrive when no birds
sang and no fish leaped in streams because all had been killed" (2).
Several governments around the globe have considered the balance of
benefits of these compounds versus their potential hazards to human health and
150
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the environment, and have decided to suspend or restrict their production and
use in the 1970's, following a period of 20-30 years of extensive application
by the military, in agriculture and industry, and by domestic consumers. In
the United States, the use of DDT was banned in 1972; two years later aldrin
and dieldin and in 1975 chlordane and heptachlor were suspended. Kepone and
mirex are no longer manufactured in the U.S.; their uses were banned in
1977. Since 1978, the use of PCBs has been restricted to "totally enclosed"
systems. The increased awareness and concern of their effects on human health
and environmental quality, and particularly several instances of accidental
local contamination such as by kepone in the James River and by hexachloro-
cyclopentadiene in Love Canal, both in the United States, by PCBs in Japan and
by PBBs in the state of Michigan (U.S.) have stimulated considerable toxico-
logical and ecological research in various model systems. As a result, a
considerable body of information concerning their toxicity, carcinogenic!ty,
teratogenicity and mutagenicity is presently available. The toxicological and
environmental effects of these compounds have been the subject of a number of
U.S. regional and of international conferences (3-8) and are the topics of
many reviews (e.g., 1, 9-26) and technical reports (e.g., 27-47). The prin-
cipal focus of the present section is on the toxicology, metabolism and
mechanism of carcinogenesis by these compounds, with emphasis on structure-
activity relationship.
5.2.2.2.2 Physicochemical Properties and Biological Effects.
5.2.2.2.2.1 PHYSICAL AND CHEMICAL PROPERTIES.
The structural formulas and spatial configurations of some carcinogenic
(or suspected carcinogen) halogenated cyclic hydrocarbons and their metabo-
ites are depicted in Figs. 11-20. Many of these compounds have been surveyed
151
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and listed in the International Agency for Research on Cancer (IARC) mono-
graphs (19-21) along with their synonyms and trade names. Their principal
physical and chemical properties are presented in Tables XXVII-XXX.
Halogenated Cycloalkanes and Cycloalkenes. Hexachlorocyclohexane
(commonly known as benzene hexachloride or BHC) is a 6-raembered cycloalkane
with a chlorine atom on each of its 6 carbon atoms. Depending on the spatial
orientation of the six chlorine atoms nine isomers are possible. Technical
grade BHC contains varying quantities of five of the most stable isomers:
oc (55-70%), /3 (5-12%)., if (10-18%), f (6-10%) and £ (3-4%). These isomers
differ greatly in both physical and biological properties. For instance, the
V-isomer, commonly known as lindane, is about 100 to 1,000 times more toxic
toward most insects than other isomers. It is also unlike other isomers in
that it has a lower melting point and a higher vapor pressure (see Table
XXVII). In general, BHC and its individual isomers are chemically quite
stable. Except for the y^-isomer, most isoraers undergo dehydrochlorination in
alkaline solutions. The rates of dehydrochlorination follow the decreasing
order of: oc. > £ > ^ > * (48). BHC is only slightly soluble in water.
Toxaphene is a mixture of at least 177 polychlorinated diterpehe deriva-
tives prepared by chlorination of camphene (49). Most of the components are
isomeric hepta-, octa-, and nona-chlorobornanes having empirical formulas of
^10^11^7* ^10^10^8 anc* CiQHgClg. Their chemical structures are as follows:
[TEXT-FIGURE 8]
152
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Table XXVII
Physicochemical Properties of Some Chlorinated Cycloalkane
and Cycloalkene Pesticides3
Compound, CAS No.
Solubility Partition
Empirical ra.p. Vapor pressure in water coefficient
formula (°C) (mm Hg) (ppm) (log P)
Halogenated Cycloalkanes
Hexachlorocyclohexane (BHC)
ct-BHC, 319-84-6
(3-BHC, 319-85-7
if-BHC (lindane), 58-89-9
S-BHC, 319-86-8
Toxaphene
8001-35-2
Mirexc
2385-85-5
Keponec
143-50-0
Halogenated Cycloalkenes
Hexachlorocyclopentadiene
77-47-4
Aldrinc
309-00-2
Dieldrinc
60-57-1
Endrinc
72-20-8
Chlordanec
57-74-9
Hentachlorc
76-44-8
tfeptachlor epoxidec
1024-57-3
Cndosulfan (Thiodan)c
115-29-7
'elodrin (Isobenzan)c
297-78-9
C6H6C16
158
310
113
138
0.02 at 20°C 10
0.005 at 20°C 5
0.03 at 20°C 10
0.02 at 20°C 10
3.80
ClQH18_nCln 65-90 0.17-0.4 at 25°C 0.4
C1QC112 485 3 x 10"7 at 25°C 0.001
2.91
C10C112°
300 1 x
at 25°C 2
c5ci6
C12HgCl6
10 0.08 at 25°C 0.8
104 6 x 10~6 at 25°C 0.07
,-7
2.74
5.0
C12H8C160 175 1.8 x 10~' at 25°C 0.05 4.6
C12H8C160 200 2 x 10~7 at 25°C 0.06 5.6
104 1 x 10~5 at 25°C insoluble —
95 3 x 10~4 at 25°C 0.05
^ — insoluble
C9H6C16°3S 70"100 ~~ insoluble —
C9H4ClgO 120 3 x 10"6 at 20°C <0.1
C10H6C18
C10H5C17
C10H5C170
Summarized from: International Agency for Research on Cancer [IARC Monogr. No. 5
(1974) and No. 20 (1979)]; D.D. Irish, In: "Patty's Industrial Hygiene and Toxi-
cology," 2nd ed., Vol. II, 1963; R.R. Whetstone, In: "Kirk-Othmer Encyclopedia of
Chemical Technology" (A. Standen, ed.), 2nd ed., Vol. 5, 1964; C.A. Edwards, "Persis-
tent Pesticide in the Environment," 2nd ed., CRC Press, 1976; "Kepone/Mirex/Hexa-
chlorocyclopentadiene: An Environmental Assessment," National Academy of Sciences,
Washington, D.C., 1978; D. Demozay and G. Marechal, In: "Lindane" (E. Ulmann, ed.),
Verlag K. Schillinger, Freiburg, Br., 1972.
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page 2 of 2
Table XXVII (continued)
(footnotes — continued)
A mixture of at least 177 polychlorinated diterpene derivatives.
For structural formula, see Fig. 11.
-------
Cl
, R =
Cl and/or CHCI.
TEXT - FIGURE 8
-------
The chlorine content of the mixture usually lies between 67% and 69% by
weight. Toxaphene is poorly soluble in water but soluble in many organic
solvents. It hydrolyzes very slowly in acid. Under alkaline conditions, at
temperatures above 120°C, or upon prolonged exposure to ultraviolet light,
however, dehydrochlorination occurs. Strobane is a technical grade product
containing a mixture of chlorinated terpene isomers arid is almost identical in
properties to toxaphene.
Hexachlorocyclopentadiene ("hex") is a very volatile and reactive hydro-
carbon, which readily reacts with various olefins by Diels-Alder addition (see
Section 2.2.4 in Vol. I) and with other organic compounds. When hex is
reacted with unsaturated compounds, followed by chlorination and/or further
Diels-Alder addition, a variety of highly chlorinated cyclic hydrocarbons with
endomethylene bridged-structures are obtained. The formation of several
chlorinated cycloalkanes and cycloalkenes from hex is outlined in Figure 11.
For instance, chlorination of the adduct formed between hex and cyclopenta-
diene by Diels-Alder reaction gives chlordane and heptachlor. When the Diels-
Alder adduct of hex and vinyl chloride is subjected to a second Diels-Alder
reaction with cyclopentadiene, the product is isodrin, which on peroxidation
yields endrin. The steric isomers of isodrin and endrin are aldrin and
dieldrin, respectively, which are named after Alder and Diels, the discoverers
of the diene synthesis. Other related chlorinated cycloalkanes derived from
hex include isohenzane (telodrin) and endosulfan (thiodan). Chemically, all
these chlorinated cyclodiene compounds are very stable; they are unreactive
toward dilute acids or basic reagents. Photodieldrin is a photochemical
conversion product of dieldrin. It may exist as a terminal residue of
dieldrin and persists in the environment (13).
153
-------
Cl C!
Hexochlqro-
cyclopentodiene
Telodrin(Isobenzan)
C!
Cl
Cl
Mirex
Fig. 11. The formation of chlorinated cycloalkanes and cycloalkenes from
hexachlorocyclopentadiene.
-------
Mirex and its ketone analog, kepone, two highly chlorinated, cage-
structured compounds, are also formed from hex by Diels-Alder reaction. The
presence in kepone of a carbonyl group, in place of two chlorine atoms present
in mirex,'increases the solubility of kepone to about 2,000 times that of
mirex (see Table XXVII). Kepone is also more volatile and chemically more
reactive than mirex, which displays only low reactivity toward acids, bases
and other chemical agents.
Halogenated Aroma tics Chlorinated derivatives of benzene [C^Hg_nCln] and
naphthalene [cir)Hg_nCln] are comP°unds in which one or more chlorine atoms
substitute for the hydrogens in the respective hydrocarbons.
[TEXT-FIGURE 9.1
Generally speaking, the chemical and physical properties of these com-
pounds vary in a regular pattern with the increase in chlorine substitution
(see Table XXVIII). With increasing chlorination, chlorobenzenes are increas-
ingly more stable toward further chlorination or other electrophilic attack.
As the degree of chlorine substitution increases, the density, melting point,
boiling point, and fire and flash points all increase, while the vapor pres-
sure and water solubility decrease. Nonetheless, among isomers with the same
degree of substitution, some variations in physicochemical characteristics may
occur. For instance, o- and p-dichlorobenzene are more readily formed by
chlorination of benzene than is m-dichlorobenzene. Unlike the other two
isoraers, which are liquid, p-dichlorobenzene is solid at room temperature.
The commercial products of chlorinated naphthalenes, known as Halowaxes, are
154
-------
Chlorinated benzene
(n=l-6)
Chlorinated naphthalene
(n=l-8)
TEXT-FIGURE 9
-------
; Table XXVIII
Physicochemical Properties of Chlorinated Benzenes'
Vapor Solubility Partition
Empirical m.p. b.p. pressure in water coefficient
formula (°C) (°C) (mm Hg) (mg/1) (log P)
Compound, CAS Np.
Monochlorobenzene
108-90-r7
1,2-Dichlorobenzene
95-50-1
1,3-Dichlorobenzene
541-73-1
1,4-Dichlorobenzene
106-46-7
1,2,3-Trichlorobenzene
87-61-6
1,2,4-Trichlorobenzene
120-82-1
C6H5C1 -45 132 12 at 25°c 500
C6H4C12 -17 180 1 at 20°C 140
C6H4C12 -25 172 1 at 12°C 123
C6H4C12 53 174 0.4 at 25°C 79
C6H3C13 54 219 1 at 40°C
C6H3C13 17 214 1 at 38°C
1,2,3,4-Tetrachlorobenzene C6H2Cl, 48 254 1 at 68°C
634-66-2
Pentachlorobenzene
608-93-5
Hexachlorobenzene
118-74-1
C6HQ5 86 277 1 at 99°C
C6C16 230 322 1 at 114°C
30
0.36
0.020
2.84
3.38
3.38
3.39
4.10
5.80
aSunmarized from: U.S. Environmental Protection Agency, "Assessment of Testing
Needs: Chlorinated Benzenes," EPA-560/11-80-0.4, Washington, D.C., 1980; D.D.
Irish, In: Patty's Industrial Hygiene and Toxicology," 2nd ed., Vol. II, 1963;
D.W.F. Hardie, In; "Kirk-Othmer Encyclopedia of Chemical Technology" (A.
Standen, ed.), "2nd ed., Vol. 5, 1964.
-------
generally mixtures of compounds with different degrees of chlorination. Their
chemical and physical properties vary with the composition of the mixtures.
Chlorinated and brominated aromatic hydrocarbons with intercyclic bonds
(biphenyls, terphenyls, etc.) form another class of toxic and carcinogenic
compounds. Like chlorinated naphthalene, they are produced commercially as
mixtures -- polychlorinated biphenyls (PCBs)', polybrominated biphenyls (PBBs),
polychlorinated terphenyls (PCTs) — which contain different percentages of
the many possible halogenated congeners, each containing a different number of
chlorine or bromine atoms per molecule. Among the biphenyls, 210 different
congeners or isomers are theoretically possible by replacement of 1 to 10
hydrogen atoms by chlorine or bromine. There are three isomeric terphenyls
(ortho-, meta- and para-) and 14 possible positions in each isomer at which
chlorine atoms can be introduced, e.g., in p-terphenyl below;
[TEXT-FIGURE 10J
In the United States, PCBs and PCTs are sold under the trade name
Aroclor. It has been estimated that Aroclors may contain as many as 40-70
different chlorinated biphenyl compounds (50-52). Each Aroclor formulation is
identified by a four-digit code; for example, the first two digits 12 indicate
biphenyls and 54 indicate terphenyls, whereas the last two digits denote the
percentage by weight of chlorine in the mixture. Hence, Aroclor 1268 is a
polychlorinated-biphenyl mixture containing 68% chlorine. Aroclor 1016 is an
exception to this nomenclature, since it is a distillation product of Aroclor
1242 and contains about 41% chlorine. Industrially, the most important formu-
155
-------
X=CI(PCB)or
X=Br(PBB);
n=l-IO v
Chlorinated terphenyl
(n=H4)
TEXT-FIGURE 10
-------
lations of PCBs appear to be those containing 21, 42, 48, 54 and 60% chlorine
by weight. Commercial PCBs (mixtures) differ greatly in physical and chemical
properties from their component individual isomers, whose chemical character-
istics depend on the degree and positions of chlorine substitution on the
biphenyl rings (Table XXIX). While most individual chlorinated biphenyls are
solid at room temperature, the mixtures are liquid of different viscosities.
In general, PCBs are chemically and thermally stable, resistant to oxidation
and to acids, bases and other chemical agents. They are only very sparingly,
if at all, soluble in water, glycerol and glycols, but soluble in most other
organic solvents and fats. The stability of PCBs, together with their high
dielectric constant and low vapor pressure, make them exceptionally useful for
many industrial uses. The physicochemical properties of PBBs and PCTs have
been less studied as compared to PCBs. The commercial PBBs known as Fire-
Master PB-6 is a solid with a very low vapor pressure and water solubility.
Although bromine is more labile than chlorine under certain reaction condi-
tions , the general physical properties of PBBs, PCTs and PCBs are similar.
PCTs have been described as non-oxidizing, inert, of low volatility and water
solubility, and resistant to alkalies, acids and corrosive chemicals (53).
Commercial DDT is a mixture of chlorinated bridged aromatics, with
1,l,l-trichloro-2,2-bis(_p-chlorophenyl)ethane (_p,_p'-DDT) as its principal
constituent. Small quantities of other isomers (e.g., ^,_p_'-DDT) and related
analogs such as 1,l-dichloro-2,2-bis(chlorophenyl)ethylene (DDE) and 1,1-di-
chloro-2,2-bis(chlorophenyl)ethane (TDE), are generally present as degradation
products or byproducts. All isomers of DDT are white crystalline solids.
They are soluble in most organic solvents but practically insoluble in
water. Under alkaline conditions or at temperatures above the melting point
(109°C), DDT is dehydrochlorinated to DDE, which is extremely stable and
156
-------
Table XXIX
Physicochemical Properties of Some PolychlorinaCed Biphenyls'
Dielectric
constant
Compound
Aroc lor
Aroclor
Aroclor
Aroclor
Aroclor
Aroclor
1221
1232
1242
12A8
1254
1260
C12
C12
C12
C12
C12
c12
Major
component
H9C1 (
HgCl2
H7C13
H6C14
H5C15
H4C16
;so%)
(29%)
(45%)
(49%)
(53%)
(42%)
25°C
-
5
5
5
5
4
-
.7
.8
.6
.0
.3
100°C
-
4
4
4
4
3
-
.6
.9
.6
.3
.7
Flash point
(°C)
141-150
152-154
1,76-180
193-196
b.p.
b.p.
Vapor
pressure Solubility
Fire point (mm Hg in water
(°C) at 20°C) (pj>b)
176 — 1, 190-5, 900b
238 — 80-1, 880b
b.p. 9.0 x 10~4 240
b.p. 8.3 x 10~4 52
b.p. 1.8 x 10~4 12
b.p. 0.9 x 10~4 3
Partition
coefficient
(log P)b
2
3
3
3
4
4
.59
.75
.89
.90
.20
.47
aSummarized from: International Agency for Research on Cancer [IARC Monogr. No. 18, (1978)]; "Polychlori-
nated Biphenyls," National Academy of Sciences, Washington, D.C., 1979; U.A. Th. Brinkman and A. Dekok,
In: "Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products" (R.D. Kimbrough,
ed.), Elsevier, New York, 1980.
Values are of those of the major components.
-------
persistent in the environment. Some important physicochemical properties of
DDT and its analogs are presented in Table XXX.
5.2.2.2.2.2 BIOLOGICAL EFFECTS OTHER THAN CARCINOGENICITY.
Toxic Effects. Knowledge about the toxic and. pharmacological effects of
these compounds (except the terphenyls) on various aquatic, terrestrial and
avian species has increased rapidly during the past decades. Much of the
information is published in various monographs and government reports, in
addition to review articles in scientific periodicals (e.g., 12, 13, 54-59).
The present section presents only highlights of the effects of these compounds
toward humans and mammals. Some representative acute toxicity data (LDcjQ
values) of these compounds are presented in Table XXXI. The toxicity of most
of these compounds is dependent on the species, sex and age of the animals, as
i
well as the route and the vehicle of administration. Organic solvents and
vegetable oils used as vehicles enhance the absorption of these highly lipid-
soluble compounds into the body and thus increase their toxicity. In general,
female animals are more sensitive than males, and young animals are more
sensitive than adults (71, 73-75a). However, each of the chemical classes
possesses characteristic toxic properties and all members in a given class
produce a similar spectrum of toxic responses on a qualitative basis, although
minor variations in different species may occur.
The chlorinated hydrocarbon pesticides including BHC, toxaphene, the
cyclodienes, mirex, keporie and DDT act primarily on the central nervous
system. The common signs of acute intoxication observed in most animal
species are hyperexcitability, irritability, tremor and convulsion. On
repeated dosage, the compounds induce various pathological lesions of the
liver, which include fatty infiltration, centrolobular hypertrophy and fonna-
157
-------
Table XXX
Physicochemical Properties of DDT and Related Compounds'
Compound,
CAS No.
Emperical ra.p.
formula (°C)
Vapor pressure
(mm Hg)
Solubility Partition
in water coefficient
(ppm) (log P)
DDTC
50-29-3
C14H9C15 108 1.9 x 10~7 at 25°C 0.001-0.04 4.96
DDDC
109
72-54-8
DDEb
72-55-9
Ethyl-DDDc
[Perthane]
72-56-0
Methoxychlorc
72-43-5
Chloroben-
zilatec
510-15-6
Dicofolc
115-32-2
C14H8C14
C18H20C12
C10H15C1302 89
88 6.5 x 10~° at 20°C
-6
< 0.01
0.12
< 0.01
0.1
C16H14C1302 35 2.2 x 10~6 at 20°C < 0.01
C14H9C150 77
5.69
4.65
aSummarized from: International Agency for Research on Cancer [IARC Monogr. No. 5,
(1974); "Special Occupational Hazard Review: DDT," National Institute for
Occupational Safety and Health, Rockville, Maryland, 1978; The Merck Index, 9th ed.,
Merck and Co., Rahway, New Jersey, 1976.
For the formula and chemical name corresponding to the acronym, see Fig1. 20.
°For structural formula , see Table XLI.
-------
p. 1 of 4
Table XXXI
Acute Toxicity of Halogenated Cycloalkanes, Cycloalkenes and Aromatics
Compound Species and Route
Halogenated Cycloalkanes
Lindane ( £"-BHC)
Toxaphene3
Mirexb
Keponeb
Halogenated Cycloalkenes
Hexachlorocyclo-
pentadiene
Aldrinb
Isodrin
Dieldrinb
Endrinb
Mouse, oral
dermal
Rat, oral
dermal
Hamster, oral
Mouse, oral
Rat, oral
dermal
Rat, oral
dermal
Mouse, Oral
Rat, oral
dermal
Mouse, oral
Rat, oral
inhalation
Mouse, oral
Rat, oral
dermal
Hamster, oral
Rat, oral
dermal
Mouse, oral
Rat, oral
dermal
Hamster, oral
Dog, oral
Mouse, oral
Rat, oral
dermal
LD5Q (mg/kg)
90
180
100
900
360
112
80
780
600
> 2,000
200
125
> 2,000
430
505
7.2 ppm (1 hr)
45
38; 39
98
320
7
23
40
45; 46
60
330
65-95
3 •
8
15
Reference
(60)
(11)
(60)
(61)
(60)
(62)
(61)
(61)
(61)
(61)
(63)
(61)
(61)
(64)
(65)
(65)
(60)
(60, 61)
(61)
(60)
(61)
(61)
(60)
(60, 61)
(61)
(60)
(62)
(66)
(61)
(61)
-------
P- 2 of 4
Table XXXI (continued)
Compound
Halogenated Cycloalkenes
Chlordaneb
Heptachlorb
Heptachlor epoxide
Endosulfanb
Telodrinb
Halogenated Benzenes and
Monochlorobenzene
1 ,2-Dichlorobenzene
1 ,3-Dichlorobenzene
1 ,4-Dichlorobenzene
1 ,2,4-Trichlorobenzene
Pentachlorobenzene
Species and Route
(continued)
Mouse, oral
Rat, oral
dermal
Hamster, oral
Mouse, oral
Rat, oral
dermal
Hamster, oral
Mouse, i.p.
Mouse, oral
i.p.
Rat, oral
dermal
Hamster, oral
Mouse, oral
i.p.
Rat, oral
i.p.
Naphthalenes
Rat, oral
Rat, oral
Rat, oral
Mouse, oral
Rat, oral
Mouse, oral
Rat, oral
Mouse, oral
Rat,: oral
LD5Q (n>g/kg) Reference
390
335; 350
530
1,720
70
100; 105
195
100
18
85
7
64
74
118
10
8
6-11
4
2,144; 2,190
1,516
400
2,950
1,625
766
756
1,175
940
(60)
(60,
(61)
(60)
(60,
(61)
(60)
(67)
(60)
(68)
(60)
(61)
(60)
(69)
(10)
(69)
(10)
(42,
(42)
(42)
(42)
(42)
(42)
(42)
(42)
(42)
61)
61)
56)
Hexachlorobenzene
32-.00
(56)
-------
Table XXXI (continued)
p. 3 of 4
Compound Species and Route ^50 (mg/kg)
Reference
Halogenated Benzenes and Naphthalenes (continued)
2,3,6,7-Tetrachloro-
naphthalene
2,3,6, 7-Te t r abromo-
naphthalene
Polyhalogenated Biphenyls
PCBs
PBBs
3,3',4,41-Tetrachloro-
biphenyl
3,3l,4,4t,5,5l-Hexa-
chlorobiphenyl
2,21,4,4',5,5'-Hexa-
chlorobiphenyl
2, 3, 3', 4, 4' ,5,5'-Hepta-
chlorobiphenyl
2,2'-Difluoro-3,3',4,4l-
5 , 5 '-hexachlorobiphenyl
DDT and Related Compounds
DDT (Technical grade)
DDTC
DDEC
Guinea pig, oral
Guinea pig, oral
Rat, oral
i .v.
Rat, oral
Guinea pig, oral
Guinea pig, oral
Guinea pig, oral
Guinea pig, oral
Guinea pig, oral
Mouse, oral
Rat, oral
dermal
Hamster, oral
Mouse, oral
Rat, oral
Hamster, oral
Mouse, oral
Rat, oral
> 3
0.242
1,295
358
21,500
0.3-1
'0.5
> 10
> 3
> 3
200
215; 217
2,510
> 10,000
110
120
> 5,000
> 5,000
880
(cited in
ref. 70)
(cited in
ref. 70)
(71)
(71)
(72)
(cited in
ref. 70)
(cited in
ref. 70)
(cited in
ref. 70)
(cited in
ref. 70)
(cited in
ref. 70)
(60)
(60, 61)
(61)
(60)
(60)
(60)
(60)
(60)
(61)
-------
p. 4 of 4
Table XXXI (continued)
Compound
DDT and Related Compounds
DDDC
DDAC
Ethyl-DDDd
[Perthane]
Methoxychlor
Chlorobenzilated
Dicofold
Species and Route ]
(continued)
Mouse, oral
Rat, oral
Rat, oral
Rat, oral
Mouse, oral
Rat, oral
Rat, oral
Rat, oral
LD5Q (mg/kg)
3,500
3,750
600
8,170
800
5,000.
1,040
1,000
Reference
(60)
(60)
(61)
(62)
(62)
(62)
(61)
(61)
aA mixture of at least 177 polychlorinated dipterpene derivatives.
For structural formula, see Fig, 11.
£
For the formula and chemical name corresponding to the acronym, see Fig.20.
d
For structural formula, see Table XLI.
-------
tion of lipospheres by proliferation of che smooth endoplasmic reticulum.
Liver cell necrosis has also been .noted in many animal species following
exposure to high doses. In addition, some of these compounds exert prominent
pathological action on the renal, reproductive, cardiovascular and endocrine,
as well as on the immune, systems (reviewed in ref. 56).
The effect of hexachlorocyclohexane on the central nervous system (CNS)
varies with the different isomers (58, 59). The o(- and T-isoraers are CNS
stimulants eliciting muscular spasms and convulsions, whereas the /3 and
O -isomers are CNS depressants. In laboratory animals, the Y-isomer has the
greatest acute toxicity but on repeated administration, it shows the lowest
toxicity among all isomers due to its relatively rapid excretion by the
kidney. In contrast, the /9-isomer has the highest toxicity following
repeated dosage, but the lowest acute toxicity.
In the DDT series, the toxicities toward Chinese hamster cell cultures
ranks in the order: DDA < DDE < DDT < ODD (75b;.
Numerous cases of human poisoning by chlorinated hydrocarbon pesticides,
resulting from accidents, suicides or occupational exposures have been
described (12, 46, 47, 56, 58). A prime case in point is the widely publi-
cized kepone accident in 1975 in a manufacturing plant in Virginia (76). As
in animals, the principal site of action of these compounds in man is the
central nervous system (17, 77, 78). Common symptoms of poisoning include
headache, malaise, nausea, dizziness, insomnia, paresthesia, muscular jerking,
convulsions and other manifestations based on neurotoxic effects. Dermatitis,
liver damage and testicular damage have also been reported (reviewed in ref.
78). Fatalities may result from heart and respiratory failure, secondary to
the convulsion.
158
-------
Chlorinated benzenes and naphthalenes, PCBs, PBBs and PCTs comprise
another group of structurally related compounds with considerable commonality
in toxicological properties. The degree of toxicity of these halogenated
aromatics is dependent on both the number and position of the halogen substi-
tutions (55, 57, 79-81; reviewed in ref. 70). For halogenated naphthalenes
and biphenyls, the most toxic .congeners or isomers within the respective class
are those with fully halogenated lateral positions (e.g., 2,3,6,7-tetrachloro-
naphthalene, 2,3,6,7-tetrabromonaphthalene, 3,3',4,4',5,5'-hexachlorobi-
phenyls) (see ref. 55). These congeners or isomers are isosteric with
2,3,7,8-tetrachlorodibenzo-£-dioxin (TCDD), which is the most toxic synthetic
organic compound known (see Section 5.2.2.3.2.2). The introduction of halo-
gen(s) into the ortho position(s) in laterally substituted PCBs substantially
decreases their toxicity (see Table XXXI), presumably because such ortho
halogen(s) prevent the PCS molecules to assume a TCDD-like coplanar
configuration.
Biochemical changes in microsomes and effects on hepatic mixed-function
oxidase (MFC) activity by halogenated aromatics are often used as indexes of
their toxicity. The structure-activity relationships of PCBs as inducers of
MFOs have been extensively studies (reviewed in ref. 70) (this topic will be
further discussed in Section 9.4 in Volume V of this series of monographs).
Essentially, PCB congeners and isomers may be divided into two separate and
distinct groups: phenobarbital-type inducers (which increase cytochrome
P-450-mediated enzyme activity) and 3-raethylcholanthrene-type inducers (which
increase cytochrome P-448-mediated enzyme activity). For example,
2,2',4,4',5,5'-hexachlorobiphenyl is a pure phenobarbital-type inducer whereas
its 3,3',4,4',5,5'-isomer is a 3-raethylcholanthrene-type inducer. The struc-
tural requirements of PCBs for 3-raethylcholanthrene-type induction appear to
159
-------
be the presence of at least two adjacent halogens in both of the lateral
positions (3,3',4,4',5,5') of the biphenyl molecule and the absence of halo-
gens in the ortho positions. The toxicity of PCBs correlates well with their
ability to act as 3-methylcholanthrene-type inducers. The ability of PCBs to
act as phenobarbital-type inducers is roughly proportional to the degree of
chlorination. The availability of two adjacent nonhalogenated free positions
decreases activity, presumably because such compounds are more easily metab-
olized (see Section 5.2.2.2.4.1). Biphenyls which are halogenated at all four
ortho positions are less active than those with only two ortho substitu-
tions. Substitution in the para position(s) is not an absolute requirement
for activity (e.g., 2,2',3,3',5,5'-hexachlorobiphenyl is highly active) of
higher chlorinated isomers. However, for lower chlorinated isomers, para-
substitution does increase inducing activity. The structure-activity rela-
tionships of PBBs as inducers of MFCs are similar to those of PCBs (80, 82).
However, PBBs are more potent (on a molar basis) in inducing mixed-function
oxidase enzyme activity than PCBs (cited in ref. 83).
Substitution in the para-position(s): (a) increases MFO-inducing activ-
ity in the lower chlorinated PCBs having free ortho-positions (see above), and
(b) it also leads to greater overall toxicity (84, 85). Similarly, in chlori-
nated benzenes the most effective isomers to induce experimental porphyria in
rats are those containing two chlorine atoms para to one another (86).
In animals, the primary target organ for these halogenated aroinatics is
the liver. They have been shown to cause hepatomegaly, porphyria, lipid
accumulation, proliferation of the smooth endoplasmic reticulum, and other
ultrastructural changes. In addition to the effect on the liver, the skin,
the mucous membranes, and the thyroid, the reproductive and immune systems may
also be affected in various animal species. Several incidents of "hyperkera-
160
-------
tosis" (a disease characterized by thickening and hardening of the skin)
involving large number of cattle, sheep and swine have been established to be
attributed to accidental poisoning by PCBs, PBBs as well as chlorinated ben-
zenes and naphthalenes (54, 55, 87, 88). Other gross symptoms in cattle which
ingested PBBs (penta-, hexa-, and hepta-) inadvertently introduced into the
feed include decreased milk production, abnormal growth of hoofs, abscesses in
the liver and other organs, impairment of the immune and reproductive systems
(87, 89). Chronic exposure to chlorinated benzenes also affects the nervous
and hematopoietic systems, the kidney and the lung (reviewed in ref. 42).
A number of incidents of acute, subchronic and chronic toxicity in humans
due to dermal or inhalational exposure to some halogenated aromatics in the
workplace have been described (27, 42, 45, 90). The major symptoms following
acute exposure are eye, skin and respiratory tract irritation, headache,
nausea and vomiting. Higher chlorinated naphthalenes and PCBs produce the
"chloracne" syndrome. After prolonged exposure, toxic effects on the liver,
and on the hematopoietic, reproductive and nervous systems have been observed.
Apart from the occupational toxicity data, much human toxicological data
have been obtained from investigations of several tragic episodes of acci-
dental poisoning. Between 1955-1959, three to five thousand people in south-
east Turkey were intoxicated by eating wheat contaminated with hexachloroben-
zene (91). The incident caused a 10% mortality and the survivors acquired the
syndrome known as "porphyria cutanea tarda," a disease of distu-bed porphyrin
metabolism manifested by skin lesions. Other clinical findings of the
patients are cutaneous photosensitivity, porphyrinuria, hyperextrichosis,
hyperpigmentation, hepatomegaly, cirrhosis and various arthritic, visceral,
urinary and neurological disorders (56, 92).
161
-------
For a period of several months in 1968, more than 1,000 people in Japan
were poisoned by consuming rice oil contaminated with Kanechlor 400 (a PCB
with 48% chlorine content, manufactured in Japan). The syndrome, known as
"Yusho" 0"rice oil disease"), is characterized by enlargement and hypersecre-
tion of the Meibomian glands of the eyes, pigmentation of the nails and mucous
membranes, hyperkeratosis, darkening of the skin and acnefonn skin eruptions
(93, 94). This outbreak has led to a number of epidemiological studies which
have recently been reviewed and updated by Kuratsune (cited in ref. 95) and by
Higuchi (16).
Since the accidental contamination of animal feed with PBBs (FireMaster
PB-6) in Michigan in 1973, several comprehensive surveys were conducted on the
health status of the farmers and residents who might have consumed the conta-
minated fana products. Compared to the population not exposed to PBBs, the
Michigan farm residents showed significantly higher prevalence of skin, neuro-
logical and musculoskeletal symptoms (96, 97), Bekesi e± al_. (98) also
reported abnormalities in lymphocyte number and function in people exposed to
PBBs; however, other investigators (99, 100) failed to confirm these findings.
Mutagenic Effects. The mutagenic potential of BHC and chlorinated cyclo-
diene pesticides has been investigated in a number of widely used test
systems. The results of some recent studies are summarized in Table XXXII.
Chlordane induced gene conversion in Saccharomyces cerevisiae strain D4
(140). Dieldrin (134, 135), endosulfan (142) and toxaphene (118; cited in
ref. 41) were reported by some investigators to give positive results in the
Ames test. Other compounds of this class, however, have been consistently
reported by numerous investigators to be nonmutagenic in various microbial
systems, with or without hepatic microsomal activation (reviewed in refs. 104,
105; see also Table XXXII). There is also no conclusive evidence that these
162
-------
p. 1 of 3
; Table XXXII
Ames Salmonella Mutagenicity and Related Genotoxicity Assays on Halogenated
Cycloalkanes, Cycloalkenes and Aromatics
Compound
Ames
test Reference
Other tests
Reference
Halogenated Cycloalkanes
Hexachlorocyclohexanes
Lindane ( }f-
Toxaphene
Mirexc
Keponec
Halogenated Cycloalkenes
Hexachlorocyclo-
pentadiene
Aldrinc
Dieldrinc
Endrinc
Chlordane0
Heptachlorc
Heptachlor epoxide
101-105
105, 110, 111
41, 118
120-123
120, 122, 123
40
102-104
101, 102, 104,
129-131
134, 135
111
21
102, 104, 116
129
- (A.B.C.D) 102-104, 106-108
+ (H) 109
+
-
-
-
(D,E,G)
(H)
(E,H)
(E,G)
(E,G)
112-114
109, 11
29, 119
124-126
124-126
- (A,E)
(G,H)
- (E)
+ (G)
40
- (A.B.C.D) 102-104, 106, 127
112, 116, 128
- (A,B,C,D, 102-104, 106, 119
E,H) 127, 132, 133
-+ (G.H) 112, 115, 116,
136, 137
- (A,C,D,G) 106, 124, 138
+ (H) 115, 139
- (A.E.G) 119, 124, 127,
128
+ (D.F.G.H) 112, 115, 136,
140
- (A,B,E,G) 102, 104, 124,
128
+ (G,H) 112, 115, 116,
141
119, 128
112
Endosulfan0
142
- (A,C,D)
106
-------
Table XXXII (continued)
p. 2 of 3
• I
Compound
Halogenated Benzenes and
Monoch lorobenzene
Dichlorobenzenes
1,2,4- and 1,3,5-
Trichlorobenzenes
Ames
test Reference
Naphthalenes
42
42, 136, 144
120, 145
1,2,4,5-Tetrachlorobenzene - 146
Hexach lorobenzene
Monobromobenzene
1,3- and 1,4-Chloro-
145
35, 131
35
Other tests3 Reference
- (A,K,M) 42, 143
+ (D) 42
- (A,D) 42
+ (M) 143
n.t.
n.t.
- (D,E) 21, 126, 147a
n.t.
n.t.
bromobenzene
1 ,2,3,4-Tetrachloro-
naphthalene
Polyhalogenated Biphenyls
PCBs
147b
105, 120, 121,
148, 149
155
n.t.
- (E,H)
150-154
PBBs
DDT and Related Compounds
DDTd
DDEC
156
101-104, 121,
129, 158, 169
110, 129, 131,
140, 158, 169
- (H)
- (A-I.L)
(E,H,J)
- (A,C,D,
G,J,L)
+ (E.H.K)
157
102-104, 106,
112, 119, 124,
159-163
75b, 106, 116,
159, 164-168,
170, 171
106, 124, 163,
168
75b, 160, 163,
166
-------
Table XXXII (continued)
p. 3 of 3
Compound
Ames
test Reference
Other tests3
Reference
DDT and 'Related Compounds (continued)
DDDC
DDA°
Ethyl-DDDe
[Perthane]
111
158
158
122
- (A.C.D,
G,J)
+ (H,L)
106, 124, 168
75b, 163, 166
- (A.C.D.E.L) 106, 163
+ (H,J) 106, 168
n.t.
DDMSd
DDNUd
DDOHd
Chlorobenzilate6
Methoxychlor6
Dicofol6
158
158
158
n.t.
n. t.
- (J)
168
104, 111, 172 - (A.B.C.D) 104, 106
171, 173 - (A,D,J) 138, 171, 174
146, 158 - (A) 127
aThe other mutagenicity and related assays are: A = Escherichia coli; B = Bacillus
subtilus; C = Serratia marcerceus; D = Saccharomycetes cerevisiae; E = mammalian
dominant lethal; F = Chinese hamster cell (V79); G = unscheduled DNA synthesis; H =
chromosomal aberration; I = Neurospora crassa; J = sex-linked recessive lethal; K =
mouse lymphoma L5178Y; L = host-mediated assay; M = Aspergillus nidulans; n.t. = not
tested.
A mixture of at least 177 polychlorinated dipterpene derivatives.
cFor structural formula, see Fig.11.
For the formula and chemical name corresponding to the acronym, see Fig. 20.
eFor structural formula, see Table XLI.
-------
compounds are mutagenic in mammalian systems. Dieldrin and chlordane were
reported to be weakly mutagenic in the induction of ouabain-resistant mutants
in Chinese hamster V79 cells (136). Using SV-40 transformed human cells,
Ahmed ££_al_. (112) demonstrated that aldrin, dieldrin, chlordane, heptachlor
and heptachlor epoxide all induced unscheduled DNA synthesis either directly
or following metabolic activation. However, DNA repair was not observed with
chlordane, heptachlor or endrin in primary hepatocyte cultures derived from
the rat, mouse or hamster (124). No evidence of dominant lethal effects in
mice were found with any of the chlorinated pesticides tested so far: lindane
(113, 119), dieldrin (119, 132, 133), isodrin, aldrin, endrin, toxaphene
(119), heptachlor, heptachlor epoxide, chlordane (119, 128) and hexachloro-
cyclopentadiene (40). In mouse lymphoma L5178Y cells, hexachlorocyclopenta-
diene did not increase the incidence of forward mutations (40). When tested
in the host-mediated assay,
-------
Information, on the mutagenic activity of halogenated benzenes is scanty
and the data available are quite ambiguous (Table XXXII). Mono- and dichloro-
\.
benzenes have been tested in Aspergillus nidulans for their ability to induce
reverse mutations (143). Positive results were obtained with all three
isomers of dichlorobenzene, but not with the monochloro derivative. The
mu'tagenicity of the dichlorobenzenes decreases in the order: 1,4- > 1,3- >
1,2- positions of the chlorine atoms. The activity of 1,4-dichlorobenzene was
about twice that of 1,2-dichlorobenzene. However, when tested in
Saccharomyces cerevisiae strain D3, monochlorobenzene was rautagenic but not
1,2- or 1,3-dichlorobenzene; the results with 1,4-dichlorobenzene were incon-
sistent (cited in ref. 42). All four compounds were negative when tested in
Salmonella typhimurium (cited in ref. 42; 144, 145) and Escherichia coli
(cited in ref. 42). Monochlorobenzene was also found inactive in the induc-
tion of specific locus forward mutations in the mouse lymphoma L5178Y assay
system (cited in ref. 42). Moreover, several brominated and higher chlori-
nated benzenes were reported to be nonmutagenic in various tester strains of
Salmonella typhimurium with or without metabolic activation. The latter
compounds include bromobenzene (131; cited in ref. 35), 1,3-bromochloroben-
zene, 1,4-bromochlorobenzene (cited in ref. 35), 1,2,4-trichlorobenzene (120),
1,3,5-trichlorobenzene (145), 1,2,4,5-tetrachlorobenzene (146) and hexachloro-
benzene (145). Hexachlorobenzene did not significantly increase the number of
revertants in Saccharomyces cerevisiae (cited in ref. 21). The compound also
failed to induce dominant lethal mutations in the rat (126, 147a). There is a
scarcity of information on the mutagenicity of halogenated naphthalenes;
1,2,3,4-tetrachloronaphthalene has been found not mutagenic in the Ames test
(174b).
164
-------
A dominant lethal study in rats gave no evidence for the mutagenicity of
Aroclors 1242 and 1254 (151). Cytogenetic analysis of human lymphocyte cul-
ture (153), Drosophila (154) as well as the bone marrow cells (152) and
spermatogonia (150, 152) of rats exposed to relatively high levels of several
commercial products of PCBs showed no significant chromosomal aberrations. A
number of sources (105, 120, J21, 148, 149) indicate that Arochlor 1254 and
several chlorinated biphenyl isomers (4-chloro-, 2,4,2',4'-, 2,5,2',5'- and
3,4,3',4'-tetrachloro-, and 2,4,6,2',4',6'-hexachloro-) are not mutagenic in
strains TA1535, TA1537, TA98 or TA100 of Salmonella typhimurium (tested with
or without liver microsomal activation). Sayler et al. (175) showed recently
that several potential bacterial biodegradation products of PCBs are
nonmutagenic either in the sister chromatid exchange assay or in the
Salmonella test. However, Wyndham _e_t _al_. (155) observed mutagenic effects
with 4-chlorobiphenyl, 2,5,2',5'-tetrachlorobiphenyl and several other PCBs in
the TA1538 strain (sensitive to frameshift mutations) assayed with the addi-
tion of rabbit liver microsomal fraction. Surprisingly, the lowest chlori-
nated 4-chlorobiphenyl was the most active, whereas the activity of the higher
chlorinated 2,5,2',5'-tetrachlorobiphenyl, Aroclors 1221, 1254 and 1268
decreased with the increase in their chlorine contents. Similarly, 4-bromobi-
phenyl was shown to be highly mutagenic to the strain TA1538 (156). Fire-
Master PB-6, the commercial PBB product did not induce chromosomal abnor-
malities in bone marrow cells of mice (157). The mutagenicity of PCBs and
PBBs is summarized in Table XXXII. No information on the mutagenicity of PCTs
was found in the literature at the time of this writing.
The mutagenicity of DDT and its derivatives has been discussed in many
reviews (34, 46, 56, 106, 176-178). The test results on this chemical group
in various mutagenicity assay systems are summarized in Table XXXII. With the
165
-------
exception of ODD (158) and ethyl-DDD (122) in one study with Salmonella, DDT
and other derivatives show no mutagenic activity in various bacterial and
fungal systems. Implications of their genetic effects have largely been based
on their ability to cause chromosomal aberrations and their weak mutagenicity
in one or more non-microbial systems. Although no significant increase in
cytogenetic abnormalities was found in the Chinese hamster cell line V79 (160)
and bone marrow cells of rats (165), significantly higher number of chromo-
somal gaps, breaks or translocations were observed in the Chinese hamster cell
line B14 F28 (75b), bone marrow cells of mice (116, 164), and a kidney cell
line from rat kangaroo (166), as well as human lymphocytes (106) and blood
culture (170) exposed to DDT. DDE (75b, 160, 166), ODD (75b, 166) and DDA
(106) have also been shown to cause significant increases in chromosomal
aberration in one or more of these systems. In Chinese hamster cells, DDT and
DDD exhibited the highest cytogenetic activity, DDE was intermediate and DDA
the least active (75b). The j^p'-chloro isomers of DDT, DDD and DDE produced
twice as many chromosome breaks in a rat kangaroo cell line than the corre-
sponding o_>2.'~ isomers (166). Whereas DDT was inactive in dominant lethal
tests with mice (119, 162, 163), it was found marginally positive in similar
tests with rats (159, 165, 167). DDT, as well as DDA, were also reported to
induce sex-linked recessive lethals in Drosophila (168). In both the Chinese
hamster cell line V79 (160) and in mouse lymphoma L5178Y cells (172), DDE
produced an increased frequency of forward mutations. In the host-mediated
assay in mice, a significant increase in mutation rate due to DDD was observed
(163).
Reproductive and Teratogenic Effects. The reproductive effects of these
mpounds have been of interest to researchers since the discoveries in the
1960's that chlordane, DDT and other chlorinated hydrocarbons are potent
166
-------
inducers of mixed function oxidases (179-183), which may affect the metabolism
of androgenic and estrogenic steroids (184-187). Furthermore, recent evidence
indicates that many of these organochlorine pesticides may compete with
steroids for binding to the uterine cytosolic estrogen receptors; this type of
interaction probably accounts for their estrogenic effects in various
mammalian species (188-191).
Several studies have shown that chronic administration of lindane
( Y-BHC) causes delayed sexual maturity, lengthened oestrus cycle, diminished
fertility and viability of fetuses in rats, mice and rabbits (39, 192, 193).
Lindane ( \ -BHC) crosses the placenta (cited in ref. 108) and, in accordance
with this finding, in a four-generation feeding study with rats, significant
incidence of spastic paraplegia was observed in Fj and F2 animals (39).
However, no indication of teratogenic effects of lindane ( V-BHC) was found in
other studies with mice (cited in ref. 108), rabbits (194) or rats (cited in
ref. 108; 194, 195).
Toxaphene given orally to rats, mice or guinea pigs in multi-generation
studies or during gestation did not result in any effects on fertility, litter
size, neonatal viability, or weanling body weight (cited in ref. 41). Gross
and microscopic examination also showed no evidence of deformities in the
offspring. However, Chernoff and Carver (196) observed a dose-related reduc-
tion in fetal weight as well as in the average number of sternal and caudal
ossification centers in rats. Significant incidences of encephaloceles were
also noted in one or more offspring in five litters of mice receiving
maternally toxic doses.
Negative results were reported in a teratogenicity study involving
administration of oral doses of hexachlorocyclopentadiene (hex) up to 100
167
-------
mg/kg/day to 30 pregnant rats (cited in ref. 40). However, marked repro-
ductive and teratogenic effects of other chlorinated cyclodienes have been
demonstrated in various animal species. Disturbances of the estrus cycle were
seen in female rats (197) and dogs (198, 199) treated with aldrin. In dogs,
aldrin also caused reduction in the number of pregnancies, decreased milk
production and a high incidence of stillbirths (198). Administration of a
single oral dose of aldrin to hamsters resulted in fetal mortality, growth
retardation and congenital abnormalities including open eyes, webbed feet,
cleft palate, cleft lips, fused ribs, exophthalmia, microcephaly and
exencephaly (200). Similar effects were also observed in mice in multi-
generation studies (201), as well as in mice given aldrin during gestation
(200).
Dieldrin exposure caused alterations of the estrus cycle (202), adverse
effects on fertility, gestation viability and lactation (199, 203), decreased
litter size (199, 204), as well as various fetal anomalies (200, 205) in the
mouse. Reduction in the number of pregnancies was observed in rats (73) and
dogs (198) given dieldrin. The compound crosses the placenta in rabbits
(206), rats and guinea pigs (207) and has also been shown to be teratogenic in
rats (205) and hamsters (200). The anomalies produced included both soft- and
skeletal-tissue malformations. However, no significant teratogenic effects of
dieldrin were evident in two other studies with rats and mice (208, 209).
Photodieldrin was also considered to be nonteratogenic in the two species
(208). Endrin, the stereoisomer of dieldrin, causes increases in fetal and
postnatal mortality in a number of animal species (cited in ref. 30). The
compound exerted similar teratogenic effects as dieldrin in hamsters and as
aldrin in hamsters and mice (200). A recent study by Kavlock ££__£!.• (210),
however, failed to show any teratogenicity or dose-related embryo lethality in
rats or mice treated with endrin throughout the period of organogenesis.
168
-------
Two large-scale feeding tests were conducted in Swiss mice to investigate
the influence of telodrin (isobenzan) on reproductive performance (211).
i.
Sublethal doses of telodrin in the diet did not affect parent mortality,
fertility, or fecundity; adverse effects on the offspring were also not found.
Chlordane significantly reduced the number of pregnancies (184) and
viability of the offspring in mice (212).. Similarly, Ambrose et_ _al_. (213)
observed decreased fertility in male and female rats and decreased survival of
the offspring. However, no teratogenic effects were found in rats fed chlor-
dane during pregnancy (214).
The teratogenic potential of heptachlor has been tested in rats in a
multi-generation study (215). The compound caused a marked decrease in litter
size, early infant mortality, and the development of cataracts in the off-
spring.
Endosulfan administered to female rats during gestation produced dose-
dependent fetal mortality and resorption of fetuses. Various skeletal malfor-
mations were encountered in the progenies (216).
Mirex and kepone have been repeatedly demonstrated to exert similar
adverse effects on the reproduction of rats and nice. Both compounds caused
significant reduction in fertility and litter size (125, 191, 211, 217-219) as
well as reduction of fetal birth weight and survival rate (125, 191, 219,
220). Placental and lactogenic transfer of mirex (125, 219) and kepone (218)
have been documented. Offspring of rats given oral doses of mirex developed a
high incidence of cataracts (219) and various visceral anomalies (125).
Administration of kepone to pregnant rats induced central nervous system
impairment in the offspring soon before and after birth (221). Teratogenic
effects of these two compounds in humans have not been reported. However,
169
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testicular damage, production of abnormal sperm and sterility have been
observed in some exposed workers (76, 77, 222). Traces of mirex have also
been detected in some human milk samples (223).
Chronic administration of 1,2,4-trichlorobenzene did not affect the
growth, viability or reproductive function of rats (224). However, reduction
t
in spermatogenesis and atrophy of seminiferous tubule tissues have been noted
in dogs exposed to monochlorobenzene (42). A four-generation reproduction
study also demonstrated various adverse effects on fertility, viability and
lactation in rats ingesting hexachlorobenzene (225). Placental transfer of
pentachloro-, hexachloro-, and hexabromo-benzene have been reported in the rat
(226, 227). Fetal tissue accumulation is the highest with hexachlorobenzene
(226). Hexachlorobenzene also crosses the placenta and accumulates in various
fetal tissues of mice (228) and rabbits (229). Teratogenicity studies in rats
showed that significant increase in the fetal incidence of extra ribs and
sternal defects is brought about by pentachlorobenzene but not by hexabromo-
benzene (230). Hexachlorobenzene, on the other hand, produces cleft palates
and kidney malformations in the mouse (231). The compound has also been
detected in human milk samples (232).
Little information is available on the reproductive and teratogenic
effects of halogenated naphthalenes. Destruction of spermatogenesis was
reported in a bull experimentally poisoned with highly chlorinated naphtha-
lenes (233).
In contrast, reproductive dysfunction due to exposure to PCBs has been
amply documented in a wide variety of animal species including the rat (71,
90, 234), mouse (235, 236), rabbit (237), monkey (187, 238) and mink (239).
Irregular menstrual cycle, decreased mating performance, early abortion as
170
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well as resorption are Che most commonly observed effects. Studies with
several PCB compounds of various chlorine contents revealed that the repro-
ductive effects^decrease with increasing chlorination (90).
Numerous reports have shown that PCBs pass the placenta and are excreted
in milk in humans (240-242) as well as in other mammals (243-246). Although a
number of studies failed to demonstrate the definite teratogenicity of PCBs in
rats (234, 243; cited in ref. 90), rabbits (237) or monkeys (244), Watanabe
and Sugahara (247) recently observed significant incidences of cleft palate,
cleft lip, brachydactyly and syndactyly in the offspring of ddY strain mice,
subcutaneously injected during pregnancy with Kanechlor-500 (a Japanese PCB
product). Marks _ejt_al_. (248) have tested the teratogenicity of
3,3'4,4'5,5'-hexachlorobiphenyl by administering the compound to pregnant CD-I
i
mice on days 6-15 of gestation by gavage, at doses of 0.1, I, 2, 4, 8, and 16
mg/kg/day. A significant increase in the average percent of malformed fetuses
(cleft palate and hydronephrosis predominantly) per litter versus the controls
was observed at doses of 2 mg/kg and above. Teratogenic effects of PCBs have
also been noted in dogs (249) and chickens (250, 251), which showed various
skeletal deformities. Infants born to humans or to nonhuman primates exposed
(accidentally or experimentally) to PCBs were undersized and hyperpigraented at
birth; after nursing on PCB-containing milk the infants developed typical
signs of PCB toxicity (244, 252). In several cases, gingival hypertrophy,
exophthalmia and abnormalities in the fontalles and sagittal suture were also
noted in the newborns of "Yusho" patients (252).
Reduction in fetal weight and viability has been found in rats and mice
upon maternal exposure to PBBs (253, 254). Polybrorainated biphenyls exhibited
weak teratogenicity in mice, causing encephaly, cleft palate and hydrone-
phrosis (253). However, in rats, several investigators (255, 256) reported no
171
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gross malformations in the offspring following feeding the mothers PBBs during
pregnancy. On the other hand, Beaudoin (257) observed significant incidences
of cleft palate and diaphragmatic hernia in the progenies of rats which
received 'high acute doses of PBBs. Vaginal opening in female pups was delayed
by either prenatal or postnatal nursing exposure to PBBs (256). An inhibitory
effect of PBBs on the development of rat embryos has been demonstrated in an
in vivo/in vitro combined assay system (258).
Low level exposure to DDT exerts little, if any, reproductive effects in
rats (73, 259-262), mice (211, 263) or dogs (264). At high doses, however,
infertility and reduction in litter size, viability, mammary gland develop-
ment, and milk production were reported (198, 265-268). Various detrimental
effects of DDT on the development of spermatogenesis in male rats have also
been described (269, 270). Thus far, DDT has not been implicated as a tera-
togen. However, several investigators (188, 260, 261, 271) suggested that the
potent estrogenic activity of DDT in mammals might have significant effects on
the development of neonates. The estrogenic action of DDT (technical grade)
is due largely to the presence of _o,_p_'-DDT since _p_,_p_'-DDT is several-fold more
potent as an estrogenic agent than DDT (technical grade) or its major consti-
tuent, _p_,p'-DDT (272). Structural observations regarding estrogenic activity
of various diphenylethane compounds in rats indicated that there is activity
when a _p_- or £*-position is unsubstituted (-H), or is substituted by a hydroxy
or methoxy group. Halide or alkyl groups in the _£_,_£' -position rendered the
compounds inactive. Moreover, a stable ethane chain, e.g., the trichloro-
ethane or the inert vinyl halide group, is required for activity; if either
carbon atom of the ethane chain bears an oxygenated group (alcohol, aldehyde
or acid), no estrogenic activity is observed because of the rapid metabolism
of the compounds (273). Estrogenic activity in female rats varies in the
172
-------
order: _p_,_p'-DDT > DDT (technical grade) > nethoxychlor > _p_,_p'-DDT or _o_,_p_'-DDE
> _o,£'-DDMU. jo,£'-DDD, m_,£f-DDD, £,£'-DDD (IDE), p_,_p'-DDE, £,£T-DDA,
£,£'-DDMU or £,£'-ethyl-ODD exhibited little or no activity (272, 273).
Technical grade methoxychlor is four times more estrogenic than the pure
£,£'-methoxychlor in immature female rats (273). High doses of methoxychlor
elicited typical estrogenic effects such as early vaginal opening, constant
estrus, larger uteri, smaller ovaries, and consequently reduction in mating
performance and fertility in the rats (274, 275). Impaired sperraatogenesis in
male animals (276, 277) and arrested folliculogenesis in the females (277)
were also noted after treatment with the compound. Khera et al. (278)
observed a dose-related increase in the incidence of wavy ribs in the off-
spring of rats fed 100, 200 or 400 mg/kg/day methoxychlor on days 6 to 15 of
gestation.
No indication of teratogenicity was found in mice given dicofol in the
diet up to 500 ppm over five generations (279).
5.2.2.2.3 Carcinogenicity and Structure-Activity Relationships.
5.2.2.2.3.1 OVERVIEW.
During the last two decades, considerable research on the carcinogenicity
of the chlorinated cyclic hydrocarbon pesticides has been carried out. In
1969, aldrin, dieldrin, heptachlor, mirex, DDT, chlorobenzilate and strobane
(a chlorinated terpene) were judged "positive" for tumor induction by "The
Secretary's Commission on Pesticides and Their Relationship to Environmental
Health" of the U.S. Department of Health, Education, and Welfare (280). Since
then, additional data have become available from the National Cancer Institute
(NCI) carcinogenesis bioassay program as well as from other independent
studies. In these studies an increasing number of chlorinated cyclic hydro-
173
-------
carbons have been demonstrated to possess various degrees of carcinogenic
activity in experimental animals. The International Agency for Research on
Cancer (IARC) Working Group considered the evidence for the carcinogenicity of
lindane, toxaphene, chlordane, mirex and kepone in experimental animals to be
"sufficient" (21). Several reviews on the carcinogenicity of these compounds
have been published (19, 21, 176, 178, 281-286).
As a class, the chlorinated cyclic hydrocarbon pesticides are hepatic
carcinogens, more generally toward mice than toward other rodents. The rela-
tive potency of several cycloalkanes and cycloalkenes in the induction of
hepatomas is shown in Table XXXIII, which summarizes the recent results of the
National Cancer Institute/National Toxicology Program (NCI/NTP) carcinogenesis
studies on these chemicals in B6C3F1 mice. Dieldrin, aldrin, heptachlor,
kepone, chlordane, and toxaphene all elicited high incidences of liver tumors
in the mice. Moderate to weak hepatocarcinogenicity was also shown by the
NCI/NTP studies in male and/or female B6C3F1 mice ingesting the DDT analogs
DDE, dicofol, ethyl-DDD or chlorobenzilate. Table XXXIV presents the relative
hepatocarcinogenic potencies in this group of agents.
Reuber (284, 287, 288) and Tomatis and Turusov (289) have described in
detail the histopathology of liver tumors induced by this group of compounds
in mice. Carcinomas of the liver are preceded by the development of hyper-
plastic nodules which arise from the cells adjacent to the central veins.
Malignancy of the carcinomas is evidenced by their metastases to the lungs and
growth en transplantation to isologous hosts. Occasionally, cholangiocellular
carcinomas, hemangiosarcomas, leiorayosarcomas and reticulum cell sarcomas
develop.
174
-------
Table XXXIII
Relative Carcinogenic Potency of Chlorinated Cycloalkanes and Cycloalkenes
in B6C3F1 Mice by Oral Administration3
Incidence (%)
Compound
Lindane
( y-BHC)f
Toxaphene^
Keponeh
Aldrinh
Dieldrinh
Photodi-
eldrin1
Endrinh
Chlordaneh
Heptachlorh
Endosulfanh
Sex
M
F
M
F
M
F
M
F
M
F
M
F
M
F
M
F
M
F
M
F
Dose (ppm)
80 or 160
80 or 160
99 or 198
99 or 198
20 or 23
20 or 40
4 or 8
4 or 8
2.5 or 5.0
2.5 or 5.0
3.4 or 7.5
0.32 or 0.64
1.6 or 3.2
2.5 or 5.0
29.9 or 56.2
30.1 or 63.8
6.1 or 13.8
9 or 18
3.5 or 6.9
2.0 or 3.9
Significant neoplasms Control
Hepatocellular carcinoma
None
Hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma
None
Hepatocellular carcinoma0
None
None
None
None
None
Hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma
None
None
10e
—
8
0
16
0
15
—
17
—
—
—
—
—
10
0
11
4e
—
—
Low
dose
38
—
69
10
81
52
33
—
24
—
—
—
—
—
33
6
24
6
—
—
High
dose
20
—
98
69
88
47
56
—
36
—
—
—
—
—
83
69
72
71
—
—
Summarized from: National Cancer Institute (NCI)/National Toxicology Program
Carcinogenesis Technical Reports No. 8, 9, 12, 14, 17, 21, 22, 37, 62 (1977-1979)
and NCI brief Communication on Kepone (1976).
Significant incidence at low dose level only.
Significant incidence at high dose level only.
Matched controls unless as indicated.
ePooled controls.
BHC is benzene hexachloride, the common name for hexachlorocyclohexane.
SA mixture of at least 177 polychlorinated dipterene derivatives.
For structural formula, see Fig. 11.
xFor structural formula, see Fig. 14.
-------
Table XXXIV
Relative Carcinogenic Potency of DDT and Analogs in B6C3F1 Mice
by Oral Administration3
Incidence (Z)
Compound
DDTC
DDE
ODD (TDE)C
Ethyl-DDD
(Perthane)
Methoxychlorc
Chloroben-
zilate
Dicofol
Sex
M
F
M
F
M
F
M
F
M
F
M
F
M
F
Dose (ppm)
22 or 44
87 or 175
148 or 261
148 or 261
411 or 822
411 or 822
2,500 or 5,000
2,828 or 6,200
1,746 or 3,491
997 or 1,994
4,231 or 7,846
3,200 or 5,908
264 or 528
122 or 243
Matched
Significant neoplasms control
None
None
Hepatocellular carcinoma
Hepatocellular carcinoma
None
None
None
Hepatocellular adenoma
or carcinoma
None
None
Hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma
None
—
—
0
0
—
—
—
5
—
—
21
0
17
—
Low
dose
—
—
17
40
—
—
—
6
—
—
67
22
44
—
High
dose
—
—
36
71
—
—
—
23
—
—
49
26
74
—
aSumraarized from: National Cancer Institute (NCl)/National Toxicology Program
Carcinogenesis Technical Reports No. 35, 75, 90, 131, 156 (1978-1979).
For structural formulas, see Table XLI.
cCarcinogenic in other strains of mice and/or in rats (see Table XLI).
-------
With the exception of lindane (X-BHC), toxaphene, aldrin, dieldrin,
mirex, kepone, DDT, £,_p'-DDD, chlorobenzilate and methoxychlor, no other
halogenated cyclic hydrocarbon pesticides have been found to produce signifi-
cant carcinogenic effects in rats. Endrin, photodieldrin, endosulfan and
telodrin appear to be noncarcinogenic toward both mice and rats.
Information is meager on the carcinogenicity of halogenated benzenes,
naphthalenes, biphenyls and terphenyls. Nonetheless, pathological and bio-
chemical data point to a definite carcinogenic potential of these chemicals,
particularly toward the liver (290, 291). The limited data available from
recent studies show that hexachlorobenzene, PCBs, PBBs and PCTs are indeed
carcinogenic, producing hepatocellular carcinomas and neoplastic nodules in
laboratory rodents. The carcinogenicity of PCBs (20, 45, 290) and PBBs (20)
has been reviewed.
5.2.2.2.3.2 HALOGENATED CYCLOALKANE PESTICIDES.
Hexachlorocyclohexane (BHC) and Its Isomers. Technical grade BHC, as
well as its major isomers, o(-, S- and Y'-BHC (lindane), induce liver neo-
plasms and hyperplastic nodules in mice and rats. Mice are more susceptible
to the carcinogenic effects than rats, and males appear to be more so than
females. There are also considerable variations in the susceptibility of
different strains of mice. The carcinogenicity of technical grade BHC and its
isomers has been reviewed by Reuber (292, 293). The dosage, strain and sex of
the animals, and the liver tumor incidence in the carcinogenicity tests with
r>HC in mice and rats are given in Table XXXV and Table XXXVI, respectively.
The carcinogenicity of BHC (in male dd strain mice) was first reported by
Nagasaki _e_t _al_. (294, 295, 305). All 20 animals fed a diet containig 660 ppm
technical- grade BHC (containing approximately 67% sC-isomer, 11% /3-isomer,
175
-------
p. 1 of 2
Table XXXV
Hepatocarclnogenlclty of Hexachlorocyclohexane (BHC) in Mice
by Oral Administration
Compound Strain Sex
BHC dd M
( technical
grade)b F
ICR-JCL M
«*-BHC dd M
F
ICR-JCL M
DDY M
'F
ICR M
F
DBA/ 2 M
F
C3H/He M
F
C57BL/6 M
F
fi-BHC dd M
F
ICR-JCL M
CF-1 M
F
Dosage
(Ppo)
660, 600 or 300
100, 66 or 6.6
'600
300
100
600
600 or 300
500
250
100
100
600
300
100
600
500
500
500
500
500
500
500
500
500
500
600, 500, 300,
250 or 100
600, 300 or 100
600
200
200
Tumor
incidence
(Z)a
100
0
100
60
0
100
100
85
26
13
0
75
67
0
100
65
25
39
21
6
7
0
10
0
0
0
0
Tumorc
73d
43e
Reference
(294-296)
(294-296)
(296)
(296)
(296)
(297)
(296)
(298)
(298)
(296)
(298)
(296)
(296)
(296)
(297)
(299)
(299)
(299)
(299)
(299)
(299)
(299)
(299)
(299)
(299)
(296, 298)
(296)
(297)
(300)
(300)
-------
Table XXXV (continued)
p. 2 of 2
Compound
f-BHC
(Llndane)
f-BHC
* + f (BHC)
-------
Table XXXVI
Induction of Liver Hyperplaatic Nodules and Carcinomas by Hexachlorocyclohexane (BHC) in Rats
by Oral Administration
Compound
BHC
(Technical
grade)3
<*-BHC
/S-BHC
V-BHC
( lindane)
-------
15% /-isomer, 6% £-isomer and 1% others) developed tumors in the liver after
24 weeks. No liver lesions were found in the 14 controls or in the 20 mice
receiving only 66 ppm or 6.6 ppm of the BHC mixture in the diet. Similarly,
Hanada _et_'_al>. (296) administered 600 or 300 ppm crude BHC for 32 weeks
followed by basal diet for 5 to 6 weeks and observed 100% incidence of hepa-
toraas in male dd strain mice and high incidences in females ingesting 600 ppm
(100% incidence) or 300 ppm (60% incidence). Under the same experimental
conditions, hepatomas were not found in the controls or in mice of either sex
receiving 100 ppm of the compound. In studies with male IRC-JCL strain mice,
Goto _e£_al_. (297) observed liver tumors in all 10 animals fed a diet con-
taining 600 ppm technical grade BHC for 26 weeks.
The induction of liver tumors in mice of dd strain by purified isomers of
BHC has also been studied (298, 306). When male dd strain mice were given
o(-, |3-, ^- or d -BHC singly or in various combinations in the diet for 24
weeks, liver tumors were observed at the end of the administration period only
in mice receiving 250 ppm (26% incidence) or 500 ppm (85%) oC'-BHC, 250 ppm
*-BHC plus 250 ppm f-BHC (50%), 250 ppm c*-BHC plus 250 ppm f-BHC (42.8%)
or 250 ppm c*-BHC plus 250 ppm a -BHC (25%). No liver tumors were found in
the controls or in mice given a lower dose (100 ppm) of
-------
Studies by Goto et al. (297) in several other strains of mice show that
o< ~» $~ and Y"-BHC (lindane) all induce liver tumors, although the X,-isomer
appears to be more potent. In groups of 10 male IRC-JCL strain mice fed
various isomers of BHC at levels of 600 ppm for 26 weeks, hepatomas arose in
100% and 50% of the mice ingesting diets containing
-------
rats and nale Syrian golden hamsters were given basal diet containing 500 ppm
o<-BHC or basal diet alone, for 24 weeks. Upon gross and microscopic examina-
t.
tion, significant carcinogenic lesions of the liver were found only in mice,
but not i'n rats or hamsters. Among the various strains of mice tested, the
DDY strain was the most susceptible and the C57BL/6 strain the least suscept-
ible to the hepatocarcinogenic,action of o<-BHC. Male mice exhibited higher
susceptibility than females.
Early studies by Fitzhugh _e_t _al_. (307) failed to detect neoplastic
lesions in the livers of male and female Wistar rats fed diets containing up
to 800 ppm technical grade <*-, y3~, or f-BHC (lindane) for their lifespan.
Under the experimental conditions used in the U.S. National Cancer Institute
bioassay program (301), Y"~BHC (lindane) was also inactive in Osborne-Mendel
rats. Ito _e_t _al_. (304) observed no histopathological changes in the livers of
male Wistar rats receiving 500 ppm «' -BHC, 500 or 1,000 ppm /3-BHC, 500 ppm
(-BHC or 500 or 1,000 ppm ^-BHC for up to 48 weeks. However, hepatocellular
carcinomas were found by these authors in 3 of 13 (23%) and 1 of 16 (6%) rats
fed 1,500 ppm and 1,000 ppm o<-BHC, respectively, for a period of 72 weeks.
In addition, 77% and 76% of the respective groups of rats and 42% of rats
which ingested 1,000 ppm o<-BHC for 48 weeks had hyperplastic nodules in the
liver. Reviewing several Food and Drug Administration studies reported
between 1947 and 1950 (most of them as memoranda), Reuber (203) indicated the
development of small number of preneoplastic and neoplastic lesions of the
liver and other organ systems in Wistar and Osborne-Mendel rats treated with
either technical grade or various isomers of BHC.
Halogenated Cycloalkane Pesticides Other than Hexachlorocyclohexane.
Besides hexachlorocyclohexane, several other halogenated cycloalkanes (toxa-
phene, strobane, mirex and kepone) have been tested for carcinogenic!ty. The
major findings of these studies are summarized in Table XXXVII.
178
-------
Toxaphene is one of the most carcinogenic compounds among the chlorinated
hydrocarbon pesticides. It has been shown to be highly tumorigenic toward the
liver of mice and the thyroid and pituitary of rats in a U.S. National Cancer
Institute bioassay (313). In this study, groups of 50 B6C3F1 mice of each sex
were given 99 or 198 ppm toxaphene in the feed for 80 weeks and then observed
for an additional 10 or 11 weeks; groups of 50 male or female Osborne-Mendel
rats were administered toxaphene at one of two doses (556 or 1,112 ppm to
males; 546 or 1,080 ppm to females) for 80 weeks and then killed 28 or 30
weeks later. Carcinomas of the liver were observed in 69% male mice treated
with the low dose of toxaphene and in 98% male mice treated the high dose.
The respective liver tumor incidences in the female mice were: 10% (low dose)
and 69% (high dose). Only 8% of the male controls and none of the female
controls developed the tumors (see Table XXXIII). Significant increases in
the incidence of follicular-cell carcinomas and adenomas of the thyroid were
found in both male (26%) and female (17%) rats in the high dose group compared
to the untreated males (5%) and females (2%). There was also a significant
increase in carcinomas and adenomas of the pituitary (59%) in female rats in
the high-dose group (vs. 33% in controls). However, it was concluded that the
pituitary neoplasms observed in the study may not be related to the chemical
since spontaneous incidences (as high as 50 to 60%) of this tumor type have
been noted in historical controls.
Strobane, another technical product consisting of polychlorinated ter-
penes closely related to toxaphene, has also been shown (308) to cause signi-
ficant increases in the incidence of hepatomas in male (C57BL/6 x C3H/Anf)Fj
mice (61% vs. 0% in controls) and of lyraphomas in male (C57BL/6 x AKlOFj mice
(33%_vs_. 12% in controls). In this study, groups of 18 male and 18 female
hybrid mice were given strobane at daily doses of 4.64 mg/kg by stomach tube
for 3 weeks, then at a concentration of 11 ppm in the diet for 75 more weeks.
179
-------
Table XXXVII
Carcinogenicity of Halogenated Cycloalkane Pesticides
Other Than Hexachlorocyclohexane by Oral Administration
Compound
Species and Strain
Principal Organs
Affected
Reference
Toxaphene3 Mouse, B6C3F1
Rat, Orborne-Mendel
Strobane Mouse,
(C57BL/6 x C3H/Anf)Fl;
(C57BL/6 x AKR)F1
Mirexc Mouse,
(C57BL/6 x C3H/Anf)Fl;
(C57BL/6 x AKR)F1
Rat, CD
Keponec Mouse, B6C3F1
Rat, Osborne-Mendel
Unspecified
Liver
Thyroid, pituitary
Liver, hematopoietic
tissue
Liver
Liver
Liver
Liver
Liver, lung,
reproductive and
endocrine tissues
(301)
(301)
(308)
(308)
(309)
(310, 311)
(310, 311)
(17, 312)
*A mixture of at least 177 polychlorinated dipterpene derivatives.
bA technical grade product, almost identical in properties to toxaphene,
containing a mixture of polychlorinated terpene isomers.
"For structural formula, see Fig. 11.
-------
Mirex was assayed for carcinogenic!ty in male and female (C57BL/6 x
C3H/Anf)Fj and (C57BL/6 x AKR)Fj mice (308). Doses of 10 mg/kg and 26 ppra
v
mirex were administered to groups of 18 mice following the same routes and
schedule as in the strobane study (308) described above. Significant inci-
dences of hepatoraas were observed in mice of both strains compared to the
controls. Six of 18 males and' 10 of 16 females of the first strain and 5 of
15 males and 10 of 16 females of the second strain developed liver tumors
after administration of mlrex. The liver tumor incidences in the male and
female controls were 8/79 and 0/87 in the first strain and 5/90 and 1/80 in
the second strain. Ulland et al. (314, 315) have conducted a two-year study
on the chronic toxicity and carcinogenicity of mirex in Charles River CD
rats. Mirex was fed to groups of 26 rats of each sex at doses of 50 and 100
ppm (maximal tolerated dose, MTD) for 18 months. The animals were killed 6
months after the treatments. Analysis of the preliminary data first indicated
to the investigators that mirex was noncarcinogenic (314). However, subse-
quent reclassification of the liver lesions according to newer guidelines
established by the U.S. National Cancer Institute for rat liver tumors (316)
and re-evaluation of the data revealed a dose-related carcinogenic effect of
mirex toward the liver (315). Hepatocellular carcinomas and preneoplastic
nodules of the liver were identified in 7 of 56 rats of the low-dose group and
in 16 of 56 rats of the high-dose groups. In addition, a spectrum of liver
lesions characteristic of early response to liver carcinogens were seen in all
treated animals. None of the 40 untreated controls had tumors or preneo-
plastic lesions in the liver. Nonneoplastic lesions present in the hearts and
kidneys of the treated groups were regarded by the authors (309, 315) to be
unrelated to the treatment. However, those lesions were interpreted by Reuber
(317) to be due to mirex administraCion.
180
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Kepone (Chlordecone) is unequivocally a liver carcinogen toward the mouse
and the rat, based on a U.S. National Cancer Institute bioassay (311). Groups
v
of 50 B6C3F1 mice and 50 Osborne-Mendel rats of each sex were administered
kepone in the diet for 80 weeks and then observed for an additional 10 (for
mice) and 32 (for rats) weeks. Significant incidences of liver tumors were
induced at dietary levels of 23 or 20 ppm (male) and 40 or 20 ppm (female) in
mice and at 24 ppm (male) and 26 ppm (female) in rats. The incidences of
hepatocellular .carcinomas in male and female mice receiving high doses of
kepone were 88% and 47%, respectively (compared with 16% in male and 0% in
female controls); the corresponding incidences in the low-dose male and female
mice were 81% and 52% (see Table XXXIII). In treated rats, the liver tumor
incidence was 7% in the males and 22% in the females (none of the controls
developed liver tumors). Furthermore, kepone-treated rats of both sexes
showed extensive liver hyperplasia which was not seen in controls (310).
Unpublished studies conducted by Larson ^t _al_. in the early 1960's were
reviewed by Reuber (312) and by Epstein (17). In these studies, groups of AO
male and 40 female rats of an unspecified strain were fed technical grade
kepone for 24 months at dietary levels of 1, 5, 10, 25, 50 and 80 ppm. After
25 weeks of treatment, all male and female rats at the two highest dose levels
died; survival rates in other treated groups were also low. In 38% of the
males and 43% of the females, which ingested the 5, 10 or 25 ppm kepone diets
and survived for 85 weeks or longer, hepatocellular carcinomas occurred (none
of the controls bore such tumors). Significant incidences of neoplasms in
organs other than the liver (sarcomas of the lung and carcinomas of the repro-
ductive and endocrine systems) were also observed in low-dose groups (312).
181
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5.2.2.2.3.3 HALOGENATED CYCLOALKENES: CYCLODIENE PESTICIDES.
Hexachlorocyclopentadiene (hex). Hexachlorocyclopentadiene (hex) is
\.
structurally related to a number of chlorinated cyclodiene pesticides which
are strongly carcinogenic in rodents (see below). As a cyclopentene vinyl
halide, hex maybe metabolized to an elec.trophilic intermediate. Nonetheless,
the existing toxicological studies on hex are not adequate for the evaluation
of its carcinogenicity. The carcinogenesis bioassay of hex in the U.S.
National Toxicology Program is in progress at the time of this writing.
Treon _ejt _al^ (65) reported various pathological lesions, but no neo-
plasms, in the liver and kidney of guinea pigs, rabbits and rats which sur-
vived the inhalation of 0.15 ppm hex for 7 hours/day, 5 days/week over a
period of 216 days. However, in this study, only 2 to 4 animals of each
species were used. In another study (318), no oncogenic effects were noted in
90 albino rats administered daily peroral doses of 2, 0.2 and 0.02 ug/kg hex
for' six months, an exposure period too short for appropriate evaluation of
carcinogenicity. A short-term in vitro test of hex for malignant transforma-
tion of BALB/3T3 cells (cited in ref. 40) indicated no significant carcino-
genic effects (however, hex was quite toxic to the cells).
Aldrin and Dieldrin. The carcinogenicity of aldrin and dieldrin has been
extensively studied in several animal species and at a wide range of dose
levels. The data on mice clearly indicate that both chemicals are potent
liver carcinogens. Evidence of carcinogenicity in rats is, however, equi-
vocal. Hamsters appear to be resistant to the carcinogenic action of
dieldrin. No positive carcinogenic effects have been reported as yet for
either compound in dogs and monkeys. The carcinogenicity studies of aldrin,
dieldrin and other halogenated cycloalkenes in various strains of animal
species are summarized in Table XXXVIII.
182
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p. 1 of 4
Table XXXVIII
Carcinogenicity of Halogenated Cycloalkene Pesticides
Species
Aldrink
Mouse
Rat
Dog
Dieldrink
Mouse
Rat
Strain Dose level (ppm)
C3HeBe/Fe
C3HeB/FeJ; CBA/J
B6C3F1
Osborne-Mendel
Osborne-Mendel
Osborne-Mendel
Osborne-Mendel
or Sprague-Dawley
Osborne-Mendel
Carworth
Holtzraan 285
Mongrel
Beagle
C3HeB/Fe; Swiss
C3HeB/FeJ & CBA/J
CF1
B6C3F1
(C57BL/6J x
C3HeB/FeJ)F1
Osborne-Mende 1
Osborne-Mendel
Osborne-Mendel
Carworth
, 10
15
4 or 8
0.5-150
5
20-50
20 or 50
30 or 60
2.5-25
(final dose)
8 or 20
1 or 3
10
15
0.1-20
2.5 or 5.0
10d
0.5-150
29 or 65
20-50
0.1-10
Carcinogenicity
Liver tumors
Liver tumors
Liver tumors
Multiple site
tumors (low
dose); liver
tumors (high
dose)
None
Liver tumors*
Lymphoreticular
tumors
Inconclusive
None
None
Nonec
Nonec
Liver tumors
Liver tumors
Liver tumors
Liver tumors
Liver tumors
Multiple site
tumors (low
dose); liver
tumors (high
dose)
Inconclusive
Liver tumors3
Liver tumors
Reference
(319; cited in refs.
320, 321)
(322)
(323)
(324; cited in ref.
321)
(325)
(326)
(327)
(323)
(73, 328)
(322)
(324)
(73, 329)
(319; cited in refs.
284, 321
(322)
(300, 330)
(323)
(331)
(324; cited in ref.
321)
(323)
(326)
(329; cited in ref.
marginal signif. 321)
-------
Table XXXVIII (continued)
p. 2 of 4
Species , Strain
Dieldrink (continued)
Rat Carworth
Holtzman
Fischer 344
Hamster Syrian golden
Dog Mongrel
Beagle
Monkey Rhesus
Photodieldrin1
Mouse B6C3F1
Rat Osborne-Mendel
Endrin^
Mouse C3H
B6C3F1
Rat Carworth
Osborne-Mendel
Osborne-Mendel
Chlordanek
Dose level (ppm)
2.5-25
285 (final dose)
2-50
20-180
8
0.1, 1 or 3
0.01-5.0
0.32, 0.64
3.2, 6.4
~ 0.3 or 3
1.6 or 3.2 (male)
2.5 or 5 (female)
1 to 100
2-12
2.5 or 5 (male)
3 or 6 (female)
Mouse CD-I 25, 50
B6C3F1 2.9 or 56.2 (male)
30.1 or 63.8 (female)
C57BL/6N 25 or 50
Rat Unspecified
5-300
Carcinogenicity
None
None
None
None
Nonec
Nonec
None6
None
None
Inconclusive
None
None
None
None
None
None
Hepatocellular
carcinoma
Hepatocellular
carcinoma
Hepatocellular
carcinoma
Hepatocellular
carcinoma
None
Reference
(73, 322)
(328)
(332)
(333)
(324)
(73, 329)
(334)
(344)
(344)
(Cited in ref. 284)
(335)
(335)
(336)
(326)
(335)
(335)
(Cited in ref. 337)
(Cited in ref. 338)
(338)
(339)
(214; cited in ref. 9]
Osborne-Mendel
203.4 or 407.0
(male)
120.8 or 241.5
(female)
Inconclusive (338)
Inconclusive (338)
-------
Table XXXVIII (continued)
p. 3 of 4
Species Strain
Heptachlork
Mouse C3H
CD-I
B6C3F1
Rat CF
Wistar
Osborne-Mendel
Heptachlor Epoxide
Mouse C3H
CD-I
Rat CFN
Endosulfan (Thiodan)
Mouse (C57BL/6 x
C3H/Anf)Fl;
(C57BL/6 x
AKR)F1
B6C3F1
Rat Osborne-Mendel
Dose level (ppm)
10
l-10f
6.1 or 13.8
(male)S
9.0 or 18
(female )S
1.5-10
50 mg/kg
(total dosage)"
25.7-38.9
10
l-10f
0.5-10
3 or 6
3.5 or 69
(male)
2.0 or 3.9
(female)
408 or 952
(male)
223 or 445
(female)
Carcinogenicity
Hepatocellular
carcinoma
Hepatocellular
carcinoma
Hepcaocellular
carcinoma
Hepatocellular
carcinoma
Multiple site
tumors
Endocrine tumor1
Thyroid , gland
tumorsJ
Hepatocellular
carcinoma
Hepatocellular
carcinoma
Hepatocellular
carcinoma and
multiple site
tumors
Pulmonary,
gastric and
liver tumors
(marginal)
None
None
Reference
(Cited in ref. 337)
(Cited in ref. 337)
(340)
(340)
(Cited in ref. 337)
(337, 341)
(340)
(Cited in ref. 337)
(Cited in ref. 337)
(Cited in ref. 337)
(342; see also refs.
36, 308)
(343)
(343)
-------
p.. 4 c : I--
Table XXXVIII (continued)
Species Strain Dose level (ppm) Carcinogenicity Reference _
Telodrink
Mouse (C57BL/6 x ,0.646 None (308)
C3H/Anf)Fl;
(C57BL/6 x
AKR)Fl
Statistically significant tumor incidence found during independent reevaluation (Reuber,
reviewed in ref. 321).
Observed in Osborne-Mendel rats at the 20 ppm level.
Exposure for only 3 years.
Plus daily dose of 12.5 ug dieldrin by gavage.
G
Exposure only for 2 years.
Mixture of 25% heptachlor and 75% heptachlor epoxide.
^Technical grade heptachlor (contains approximately 72% heptachlor, 20% chlordane end
small amount of more than 15 other compounds).
Administered by gavage on 5 successive occasions at 2-day intervals.
Incidence statistically significant in male rats.
-^Incidence is statistically significant in female rats.
^
For structural formulaj see Fig. 11.
For structural formula, see Fig. 14.
-------
In 1962, Davis and Fitzhugh (319) reported first the carcinogenicity of
aldrin and dieldrin in C3HeB/Fe (C3H) mice. Feeding aldrin or dieldrin at 10
ppm to groups of over 200 mice of both sexes for two years significantly
increased the incidence of hepatomas: 16% for the aldrin-fed mice and 17% for
the dieldrin-fed mice compared with 4% for the controls. Since the mortality
of animals during the experiment was high, the liver tumor incidences were
believed to have been underestimated. Independent reevaluation of the his to-
logical material from this study and a followup experiment was later carried
out by Reuber (320; reviewed in ref. 321). Carcinomas of the liver in 82% of
male mice and 80% of female mice ingesting aldrin and in 97% of male mice and
87% of female mice given dieldrin were observed. The malignancy of these
tumors was confirmed by transplantation studies and by the development of
pulmonary metastases (320; reviewed in ref. 321). Limited data from a 1964
abstract (322) also indicates that aldrin (15 ppm) and dieldrin (15 ppm) are
hepatocarcinogenic toward C3HeB/FeJ and CBA/J mice.
In a carcinogenesis bioassay study by the U.S. National Cancer Institute
(323), both aldrin and dieldrin produced a significant dose-related increase
in the incidence of hepatocellular carcinomas in male B6C3F] mice (Table
XXXIII).
Walker and coworkers (300, 330) have conducted a series of experiments on
dieldrin using CF-1 mice. In one study, dieldrin was fed to 20 mice of either
sex at a dietary level of 10 ppm for up to 110 weeks. Benign and malignant
liver neoplasms were found in 100% and 87% of the treated males and females,
respectively; whereas 24% and 23% of the corresponding controls had these
lesions (300). In other studies by the same group of investigators, con-
tinuous feeding of 0.1 to 20 ppm dieldrin clearly demonstrated dose-dependent
induction of liver tumors in the mice (330). Most importantly, the results
183
-------
showed Chat a significant incidence of hepatomas was detectable even at the
lowest dose (0.1 ppm) used and the tumors appeared as early as 4 to 8 weeks
following treatment at the level of 10 ppm.
Of 70 male (C57BL/6J x C3HeB/FeJ)F1 mice given daily dose of 12.5 ug
dieldrin by gavage plus 10 ppm of the insecticide in food from 1 week until 90
weeks of age, 30% developed liver tumors; only 1 of 58 controls (2%) bore
liver tumor (331). Liver carcinomas (incidence not reported) have also been
noted in Swiss-Webster mice receiving 10 ppm dieldrin in the diet for 18
months (cited in refs. 284, 321).
Much higher doses of aldrin or dieldrin were generally used in carcino-
genicity tests in rats than in mice. As a result, carcinogenicity data in
rats were difficult to evaluate because of poor survival. In one study using
weanling Osborne-Mendel rats, groups of 12 males and 12 females were main-
tained on diets containing 0, 0.5, 2, 10, 50, 100 or 150 ppm of aldrin or
dieldrin for 2 years. Significantly high mortality of rats was noted at doses
of 50 ppm and above. Although no significant incidence of tumors was induced,
probably because of 'their shorter life-span, pronounced liver lesions charac-
teristic of "chlorinated insecticide" treatment were observed in rats of these
high-dose groups. At lower doses (0.5 to 1 ppm) of aldrin and dieldrin,
there was considerable increase in the number of multiple site tumors such as
fibrosarcomas, mammary fibroadenomas and carcinomas, pulmonary lymphosarcomas
and thyroid adenomas (324). These multiple site tumors were later confirmed
and found to be statistically significant by several pathologists (cited in
ref. 321) during their independent reevaluation of the data and of the histo-
logical samples. In addition, high incidences of hyperplastic nodules of the
liver and a total of 19 liver carcinomas were identified in groups treated
with aldrin and dieldrin; no such.lesions were seen in controls. The inci-
184
-------
dence of liver carcinoma (5/18) induced by 100 ppm dieldrin is statistically
significant. Moreover, it should be pointed out that among the 19 liver
carcinomas observed in the aldrin and dieldrin tested groups, 14 were at dose
levels higher than 50 ppm. This finding probably explains the failure to
induce tumors of the liver in a study (325) in which a low dose diet
containing 5 ppm aldrin was given, to 30 male and 30 female Osborne-Mendel rats
for 25 months.
In a 1970 study by Deichmann _e_tjil_. (326) using Osborne-Mendel rats,
aldrin and dieldrin were fed to groups of 50 males and 50 females at dietary
concentrations of 25, 30 or 50 ppm for up to 31 months. The authors reported
that 48% of the controls but only 32% of the tested animals bore tumors.
However, later reexamination of the histology samples from 36 males and 40
females fed the 30 ppm dieldrin level by Reuber (reviewed in ref. 321) indi-
cated that Deichmann and coworkers have underestimated the incidence of
malignant tumors by an approximately 3-fold factor.
In a more recent study, Deichmann ^Jtjil_. (327) fed groups of 50 female
Osborne-Mendel and Sprague-Dawley rats aldrin at the 20 and 50 ppm level for
the lifespan of the animals. Although none of the animals developed tumors in
the liver, neoplasms at other sites, particularly in lymphoid tissues, the
uterus and the mammary glands, were noted in rats of both strains. The inci-
dence (18%) of malignant lymphoreticular tumor in Osborne-Mendel rats ingest-
ing 20 ppm aldrin was significantly increased compared to the controls (4%).
However, according to the authors' interpretation, the tumors were due to
viruses and not to the administration of aldrin.
The U.S. National Cancer Institute (NCI) has bioassayed technical grade
aldrin and dieldrin in Osborne-Mendel and Fischer 344 rats. In the study with
185
-------
Osborne-Mendel rats (323), groups of 50 males and 50 females were administered
aldrin (30 or 60 ppm) or dieldrin (29 or 65 ppra) in the feed for 59-80 weeks
and observed for an additional 31-52 weeks. No significant increases in tumor
incidence were observed in comparison to matched controls. When compared to
the pooled controls, however, there were.significant increases in the inci-
dence of folliclular.-cell adenomas and carcinomas of the thyroid in both male
and female rats fed 30 ppm aldrin. The incidence of adrenal adenomas was also
significantly increased in female rats treated with 30 ppm aldrin or 29 ppm
dieldrin. Since these tumor incidences were not significant in the high-dose
groups or when they were compared with matched controls, it was concluded that
the occurrence of these tumors might not be related to the treatment. In
another NCI bioassay (332) dieldrin was given to 24 Fischer 344 rats of both
sexes in the feed at concentrations of 2, 10 or 50 ppm for 104-105 weeks. A
variety of tumors, predominantly interstitial-cell tumors and granulocytic
leukemia were found in both the treated and control rats. However, the inci-
dences of these tumors were not statistically significant and the tumors were
considered to be of spontaneous origin.
Walker _e£ _al_. (329) administered dieldrin to 25 male and 25 female
Carworth rats at dietary levels of 0.1, 1.0 and 10 ppm for 2 years. Forty-
five rats of either sex were fed control diet. At the end of the study, only
groups of 9 to 15 treated and 18 control rats survived. Incidences of tumors,
predominantly thyroid tumors and mammary tumors, were reported to be similar
in treated and control groups. No liver tumors were found; however, liver
parenchymal lesions characteristic of exposure to organochlorine insecticides
were evidenced in the high-dose (10 ppm) groups. Moreover, the incidence of
total tumors in female rats, at the two low dose levels combined, was later
found (cited in ref. 321) to be close to statistical significance.
186
-------
In a chronic toxicity study conducted in 1955, groups of 40 Carworth rats
of each sex were fed aldrin or dieldrin at levels of 2.5, 12.5 and 25 ppm for
2 years. No carcinogenicity data were presented (73). A later publication by
one of the authors (328) reported that many tumors were seen in the 1955
study; the incidence of tumors, however, was not significnatly different from
that of the controls. Mb tumors were noted in groups of 15 Holtznan rats fed
aldrin or dieldrin for 54 weeks initially at 15 ppm and then increased every
two weeks by 10 ppm until a level of 285 ppm was reached (322).
Hamsters are probably more resistant to high doses of dieldrin than are
mice or rats. As 147 male and 145 female Syrian golden hamsters were given
dietary concentrations of 0, 20, 60 and 180 ppm dieldrin for the lifespan, the
survival rate of treated animals was comparable to that of controls. There
were no significant differences in the incidences of various tumors between
the treated and control groups. However, one male and one female hamster fed
180 ppm dieldrin bore a hepatoma which was not seen in the controls. More-
over, a dose-dependent increase in the incidence of hepatic cell hypertrophy
was noted in the treated groups (333).
There are a number of subchronic toxicity studies on aldrin and dieldrin
in dogs. No tumors were observed in studies in which beagle (73, 329) and
mongrel (324) dogs were fed 1 to 20 ppm aldrin or 0.1 to 8 ppm dieldrin for
about 2 years and then sacrificed, a period far too short for meaningful
carcinogenicity evaluation in this species. The same holds for another study,
in which 0.01, 0.1, 0.5, 1.0 and 5.0 ppm dieldrin was fed to 31 rhesus monkeys
for 3 years (average lifespan of monkeys is 20 years) and then the animals
were sacrificed; no carcinogenic effects were noted (334).
187
-------
Photodieldrin. The carcinogenic activity of photodieldrin has been
studied by feeding to B6C3F1 nice and Osbome-iMendel rats (344). No signifi-
cant incidences of tumors were observed 13 weeks after groups of 50 male and
50 female mice were fed photodieldrin at either 0.32 or 0.64 ppm for 80 weeks
(Table XXXIII). In female rats, a significant increase of incidence of fol-
licular-cell adenomas and of papillary adenomas of the thyroid occurred
following dietary administration of 3.4 ppm photodieldrin. There was also a
dose-dependent induction of benign mammary tumors in females. In male rats,
the incidence of hemangiomas exhibited a dose-related increase which was
statistically significant. However, it was concluded that these tumors may
not be due to the treatment, since the increase of the incidences of tumors in
some of the high-dose groups was not consistently signficant, and in other
cases, not statistically significant when compared to the matched or pooled
controls.
Endrin. Endrin is probably not carcinogenic in either the mouse or the
rat (Table XXXVIII). Reuber (312) evaluated the results of an unpublished
study in which 0.3 or 3 ppm of endrin was administered to C3H mice for 18
months. The study was reported as inconclusive, but no details were given.
In groups of 50 B6C3F1 mice which were administered endrin (at the time-
weighted average doses of 1.6. or 3.2 ppm for males and 2.5 or 5 ppm for
females) in the feed for 80 weeks and then observed for 10 or 11 weeks, the
incidences of liver tumors were not significantly higher than those in the
controls (335).
The tumors which were observed, in Carworth rats ingesting 1 to 100 ppm
endrin (336) or in Osborne-Mendel rats receiving up to 12 ppm endrin (326,
335) were also not clearly attributable to endrin administration.
188
-------
Chlordane. The carcinogenic!ty of chlordane has been clearly demon-
strated in mice; the results in rats, however, are inconclusive (Table
XXXVIII).
In groups of 100 Charles River CD-I mice of both sexes which were given
chlordane at dietary levels of 5.0, 25 and 50 ppm for 18 months, a dose-
related incidence of nodular h'yperplasia of the liver was noted (an unpub-
lished report cited in ref. 337). Subsequent reevaluation of the study
revealed that chlordane also induced significant incidences of hepatoraas in
the 25 and 50 ppm test groups (64-82% compared to 9% in controls).
Evidence of the hepatocarcinogenicity of chlordane in mice was further
substantiated by a U.S. National Cancer Institute bioassay study (338) in
which groups of 50 male and 50 female B6C3F1 mice were administered low or
high concentrations of chlordane in the feed for 80 weeks, then observed for
an additional 10 weeks. Highly significant incidences of hepatocellular
carcinomas that showed a dose-dependent relationship were observed in both
male and female mice (Table XXXIII).
Becker and Sell (339) have reported the induction of liver neoplasms in
male C57BL/6N mice by technical grade chlordane (which contained approximately
90% chlordane and 10% heptachlor). Feeding the material to mice from 5 weeks
of age on for more than 36 weeks elicited "benign proliferative lesions" of
the liver in 2% of the mice at the 25 ppm level and in 7% of the mice at the
50 ppm level. A total of 67 hepatocellular carcinomas were noted in 16
mica. (This represents 27% of the survivors; the original number of mice and
the length of the study were not specified.) No histological alterations nor
gross tumors of the liver were detectable in more than 200 control animals.
Some of the chlordane-induced hepatomas demonstrated growth 1.5 to 3 months
after transplantation.
189
-------
There are only limited data on the carcinogenicity of chlordane in
rats. In 1952, Ingle (214) conducted a chronic toxicity study of chlordane in
v
rats of an unspecified strain. The compound was administered to the rats for
2 years at dietary concentrations of 5 to 300 ppm. Except for some slight
cellular alterations in the hepatic cells at 10 ppm or higher levels, no
evidence of carcinogenic effects were found in the treated aninals. Similar
results were obtained from a second study on chlordane conducted .in 1955 by
the same author (cited in ref. 9).
More recently, analytical grade chlordane has been submitted to bioassay
in Osborne-Mendel rats by the U.S. National Cancer Institute (338). Groups of
50 males and 50 females were given the test compound in the diet for 30 weeks
and then maintained on basal diet for 29 weeks more. The time-weighted
average doses used were 203.5 and 407 ppm for the male rats, and 120.8 and
241.5 ppm for the female rats. There was no significant evidence for liver
tumors or for tumors of the pituitary gland, mammary gland and uterus.
Although in treated rats of both sexes the incidences of follicular-cell
thyroid adenomas and carcinomas (considered together) and the incidences in
treated males of malignant fibrous histiocytomas were statistically signi-
ficant, these lesions were suspected to be not attributable to the treatment.
Heptachlor and Heptachlor epoxide. The carcinogenicity studies on hepta-
chlor and heptachlor epoxide, most of them conducted by industry and the U.S.
National Cancer Institute, have been extensively reviewed by Epstein (337).
The data in mice unequivocally show that both heptachlor and its epoxide are
hepatocarcinogenic. Despite some shortcomings in methodology and documenta-
tion in studies with rats, the data are also indicative of carcinogenic activ-
ity (Table XXXVIII).
190
-------
In a two-year study with C3H mice, groups of 100 males and 100 females
received 10 ppm of heptachlor or heptachlor epoxide in the diet. The data
show that both heptachlor and its epoxide induce a highly significant inci-
dence of liver carcinomas in both male and female mice. As compared to 30% in
male and 4% in female control mice, the incidences of liver carcinomas in the
corresponding groups fed heptachlor and heptachlor epoxide were 74%, 73% and
92%, 95%, respectively (cited in ref. 337).
In accord with these results, highly significant incidences (see Table
XXXIII) of hepatocellular carcinomas were found in groups of 50 male or female
B6C3F1 mice fed diets supplemented with technical grade heptachlor (containing
72% heptachlor, 20% chlordane and small amount of more than 15 other com-
pounds) at low and high concentrations for 80 weeks (340).
Moreover, there was a dose-related incidence of "liver masses" and
"nodular hyperplasia" of the liver in groups of 100 male and 100 female CD-I
mice fed a mixture of 25% heptachlor and 75% heptachlor epoxide at levels of
1, 5 and 10 ppm for 18 months, beginning at 7 weeks of age (cited in ref.
337). A significant incidence of hepatoraas was induced in mice of both sexes
receiving the mixture at the 10 ppm level and in males which .received 5 ppm
diet.
Early in 1955, the carcinogenic potential of heptachlor was investigated
in CF rats (cited in ref. 337). Groups of 20 males and 20 females were
administered heptachlor of unspecified purity in diets at levels of 0, 1.5, 3,
5, 7 and 10 ppm for a period of 100 weeks. There was a high incidence of
liver lesions characteristic of exposure to chlorinated hydrocarbons in rats
of both sexes at the two highest levels. Tumors at multiple sites (lyraphomas,
osteogenic sarcomas, thyroid carcinomas and subcutaneous fibrosarcoraas) were
191
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present in all groups. Compared to the controls, the incidence of malignant
tumors was statistically significant in the 7 and 10 ppm female groups.
Similarly, there were multiple site tumors (including hepatomas) in male
and female CFN rats fed heptachlor epoxide at levels of 0.5, 2.5, 5.0, 7.5 and
10 ppm for 108 weeks (cited in ref. 337). There was a significant incidence
of liver carcinomas in the 5.0'and 10 ppm female groups.
Cabral ££ al_. (341) conducted a study in which 95 male and female
suckling Wistar rats were administered 10 mg/kg body weight heptachlor (96.8%
pure) in corn oil by gavage 5 successive times at 2-day intervals. Although
at the time of autopsy (between 106-110 weeks), the incidence of "endocrine"
and "non-endocrine" tumors in the treated rats was believed to be comparable
to that in the controls, subsequent analysis of the data indicated a statis-
tically significant incidence of "endocrine tumors" in the male test groups
(cited in ref. 337).
Under the conditions of the National Cancer Institute bioassays, it was
concluded that heptachlor is not hepatocarcinogenic in Osborne-Mendel rats
(340). However, there was a dose-related increase in neoplasms of thyroid
follicle cells in female rats. The incidence (37%) of thyroid adenomas and
carcinomas in the high-dose (51.3 ppm) females was statistically significant.
Endosulfan (Thiodan). An early carcinogenesis study (342) of endosulfan
sponsored by the U.S. National Cancer Institute was conducted using two stocks
of hybrid mice: (C57BL/6 x C3H/Anf)F1 and (C57BL/6 x AKlOFj. In this study,
groups of 18 male or female weanling mice were given endosulfan by gavage at a
dose of 2.15 mg/kg daily for 3 weeks, then placed on a diet supplemented with
3 or 6 ppm endosulfan for 17 months more. Increased incidences of pulmonary
adenomas and other tumors in the endosulfan-treated mice were observed (342;
192
-------
see also ref. 36). As compared to a 6% pulmonary tumor incidence in the
controls, 34% aqd 14% incidences were observed in the low-dose and high-dose
groups, respectively. Low incidences of hepatomas (12%) and gastric papilloma
(23% in the 3 ppm group and 25% in the 6 ppm group) were found in the dosed
mice but not in the controls. However, Innes et al. (308) who summarized the
same data concluded that endosulfan causes no significant increase of tumors
in mice.
Re-investigation of endosulfan for possible carcinogenicity was later
made using B6C3F1 mice and Osborne-Mendel rats following the current bioassay
protocol of the U.S. National Cancer Institute (343). Technical grade endo-
sulfan of 98.8% purity was mixed in the feed at low and high concentrations
and administered to 50 male and 50 female animals of each species. The two
dietary concentrations were 3.5 and 6.9 ppm for the male mice, 2.0 and 3.9 ppm
for the female mice, 408 and 952 ppm for the male rats and 223 and 445 ppm for
the female rats. After 78 weeks of treatment, the mice and rats were observed
for an additional 14 and 33 weeks, respectively. Due to high early mortality
in the male groups of both species, the bioassay was, however, terminated
early, so that no conclusions regarding the carcinogenicity of endosulfan to
the males can be drawn from the study. Statistical analysis of the incidences
of the late-developing tumors among the females indicates that endosulfan is
neither carcinogenic in B6C3F1 mice nor in Osborne-Mendel rats.
Telodrin (Isobenzan). Among a large number of pesticides and industrial
chemicals, telodrin was also tested for tumorigenicity in (C57BL/6 x
C3H/Anf)F1 and (C57BL/6 x AKR)F1 mice (308). Groups of 18 males or females
were administered daily doses of 0.215 mg/kg telodrin in 0.5% gelatin by
gavage between days 7 and 28 of age, then were given 0.646 ppm telodrin in
feed for 17 months. The compound did not induce a significant incidence of
tumors in mice.
193
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5.2.2.2.3.4 HALOGENATED BENZENES AND NAPHTHALENES.
Although halogenated benzenes and naphthalenes are highly suspected to be
carcinogenic, information is very scanty on their carcinogenic activity.
Except for hexachlorobenzene (Table XXXIX), no carcinogenicity studies on
other halogenated benzenes are available presently in the literature. Toxico-
s
logical studies conducted for a period of about 5-9 months in several rodent
species did not reveal any tumorigenic property of monochlorobenzene (345),
1,2-dichlorobenzene (346), 1,4-dichlorobenzene (347), 1,2,4-trichlorobenzene
(297,348), 1,2,4,5-tetrachlorobenzene (349) and pentachlorobenzene (350).
Exposure of beagle dogs to a dietary dose of 5 mg/kg of 1,2,4,5-tetrachloro-
benzene daily, for 2 years, induced no tumors (351). Carcinogenesis bioassays
in the U.S. National Toxicology Program on monobromobenzene, monochloroben-
zene, 1,2-dichlorobenzene and 1,4-dichlorobenzene, have been completed.
However, no published reports are available at the time of this writing.
The carcinogenicity of hexachlorobenzene, summarized in Table XXXIX, was
first reported in hamsters (355, 356). Six-week-old Syrian golden hamsters
were fed the test compound for their lifespan, at dietary levels of 50 ppra (30
males and 30 females), 100 ppra (30 males and 30 females) and 200 pptn (59 males
and 60 females). After 74 weeks of treatment, hamsters receiving 50, 100 and
200 ppm showed a 56%, 75% and 92% overall tumor incidence, respectively,
compared with 10% in the controls. There was a clear dose-response relation-
ship in the average number of tumors per hamster and in the percentage of
animal with more than one tumor. The predominant tumor types were benign
i
hepatoma, haemangioendothelioma of the liver and spleen, and thyroid adenomas.
Subsequent investigations in mice and rats further substantiate the
hepatocarcinogenic activity of hexachlorobenzene. Benign hepatomas were noted
194
-------
Table XXXIX
Carcinogenicity of Hexachlorobenzene by Oral Administration
Species
Mouse
Rat
Hamster
Strain
Swiss
Agus; MRC Wistar
Syrian golden
Dose level
(ppm)
50
300, 200 or 100
100
200, 100 or 50
Carcinogenicity
None
Liver tumor1
Liver tumor
Liver, spleen
Reference
(352, 353)
(352, 353)
(354)
(355, 356)
and thyroid
gland
-------
in Swiss mice fed 100 ppm (30 males and 30 females) and 200 ppm (50 males and
50 females) hexachlorobenzene for 101-120 weeks, but not in the controls or in
groups ingesting 50 ppm hexachlorobenzene. The hepatoma incidence was 10% in
both males and females at 100 ppm, and 16% and 34%, respectively, in aales and
females at 200 ppm (352, 353). In addition, 5% of mice (30 males and 30
females) fed 300 ppm hexachlorobenzene for 15 weeks developed hepatonias
(353). Multiple liver-cell tumors were seen in all 14 female Agus rats fed
100 ppm hexachlorobenzene for up to 90 weeks as well as in 4 of 6 female HCR-
Wistar rats ingesting hexachlorobenzene at the same dose level for 75 weeks.
None of the matched controls had tumors (354).
No carcinogenicity studies of halogenated naphthalenes are available in
the literature. However, there are reports showing that exposure of animals
to chlorinated naphthalenes results in pathological changes which may be
indicative of prenoeplastic effects. These changes include epithelial hyper-
plasia in rabbit ears (357) and squamous metaplasia in gonadal tissues of
cattle (358). Furthermore, the metabolism of halogenated naphthalenes most
probably proceeds via the production of arene oxide intermediates (Section
5.2.2.4.1.3) which are known to bring about carcinogenesis and mutagenesis.
5.2.2.2.3.5 HALOGENATED AROMATICS WITH INTERCYCLIC BOND: POLYHALO-
GENATED BIPHENYLS AND TERPHENYLS.
The ability of polyhalogenated. biphenyls to elicit persistent prolifera-
tive liver lesions (hyperplasia, metaplasia, etc.) in rodents upon acute or
subchronic exposure (359-363) suggests that these compounds may have the
potential to induce tumors. Allen and Norback (364) proposed that the gastric
mucosal hyperplasia noted in primates which ingested polychlorinated biphenyls
(PCBs) or polychlorinated terphenyls (PCTs) for 3 months might eventually lead
195
-------
to neoplastic transformation. To date, liver tumors have been detected in
mice fed PCTs and in both mice and rats fed PCBs or polybrominated biphenyls
(PBBs). Polyctilorinated biphenyls have also been shown to induce adenocar-
cinomas in the glandular stomach of rats (365). The carcinogenicity of PCBs,
PBBs and PCTs in various strains of mice and rats is presented in Table XL.
Reviews on some of the carcinogenicity studies on PCBs and PBBs have appeared
(20, 290, 376).
Polychlorinated Biphenyls (PCBs). Nagasaki _ejt _al_. (366) reported first
in 1972 the carcinogenic action of PCBs in mice. Liver neoplasms were noted
during autopsy in 7 of 12 male dd strain mice fed a diet containing 500 ppm
Kanechlor-500 for 32 weeks. Histopathologically, the neoplasms in 5 of the 7
tumor-bearing animals were hepatocellular carcinomas (306). Histological,
changes in the liver were also seen in mice fed Kanechlor-500 at 250 and 100
ppm levels. The livers of the controls and of mice fed similar levels of PCBs
having a lower content of chlorine (Kanechlor-400 and Kanechlor-300) displayed
no such pathological effects (306, 366). Kimbrough and Linder (367)
reported a 100% incidence of adenofibrosis and a 41% incidence of hepatomas
in 22 male BALB/cJ mice which survived after receiving 300 ppm Aroclor 1254 in
the diet for 11 months. One of 24 mice fed Aroclor 1254 for only 6 months,
followed by basal diet for 5 months, also had a hepatoma. No tumors were
observed in 100 control mice.
Kimura and Baba (368) fed groups of 10 male and 10 female Donryu rats
Kanechlor-400 at dietary levels of 38.5-616 ppm over a period of 400 days.
Multiple adenomatous nodules of the liver were found in 6 of 10 female treated
rats. The treated males and the controls of each sex did not have these
lesions. Ito_e_t_al_. (361) observed significant incidences of nodular hyper-
plasia of the liver in Wistar rats fed Kanechlor-500, Kanechlor-400 or
196
-------
Table XL
Carcinogenicity of Halogenated Biphenyls and Terphenyls by Oral Administration
Compounds
PCBs
PBBs
Species and strain
Mouse, dd
Mouse, BALB/c
Rat, Donryu
Rat, Wistar
Rat, Sherman
Rat, albino
Rat, F344
Mouse, B6C3F1
Rat, F344
Rat , Sherman
Rat , Sprague-Dawley
Principal organs
affected
Liver
Liver
Livera
Liver3
Liver
Liver
Stomach
Liver
Liver
Liver
No significant
effect0
Reference
(306,
(367)
(368)
(361)
(359,
(370)
(365,
(372)
(372)
(373)
(374)
366)
369)
371)
PCTsc
Mouse, ICR
Liver
(375)
Hyperplastic nodules.
Hepatocellular adenomas and carcinomas were found in the dosed groups but not
in the controls; the incidences were not statistically significant. Higher
but not statistically significant incidences of lymphomas and leukemias were
also observed in the dosed groups.
cExposed for only 8 months.
Contains 95% polychlorinated terphenyls and 5% polychlorinated biphenyls.
-------
Kanechlor-300 at doses of 100, 500 and 1,000 ppm for 28-52 weeks. In addi-
tion, cholangiofibrpsis was detected in the liver of rats given any of the 3
V.
compounds at 1,000 ppm level. No such lesions were found in control rats.
.In.a preliminary study in which groups of male and female Sherman strain
rats were fed Aroclor 1260 or Aroclor 1254 at 0, 20, 100, 500 and 1,000 ppm
/
for 8 months, Kimbrough et al_. (359) noted adenofibrosis in groups at the 100,
500 and 1,000 ppm dietary levels. In a subsequent study, in which 200 female
rats of the same strain were given a diet supplemented with 100 ppm of Aroclor
1260 for approximately 21 months, 79% of 184 treated rats that survived had
neoplastic liver nodules and 14% had hepatocellular carcinomas (369). In the
study of Wassennan _e_t _al_. (370) administration of 200 ppm Arochlor 1254 in the
drinking water to 6 female albino rats for 28 months produced multiple liver
adenomas. The morphology of these has been extensively described.
In a U.S. National Cancer Institute bioassay of PC3s in Fischer 344 rats,
groups of 24 males or females were given 0, 25, 50 or 100 ppm of Aroclor 1254
in the diet for 104-105 weeks. Although the tumor incidences were not stati-
stically significant, adenomas and carcinomas of the liver and gastrointes-
tinal tract were observed in dosed rats but not in untreated animals, suggest-
ing that the lesions may be related to treatment. Additionally, there was a
significant dose-related trend in the combined incidences of lymphomas and
leukemias in male rats (371). Subsequent histological reexamination of the
stomach specimens detected additional incidences of gastrointestinal meta-
plasia and stomach adenocarcinomas (365).
Polybrominated Biphenyls (PBBs). Gross and histological inspection of
tissues of Sprague-Dawley rats fed octabromobiphenyl at doses of 0.01, 0.1 or
1 mg/kg/day for 8 months revealed no overt indication of adverse effects due
197
-------
to treatment (374). However, pronounced neoplastic nodules were found in the
livers of Sherman strain rats 14 months after they received a single dose of
».
100 mg polybrominated biphenyl mixture (FireMaster FF-1) by gavage (362).
Similar liver lesions emerged in rats as early as 6 months after exposure to
multiple doses of PBBs (363).
In 1981, Kimbrough _ej£ _aJU (373) reported the results of three studies on
the induction of liver tumors in female Sherman strain rats by PBBs. In one
study, 65 two-month old rats were given, by stomach tube, a single dose of
1,000 mg PBBs/kg body weight as a 5% solution in corn oil. Twenty-three
months after dosing, a 41.4% incidence of hepatocellular carcinomas was
observed. In another study, 19 of 28 rats (67.8%) which survived 24 months
after receiving by gavage a total of 12 doses of 100 mg PBBs/kg in corn oil
twice weekly every 3 weeks developed hepatocellular carcinomas. In both
studies, adenofibrosis of the liver was also noted. In the third experiment,
a group of 16 rats was given a single dose of 200 mg PBBs/kg by gavage. A
31.2% incidence of hepatocellular neoplastic nodules was observed 22 months
after dosing. The livers of all controls appeared to be normal.
As described in a 1981 draft report, the'PBB mixture, FireMaster FF-1, is
hepatocarcinogenic toward both Fischer 344 rats and B6C3F1 mice under the
conditions of the U.S. National Cancer Institute bioassay procedure (372). In
this bioassay, PBBs were administered to 50 rats and 50 mice of each sex by
gavage at doses of 0, 0.1, 0.3, 1.0, 3.0 or 10.0 mg/kg body weight 5 days/week
for 25 weeks. Twenty-three months after the last treatment there were dose-
related incidences of neoplastic liver nodules in male and female rats exposed
to PBBs. Significant incidences of hepatocellular carcinomas and cholangio-
carcinomas were observed in rats of both sexes at the highest dose level (10.0
mg/kg). Similarly, hepatocellular carcinomas were observed with significantly
198
-------
increased incidence in both male and female mice at the dose of 10.0 rag/kg.
The liver tumors in female mice had a high tendency to raetastasize.
V
Polychlorinated Terphenyls (PCTs). Kanechlor C, a mixture of 95% poly-
chlorinated terphenyls and 5% polychlorinated biphenyls, has been tested in
ICR strain mice (375). Groups of 35 weanling males were fed the compound at
doses of 0, 250 or 500 ppm for 24 weeks. Forty weeks after the beginning of
treatment, nodular hyperplasia of the liver was found in 11% and 29% of the
surviving mice given the'low and high dose levels, respectively. A 14.3%
incidence of hepatocellular carcinomas was observed in mice receiving the high
dose (500 ppm).
5.2.2.2.3.6 HALOGENATED BRIDGED AROMATICS: DDT AND RELATED COMPOUNDS
For more than three decades, extensive research was carried out for
regulatory purposes all around the globe to investigate the potential carcino-
genic effects of DDT. This resulted in a large volume of official -and unoffi-
cial documents. Several comprehensive reviews on the carcinogenic!ty of DDT
are available (e.g., 19, 34, 46, 289). The carcinogenic!ty data on DDT in
experimental animals are suggestive but not altogether convincing. Much of
the early evidence on the hepatocarcinogenicity of DDT and some of its deriva-
tives was obtained from studies in mice. Tumors in organs other than the
liver have also been reported in this species upon long term exposure to the
compounds. Most of the data are, until recently, contradictory for the rat;
no carcinogenic effects for DDT have been shown in hamsters. The carcino-
genicity data on DDT and related coraopunds are summarized in Table XLI.
DDT. In 1968, the International Agency for Research on Cancer initiated
an extensive investigation on the carcinogenic potential of DDT. The studies
were carried out in laboratories of four countries in Europe, using three
199
-------
Table XLI
Carcinogenicity of DDT and Related Compounds
p. 1 of
Compound
R R1 R
t nil
Species and strain
Route
Principal target
organ affected
Reference
DDT
[text-figure 11]
-Cl -H -CC1.
Mouse, CF-1
Mouse, BALB/c
Mouse, A
Mouse, Swiss
Mouse, C3H, C3Hvy
Mouse, B6C3F1
Rat, Osborne-Mendel
Rat, Osborne-Mendel
Rat, Osborne-Mendel
oral
oral
Mouse, oral
(C57B1/6 x C3H/Anf)Fj,
(C57B1/6 x AKR)F,
oral
oral, s.c.
topical
oral
oral
oral
oral
oral
Liver
Liver, hemato-
poietic tissue
and lung
Liver, lyraphoid
tissues
Lung
Liver, lung,
lymphoid tissues
None
Liver
None3
Liver
None
None3
(300, 330, 377-380)
(263, 381, 382)
(308)
(383)
(384)
(384)
(Cited in ref. 284)
(385)
(386)
(325, 387)
(385)
-------
TEXT-FIGURE 11
-------
Table XLI (continued)
p. 2 of
Compound R R1 R' '
DDT (cont'd)
4
ODD (TDE) -Cl -H -CHC12
o_,£' -ODD -Clb -H -CHC12
Ethyl-DDD ~C2H5 ~H ~CHC12
(Perthane)
Species and strain
Rat, Fischer
Rat, Wistar
Rat , MRC Porton
Hamster, Syrian golden
Mouse,
(57BL/6 x C3H/Anf)Fj,
(C57BL/6 x AKR)F1
Mouse, CF-1
Mouse, B6C3Fj
Rat, Osborne-Mendel
Mouse,
(C57BL/6 x C3H/Anf)Fj,
(C57BL/6 x AKR)F!
Mouse, Swiss
Rat, Wistar
Rat, Sprague-Dawley
Mouse,
(C57BL/6 x C3H/Anf)F, ,
Route
oral
oral
oral
oral
oral
oral
oral
oral
oral
i. p.
oral
i.p.
oral
Principal target
organ affected
None
None
Liver
None
Inconclusive
Liver, lung
None
None
Inconclusive
Lung
Testis
Multiple-site
Inconclusive
Reference
(388)
(389) ,
(390)
(391-393)
(308)
(394)
(385)
(385)
(308)
(395)
(396)
(395)
(308)
(C57BL/6 x AKR)FJ
-------
Table XLI (continued)
p. 3 of
Compound
Ethyl-DDD
(Perthane)
(cont'd)
DDE
Chloro-
benzilate
Dicofol
Methoxy-
chlor
R R' R'1 Species and strain
Mouse, B6C3F1
Rat, F344
Rat, albino
-Cl None =CC12 Mouse, CF-1
Mouse, B6C3F1
-Cl -OH -C(0)OC2H5 Mouse,
(C57BL/6 x C3H/Anf)F1,
(C57BL/6 x AKR)Fj
Mouse, B6C3F1
-Cl -OH -CC13 Mouse, B6C3F1
Rat, Osborne-Mendel
-OCH3 -H -CC13 Mouse, C3H/anf
Mouse, B6C3F1
Mouse, BALB/c
Route
oral
oral
oral
oral
oral
oral
oral
oral
oral
8.C. ,
topical
oral
oral
Principal target
organ affected
Liver
None
None
Liver
Liver
Liver
Liver
Liver
None
None
None
Liver, testis and
Reference
(397)
(397) -
(398)
(394)
(385)
(308, 339)
(400)
(401)
(401)
(402)
(403)
other organs
(Cited in ref. 404)
-------
Table XLI^reontinued)
Compound R R1 R' '
Methoxy-
chlor
(cont'd)
Species and strain
Mouse, C3H
Rat, unspecified
Rat, Osborne-Mendel
Rat, Osborne-Mendel
Route
oral
oral
oral
oral
Principal target
organ affected
Liver
None
None
Liver, ovary
Reference
(Cited in
(325, 387,
f
(Cited in
ref. 404)
403, 405)
ref. 404)
1High early mortality in treated animals. '
'Chlorine substitution in ortho position of one ring and in para position in the other ring.
-------
strains of mice, and one strain of rats (289). Although the Russian study in
Leningrad on rats gave negative results, long-term administration of technical
grade DDT to mice in other laboratories consistently produced significantly
higher incidences of neoplasms. In the study conducted in Lyon (France),
groups of 60 male and 60 female CF-1 mice were fed technical grade DDT at
dietary concentrations of 0, 2, 10, 50 and 250 ppm for two consecutive genera-
tions. Exposure to all four levels of DDT gave rise to significant increase
of liver tumors in male mice. In females, significant incidences of hepatomas
were observed in groups maintained at the 50 ppm and 250 ppm levels. Four of
the liver tumors in the treated groups (referred to as "hepatoblastoma") meta-
stasized to the lungs (377, 380). Similar results were obtained in a later
study in which DDT was administered to CF-1 mice for six consecutive genera-
tions (379).
Similar raultigeneration studies were carried out in Milan (Italy) using
BALB/c mice (381, 382). Each of three dose levels of DDT (2, 20 and 250 ppm)
was given to two colonies of mice in the diet for their lifespan. Whereas no
liver tumors were found in the matched controls, they occurred in more than
40% of mice in all four generations which received the highest dose level of
DDT.
Interestingly, the study in Moscow (383) detected significant increases
over the control (7%) of lung tumors rather than liver tumors in F2 (24%), F.J
(46%) and F, (43%) generations of A-strain mice, given 10 ppm DDT in sunflower
seed oil by gavage for their entire lifetime. Eleven of 30 mice (FQ genera-
tion) receiving 50 ppm DDT also had lung adenomas. The findings appear to be
in line with the observations made in an earlier in vitro study (406) that
hyperplastic lesions and nodular proliferation of the epithelium occurred in
culture of embryonic lung tissue of A-strain mice exposed to 10 ppm DDT trans-
placentally.
200
-------
The carcinogenic effects of DDT toward the liver and lung in mice have
also been shown by several independent investigations. Walker ot_ _al_. (330)
administered DDT to groups of 30-32 CF-1 mice of both sexes at dietary concen-
trations of 50 or 100 ppm for 2 years. Liver tumors of both benign and malig-
nant types were observed in 13%, 37% and 53% males given 0, 50 and 100 ppm
DDT, respectively. The corresponding tumor incidences in females were 17%,
50% and 76%. Also, in a similar study (300), in which 100 ppm DDT was fed to
30 male and 30 female CF-1 mice for up to 26 months, significant incidence of
liver tumors occurred. As compared to 24% and 23% liver tumor incidences in
male and female controls, 77% and 87% were found in the respective DDT-treated
mice.
Innes et al. (308) reported the induction of hepatomas in two hybrid
strains of mice given DDT. Groups of 18 mice of both sexes in the two strains
were administered single doses of 46.4 mg/kg DDT by gavage from day 7 to day
28 of age and were then maintained on a diet containing 140 ppm DDT until 18
months of age. Hepatomas were seen in 11/18 male and 4/18 female (C57BL/6 x
CSH/AnfjFj mice compared to 8/79 male and 0/87 female controls, and in 7/18
male and 1/18 female (C57BL/6 x AKR)F1 mice compared to 5/90 male and 1/82
female controls. Six of 18 females of the second strain also developed malig-
nant lymphomas whereas only 4 of 82 control females bore such tumors. Two
separate unpublished reports cited in a review by Reuber (284) also recorded
the positive hepatocarcinogenic effects of DDT in C3H and C3HVV strain mice
which ingested, respectively, 100 and 250 ppm DDT for 24 and 18 months.
Tomatis ^jt _al_. (378) noted that the induction of liver tumors in mice did
not always require long-term exposure. When groups of CF-1 mice were given
250 ppm DDT in the feed for 15 or 30 weeks, significant incidences of
hepatomas were observed at 65, 95 and 120 weeks from the beginning of the
201
-------
experiment. The incidence of liver tumors was higher after 30 weeks than
after 15 weeks of exposure, indicating that the hepatocarcinogenicity of DDT
is dose-related.
In 1977, Kashyap _e£ al_. (384) carried out a series of carcinogenicity
studies on DDT in Swiss mice, using four different administration routes.
Groups of 30 6-8 weeks old mice of either sex were treated with technical
grade DDT either (a) orally in the diet (100 ppm), (b) orally by stomach tube
in 0.1 ml olive oil (10 mg/kg body weight), (c) subcutaneously (0.25 mg in 0.1
ml olive oil twice a month), or (d) by skin painting (0.25 mg in 0.1 ml olive
oil, twice weekly). The duration of treatment was 80 weeks, after which the
animals were observed for an additional 80 weeks. Significant increases in
the incidences of lymphomas, and liver and lung tumors were recorded in mice
of both sexes receiving DDT orally or subcutaneously, but not by dermal appli-
cation.
Another major observation of multiple-site tumor induction by DDT was
made in BALB/c mice during a five-generation feeding study (263). Compared to
a 3% tumor incidence in 406 controls, 29% of 683 mice treated with 2.8-3 ppm
DDT for their lifespan developed a variety of tumors which were predominantly
lung carcinomas, leukemias, lymphomas and reticulosarcomas of the liver,
kidney and spleen.
On the other hand, a number of bioassays reported in the literature
failed to detect any carcinogenicity of DDT in the mouse or the rat. Despite
the well-known sensitivity of newborn mice toward chemical carcinogens (407),
a single dose of 15,000 mg/kg DDT did not exhibit any carcinogenicity 6 months
after subcutaneous injection to 42 neonatal ICR Swiss mice (408). This dose
indicates a surprisingly high tolerance of newborn mice to the toxicity of DDT
202
-------
via subcutaneous route (compare to the oral LD^g values in Table XXXI). The
oncogenic activity of DDT has also been tested in an in vitro mouse cell
transformation system (409). Exposure of C3H mouse embryo cells to 2.8-42.6
uM DDT produced only a low frequency of transformed foci which, moreover, did
not "take" following inoculation into syngeneic mice. Under the conditions of
the National Cancer Institute bioassay procedure, in which groups of 50 male
and 50 female B6C3F1 mice and Osborne-Mendel rats were fed high and low doses
of DDT for 78 weeks, no evidence of carcinogenicity was found 15 to 35 weeks
after the dosing period. A high early mortality was noted in both species.
The time-weighted average dietary concentrations of DDT used were: 22 and 44
ppm for male mice, 87 and 175 ppm for female mice, 321 and 642 ppm for male
rats and 210 and 420 ppm for female rats (385).
The absence of carcinogenic activity of DDT toward rats was also noted in
a study in which 15 male and 15 female Fischer rats were administered 10 mg of
DDTby gavage 5 days/week for 52 weeks, and then were observed for up to 6
months. The average survival of the animals in this study was 14 months
(388). Deichmann and associates (325, 387) carried out two feeding studies
with DDT using Osborne-Mendel rats. No significant tumor incidence was found
in rats which received up to 200 ppm DDT for more than 24 months.
The first indication of the tumorigenic potential of DDT in rats came
from a 1947 study by Fitzhugh and Nelson (386). Two 2-year studies were
conducted using Osborne-Mendel weanling rats. In the first experiment, groups
of 12 male rats were fed diets supplemented with 0, 100, 200, 400 or 800 ppm
technical grade DDT. The second experiment used male rats but also included
groups of 12 female rats which received DDT at the same dietary concentra-
tions. Of the 75 treated rats surviving 18 months, four had one or more
hepatic cell tumors and 11 had "nodular adenomatoid hyperplasia" in the
203
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liver. The control rats had no liver lesions. Fitzhugh and Nelson (386)
concluded that there was a definite but minimal tendency to hepatic tumor
formation in both series of experiments with DDT.
The weak hepatocarcinogenic activity of DDT in the rat was not confirmed
until 1977 when Rossi _e_t _al_. (389) reported the induction of liver tumors by
DDT in Wistar rats. In this study, technical grade DDT was given to 37 male
and 36 female rats at the dietary level of 500 ppm, commencing at 7 weeks of
age. After up to 145 weeks of treatment, 9 of 27 (33%) surviving males and 15
of 28 (54%) surviving females developed liver tumors. None of the control
rats had neoplastic lesions.
In 1982, Cabral et _al_. (390) reported the dose-related hepatocarcinogenic
effect of DDT in female MRC For ton rats (Wistar-derived). The liver tumor
i
incidences in female rats fed diets containing 0, 125, 250 and 500 ppm tech-
nical grade DDT for 144 weeks were 0%, 7.7%, 14.8%, and 26%, respectively.
«
The increase in liver tumor incidence in male rats was not statistically
significant.
The carcinogenic potential of DDT has been investigated in the hamster by
Shubik and coworkers (391-393). The data indicate no carcinogenic effect of
DDT in this species. Groups of 30 Syrian golden hamsters of both sexes, aged
7-8 weeks, were placed on a diet containing DDT at 0, 125, 250, 500 or 1,000
ppm for their lifespan; the liver tumor incidence in the DDT-administered
groups (4-28%) was not significantly higher than that in the controls (6-19%).
DDT Analogs. Several structural analogs of DDT have been tested in two
series of studies by the U.S. National Cancer Institute. The first series of
studies used two hybrid strains of mice and were reported in 1969 as a pre-
liminary note (308). In these studies (see Table XLI), groups of 18 male and
204
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18 female weanling mice of each strain were administered the test compound at
the maximal tolerated dose orally, first by stomach tube daily for 21 days,
then for about 18 months in the diet. Chlorobenzilate induced a significant
incidence of liver tumors in male mice of both strains (53% and 41% in the
experimental groups vs. 0% and 6% in the controls, respectively). Subsequent
histological reexamination of the' tissues by Reuber (399) also detected hyper-
plasia and carcinomas of the forestomach in 13 of 18 (72%) females of one
mouse strain treated with chlorobenzilate; only 5 of 17 (28%) of the matched
controls had such lesions. The data obtained with _p,_p'-DDD, _o_,_p_'-DDD and
_p_,_p_'-ethyl-ODD (perthane) were ambiguous.
The second series of studies by the U.S. National Cancer Institute were
performed under the current carcinogenesis bioassay guidelines (410) and
reported in 1978 and 1979 (385, 397, 400, 401, 403). In addition to the con-
firmation of the hepatocarcinogenicity of chlorobenzilate in mice of both
sexfes, significant incidences of hepatocellular carcinomas and adenomas were
observed in female mice treated with _p_,p'-ethyl-DDD (perthane), in male mice
treated with dicofol and in mice of both sexes treated with _p_,_p_'-DDE. Under
the conditions of these bioassays, oral administration of £,jp'-DDD (IDE) and
methoxychlor were not carcinogenic in male and female B6C3F1 mice. The car-
cinogenicity data of these DDT analogs in B6C3F1 mice are summarized in Table
XXXIV. In these tests the above DDT analogs did not induce tumors in Osborne-
Mendel or Fischer 344 strain rats.
The carcinogenic effect of _o,_p'-DDD, jp,_p_'-DDD, _p,_p_'-DDE, jp,_p_'-ethyl-DDD
(perthane) and methoxychlor has also been investigated by other workers, using
Different strains of mice and rats. Confirmatory results of the hepatocar-
cinogenicity of 2.*_£.'~DDE in che mouse was obtained by Tomatis £££!_• (394);
these workers found 74% and 98% hepatoma incidences in 53 male and 55 female
205
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CF-1 mice receiving 250 ppm _P_,_P_?-DDE in the diet for about 2 years, compared
to 34% and 1% in the untreated males and females, respectively. Consistent
with the finding of the U.S. National Cancer Institute in the second series of
studies that p,p'-ethyl-DDD (perthane) is not carcinogenic in the rat, no
evidence of carcinogenicity attributable to treatment was seen in albino rats
given the compound in the diet at concentrations up to 5,000 ppm for 24 months
(398).
Three compounds, _p_,_p_'-DDD, £,_p_'-DDD (IDE) and methoxychlor, which were
found inactive the U.S. National Cancer Institute bioassays, were, however,
found in some studies to be carcinogenic toward the liver, lung, testis and
other organs of mice and/or rats. For example, Weisburger (395) noted that
the tumor incidence in female Swiss mice and Sprague-Dawley rats of both sexes
receiving j^,£'-DDD at the MTD (maximal tolerated dose) and at 1/2 MTD by
intraperitoneal injection 3 times/week for 24 weeks was 1.5-2 fold higher than
that in controls. The predominant tumors in mice were lung carcinomas and in
rats were breast sarcomas, parathyroid tumors and lymphosarcomas. Long-term
exposure of male Wistar rats to o,p'-DDD resulted in the development of
testicular tumors (396).
Among 59 male and 59 female CF-1 mice fed a diet containing 250 ppm
_p.»_p_'-DDD for their entire lifetime, 51 males (86%) and 43 females (73%) bore
lung tumors; the incidences of lung tumors in the respective controls were 54%
and 41%. In addition, liver tumors were seen in 52% of the exposed males and
34% of the control males. Exposure to _p,_p'-DDD (125 ppm) plus _?,_£/-DDE (125
ppm) resulted in a marked increase in the incidence and earlier appearance of
J.iver tumors in both sexes (394).
206
-------
Administration of methoxychlor to groups of 50 male and 50 female C3H/Anf
mice by subcutaneous injections (10 mg/mouse) or repeated skin application
(0.1 or 10 mg in 0.2 ml acetone once weekly until death) did not induce tumors
during an extended period of observation (402). However, significant inci-
dences of liver neoplasms were observed in BALB/c and C3H mice ingesting
methoxychlor at dietary dose leVel of 750 ppm for periods up to 2 years.
There were also significantly higher incidences of multiple-site carcinomas in
BALB/c mice treated with methoxychlor as compared to the controls. In male
mice, carcinomas of the testis and lung were the predominant tumor types
(cited in ref. 404).
Hodge _e_£ _al_. (405) fed methoxychlor to groups of 25 male and 25 female
weanling rats (strain unspecified) at levels of 0, 25, 200 and 1,600 ppm for 2
years. Histopathological examination revealed no adverse effects attributable
to the treatment with methoxychlor. Similarly, feeding of methoxychlor at
concentration of 80 ppm (387) or 1,000 ppm (325) to groups of 30 young
Osborne-Mendel rats of both sexes for 24-27 months induced no tumors. How-
ever, in one study (cited in ref. 404) methoxychlor was reported to be car-
cinogenic toward the liver in both male and female Osborne-Mendel rats and
toward the ovary of female Osborne-Mendel rats. When groups of 12 rats were
administered dietary levels of 0, 10, 25, 100, 200, 500 or 2,000 ppm methoxy-
chlor for 104 weeks, liver carcinomas were found in 3 of 8 (38%) male rats and
3 of 9 (33%) females at the highest dose level. In addition, 5 of 10 (50%)
female rats ingesting 500 ppm and 1 of 10 (10%) given 100 ppm developed car-
cinomas of the ovary. No such tumors were found in the liver or ovary of the
controls.
207
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5.2.2.2.3.7 MODIFICATION OF CARCINOGENESIS.
Since many halogenated cyclic hydrocarbons are well-known inducers of
hepatic microsomal mixed-function oxidases (e.g., 411-413) and, thus, enhance
the metabolism of xenobiotics, they have the potential to alter the effective
level of reactive intermediates of other procarcinogens in the liver or other
target tissues. Indeed, several halogenated cyclic hydrocarbons have been
shown to exhibit protective effects to various degrees against the carcino-
genic action of other cancer-causing chemicals. For instance, the o<-isomer
of hexachlorocyclohexane (o<-BHC) inhibits the induction of hepatomas in rats
when administered together with liver carcinogens such as 3"-methyl-4-
dimethylaminoazobenzene (414), ethionine (414), aflatoxin B, (415) or
2-acetylaminofluorene (416). Pretreatment with toxaphene (417) or chlordane
(418) was shown to decrease the incidence of lung tumors induced in A/J mice
by benzofajpyrene and urethan, respectively. Likewise, DDT reduces the inci-
dence of 7,12-dimethylbenz[a]anthracene-induced mammary tumors and leukemia in
Sprague-Dawley rats C419). There are also reports on the inhibitory effect of
PCBs on liver tumorigenesis in rats when administered together with 3f-methyl-
4-dimethylaminoazobenzene, 2-acetylaminofluorene or diethylnitrosamine
(420). Although other factors may be involved, the protective effects are
attributed to enhanced hepatic detoxication of the carcinogens (414, 415, 417,
419, 420).
On the other hand, several halogenated cyclic hydrocarbons have also bren
reported to potentiate tumorigenesis by acting additively or synergistically
in tumor induction. In mice exposed simultaneously to dieldrin and DDT, the
incidence of liver tumors is markedly increased compared to that in mice
treated with DDT alone (330). Low levels of DDT enhance the incidence of
cervical carcinomas induced by 3-methylcholanthrene in mice (421) as well as
208
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the percentage of hepatoma-bearing rats administered 2-acetylaminofluorene
(388, 422, 423). The hepatocarcinogenicity of polychlorinated terphenyls in
ICR mice was significantly potentiated by concurrent exposure to hexachloro-
benzene (375). Similarly, inclusion of PCBs in the diet resulted in increased
liver tumor incidence in dd strain mice treated with hexachlorocyclohexane
(306). Whereas simultaneous administration of PCBs and diethylnitrosamine or
3' -methyl-4-dimethylaminoazobenzene brought about a lower incidence of liver
tumors in rats (420), sequential exposure to PCBs after diethylnitrosamine or
3'-methyl-4-dimethylaminoazobenzene increased the liver tumor incidence in
rats (424-426). It has also been reported that -a PCS mixture promotes the
appearance of gamma-glutamyltranspeptidase-positive foci initiated by diethyl-
nitrosamine in the rat liver (427). Studies on the modification of chemical
carcinogenesis by halogenated cyclic hydrocarbons will be treated in detail in
Vol. IV of this series of monographs.
11 5.2.2.2.4 Metabolism and Mechanism of Action.
5.2.2.2.4.1 METABOLISM.
5.2.2.2.4.1.1 Metabolism of Halogenated Cycloalkanes.
Hexachlorocyclohexane (BHC). Hexachlorocyclohexane Isomers are rapidly
absorbed and metabolized in mammals. Following a single oral dose, excretion
is complete within 96 hours. The order of absorption and metabolism among the
BHC isomers is: f > £ > of » £ (428). The metabolism of I"-BHC (lindane)
has been most extensively studied because of its wide application as an insec-
ticide. The data available suggest a metabolic scheme for Y-BHC (lindane) as
outlined in Fig. 12.
Several metabolic pathways have been proposed for lindane in rodents. It
is generally accepted that dehydrochlorination to • -2,3,4,5,6-pentachloro-
209
-------
[2.3.4.6-TeCCOL]
[0] [2Hl
L2.4.6-TCPJ
L''l< ,LI !•!!•; 12
-------
LEGEND TO FIGURE 12
i
Fig. 12. Metabolic pathway of j-hexachlorocyclohexane (lindane:
/-BHC) in mammals. The abbreviations used are: V-PCCH = Y~2,3,4,5,6-
pentachlorocyclohex-1-ene; HCCK =/hexachlorocyclohexene; PCCOL =
2,3,4,5,6-pentachloro-2-cyclohexene-l-ol; PGP = pentachlorophenol; TeCCOL =
tetrachlorocyclohexenol; TeCP = tetrachlorophenol; TCPs = trichlorophenol
isomers; DCPs = dichlorophenol isoraers. The metabolites, 2, 3, 4, 6-TeCP
and Z, 4, 6-TCP are carcinogenic to mice and rats (see Section 5. Z. Z. 5. 3
on the carcinogenicity of phenols).
-------
cyclohex-1-ene ( f-PCCH) is the rate-limiting step for its degradation (429-
431). Biotransformation of )f-PCCH to isomeric tetrachlorophenols (TeCP),
trichlorophenols (TCP) and dichlorophenols (DCP) occurs via isomeric tetra-
chlorocycl'ohexanols (TeCCOL) and pentachlorophenol (PGP), the former (TeCCOL)
being yielded by oxidative dechlorination of iT-PCCH whereas the latter (PCP)
by dehydrogenation of 2,3,4,5,6^pentachloro-2-cyclohexen-l-ol (PCCOL) which is
produced by the epoxidation of f-PCCH (430, 432). The phenolic products are
excreted either as free phenols or as conjugates of sulfuric or glucuronic
acid (429, 430, 432).
An alternative metabolic route is via initial C-hydroxylation of lindane
by cytochrome P-450 dependent mixed-function oxidase of liver microsomes,
leading to hexachlorocyclohexene (HCCH) (433) or pentachlorocyclohexanone
(434, 435). Further hydroxylation of hexachlorocyclohexene (HCCH) can yield
2,3,4,5,6-pentachloro-2-cyclohexen-l-ol (PCCOL) and reduction of pentachloro-
cyclohexanone followed by dehydration can lead to Y-2,3,4,5,6-pentachloro-
cyclohex-1-ene (V-PCCH). In addition, formation of 2,4,6-trichlorophenol
(2,4,6-TCP), a metabolite of lindane as well as of other isomers of hexa-
chlorocyclohexane (430-432, 435), has been suggested to proceed through double
dehydrochlorination of the pentachlorocyclohexanone intermediate (434, 435).
The identification of other metabolites such as if-3,4,5,6-tetrachloro-
cyclohex-1-ene (436) and isomeric polychlorinated benzenes (437) has led
several investigators (430, 436) to speculate that the degradation of lindane
to water-soluble metabolites in mammals might also proceed via other pathways
reported to occur in insects.
The metabolism of <*-, $- and i-isomers of BHC is believed to follow
pathways similar to those of lindane ( f-BHC) (13, 431).
210
-------
Toxaphene. There is a-paucity of information concerning the metabolic
fate of toxaphene (for chemical structure see Section 5.2.2.2.2.1) in the
V
mammalian system. The limited experimental results indicate that biotransfor-
i
mation of toxaphene involves reductive dechlorination, dehydrochlorination,
and hydroxylation.
/
In vitro studies by Khalifa _e_t _al_. (438) have shown that toxaphene under-
goes reductive dechlorination as well as dehydrochlorination. Metabolism of
toxaphene by rat liver microsomes requires NADPH under anaerobic conditions
and is potentiated by the presence of piperonyl butoxide, indicating that the
hepatic microsomal mixed-function oxidase system may be involved. In several
chemical and biological systems, a number of polychlorobornane components of
toxaphene undergo facile reductive dechlorination at the geminal-dichloro
group and sometimes dehydrochlorination; the dichloromethyl substituents of
these compounds are less susceptible to attack than the ring geminal-dichloro
grcfup (439).
Crowder and Dindal (440) found that in rats, 52.6% of an oral dose
of -^"Cl-toxaphene is excreted in the urine and feces within 9 days and most of
the radioactivity is recovered as chloride. In a study by Ohsawa et al.
(441), more than 90% of ^"Cl-toxaphene administered to rats was excreted in
the urine and feces within 14 days. Upon extraction, about 50% of the radio-
activity occurred as chloride. Terpene carboxylic acids, terpene alcohols and
their glucuronides or sulfates were suspected to be some of its partially or
completely dechlorinated metabolites.
Mi rex. Mirex (structure in Fig. 11) is highly resistant to biotransfor-
mation in mammals. Several investigators (442-444) have shown that radio-
labeled mirex administered to rats is stored at high levels in the adipose
211
-------
tissue and is excreted slowly in the feces; less than 1% of the radioactivity
is found in the urine after 7 days. No metabolites of mirex are detectable in
the feces, urine or any tissues. In vitro studies with rat, mouse and rabbit
liver preparations also failed to detect any metabolite of mirex (442).
Stein ji_£ _al_. (445) reported a nonpolar mirex derivative (tentatively
identified as undecachloropentacyclodecane) in the feces of rhesus monkey
given intravenous doses of * C-rairex. The suspected metabolite was believed
to result from bacterial action in the lower gut or in the feces.
Kepone (Chlordecone). Kepone is metabolized slowly in humans and in
rodents. In studies with male workers exposed to large amounts of kepone,
Guzelian and colleagues (78, 446-448) demonstrated that the metabolic fate of
kepone in humans involves uptake by the liver, enzymatic reduction to chlor-
decone alcohol via, chlordecone hydrate, conjugation with glucuronic acid,
partial conversion to (unidentified) polar metabolites, and excretion of these
1 •''/ ' • '
substances into bile. While large quantities of chlordecone alcohol were
present in human stool, rats or mice treated with kepone produced only trace
amount of chlordecone alcohol indicating that the hepatic metabolism of kepone
is species-specific (447). The major metabolic pathways of kepone in humans
are shown in Fig. 13.
5.2.2.2.4.1.2 Metabolism of Halogenated Cycloalkenes. The metabolism of
chlorinated cyclodiene pesticides has been extensively studied. In mammals,
the major metabolic routes appear to involve oxidation or epoxidation by
microsomal mixed-function oxidases, rearrangement leading to or concurrent
with oxidative or reductive dechlorination of the hexachloronorbornene
nucleus, isomerization, hydrolytic opening of the epoxide moiety, and cleavage
of the unchlorinated ring system. Oxidative metabolism usually introduces one
212
-------
Chlordecone
(Kepone)
Cl
1 ••
Cl Cl
Chlordecone hydrate Chlordecone alcohol
UDP-a-D-
giucuronic acid
UDP-a-0-
glucuronic acid
Chlordecone glucuronide Chlordecone alcohol
glucuronide
Fig. 13. Major metabolic pathways of kepone in humans. [Adapted from
M.W. Fariss, R.V. Blanks, J.J. Saady and P.S. Guzelian: Drug Me tab. Disp. J3_,
434 (1980)].
-------
or more hydroxyl groups resulting in a more polar compound, which may readily
be excreted. Conjugation of the metabolites with glucuronic or sulfuric acid
can further facilitate their excretion. Several excellent reviews have dis-
cussed in depth the nature of metabolites and possible mechanisms of biotrans-
foraation of this class of chemicals (13, 434, 449, 450).
' - ' ' ".'•••
Hexachlorocyclopentadiene (Hex). Hexachlorocyclopentadiene is rapidly
metabolized in rats (451) and humans (450). Analysis of the urine of rats
orally treated with * C-hex revealed that there are at least four metabolites
in the fraction extracted with organic solvents. These metabolites are as yet
unidentified (451). The metabolites in the urine of humans exposed to C-hex
were suspected to be polyhydroxy compounds and their conjugates (450).
Aldrin, Dieldrin and Photodieldrin. Epoxidative conversion of aldrin to
dieldrin has been demonstrated in both in vivo (452, 453) and in vitro systems
(454, 455). It is a typical mixed-function oxidase (MFO) reaction which
requires the presence of NADPH and is enhanced by inducers of microsomal MFOs
(453, 456). The major metabolic pathways of dieldrin in rats (457-460), mice
(459, 460), rabbits (461), sheep (462) and monkeys (463) have also been shown
to involve liver microsomal monooxygenases leading to the formation of syn-12-
hydroxydieldrin and 4,5-trans-dihydroaldrindiol or their glucuronide con-
jugates. The other known excreted metabolites of dieldrin include a
dicarboxylic acid derivative (hexachlorohexahydromethanoindenedicarboxylic
acid) and dieldrin pentachloroketone (see Fig. 14), which are formed by oxida-
tive ring cleavage and skeletal rearrangement, respectively (457-460). Photo-
dieldrin is converted to several organosoluble and water-soluble metabolites
in mammalian species; among which, photodieldrin ketone (ketodieldrin) and
4,5-trans-dihydrophotoaldrindiol (Fig. 14) are the major ones (464-466).
213
-------
Cl-f Cl
Cl
Photodieldrin
Aldrin-derived dicarboxylic acid
4.5-trons-dihydrooldfindiol
Cl-f Cl
Cl
Syn-12- hydroxydieldrin
Cl-fCI
Cl
Dieldrin pentachloroketone
4,5-trans-dihydrophotoaldrlnol
Ficj . 14. Major metabolites of aldrin, dieldrin and photodieldrin in mamrnals.
-------
Isodrin and Endrin. Isodrin is converted to its epoxide, endrin as a
result of mixed-function oxidase activity in the liver endoplasmic reticulum
i
of rats (454) and rabbits (455). The five principal excreted metabolites of
endrin identified in rodents are shown in Fig. 15. In male rats, the rate of
metabolism of endrin is about 3 times higher than that of dieldrin (467).
Unlike dieldrin, which is hydroxy'lated at the methylene bridge (C-12) position
to yield exclusively the syn-alcohol, endrin is hydroxylated at C-12 to yield
predominantly anti-12-hydroxyendrin and only minute amounts of the syn-isomer
(468-470). Rapid oxidation of syn-12-hydroxyendrin gives rise to 12-keto-
endrin, a minor urinary excretion product in the rat (468, 469). Endrin also
undergoes hydroxylation at the 3-position to yield 3-hydroxyendrin (469,
470). In addition, 4,5-trans-dihydroisodrin-4,5-diol has been reported to be
a minor excreted metabolite of endrin in rodents (469, 470). The hydroxylated
metabolites are mostly excreted in the bile in rats (468) but are excreted as
sulfate and glucuronide conjugates in the urine in rabbits (470).
Chlordane and Heptachlor. The mammalian biotransforraation of chlordane
has been critically discussed by Brimfield and Street (471). A considerable
body of information on the metabolic fate in mammals of cis-chlordane and
trans-chlordane, the two major components of technical grade chlordane, is
derived from studies in rats (472-476) and rabbits (477, 478). The principal
metabolic pathways of chlordane and heptachlor are depicted in Fig. 16. The
metabolism of trans-chlordane proceeds mainly via initial dehydrogenation to
1,2-dichlorochlordene followed by epoxidation of the double bond at the
2,3-positions, to yield oxychlordane (472-475, 478). Both oxychlordane and
1,2-dichlorochlordene are further converted to various hydroxylated compounds
which are excreted in free or conjugated forms. Another major route of bio-
transformation of chlordane involves direct hydroxylation yielding •
214
-------
Cl
[-2H] CN
-CI
OH
ci-f Aci
Cl
syn-12-hydroxyendrin
;i-T Ci Ol
»!>!,
onti -12-hydroxyendrin
3-hydroxyendrin
Ck HCK
Cl
Cl-f Cl
Cl
4.5-trqns-dihydroisodrindiol
a
*0
Cl
12-kefoendrin
Fig. 15. Major metabolites of isodrin and endrin in manmals.
-------
CLCI
•fl.
frons-Chtordone
Cl
Cl
Cl
cis-Chlordane
C'vCI Cl
1,2-dichloro-
chlordene
CLCI
1-exp-hydroxydihydro-
chlordene
Cl
Heptachlor epoxide
OH
1,2-dihydroxydihydro-
chlordene
Other hydroxylated
metabolites
Fig. 16. Metabolic pathways of chlordane (cis and trans) and heptachlor
in mammals.
-------
hydroxylated metabolites with up to three hydroxyl groups on the cyclopentane
ring. The cis-isomer of chlordane is more readily metabolized by this route
(475). The isolation and identification of other metabolites in in vivo (474,
478) and in.vitro (476) studies suggest that there are additional routes for
the metabolism of chlordane. One of these minor routes involves the formation
of heptachlor (475, 476) which has long been shown to undergo rapid eppxida-
tion in animals to yield heptachlor epoxide (479, 480). In the rat, hepta-
chlor epoxide undergoes hydroxylation to 1-exo-hydroxy-epoxychlordene; this
compound and another fecal metabolite were identified as metabolic products of
heptachlor epoxide (481).
Endosulfan (Thiodan) and Isobenzan (Telodrin). The metabolic fate of
endosulfan was widely investigated in mammalian species including the rat
(482, 483), mouse (482, 484), sheep (485), dog and cow (cited in ref. 486).
The subject has been discussed in several reviews (13, 36, 486, 487). Fig. 17
shows the generalized metabolic pathways of endosulfan in mammals. Unlike
other chlorinated cyclodiene pesticides, endosulfan is not a persistent com-
pound since its cyclic sulfite group renders it readily degradable in animal
tissues. The mammalian metabolites identified so far include endosulfan
sulfate, endosulfandiol and their oxidation products. Endosulfan sulfate has
also been detected as a metabolite in humans exposed to high doses of endo-
sulfan (488). One of the oxidation products of endosulfan sulfate, endosulfan
lac tone, is also a fecal metabolite of isobenzan in rats (489).
5.2.2.2.4.1.3 Metabolism of Halogenated Benzenes and Naphthalenes. There has
been considerable interest in the metabolic fate of halogenated aromatics
because of possible relationships of metabolism to toxicological effects and
'accumulation in animal tissues. The topit has been thoroughly reviewed in
several recent publications (42, 490-492). The general scheme for the
metabolism of halogenaced benzenes in mammals is outlined in Fig. 18,
-------
Cl
Cl
Endosulfan
Cl
Cl
I Isobenzan
n 0
Cl ||
C1^T>
ClUN£xLCH2
Cl
Endosulfan lactone
xx Endosulfan a-hydroxy ether
: "X Cl
CH2OH ^ ClrrrV-CHj,
-CH2OH
Endosulfandiol
/
0
Endosulfan ether
Fig. 17. Metabolic pathways of endosulfan and isobenzan in mammals.
-------
X=CI or Br
n=l-4
Conjugate
Fig. 18. General scheme for the metabolism of halogenated benzenes in
mammals. In the formulas X * Cl or Br, n - 1-4.
-------
It is generally accepted that oxldative hydroxylation by the hepatic
mixed-function oxidases is the primary metabolic route for the conversion of
halogenated benzenes and naphthalenes to more polar substances prior to their
excretion, in mammals. The initial metabolite formed is an unstable arene
oxide which may rearrange spontaneously to yield isoraeric phenols by the "NIH
shift" or be acted upon by epox;Lde hydrase to give dihydrodiols. Arene oxide
of low-halogenated benzenes and naphthalenes can also react with glutathione
to yield eventually mercapturic acids in the presence of S-epoxide trans-
ferase. Thus, mono-, di-, tri- and tetra-halogenated benzenes or naphthalenes
are readily biotransformed to free and conjugated halogenated phenolic com-
pounds via the formation of arene oxide intermediates.
In general, the rate of oxidative metabolism decreases as the degree of
halogenation increases because of steric hindrance by the halogen atoms.
Moreover, the position of halogenation plays an important role in determining
the rate of oxidative metabolism. It has been shown that chlorinated and
brominated benzenes having two adjacent unsubstituted carbon atoms yield arene
oxides more rapidly than those without adjacent unsubstituted carbon atoms,
despite a similar degree of halogenatio.n (493-496). For example, the relative
rates of excretion of trichlorobenzene by the rabbit were approximately 3:2:1
for 1,2,3-, 1,2,4- and 1,3,5-trichlorobenzene isomers, respectively (493). As
the degree of chlorination increases, the importance of adjacent unsubstituted
carbon atoms increases. Thus, for tetrachlorobenzene, the ratios for the rate
of excretion were approximately 20:5:1 for the 1,2,3,4-, 1,2,3,5- and
1,2,4,5-tetrachlorobenzene isomers, respectively (494). In addition to oxida-
tive hydroxylation via arene oxide, the metabolism of halogenated benzenes and
.naphthalenes, particularly the higher chlorinated and brorainated compounds,
may also involve direct oxidation and reductive dehalogenation.
-------
5.2.2.2.4.1.4 Metabolism of Polyhalogenated Biphenyls and Terphenyls. As
with halogenated benzenes, polyhaloblphenyls are mainly metabolized via arene
X.
oxide intermediates by hepatic mixed-function oxidases; the phenolic compounds
are the major metabolites, although dihydrodiols, sulfur-containing metabo-
lites (497-499) and other derivatives (491, 500). have also been reported.
Several comprehensive reviews on the biodegradation of polyhalobiphenyls have
appeared (490-492, 501, 502). Fig. 19 depicts the general pattern of mam-
malian metabolism of polychlorinated biphenyls extensively investigated during
the 1970's.
Mono-, di-, tri- and tetra-chlorobiphenyls are readily metabolized in
mammals although there can be considerable variation in the rate of metabolism
of specific isomers by different species. For instance, 4,4'-dichlorobiphenyl
is metabolized much more rapidly in rats and dogs than in monkeys (503). The
•rate of metabolism and excretion of polychlorinated biphenyl congeners
decreases as the number of chlorine atoms increases. In rats, 4,4'-dichloro-
biphenyl is metabolized at approximately half the rate of 4-chlorobiphenyl
(503, 504). Evaluation of the effects of the chlorine substitution pattern on
the rate of oxidative metabolism reveals that PCBs with two adjacent unsubsti-
tuted carbon atoms are metabolized and excreted more rapidly than other
isomers, a finding that is consistent with the importance of this structural
feature for arene oxide formation. Hydroxylation is generally favored in the
para position (with respect to the internuclear bond) of the less chlorinated
phenyl ring. Moreover, carbon atoms which are para to a chloro substituent
are also readily hydroxylated (491).
Much less is known about the biotransfonnation of polybrominated bi-
Unyls (PBBs). The limited observations available (e.g., 505, 506) tend to
be consistent with the findings on PCBs, except for a slower rate of metabo-
lism, probably due to greater hindrance by the larger bromine atoms (490).
217
-------
0
(R=glutathione,-CH3,
-OCH3 or-02CH3)
Fig. 19. General scheme for the metabolism of polychlorinated biphenyls
in mammals. In the formulas R * glutathione, -CH^, -OCH-, or -CKCHo.
-------
There is little information on the metabolism of polyhalogenated ter-
phenyls. The results of a study on the metabolism of a polychlorinated ter-
phenyl mixture in rats are consistent with the general conclusion for the
metabolism of chlorinated aromatics that the rate of metabolism is inversely
related to the degree of chlorine substitution (507).
5.2.2.2.4.1.5 Metabolism of DDT and Methoxychlor. The bio transformation of
DDT has been extensively studied and reviewed (13, 23, 34, 46, 434, 508-
510).- The salient metabolic pathways of DDT in mammals are shown in Fig.
20. In humans (511, 512) and in other mammalian species (513-515), the pre-
dominant route of metabolism is reductive dechlorination 'to ODD, which is
further converted to PDA via DDMU and other metabolic intermediates. DDA is
readily excreted in the urine either as free acid or in the bile as conjugates
with cholanic acid or amino acids (516, 517). In the mouse, o£-OH-DDA is also
produced via epoxidation of DDMU (518). Another major metabolic pathway of
DDT involves dehydrochlorination to DDE (513, 519, 520), the principal storage
form of DDT in mammalian tissues. Further metabolism of DDE occurs only
slowly, yielding DDA via the same route as with ODD (519). DDE is also meta-
bolized _via_ arene oxide to yield phenolic and methyl sulfone metabolites (521,
522). Other metabolic products of DDE include DBF, DBH and DBM (510) (see
Fig. 20 for chemical structures).
Among various animal species, there is a considerable variation in the
relative importance of the two major metabolic pathways of DDT. For instance,
DDT is metabolized to DDA almost exclusively via the ODD pathway in rhesus
monkeys (516). The ratio of liver residues of DDE/ODD in mice and hamsters
administered DDT was found to be 0.5 and 0.02, respectively (520).
218
-------
ci-c-ci
Hydroxy-DDE
Cl
IDE (ODD)
Methylsulfone-DDE
H-C-CI
DDMU
DDMU-epoxide
COOH
a-OH-DDA
FIGURE
20
-------
LEGEND TO FIGURE 20
Fig.. 20. Metabolic pathway of DDT in mammals. The abbreviations used
are: DDT (£,_£.,'-DDT) = 1,1 ,l-trichloro-2,2-bis-(_p_-chlorophenyl) ethane; DDE =
l,l-dichloro-2,2-bis-(_p_-chlorophenyl) ethylene; TDE (ODD) = 1 ,l-dichloro-2,2-
bis-(_p_-chlorophenyl) ethane; DDMU = l-chloro-2,2-bis-(_p_-chlorophenyl)
ethylene; DDMS = l-chloro-2, 2-bis-(_p-chlorophenyl) ethane); DDNU = 2,2-bis(_p_-
chlorophenyl) ethylene; DDOH = 2, 2-bis(j>-chlorophenyl) ethanol; DDA =
2,2-bis(p-chlorophenyl) acetic acid; DBF = 4,4'-dichlorobenzophenone; DBH =
4,4'-dichlorobenzo-hydroxy-methane; DBM = 4,4'-dichlorobenzene-inethane. Many
of the above acronyms designating these compounds represent abbreviations
based on older chemical terminology.
-------
Methoxychlor is metabolized much more rapidly than DDT (523). Most
metabolites are demethylated, dechlorinated, or dehydrochlorinated products.
In goats, seventeen metabolites have been isolated from urine and feces; the
predominant ones are 4,4'-substituted diphenyldichloroethanes (524).
5.2.2.2.4.2 MECHANISM OF ACTION.
While an increasing number of halogenated cyclic hydrocarbons have been
shown to induce cancer in laboratory animals, there is a dearth of information
on the mechanism of their carcinogenic action. Since the correlation between
carcinogenicity and mutagenicity of these chemicals is generally poor, they
appear not to be genotoxic. Nevertheless, some of them and/or their metabo-
lites possess latent alkylating properties which may be responsible for their
carcinogenic activity. In the foregoing section, we have seen that epoxides
are produced by the metabolism of various chlorinated cyclodiene pesticides,
such as aldrin, dieldrin, isodrin, endrin, chlordane and heptachlor. These
<
epoxide metabolites, although relatively unreactive because of their large
size and complexity, often accumulate in mammalian tissues. It has been
postulated that persistent exposure to these potentially alkylating inter-
mediates (or other electrophilic substances formed during metabolic degrada-
tion of these intermediates) may induce malignant cellular transformation
(177, 525).
Initial arene oxide formation is the key step in the metabolism of halo-
genated benzenes, naphthalenes and biphenyls (496, 526-529). The role of
arene oxide electrophiles in carcinugenesis of polycyclic aromatic hydro-
carbons is well documented (e.g., 530, 531). It has been proposed that, by
analogy, the carcinogenicity of halogenated benzenes and biphenyls is also due
to the metabolic production of reactive arene oxide intermediates, since
219
-------
covalent binding of these intermediates to protein, RNA and DNA has actually
been demonstrated both in vivo and in vitro (155, 529, 532, 533). Halogena-
tion of the aromatics renders then more lipid-soluble, more slowly metabolized
and therefore more persistent in animal tissues. Consistent with this view
are the findings which suggest that liver tumors are only elicited in animals
chronically exposed to'PCBs of high degrees of chlorination (366, 369).
l-Chloro-2,2-bis-(p-chlorophenyl)ethylene (DDMU), a metabolite common to
DDT, ODD and DDT, passes through an epoxide intermediate during further meta-
bolism. The DDMU-epoxide, being a derivative of vinyl chloride epoxide, may
account for the mutagenicity and carcinogenicity of DDT (177, 518). Moreover,
resonant limit structures "a" and "b" of 4,4'-dichlorobenzophenone (DBF),
another metabolite of DDT, may interact with cellular nucleophiles in
[TEXT-FIGURE 12]
SN2 reactions; this reaction proceeds via the leaving of Cl~, since the meso-
meric effect of the carbonyl group and the inductive effect of the chorine
atoms would result in positive charges at the para position of the benzene
rings (177).
Williams (534, 535), on the other hand, favors the hypothesis that
chlorinated cyclic hydrocarbon pesticides may be carcinogenic through epi-
genetic mechanisms rather than by direct action on DNA. Using genotoxicity
tests with liver-derived cell cultures, Williams (536) found no evidence for
any DNA-damaging or mutagenic action of endrin, chlordane, heptachlor, mirex,
kepone, DDT, ODD or DDE. Genotoxic effects, however, were elicited by the
.220
-------
TEXT - FIGURE 12
-------
positive control, 7,12-dimethylbenz[a]anthracene, in all test systems (124).
On the basis of these findings, together with the observations that intercel-
lular communication ("metabolic cooperation") among liver-derived cells was
inhibited by DDT (537) the same way as by many well known tumorigenesis
promoters, Williams (534, 535) suggested that organochlorine pesticides are
epigenetic carcinogens as are typical promoters. Tuoorigenesis promoters
t
("tumor promo tors") are defined by the author (535) as non-genotoxic chemicals
which, in addition to their enhancing effects on tumorigenesis, may exhibit
weak carcinogenicities themselves through epigenetic mechanism. The molecular
basis for the promoting and weak carcinogenic activities of tumorigenesis-
promotors is not yet established. However, recent research has shown, by the
so-called "metabolic cooperation" or "contact feeding" in vitro assay, that
potent promoters such as phorbol esters inhibit the cell-to-cell transfer of
metabolic products through gap junctions from enzyme-competent to enzyme-
deficient cells (538, 539). It was suggested that promoters may act on the
cell membrane so as to block the transmission of regulatory factors from
normal to spontaneously or chemically-induced transformed cells, thus permitt-
ing the latter to undergo progressive neoplastic growth (534, 535). As dis-
cussed in Section 5.2.2.2.3.7, a number of halogenated cyclic hydrocarbons are
promo tors. Several phenolic metabolites of hexachlorocyclohexane (BHC) and
chlorinated benzenes have also been shown to promote tumorigenesis as well as
elicit weak carcinogenic effects in rodents (see Section 5.2.2.5.3). In
addition to DDT, several other halogenated cyclic hydrocarbons including <*-
and 3T-BHC (lindane), aldrin, endrin, dieldrin, heptachlor, raethoxychlor, DDE
(540), mirex and kepone (541) and PBBs (542, 543) inhibit intercellular com-
munication in Chinese hamster cells. The hepatocarcinogenic effects of these
compounds in rodent strains susceptible to spontaneous liver tumors were,
221
-------
therefore, interpreted as permitting a larger number of preexisting,
genetically altered cells to progress to tumorigenesis, through the action of
\.
these compounds on the membranes of liver cells (534, 535, 541). By the same
effect, they may also promote tumorigenesis originating from preneoplastic
cells resulting from the action of other carcinogens. In connection with this
hypothesis, several chlorinated'cyclic hydrocarbons including aldrin, chlor-
dane, kepone, DDT and PCBs were shown to inhibit membrane ATPase activity
(544-547); thus, they may impair energy-dependent cellular processes such as
cell-to-cell transport of substances for homeostatic control in normal
tissues. The lipophilic properties of these compounds would facilitate their
accumulation in the cell membrane, a condition that has been shown to be
required for alterations in membrane function (534, 537). This requirement
would account for the observation that carcinogenesis by many of these com-
pounds occurs only after a prolonged period of administration and at high dose
levels.
Another possible (epigenetic) mechanism for the hepatocarcinogenicity of
organochlorine pesticides in the mouse was proposed by Wright ot_ _al_. (548).
These authors observed little binding of radioactivity to the liver DNA of
rodents exposed to * C-dieldrin in vivo. However, degranulation of the rough
endoplasmic reticulum (RER) was noted in the livers of mouse strains suscep-
tible to carcinogenesis by dieldrin. Several studies have established that
there is a correlation between the carcinogenic and RER-degranulatory actions
of chemicals (548-550). Detachment of ribosomes from the extravesicular
surfaces of RER may lead to alterations in the pattern of cellular protein
synthesis, i.e., alteration in gene expression, which may result in changes in
cell phenotype. It was, therefore, hypothesized that degranulation of liver
RER may be related to the carcinogenic!ty of dieldrin (548).
222
-------
5.2.2.2.5 Environmental Significance.
Since the introduction of DDT and other organochlorine insecticides
^.
during and after World War II, huge quantities of these chemicals have been
produced. In the United States alone, more.than a million tons of DDT and
close to a million tons of other organochlorine pesticides (aldrin, dieldrin,
chlordane, endrin, heptachlor and,toxaphene) were manufactured between 1950
and 1970 (cited in ref. 551). The total world production of DDT up to 1976
was estimated to exceed 2 million tons (1). At one time, organochlorine
compounds were used worldwide as general pesticides against a wide range of
insect species. Although current usage of these pesticides in the U.S. is
suspended or restricted, many of them are still insecticides of choice for
protecting crops from soil insects in many developing countries (19, 551). In
recent years, the production volumes of DDT and other organochlorine insecti-
cides have sharply declined; however, many of them persist in soil and water
for,months and years, and accumulate in the food chain. DDT, for instance, at
1 Ib/acre, was estimated to endure for 30 years in a forest environment
(62). The production volumes, half-lives (t,/2) in the soil and water, and
the bioconcentration factors (BCF) of DDT and of some halogenated cycloalkane
and cycloalkene pesticides are shown in Table XLII. High tonnages of chlori-
nated benzenes, chlorinated naphthalenes, polychlorinated biphenyls and poly-
brominated biphenyls have also been produced for various industrial applica-
tions during the past decades (Table XLIII).
As the result of massive production and widespread uses, together with
their chemical stability and lipophilic properties, these chemicals have
contaminated all parts of the ecosystem and now appear in the tissues of most
(organisms. The highest concentrations of these very persistent residues
usually occur in the tissues of animals at the upper levels of the food chain,
223
-------
Table XLII
Production Volume and Persistence of Some Halogenated
Gycloalkanes and Cycloalkanes, and DDTa
Compound
DDT (I)
Chlordane (I)
Toxaphene (I)
Heptachlor (I)
Dieldrin (I)
Endrin (I.A.R)
Endosulfan (I)
Lindane (J*-BHC)
Aldrin (I)
Mirex (I,F)
Production volumec
103 (1967); 30-49 (1972)
15-29 (1972)
50-99 (1972)
5-14 (1972)
5-10 (1962); < 1 (1972)
5-10 (1972)
1-4 (1972)
(I) 1-4 (1972)
5-14 (1972)
3-4 (1951-75)d
t 1/2
in soil
(year)
2.5-35
8
11
2-12
1-7
2.2
N.D.e
1-2
5-9
12
t 1/2
in water
(day)
1,825
N.D.
N.D.
N.D.
539
N.D.
N.D.
191
7.7
N.D.
BCFf
53,600
14,100
13,100
11,200
4,670
3,970
270
130
28
N.D.
^Summarized from: S.S. Epstein, In: "Origins of Human Cancer" (H.H. Hiatt,
J.D. Watson and J.A. Winsten, eds.), Book A, Cold Spring Harbor Laboratory,
1977; C.A. Edwards, "Persistent Pesticides in the Environment," 2nd ed., CRC
Press, 1976; R.E. Lee, Jr., "Air Pollution from Pesticides and Agricultural
Processes," CRC Press, 1976; "Ambient Water Quality Criteria Documents" for:
DDT; Chlordane; Toxaphene; Heptachlor; Aldrin/Dieldrin; Endrin; Endosulfan;
Hexachlorocyclohexane," U.S. Environmental Protection Agency, Washington,
D.C., 1980; "Reviews of the Environmental Effects of Pollutants: I. Mirex
and Kepone," U.S. Environmental Protection Agency, Washington, D.C., 1978.
Primary Use: I = Insecticide; A » Avicide; R 3 Rodenticide; F * Fungicide.
f*
Production Volumes in the United States in millions of pounds in the year
indicated in parentheses.
Total production of mirex and kepone from 1951 through 1975.
6N.D. = No data available.
The calculated weighted average bioconcentration factor for the compound in
the edible portion of all fish and shellfish consumed in the United States.
-------
Table XLIII
Production Volume and Major Uses of Chlorinated Benzenes,
Chlorinated Naphthalenes, Polyhalogenated Biphenyls and Terphenyls8
Compound
Production volume
Major uses
Chlorinated benzenes
450 (1980)
Chlorinated naphthalenes
5 (1972)
Polychlorinated biphenyls 85 (1970)
Polybrominated biphenyls 5 (1974)
Polychlorinated terphenyls 20 (1974)
Solvent, insecticide, fungicide,
disinfectants, intermediates for
the synthesis of dyes,
pesticides, pharmaceutics and
organic chemicals
Dielectrics, additives for high-
pressure lubricants, wood
preservatives, synthetic waxes
and impregnant
Dielectric fluids in capacitors
and transformers; fire-resistant
heat transfer and hydraulic
fluids; plasticizers, lubricants
Flame retardant in plastics
Plasticizers, investment casting
waxes, printing inks, sealants
Summarized from: International Agency for Research on Cancer [IARC Monogr.
No. 18, (1978)]; "Assessment of Testing Needs: Chlorinated Benzenes," U.S.
Environmental Protection Agency, Washington, D.C., 1980; "Environmental Hazard
Assessment Report, Chlorinated Naphthalenes," U.S. Environmental Protection
Agency, Washington, D.C., 1975; U.A. Th. Brinkman and A. Dekok, In:
"Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related
Products (R.D. Kimbrough, ed.), Elsevier, New York, 1980.
Production volume in the United States in millions of pounds in the year
indicated in parentheses.
-------
including humans, a phenomenon commonly known as "biological amplification"
(1, 552).
*.
5.2.2.2.5.1 EPIDEMIOLOGICAL EVIDENCE.
The presence of considerable levels of cyclodierie pesticides (1, 10, 553-
555), DDT (281, 555-557) as well as PCBs and PBBs (95, 99, 552, 555) has been
consistently reported in the fat, blood, milk, and body organs, in particular
the liver, of humans in various parts of the world. Because of the persis-
tence ,of these chemicals in human tissues, together with the evidence for
their carcinogenic!ty in animals, there has been concern that populations
exposed to these chemicals may be at high risk of cancer. However, most
epidemiological studies (10, 551, 558-560; reviewed in refs. 19, 21) of highly
exposed groups failed to reveal any significant increase in cancer incidence,
i
possibly due to small cohort size, short exposure periods, or low carcinogenic
activity toward humans. Nevertheless, for several of these chemicals, cases
^
of cancer following exposure were reported. In addition, a number of studies
suggest a correlation between tissue levels and various pathological condi-
tions, including neoplasms and increased mortality.
Chlorinated Cycloalkanes, Cycloalkenes, and DDT. In a cohort study (561)
of 1,791 agricultural workers exposed to various pesticides for 6 to 23 years,
a total of 169 malignant neoplasms were observed. The incidence of bronchial
carcinomas (59 cases) was 2 times higher in the exposed group than expected.
Since the smoking habits of the exposed group did not differ from those of the
general population, exposure to pesticides, particularly to hexachlorocyclo-
hexane and DDT, was suspected to be the cause of the bronchial carcinomas.
Additionally, an excess incidence of leukemia was observed in pesticide-
exposed agricultural workers (cited in ref. 283). Two cases of leukemia
following contact specifically with lindane (562) was reported.
224
-------
Evidence exists linking the increased incidence of lymphoma observed
between 1952 and 1972 in several counties of Iowa (USA) to the high level of
dieldrin in the'drinking water (563). A case of neuroblastoma in an infant
was ascribed to maternal exposure to chlordane during the first trimester of
pregnancy (564).
The concentration of organochlorine pesticides in the fat, liver and
other organ samples taken at autopsy has been analyzed by several investi-
gators (281, 553, 565, 566). In a study of 44 autopsy cases in Hawaii, the
five subjects with the highest levels of residues of dieldrin, heptachlor
epoxide and DDT in various tissues also had a variety of carcinomas and dis-
played generalized abnormality of the liver (553). In another study, the
organochlorine pesticide content in the adipose tissues of 271 terminal
patients from Florida was analyzed. Significantly elevated concentrations of
dieldrin, DDT, DDE and ODD were found in various tissues of patients who have
carcinomas (565). Deere and Jennings (566) reported that levels of dieldrin
and DDT and its metabolites were significantly higher in the lung tissues of
26 patients from New Zealand who died from lung cancer compared to the levels
in patients who died from other diseases. Another report from.Florida (281)
showed that the total mean concentration of dieldrin, hexachlorocyclohexane,
heptachlor epoxide and DDT in the body fat of 34 individuals who died from
hepatocarcinomas was 2 to 2.5 times that of the general population.
High levels of kepone have been detected in the blood, liver, and body
fat of workers and community residents who suffered from various unusual
illnesses as a result of massive contamination of a plant site in Virginia
(19, 222). However, results of long-term surveillance regarding the occur-
rence of cancer are not available at the time of this writing.
225
-------
Chlorinated Benzenes. An epidemic of porphyria cutanea tarta* in Turkey
occurred between 1955 and 1959 as a result of inadvertent consumption of an
estimated 50-200 mg/day of hexachlorobenzene present in contaminated grain. A
recent follow-up study of 32 of the individuals revealed abnormal porphyrin
metabolism and various systemic effects 20 years after the episode (567). No
data on carcinogenic effects were reported. Nonetheless, a carcinogenic
potential for humans cannot be excluded since in laboratory animals, there
appears to be a linkage between the development of hepatic porphyria and of
carcinoma (291). Prolonged exposure to ortho-, meta- and/or para-dichloroben-
zene in the workplace or during household applications was implicated in the
development of leukemia in 2 males and 2 females (cited in ref. 42).
Polychlorinated Biphenyls (PCBs). Bahn _et__al_. (568) reported a signifi-
cant excess of malignant melanomas and probably other cancers in 31 workers
heavily exposed to Aroclor 1254. In 73 Finnish autopsy cases, the highest
levels of PCBs were found in the hepatic or adipose tissues of three subjects
who had died of either leukemia, or liver or lung cancer (569).
Japanese individuals who consumed rice oil accidentally contaminated with
PCBs were found to contain an unusually high level of the chemical in the
blood, milk, liver and other organs (reviewed in refs. 16, 20). Among 1,665
"Yusho" patients in Kyushu (Japan), there were 51 deaths recorded during the
first 9 years after PCS exposure. Among the 31 individuals whose cause of
death has been confirmed, 11 (35.4%) were caused by malignant tumors of the
liver, lung, stomach, breast or lymphoid system. The expected mortality rate
from cancer in this particular region of Japan was estimated to be 21.1% (570).
*Characterized by pigmentation of the skin, photosensitivity, and hepatic
disfunction.
226
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5.2.2.2.5.2 ENVIRONMENTAL SOURCES, OCCURRENCE AND EXPOSURE.
Despite the ban of the use of many of these pesticides, significant
levels of residues are still routinely detected in the environment. Their
distribution in soil, water, air and food has been extensively investigated.
This section presents only a cursory review of the most recent studies; no
attempt is made to cover the vast amount of literature on the subject.
Thorough discussion of the problem and detailed environmental data are given
in a number of reviews and monographs (1, 15, 19-23, 31-41, 43, 44). Also, a
comprehensive review on the transport and fate of these chemicals in the
environment is available (571).
5.2.2.2.5.2.1 Soil.
Chlorinated Cycloalkanes and Cycloalkenes, and DDT. Organochlorine
insecticides can reach soil either directly through intentional application,
or indirectly, through rain or fallout from the air. Several factors such as
i
soil type, pH, temperature, moisture, microorganism content, the extent of
cultivation, and the volatility of the compounds influence their persistence
in the soil. The half-lives of several organochlorine insecticides in the
soil are given in Table XLII. During 1968-1973, most major agricultural areas
of the United States were monitored for pesticide residues (15, 572). In
1969, the U.S. government has initiated a program (U.S. National Soil
Monitoring Program) for sampling the soil periodically for pesticide residues
in metropolitan areas (573, 574). The results of the monitoring program show
that agricultural soils are widely contaminated with low levels of organo-
chlorine pesticides. As application of these compounds has declined, their
concentration in the soil is decreasing (572). The data obtained in 1972 are
'presented in Table XLIV. Organochlorine pesticides were detected in 45% of
227
-------
1,483 agricultural soil samples collected from different sites in 37 states.
Dieldrin, found in 27% of all soil samples, was the most frequently detected
pesticide. Other compounds including DDT, aldrin, chlordane and heptachlor
epoxide, were found in 21, 9, 8, and 7% of all soil samples, respectively.
The residual level of most pesticides ranged from 0.01 to 0.25 ppm (575).
Compared to agricultural soils .in the same locations, urban soils have
generally higher pesticide residue concentrations (572, 573, 576). Soil
samples adjacent to the site of a manufacturing plant in Hopewell, Virginia,
were found to contain as much as 10,000 to 20,000 ppm kepone (17).
Chlorinated Benzenes and Naphthalenes. Exposure of the general popula-
tion to chlorinated benzenes and naphthalenes mainly occurs as a result of
their release into the environment through manufacturing, industrial use,
processing and disposal (42, 577). In 1975, the soil samples collected at 22
of 29 locations along a 150-mile segment of the lower Mississippi River in
Louisiana (USA) were found to be contaminated with hexachlorobenzene, a fungi-
cide and byproduct of chemical industries, at levels ranging from 0.02 to 0.9
ppm. The highest levels occurred downstream from heavily industrialized areas
(578). Of the 1,483 cropland soil samples collected in 37 states in 1972 in
the framework of the the U.S. National Soil Monitoring Program, 11 samples
(0.7%) contained 0.01 to 0.44 ppm hexachlorobenzene (575). Significant levels
of hexachlorobenzene have also been reported in greenhouse and field soils in
the United States (579), in Belgium (580), in the Federal Republic of Germany
(581), and in Italy (582). The average concentration of chlorinated naph-
thalenes in soil samples collected near an electronic company in North
Carolina was 240 ng/kg. Low levels of these chemicals were also found in
poils near electronic products manufacturing and. electricity generating plants
in New York and Massachusetts (577).
228
-------
Table -JTLW
Halogenated Cycloalkanes and Cycloalkenes, and DDT Detected in U.S. Cropland Soil,
Surface Water and Ambient Air
Compound
Cropland
. , a
soil
Positive Concentration
samples (%) (ppm)
Lindane (1T-BHC) 0.1
Toxaphene
Aldrin
Dieldrin
Endrin
Chlordane
Heptachlor
Heptachlor
Endosulfan
DDT
DDE
ODD
5.1
8.7
27.2
0.7
7.9
3.9
epoxide 6.6
0.2
21.2
20.9
3.2
0.02
0.22-46.58
0.01-13.28
0.01-6.18
0.01-2.13
0.01-7.89
0.01-0.60
0.01-0.72
0.08-0.25
0.01-29.45
0.01-7.16
0.01-8.20
Surface
Positive
samples (%)
1.9
n.d.d
0,4
37.6
12.7
1.0
3.0
5.5
n.d.
16.3
5.5
12.9
water
Maximum
value (ppb)
0.112
0.085
0.407
0.133
0.169
0.048
0.067
0.316
0.05
0.84
Ambient Air°
Positive
samples (%)
67.7
3.5
13.5
94.0
8.1
0.1
42.0
n.d.
2.4
98.2
95.9
5.0
Maximum
value (ng/m )
11.7 (0.9)
8,700 (1,890)
24.6 (1.6)
23.9 (1.7)
19.2 (2.6)
204 (144)
27.8 (1.0)
2,256.5 (111.9)
94.3 (5.7)
19.1 (1.8)
127 (1.6)
aNational Soils Monitoring Program; 1,483 samples from 37 states were analyzed, 1972 [A.E. Carey, J.A.
Gowen, H. Tai, W. Mitchell and G.B. Wiersma, Pest. Monit. J. 12, 209 (1979)].
bAnnual surveys by the Federal Water Quality Administration; a total of 529 samples from about 100 sampling
stations were analyzed, 1964-68 [J.J. Lichtenberg, J.W. Eichelberger, R.C. Dressman and J.E. Longbottora,
Pest. Monit. J. ^, 71 (1970)].
cNational Ambient Air Monitoring Program; a total of 2,479 samples from 14-16 states were analyzed, 1970-72
[Kurtz et al., In: "Air Pollution from Pesticides and Agricultural Processes" (R.E. Lee, Jr., ed.), CRC
Press, 1976].
dn.d. = not detectable.
6Values in parentheses are mean levels in the positive samples.
-------
Polyhalogenated Biphenyls and Terphenyls. Industrial disposal and sewage
appear to contribute the most to the contamination of the environment by these
chemicals. Approximately 18,000 tons of PCBs was estimated to be disposed of
annually into dumps and landfills in the U.S. (583). Leakage of PCBs or PCB-
containing fluids from transformers or hydraulic systems may add to the resi-
dues in the environment. Rivers and streams are probably the major means by
which they are transported within the environment, although an airborne mode
of transport from the source has also been suggested (584). Polychlorinated
biphenyls were found in soils at levels as high as 20.7 ppm 600 miles from the
single U.S. manufacturer in Illinois and 18 ppm 1,650 miles from a user in the
investment casting industry in Michigan (584). Soil samples taken from a
drainage ditch in the vicinity of a transformer salvage company in South
Dakota in 1977 contained level of PCBs reaching 46 ppm (585). As part of the
U.S. National Soil Monitoring Program, PCBs in agricultural and urban soils
have been monitored since 1971. Of the .19 cities sampled between 1971 and
1974, 12 (63%) displayed detectable levels of PCBs. However, only 2 (0.1%) of
1,483 agricultural samples collected in 37 states in 1972 contained about 1
ppm of PCBs (586). In Japan, a nationwide survey of soil samples for PCBs
from 88 sites was conducted in 1972. Polychlorinated biphenyls were found in
soil samples at levels of more than 100 ppm from 4 sites, 1.1 to 100 ppm from
9 sites and less than 1.1 ppm from 75 sites (587).
Jacobs et_ al_. (588) have investigated the distribution and persistence of
polybrominated biphenyls (PBBs) in soils of Michigan where thousands of farm
animals were accidentally poisoned by PBBs in 1973. Of soil samples collected
from 28 crop fields which had received PBB-contaminated manure, 26 had PBB
Residues at levels of up to 371 ppb. It is believed that the great majority
of farm soils in Michigan contain low levels of PBBs.
229
-------
Polychlorinated terphenyls (PCTs) were detected in soils at levels as
high as 13 ppra 20 miles from an investment casting plant located in urban
v
Chicago, Illinois (584).
5.2.2.2.5.2.2 Water.
Chlorinated Cycloalkanes and Cycloalkenes, and DDT. Since the early
1960's, about 10 years after extensive application of these pesticides, many
local or nationwide surveys of these chemicals in major waterways have been
conducted periodically in the United States (e.g., 589-594) as well as in
other countries (e.g., 595, 597; reviewed in ref. 1). The results show
widespread occurrence of their residues in natural fresh waters, and in
sediments of streams, rivers and lakes around the globe. The major sources of
water contamination arising from these compounds are: (a) drainage or runoff
from treated agricultural land, (b) discharge from industries of manufacture
and formulation, (c) direct applications to control pests, such as mosquitoes,
t
or from large-scale crop or forest spraying, anc! (d) dust or precipitation
fallout.
The entire spectrum of chlorinated hydrocarbon insecticides has been
detected in the rivers of the United States. In a 1964-68 survey (590) of
pesticides in surface waters, a total of 529 samples collected through 100
sampling stations in 9 regions were analyzed. The data show that dieldrin is
the pesticide occurring predominantly in all 9 regions, whereas DDT and its
metabolites were predominant in regions west of the Mississippi. Between 1964
and 1966, hexachlorocyclohexane was detected in 10 of 12 samples from the main
stream of the Ohio River. Endrin was found in over 30% of the total number of
samples in 1964. Both heptachlor and heptachlor epoxide occurred in 14% of
the samples in 1965. The number of occurrences reached a peak around 1965 and
230
-------
1966 and then dropped significantly for all compounds except hexachlorocyclo-
hexane, which showed only a slight decline. This trend is paralleled by the
«.
decrease of production and use of organochlorine pesticides during the 2-year
study period. Although the contaminations found were generally low, a number
of samples have exceeded the environmental limit of 0.05 ug/liter recommended
by the Committee on Water Quality Criteria (cited in ref. 590). Moreover,
since most organochlorine pesticides are relatively insoluble, large quanti-
ties of residues.usually become bound to organic or inorganic particles, or
tied up in the biota. The residues reported in the surveys are only of insec-
ticides carried on particulate matter suspended in the water. The highest
levels (0.05-0.407 ppb) of various organochlorine insecticides found in water
samples in the 1964-68 survey are listed in Table XLIV. Significant levels of
dieldrin, DDT and lindane were still frequently detected in .the streams of the
western United States during surveys between 1968 and 1971. Not unexpectedly,
the£r highest concentrations were found in water samples containing particles
from the sediments (593). In 1975, water samples collected from the James
River (Virginia, USA) and from nearby waterways receiving effluent from the
Hopewell Sewage Treatment Plant were found to contain kepone up to 4 ppb (17).
Chlorinated hydrocarbon pesticides occur only occasionally and in
extremely small quantities in the drinking water in the United States. In a
study between 1964 and 1967, dieldrin was detected in about 40% of more than
500 drinking water supplies whose source was either the Mississippi or
Missouri River. Over 30% of the samples contained endrin, DDT and DDE.
Chlordane, aldrin, heptachlor, and lindane ( V-BHC) and other isomers of hexa-
chlorocyclohexane were also found occasionally. With only few exceptions, the
concentrations of pesticides in the water samples were lower than 0.1 ppb
(589). In a more recent national survey of 106 finished water samples, 54
contained 1-10 ppt dieldrin and 6 contained 1-2 ppt DDT (598).
231
-------
Chlorinated Benzenes and Naphthalenes. Environmental contamination by
hexachlorobenzene originating from fungicidal applications and from industrial
sources has been reported in surface waters, industrial effluents, as well as
in the drinking water in various U.S. and European sites (21, 599). Although
the average concentration in most water samples is less than 2 ppb, levels as
high as 90.3 ppb have been detected in samples from the lower section of the
Mississippi River (578). In a survey published in 1980 of 3,200 industrial
water and wastewater samples in the United States, 147, 178 and 20 samples
were found to contain more than 10 ppm of mono-, di-, and trichlorobenzenes,
respectively (42). In another survey, raonochlorobenzene was also detected in
finished drinking water in nine out of ten U.S. cities sampled (59S); the
levels ranged from 0.1 to 5.6 ppb.
The presence of chlorinated naphthalenes in water samples has not been
widely investigated (577). Law and Goerlitz (600) reported the occurrence of
55 ug/kg chlorinated naphthalenes in sediments from a stream, tributary to San
Francisco Bay. Similarly, Crump-Wiesner £t__al_. (601) detected 1,250-4,000
ug/kg chlorinated naphthalenes in sediment samples collected from a south
Florida drainage ditch; an average level of 5.7 ug/liter was found in the
water samples taken above the sediments.
Polyhalogenated Biphenyls and Terphenyls. Polychlorinated biphenyls have
become a major contaminant category of aquatic environments all over the
world. Sewage effluents and industrial disposal into waterways are believed
to be the main sources of water pollution by these chemicals. It was esti-
mated in 1972 that some 4,000 to 5,000 tons of PCBs entered the U.S. waterways
annually through dumps, leaks, spills and landfills. The amount of PCBs
entering the Great Lakes alone was of the order of 100 tons annually (583).
As may be expected from their low solubility and highly lipophilic nature,
232
-------
[most of the PCBs released into the rivers and lakes are adsorbed to sediments
or stored in tissues of aquatic organisms. The quantity of PCBs transported
to the oceans in solution or suspension from North American rivers amounted to
about 200 tons/year; the total input (also by localized industrial discharge
and aerial fallout) of PCBs into the oceans around North America was estimated
in 1972 to be 15,000 tons (583, 602).
Results obtained from national and regional monitoring studies have shown
that PCBs occur ubiquitously and at significant concentrations in surface
waters and particularly in the sediments of drainage basins in the United
States (600, 601, 603-607). By 1972, PCBs have been identified in surface and
groundwater samples from 13 states which represent almost every region of the
country; the concentration ranged from 0.1 to 4.0ug/liter. Among sediment
samples taken at random from 17 states, 14 contained PCBs in the range of 5.0
to 3,200 ug/kg. Across the United States, one out of every five sediment
samples contained residues of PCBs (601). In general, the highest levels of
PCBs were found in basins east of the Mississippi River (604).
Low levels of PCBs have also been detected in the surface water of Tokyo
Bay and of other water bodies in Japan (587), of the Rhine River, Lake
Constance and other waterways in European countries (608, 609.) as well as of
the Pacific Ocean and the Gulf of Mexico (44). The PCB levels in the sediment
samples at these sites were generally several times higher than those in the
overlying water.
Studies in 1974 found 0.01 to 0.07 ug/1 levels of polybrominated bi-
phenyls (PBBs) in river water samples taken as far as 12 miles downstream of a
plant in Michigan, where PBBs were produced. Follow-up surveys from 1975 to
1977 showed a decline in PBB levels in the river. However, high concentra-
233
-------
tions of PBB residues were detected in sediment samples collected in 1974
through 1977; the mean concentrations were 6,200 iig/kg near the plant and 100
ug/kg 29 miles downstream of the plant (610).
No information is available on the distribution of polychlorinated ter-
phenyls (PCTs) in the water bodies of the United States. However, there are
reports on the occurrence of PCTs in the water of the Rhine River, at an
average concentration of 0.07 ppb (611). Detectable levels of PCTs have also
been found in tissues of water fowls or fish from Canada (612) and Yugoslavia
(613). The contamination of water by PCTs in Japan was reported not to be
extensive (614).
5.2.2.2.5.2.3 Air.
Chlorinated Cycloalkanes and Cycloalkenes, and DDT. Since about 85% of
all these pesticides used in agricultural and forest lands are applied through
aerial or surface spray operations, spray dissemination has become the prin-
^
cipal source of residues in the air. However, considerable quantities of
these compounds also enter the atmosphere by volatilization from crops, soil
and water. On account of their persistent properties, chlorinated hydrocarbon
pesticides can remain in the air for long periods of time and have the poten-
tial of being transported to long distances by wind currents. Transport
through air has resulted in the dispersion of dieldrin, chlordane, DDT, DDE
and ODD to such remote areas as Antarctica (615), Bermuda (616) and Barbados
(617), suggesting probable global pollution of the atmosphere by these
chemicals.
Airborne residues of chlorinated hydrocarbon pesticides have been
detected periodically in both agricultural and urban areas of the United
States since 1963 (618; reviewed in refs. 19, 21). Data from various regional
234
-------
and national monitoring programs have illustrated the widespread contamination
of the atmosphere by these chemicals. During 1970-1972, a total of 2,479
ambient air samples were collected from 14-16 states for pesticide analysis.
Dieldrin, o^-BHC, DDT and DDE were found in almost every sample analyzed
during the 3-year period. Lindane ( Sf'-BHC) and heptachlor were also detected
with high frequencies. . Toxaphene, endosulfan and chlordane occurred in only a
small number of samples; however, their concentrations in the air were higher
than those of other compounds detected (619). The frequencies of positive
samples and the levels of chlorinated hydrocarbon pesticides found in ambient
air in this study are summarized in Table XLIV. The levels of kepone in air
samples taken about 200 yards from the production plant in Hopewell, Virginia
•3
ranged from 3.0 to 55 ug/m in 1974; levels at more distant areas in 1975 were
from 1.4-21 ng/m3 (17).
Chlorinated Benzenes and Naphthalenes. Chlorinated benzenes, especially
the* lower-chlorinated compounds, are relatively volatile and are released in
large quantities into the atmosphere during manufacture or application.
Approximately 30-50% of the monochlorobenzene, 5-10% of the 1,2-dichloroben-
zene and 70-90% of the 1,4-dichlorobenzene produced annually are estimated to
be ultimately released into the air (cited in ref. 33). Analysis of the air
samples from industrial areas of New Jersey, Alabama and Nevada detected
monochlorobenzene levels as high as 40 ug/m3 (8 ppb) and each of the three
isomers of dichlorobenzene at levels up to 33 ug/m^ (5.5 ppb). Low levels of
1,2-dichlorobenzene were also detected in the Los Angeles area (cited in ref.
33).
The ambient air concentrations of chlorinated naphthalenes near a produc-
tion plant were reported to range from 0.25 to 0.29 ug/m3 (cited in ref. 39).
235
-------
Polyhalogenated Biphenyls. Prior to curtailment of production and use in
1970, the total rate of loss of PCBs into the atmosphere in the United States
v
was estimated to be 1,500 to 2,000 tons/year, mainly by vaporization and open
burning (583). In the early 1980's substantial levels of PCBs are still being
detected in the air, in precipitation and in dry fallout in some regions of
the country, due partly to the persistent nature of the compounds and partly
to the continued release of these materials still in use. The routes of
transport of PCBs in the environment were estimated in 1975 to be nearly as
widespread as they were in 1972 (620). Analysis of ambient air samples col-
lected from suburban areas of Florida, Mississippi and Colorado in 1975
revealed that PCBs were present at all sampling sites, at an average concen-
tration of about 100 ng/m (621). There are also recent reports on the occur-
rence of PCBs in the atmosphere over the North Atlantic, the Gulf of Mexico,
the North Pacific Ocean, as well as in various urban, suburban and rural areas
of , the United States (cited in ref. 44, 622). Available data indicate that
the levels of PCBs in the atmosphere range from 0.5 to 36 ng/ra-* in urban and
suburban areas, and from 0.002 to 1.6 ng/m in oceanic and continental rural
areas (44).
In Japan, a nationwide survey showed that air samples from urban areas of
i
large cities such as Tokyo contained about 20 ng/m PCBs, whereas those from
medium-sized cities such as Matsuyama had about 2-5 ng/m (587).
There is much less information on the occurrence of polybrominated bi-
phenyls in the atmosphere. Air samples collected 900 meters downwind from a
manufacturing plant in New Jersey contained 0.06 ng/m of hexabromobiphenyls
(623).
236
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5.2.2.2.5.2.4 Food.
Chlorinated Cycloalkanes and Cycloalkenes, and DDT. Residues of chlori-
nated hydrocarbon pesticides in food constitute the most important source of
intake for the general population, since small amounts of-these chemicals in
soil, water and air are eventually taken up by food plants and animals. More
than 90% of human exposure to these chemicals is believed to result from
residues in food (10). Since the early 1960's, numerous surveys have been
conducted on the occurrence of these pesticides in human diets in the United
States, Canada, Japan and several European countries (reviewed in ref. 1).
The most frequently detected compounds were DDT and its metabolites, dieldrin
and the hexachlorocyclohexane isomers. Dairy products, meat, poultry and fish
were the food groups that had the highest levels of residues. Based on the
analysis of the total diet samples collected from 25 U.S. cities, the combined
average total intake of all chlorinated hydrocarbon insecticides was estimated
to''be about 0.1 mg/man/day between 1964 and 1966 (624). Although the levels
and frequencies of many chlorinated hydrocarbon pesticides in food are declin-
ing from year to year, residues were still found to occur in 52% of 360 food
combination groups (called "composites") from 30 grocery markets in thirty
different U.S. cities between 1972 and 1973 (625). The highest levels of
these residues found in various food categories are presented in Table XLV.
In 1982, milk samples from several dairy farms and a milk plant in Hawaii were
shown to contain extraordinarily high levels of heptachlor. It was suspected
that Hawaii residents might have consumed highly contaminated milk and milk
product for at least a year. The source of contamination was from feeding
cattle pineapple leaves upon which heptachlor had been sprayed to protect the
plants against mealybugs (626).
237
-------
Table XLV
Chlorinated Cycloalkanes and Cycloalkenes, and DDT and Related Compounds
in Human Dieta
DDT
and related
Food categories compounds
Dairy products 0.012
Meat, fish & poultry 0.114
Potatoes 0.005
Leafy vegetables 0.006
Legume vegetables T
Root vegetables 0.006
Garden fruits 0.009
Fruit vegetables 0.044
Oil, fat and shortening 0.021
Sugar and adjuncts T
Concentration
Hexachloro-
cyclohexane
(BHC) Dieldrin
0.004 0.005
0.003 0.01
n.d. 0.007
n.d. T
n.d. T
n.d. n.d.
0.006 0.012
n.d. T
0.005 0.004
0.005 n.d.
(pom)b'c
Heptachlor/
Heptachlor
epoxide
0.002
0.002
T
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d. •
Endosul .:
n.d.
n.d.
0.015
0.0439
n.d.
n.d.
0.002
n.d.
n.d.
n.d.
aA total of 360 food combination groups (called "composites") belonging to 10 food
categories from 30 grocery markets in 30 U.S. cities were analyzed, 1972-73 [R.D.
Johnson and D.D. Manske, Pest. Monit. J. _9_, 157 (1976)].
Highest levels detected; T = trace; n.d. = not detectable.
C
As high as 0.005 ppm of endrin was detected in potatoes; garden fruits also
contained trace and up to 0.002 ppm of chlordane and aldrin, respectively.
-------
Like other compounds of this class, kepone bioaccuraulates in aquatic
ecosystems. Several species of fish from the James River near Hopewell
v
(Virginia) were found to contain 0.01-2.0 ppra of kepone. Clams and oysters
•sampled at locations 8-64 miles from the manufacturing plant contained kepone
at levels of 0.2-0.8 ppm (17).
Halogenated Benzenes and Naphthalenes. The contamination of various food
products by hexachlorobenzene has been reviewed (21). Residues of hexachloro-
benzene have been detected in dairy products, fruits, vegetables, meat,
poultry and fish in the United States, Canada, Japan and several European
countries. Between 1972 and 1973, the levels of hexachlorobenzene in food
"composites" in thirty U.S. cities ranged from 0.006 to 0.041 ppm (625).
Trace to 6.7 ppm of monochlorobenzene, and various isomeric di-, tri- and
tetrachlorobenzenes were found in fish from Michigan, Pennsylvania, New York,
Ohio, Louisiana and Alabama. Low levels (trace to 0.05 ppm) of 1,4-di-,
l,2\4-tri- and 1,2,4,5-tetrabromobenzenes have been detected in fish caught
near a bromocarbon producer in Michigan (627).
Fruit from apple trees grown on chlorinated naphthalene-contaminated soil
contained 0.09 ppm of residue. Chlorinated naphthalenes have also been
detected in fish at a concentration of 0.039 ppm (cited in ref. 33).
Polyhalogenated Biphenyls and Terphenyls. Although these chemicals are
never intentionally used on agricultural products or processed food, contami-
nation of the food supply does occur. In fact, the major exposure of the
general population to these compounds is via the diet. The primary sources of
food contamination are: (a) environmental contamination (e.g. , fish in con-
taminated waterways) ; (b) industrial accidents such as leakage and spillage,
or inadvertent addition to animal feeds, feed ingredients or food (e.g., the
238
-------
-"Yusho" incident in Japan and the contamination of animal feed by PBBs in
Michigan); and (c) migration to food (e.g., baby foods, cereal products, etc.)
packaged in contaminated paper products.
Since late 1969, food sampling programs have been conducted by the U.S.
Food and Drug Administration (FDA) and the U.S. Department of Agriculture. In
f
early surveys, it was noted that fish, meat and poultry, milk, cheese, eggs
and byproducts used in animal feed (such as grains and cereal) often contain
high levels of PCBs (625, 628). Data from more recent studies show that the
frequency and levels of PCB residues have declined significantly in all
categories of food except fish, the product which is contaminated primarily
through the environment. The percentage occurrence of PCBs in fish samples
examined which contained detectable amounts of PCBs remained between 33% and
47% from 1971 to 1975 (628). The highest level of PCB residues occur in fish
from highly polluted coastal waters and from some inland waterways around
heavily industrialized areas. For instance, concentrations of PCBs in certain
species of fish from the Hudson River, the Great Lakes and Long Island Sound
have been in excess of the FDA tolerance level of 5 ppm (95). The typical
concentrations in most species of fish in the North Atlantic range from 0.01
to 1.0 ppm. It was estimated (95) that since 75 million U.S. consumers eat
more than the national average of 18.7 g fish per day, the exposure of these
consumers to PCB residues in ingested fish, based on a PCB level of 1 ppm,
would be more than 18.7 ug/day.
In Japan, a survey of the PCBs content of complete meals prepared from
food purchased at markets was conducted in 1972. The results indicate that
(the total intake of PCBs from diets varies between 3.8-50jug/person/day, with
a daily average of 16 .ug per capita. Of the PCBs ingested in one-week samples
diets, 80%.was from fish, 6% from meat and 6% from eggs (587). A national
239
-------
survey in 1972 showed chat 16% of sea-water fish and 18% of fresh-water fish
contained more than 1 ppm PCBs in the edible parts (587).
Subsequent to an incident when PBBs were accidently mixed with cattle
feed in place of magnesium oxide, approximately 10 thousand Michigan residents
were heavily exposed to PBBs from consuming meat, milk and eggs. In a survey
in 1974 of 22 contaminated farm premises in Michigan, PBBs levels as high as
595 mg/1 and 59.7 mg/kg were found in milk and eggs, respectively (20). Trace
to l.l ppm of PBBs has also been reported in fish taken from rivers near
chemical plants in Michigan as well as in West Virginia (627).
The occurrence of PCTs in food has not received as much attention as PCBs
or PBBs, although the extent of contamination with PCTs in food packaging
materials was found to be similar to that with PCBs (629). In Japan, only
negligible amounts of PCTs were found in foodstuffs such as dairy products,
fish, meat, edible oils, and vegetables (614).
240
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REFERENCES TO SECTION 5.2.2.2
t
1. Edwardsj C.A.: "Persistent Pesticides in the Environment," 2nd ed.
CRC Press, Cleveland, Ohio, 1976. 170 pp.
2. Keller, E.: Chemistry 43, 8 (1970).
3. NIEHS: "Conference on PCBs," Environmental Health Perspectives
Experimental Issue No. 1, National Institute of Environmental Health
Sciences, Research Triangle Park, North Carolina, 1972.
4. NIEHS: "Workshop on Scientific Aspects of Polybrominated Biphenyls,"
Environmental Health Perspectives Volume 23, National Institute of
Environmental Health Sciences, Research Triangle Park, North
Carolina, 1978, 369 pp.
. 5. Lundstrom, S. (ed.): PCB Conference II. Stockholm, Sweden, Dec. 14,
1972. National Swedish Environment Protection Board. Publications
1973:4E, Sweden, 1973, 138 pp.
6. USEPA: "National Conference on Polychlorinated Biphenyls," EPA-
f
560/6-75-004. U.S. Environmental Protection Agency, Washington,
D.C. 1976.
7. Snelson, J.T.: Ecotoxicol. Environ. Safety 1, 17 (1977).
8. Nicholson, W.J., and Moore, J.A. (eds.): "Health Effects of
Halogenated Aromatic Hydrocarbons," Annals New York Academy of
Sciences Volume 320, N.Y. Acad. Sci., (1979), 730 pp.
9. Ingle, I.: "A Monograph on "hlordane. Toxicological and
Pharmacological Properties," University of Illinois, Urbana,
Illinois, 1965, 88 pp.
10. Jager, K.W.: "Aldrin, Dieldrin, Endrin and Telodrin." Elsevier, New
York, 1970, 234 pp.
241
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11. Ulmann, E. (ed.): "Lindane. Monograph of an insecticide." Verlag
K. Schillinger, Freiburg i. Breisgan, 1972, 384 pp.
12. Kay, K.: Environ. Res. 6, 202 (1973).
13. Brooks, G.T.: "Chlorinated Insecticides Vol. II," CRC Press,
Cleveland, Ohio, 1976, 197 pp.
14. Hrdina, P.D., Singhal, R.L., and Ling, G.M.: Adv. Pharmacol.
Chemother. 12, 31 (1975).
15. Lee, R.E., Jr. (ed.): "Air Pollution from Pesticides and
Agricultural Processes." CRC Press, Cleveland, Ohio, 1976, 264 pp.
16. Higuchi, K. (ed.): "PCB Poisoning and Pollution," Academic Press,
New York, 1976, 184 pp.
17. Epstein, S.S.: Sci. Total Environ. 9, 1 (1978).
18. Pollock, G.A., and Kilgore, W.W.: Residue Rev. 69, 87 (1978).
19. IARC: "Some Organochlorine Pesticides." IARC Monographs on the
Evaluation of Carcinogenic Risk of Chemicals to Man, Vol. 5.
International Agency for Research on Cancer, Lyon, 1974, 241 pp.
20. IARC: "Polychlorinated Biphenyls and Polybrominated Biphenyls."
IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals
to Humans, Vol. 18, International Agency for Research on Cancer,
Lyon, 1978, 140 pp.
21. IARC: "Some Halogenated Hydrocarbons." IARC Monographs on the
Evaluation of Carcinogenic Risk of Chemicals to Humans, Vol. 20,
International Agency for Research on Cancer, Lyon, 1979, 609 pp.
22. WHO: "Polychlorinated Biphenyls and Terphenyls." Environmental
Health Criteria No. 2, World Health Organization, Geneva, 1976, 85
pp.
242
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23. WHO: "DDT and Its Derivatives." Environmental Health Criteria No.
9, World Health Organization, Geneva, 1979, 194 pp.
24. Kimbrough, R.D. (ed.): "Halogenated Biphenyls, Terphenyls,
Naphthalenes, Dibenzodioxins and Related Products." Elsevier/North
Holland, Amsterdam, 1980, 406 pp.
25. Ashwood-Smith, M.J.: Mutat. Res. 86, 137 (1981).
26. Khan, M.A.Q., and Stanton, R.H. (eds).: "Toxicology of Halogenated
Hydrocarbons. Health and Ecological Effects." Pergamon Press, New
York, 1981, 396 pp.
27. USEPA: "Environmental Hazard Assessment Report: Chlorinated
Naphthalenes." EPA-560/8-75-001. U.S. Environmental Protection
Agency, Washington, D.C., 1975.
28a. USEPA: "Chlordane and Heptachlor in Relation to Man and the
Environment." EPA-540/4-76-005. U.S. Environmental Protection
Agency, Washington, D.C., 1976.
28b. USEPA: "Reviews of the Environmental Effects of Pollutants: I.
Mirex and Kepone." EPA-600/1-78-013. U.S. Environmental Protection
Agency, Cincinnati, Ohio, 1978.
29. USEPA: "Reviews of the Environmental Effects of Pollutants: X.
Toxaphene." EPA-600/1-79-044. U.S. Environmental Protection Agency,
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601. Crump-Wiesner, H.J., Feltz, H.R., and Yates, M.L.: Pest. Monit. J.
_8, 157 (1974).
602. Harvey, G.R., Steinhauer, W.G., and Teal, J.M.: Science 180, 643
(1973).
603. Veith, G.D., and Lee, G.F.: Water Res. 5, 1107 (1971).
604. Dennis, D.S.: Polychlorinated Biphenyls in the Surface Waters and
Bottom Sediments of the Major Drainage Basins of the United States.
In "Proceedings of the National Conference on Polychlorinated
283
-------
Biphenyls," EPA-560/6-75-004, U.S. Environmental Protection Agency,
Washington, D.C., 1976, p. 183.
605. Glooschenko, W.A., Strachan, W.M.J., and Sampson, R.C.J.: Pest.
Monit.'J. 10, 61 (1976).
606. Nadeau, R.J., and Davis, R.A.: Bull. Environ. Contarn. Toxicol. 16,
436 (1976).
607. Kleinert, S.J.: Sources of Polychlorinated Biphenyls in Wisconsin.
In "Proceedings of the National Conference on Polychlorinated
Biphenyls," EPA-560/6-75-004, U.S. Environmental Protection Agency,
Washington, D.C., 1976, p. 124.
608. Eichner, M.: Z. Lebensmittelunters 161, 327 (1976).
609. Elder, D.: Marine Pollut. Bull. 7, 63 (1976).
610. Hesse, J.L., and Powers, R.A.: Environ. Health Persp. 23, 19 (1978),
611. Freudenthal, J., and Greve, P.A.: Bull. Environ. Contam. Toxicol.
10_, 108 (1973).
612. Zitko, V., Hutzinger, 0., Jamieson, W.D., and Choi, P.M.K.: Bull.
Environ. Contam. Toxicol. 7. 200 (1972).
613. Jan. J., Malnersic, S., and Zupancic, L.: Arh. Hig. Rada Toksikol.
_29_, 133 (1978).
614. Doguchi, M.: Ecotoxicol. Environ. Safety 1, 239 (1977).
615. Tatton, J. O'G., and Ruzicka, J.H.A: Nature (London) 215, 346
(1967).
616. Bidleraan, T.F., and Olney, C.E.: Science 183, 516 (1974).
617. Risebrough, R.W., Huggett, R.J., Griffin, J.J., and Goldberg, E.D.:
Science 159, 1233 (1968).
618. Lewis, R.G., and Lee, R.E., Jr.: Air Pollution from Pesticides:
Sources, Occurrence, and Dispersion. In "Air Pollution from
284
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Pesticides and Agricultural Processes," (R.E. Lee, Jr., ed.), CRC
Press, Cleveland, Ohio, 1976, p. 5.
619. Kutz, F.W., Yobs, A.R., and Yang, H.S.C.: National Pesticide
Monitoring Programs. In "Air Pollution from Pesticides and
Agricultural Processes," (R.E. Lee, Jr., ed.), CRC Press,
Cleveland, Ohio, 1976, p. 95.
620. Nisbet, I.C.T.: Environmental Transport and Occurrence of PCB's in
1975. In "Proceedings of the National Conference on Polychlorinated
Biphenyls," EPA-560/6-75-004, U.S. Environmental Protection Agency,
Washington, D.C., 1976, p. 254.
621. Kutz, F.W., and Yang, H.S.C.: A Note on Polychlorinated Biphenyls in
Air. In "Proceedings of the National Conference on Polychlorinated
Biphenyls," EPA-560/6-75-004, U.S. Environmental Protection Agency,
Washington, D.C., 1976, p. 182.
622. Buckley, E.H.: Science 216, 521 (1982).
623. DeCarlo, V.J.: -Ann. N.Y. Acad. Sci. 320, 678 (1979).
624. Duggan, R.E., and Wetherwax, J.R.: Science 157, 1007 (1967).
625. Johnson, R.D., and Manske, D.D.: Pest. Monit. J. 9, 157 (1976).
626. Smith, R.J.: Science 217, 137 (1982).
627. Lombardo, P.: Ann. N.Y. Acad. Sci. 320, 673 (1979).
628. Jelinck, C.F., and Corneliussen, P.E.: Levels of PCB's in the U.S.
Food Supply. In "Proceedings of the National Conference on
Polychlorinated Biphenyls," EPA-560/6-75-004, U.S. Environmental
Protection Agency, Washington, D.C., 1976, p.147.
629. Villeneuve, D.C., Reynolds, L.M., Thomas, G.H., and Phillips, W.E.:
J. Assoc. Off. Anal. Chem. 56, 999 (1973).
285
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SOURCE BOOKS AND MAJOR REVIEWS FOR SECTION 5.2.2.2
1. International Agency for Research on Cancer: "Some Organochlorine Pesticides"
IARC Monographs on Evaluation of carcinogenic Risk of Chemicals to Man,
Vol. 5, Int. Agency Res. Cancer, Lyon, France, 1974, 241 pp.
2. International Agency for Research on Cancer.- "Polychlorinated Biphenyls
and Polybrominated Biphenyls" IARC Monographs on Evaluation of Carcinogenic
Risk of Chemicals to Humans, Vol. 18, Int. Agency Res. Cancer, Lyon, France,
1978, 140 pp.
3. International Agency for Research on Cancer: "Some Halogenated Hydrocarbons"
IARC Monographs on Evaluation of Carcinogenic Risk of Chemicals to Humans,
Vol. 20, Int. Agency Res. Cancer, Lyon, France, 1979, 609 pp.
4. Nicholson, W.J., and Moore, J.A. (eds.): "Health Effects of Halogenated
Aromatic Hydrocarbons" Annals New York Academy of Science, Volume 320,
New York Academy of Science, New York, 1979, 728 pp.
5. Brooks, G.T.: "Chlorinated Insecticides, Vol. I. Technology and Application"
CRC Press, Boca Raton, Florida, 1974, 249 pp.
6. Brooks, G.T.: "Chlorinated Insecticides, Vol. II. Biological and Environmental
Aspects" CRC Press, Boca Raton, Florida, 1976, 197 pp.
7. Edwards, C.A.: "Persistent Pesticides in the Environment" 2nd ed.,
CRC Press, Boca Raton, Florida, 1976, 170 pp.
8. Higuchi, K. (ed.): "PCB Poisoning and Polution," Academic Press, New
York, 1976, 184 pp.
9. Jager, K.W.: "Aldrin, Dieldrin, Endrin and Telodrin," Elsevier, New
York, 1970, 234 pp.
10. Khan, M.A.Q. , and Stanton, R.H. (eds.) .- "Toxicology of Halogenated
Hydrocarbons -- Health and Ecological Effects" Pergamon Press, New
York, 1981, 396 pp.
286
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11. Kimbrough, R.D. (ed.): "Halogenated Biphenyls, Terphenyls, Naphthalenes,
Dibenzodioxins and Related Products," Elsevier/North-Holland, Amsterdam,
1980, 406 pp.
12. Lee, R.E., Jr. (ed.): "Air Pollution from Pesticides and Agricultural
Processes" CRC Press, Boca Raton, Florida, 1976, 264 pp. '
13. Ulmann, E. (ed.): "Lindane" Schillinger Verlag, Freiburg i. Breisgau,
1972, 384 pp.
14. Deichmann, W.B. (ed.): "Pesticides and the Environment: A Continuing
Controversy" Intercontinental Medical Book Corp., New York, 1973, 568 pp.
15. Allen, J.R., Hardgraves, W.A., Hsia, M.T.S., and Lin, F.S.D.: Pharmac.
Ther. 7, 513-547 (1979).
287
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Notes Added After Completion of Section 5.2.2.2
MUTAGENICITY
In accordance with earlier findings, recent rautagenesis test results have
shown that lindane (V~hexachlorocyclohexane), hexachlorocyclopentadiene,
chlordane, dieldrin, heptachlor, endosulfan, methoxychlor and chlorinated
benzenes are not mutagenic in the Ames strains of Salmonella typhimurium in
the absence or presence of liver microsomes (1-4). In addition, monofluoro-,
difluoro- and hexabromobenzene, 2-, 3-, and 4-monobromobiphenyl and different
hexabromobiphenyls have been reported to exhibit no mutagenicity in the Ames
test (2, 3). Hexachlorocyclopentadiene is also negative in the sex-linked
recessive lethal assay in Drosophila melanogaster (5). When tested in the
Rauscher Leukemia Virus assay, methoxychlor did not display any mutagenic
activity (5).
However, positive cytogenetic effects of technical-grade hexachlorocyclo-
hexane have been demonstrated in a dominant-lethal assay in Swiss mice (6).
The mutagenic activity of toxaphene in the Ames tests was confirmed (7).
Additional evidence for the mutagenicity of toxaphene has been provided by
results from the ad-3 forward-mutation test in Neurospora crassa (8). This
polychlorocamphene insecticide induces both multilocus deletions and intra-
cistronic mutations (a mixture of base-pair substitutions and fratneshift
mutations) in the ad-3 region. Methoxychlor showed positive response in the
u/
mouse lymphoma L578Y cell assay, as well as in the BALB/c 3T3 cell transfor-
\
mat ion test (1).
TERATOGENICITY
The teratogenic potential of hexachlorocyclopentadiene has been investi-
gated in rats (9), mice and rabbits (10). No teratogenic effect was detected
-------
in either species administered the compound up to 75 mg/kg/day from day 6 to
15 (rats and mice) or from day 6 to 18 (rabbits) of gestation.
Although exposure of pregnant animals to chlordane has not been shown to
cause structural abnormalities in newborns, severe depression of the func-
tional cell-mediated immune response has been noted in the offspring of mice
treated with chlordane at daily doses of 8.0 mg/kg throughout gestation (11).
Two women who worked in a chicken farm contaminated with dieldrin had an
estimated daily intake of 0.7-3.5 rag dieldrin during the second trimester of
pregnancy either by inhalation, skin contact, or by eating contaminated
eggs. They were reported to have delivered healthy, full-term babies (12).
A teratological study in rats exposed to 75, 200 or 500 ppm 1,4-dichloro-
benzene vapor from day 6 through day 15 of gestation did not reveal any sign
of embryo- or foetotoxicity or teratogenicity (4). Furthermore, there is no
evidence for teratogenic effects in rats given daily oral doses of 50, 100 or
200 mg/kg tetrachlorobenzene isomers during the period of organogenesis (13).
CARCINOGENICITY
Update Table IV summarizes the results of recent carcinogenesis studies
on organochlorine pesticides and halogenated aromatics.
Munir j2j^.al_. (14) reported that chronic administration of 500 ppm hexa-
chlorocyclohexane (technical grade) in the diet induced 100% hepatomas in
Swiss mice. However, no carcinogenic effects were observed in rats and
hamsters receiving the same treatment (14). oC-Hexachlorocyclohexane produced
a strong neoplastic response in the liver of HPB strain mouse; adenomas were
found in 23 of 24 mice ingesting 500 ppm ^-hexachlorocyclohexane in the diet
for 38 to 50 weeks (15).
-------
Update Table IV
Recent Carcinogenesis Studies of Halogenated Cyclic Compounds3
•
Compound
Hexach lorocyc lohexane
(technical grade)
-------
In confirmation of earlier findings (see Section 5.2.2.2.3.3), dieldrin
was found to increase the spontaneous liver tumor incidence of CF-1 mice
(16). Hamsters appear to be resistant to tumor induction by DDT. However,
Rossi et al. (17) reported that Syrian golden hamsters given dietary doses of
500 or 1,000 ppm DDE developed significant incidences of hepatocellular tumors
late in life.
Carcinogenesis bioassay results obtained by the U.S. National Toxicology
Program provided some evidence for the carcinogenic activity of monochloroben-
zene in the rat (18). In a 103-week study, monochlorobenzene was given to
groups of 50 Fischer 344 rats and B6C3Fj mice of both sexes by oral admini-
stration in corn oil, 5 days a week. The doses were 60 and 120 mg/kg/day for
male and female rats and for female mice. The doses for male mice were 30 and
60 mg/kg/day. Significantly increased incidence of liver neoplastic nodules
was observed in the high-dose male rats (25%) in comparison to the vehicle
control rats (4%). Under similar experimental conditions, 1,2-dichlorobenzene
was not carcinogenic in either species (19); the data on the carcinogenesis
bioassay of 1,4-dichlorobenzene are being analyzed at the time of this writ-
ing. The results from a recent long-term inhalation study in which groups of
male and female rats (Wistar-derived strain) and female mice (Swiss strain)
were exposed for 5 hr/day, 5 days/week, to 1,4-dichlorobenzene at concentra-
tions of 0, 75 or 500 ppm for 76 weeks (rats) or 57 weeks (mice), indicate
absence of carcinogenic activity (4). In a subchronic inhalation study, in
which male and female CD rats were exposed to vapor of 1,3,5-trichlorobenzene
at concentrations of 10, 100 or 1,000 mg/nr 6 hr/day, 5 days/week, for up to
13 weeks, squamous hyperplasia and metaplasia in the respiratory epithelium of
the nasal passages were noted in the high-dose group (24). Hexachlorobenzene
is not only a liver carcinogen in rats, mice and hamsters (see Section
-------
5.2.2.2.3.4); it also induces kidney neoplasms in the rat (20). In groups of
male and female Sprague-Dawley rats fed hexachlorobenzene at dietary doses of
0, 75 and 150 ppm for up to 2 years, the incidences of renal cell adenomas in
the control, low-dose and high-dose male rats were 7/54, 41/52 and 42/56,
respectively. In female rats, the respective tumor incidences were 1/52, 7/56
and 15/54. 4-(Trichloromethyl)-chlorobenzene (also known as jv-chlorobenzotri-
chloride), an industrial chemical structurally related to monochlorobenzene,
is carcinogenic in the mouse when administered orally or dermally (see Notes
Added After Completion of Section 5.2.2.1 for detailed discussion).
.Following chronic Aroclor 1260 intake (100 ppm for 16 months followed by
50 ppm for 8 months in the diet), hepatocellular tumors developed in 95% of 47
female and 15% of 46 male Sprague-Dawley rats. During the study period, only
one liver tumor occurred in 81 rats fed the control diet (21, 22). The con-
gener(s) responsible for the carcinogenic activity of PCBs is still unknown.
Weltman and Norback (23) reported that there was no increased incidence of
hepatic neoplasms in Sprague-Dawley rats fed a diet containing 100 ppm
2,3,6,2',3',6'-hexachlorobiphenyl for 29 months.
The carcinogenesis bioassay of PBBs in Fischer 344 rats and B6C3F^ mice,
which was previously described in a draft report (see Section 5.2.2.2.3.5),
has been published (25).
METABOLISM AND MECHANISM OF ACTION
While the biotransformation of lindane ( (T-hexachlorocyclohexane) in
animals has been quite well established, less information is available on the
metabolism of other isomers of hexachlorocyclohexane. Recently, Macholz et
al. (26, 27) described the detection and identification of various phenolic
metabolites in tissues and urine of rats administered the o^-or R-isomer of
-------
hexachlorocyclohexane orally. As in lindane metabolism, the initial step in
the biotransformation of ^.-hexachlorocyclohexane is the dehydrochlorination
to pentachlorocyclohexene isomers (26). Pharmacokinetic studies indicate that
the retention of ^-hexachlorocyclohexane in fatty and cerebral tissues of
rats is 10-20 times greater than that of lindane (28). Co-administration of a
hepatotoxic dose of chlorobenzene to the rat can, however, decrease the rate
of the excretion of lindane metabolites (29). Recent studies with human liver
microsomes have shown that there is a potentially substantial hepatic
metabolism of lindane in humans. Human liver microsomes metabolize lindane by
dehydrogenation, dehydrochlorination and hydroxylation, as does the microsomal
monooxygenase system of rodents (30).
The role of metabolism in the carcinogenic action of hexachlorocyclo-
hexane is still unclear. Oesch and coworkers (31) investigated the effects of
lindane-treatment on the liver weight and on the activities of several drug
metabolizing enzymes in CF-1 mice (in which strain lindane induces hepatomas)
and in B6C3Fi mice and Osborne-Mendel rats (which are considered refractory to
lindane-induced tumorigenesis) (see Section 5.2.2.2.3.2; Table XXXV and Table
XXXVI). Interestingly, these authors observed a large increase in liver
weight in the susceptible CF-1 strain mice treated with lindane. Moreover,
both untreated and treated CF-1 mice showed higher monooxygenase activity and,
after treatment with lindane, lower epoxide hydrase activity than non-
susceptible rodents. Based on these findings, the authors speculated that the
high monooxygenase activity together with the low epoxide hydrase activity in
the liver of CF-1 mice might lead to an accumulation of monooxygenase-
dependent reactive metabolite(s) which binds to cellular macromolecules.
Furthermore, as a result of increased DNA replication and liver cell proli-
feration during liver enlargement an amplification of DNA damage may occur
-------
(31). Recently, various isomers of hexachlorohexane have been shown to bind
in vivo to mouse liver DNA (32, 33) or in vitro to calf thymus DNA (33).
However, the following findings in these DNA-binding studies suggest that the
genotoxic effects of hexachlorocyclohexane isomers may not be the sole factor
for the tumor induction: (a) Both 0^- and ^-isomers of hexachlorocyclohexane
produced similar levels of DNA damage although the {^-isomer is a much more
potent carcinogen; (b) The binding of lindane to liver DNA in the susceptible
CF-1 mice is not higher than in the rat or in non-susceptible mouse strains;
(c) The level of DNA binding is much lower than would be expected to be a
genotoxic carcinogen.
Structure-activity studies (34, 35) have shown that there are consider-
able difference in certain biological properties among kepone (chlordecone),
mirex and several of their dechlorination products. For instance, mirex and
8-monohydromirex (photorairex) are about 2 times more potent than kepone in
inducing hepatic mixed-function oxidase(s) activity in the mouse. On the
other hand, 8-monohydromirex is closer to kepone in many toxicological mani-
festations than to mirex (34). Regarding the changes brought about in the
permeability of the mitochondrial inner membrane (from rat liver), the follow-
ing order of potency was observed: chlordecone alcohol _>. kepone (chlordecone)
> monohydrochlordecone > dihydrochlordecone. Mirex and a dioxolane-chlorde-
cone adduct, which lack a carbonyl or a hydroxyl moiety in their molecules,
did not affect the membrane permeability of rat liver mitochondria (35).
Furthermore, it has been demonstrated that kepone, but not mirex, potentiates
the hepatotoxicity of carbon tetrachloride in the rat (36, 37). The totality
of these findings indicates that, although structurally similar, the carcino-
genic activity of kepone and mirex is grounded in different mechanisms.
-------
"Dose-time to tumor" relationship analysis suggests that the hepatocar-
cinogenicity of dieldrin in CF-1 mouse is not determined by the sum of all
consecutive doses but by the level of daily exposure and, presumably, the
duration of treatment (16). The results of these analysis are in variance
with those for several genotoxic carcinogenic chemicals which exhibit, in a
double logarithemic system of coordinates, a linear relationship between the
median total dose or the median tumor induction period and the daily dose
level (cited in 16). Based on these observations, along with other findings
(38), it has been suggested that dieldrin, lindane, DDT and other related
compounds may act as promotors of tumorigenesis, rather than as carcinogens
per se. These compounds display activity in certain animal species possibly
by enhancing the effect of a genetically-linked oncogenic factor (16). In
connection with this hypothesis, there is evidence for the induction of endo-
genous avian tumor virus gene expression in chick embryo cells by the DDT
metabolites, DDA and DDE (39). The induction of an endogenous virus could
lead to the formation of recombinant transforming viruses or to the expression
of silent genes. Current research in viral oncology suggests that the pro-
ducts of some viral oncogenes can increase the availability of diacylglycerol,
a new second messenger located at the inner cell membrane. Diacylglycerol,
along with calcium (40). and several tumorigenesis-promotirig phorbol-esters
(41, 42), activate protein kinase C which has been suggested to be involved in
the control of cell division and differentiation (see 43-45). In addition to
oncogene induction, lipophilic organochlorine pesticides may penetrate the
cell membrance and substitute for diacylglycerol in activating the kinase.
This hypothesis framework appears to be related to the epigenetic mechanism of
carcinogenesis involving inhibition of intercellular communication (see
Section 5.2.2.2.4.2), since protein kinase C may act on components of the cell
-------
membrane and thus affect its permeability. Recently, chlordane has been added
to the list of tumorigenesis-promoting agents that inhibit intercellular
communication (46). On the other hand, incubation of chlordane with mouse
liver microsomes resulted in irreversible binding of chlordane metabolite(s)
to endogenous protein and RNA and to added DNA (47). Experimental evidence
rules out oxychlordane, but not other epoxide metabolites, to be involved in
the binding (47).
Chronic feeding of DDT to rats was found to significantly reduce the
hepatic level of S-adenosylmethionine (48). As low S-adenosylmethionine level
may result in hypomethylation of DNA and may affect the activity of essential
enzymes, it has been suggested that hepatocarcinogenesis of DDT may be due in
part to hepatic methyl insuffiency (48).
Recent research suggests that organochlorine pesticides, PCBs and PBBs
may act as other tumorigenesis promoters, by way of inhibiting intercellular
communication (see Section 5.2.2.2.4.2). Interestingly, Tsushimoto et al.
(49) noted that PBB congeners which inhibit "metabolic cooperation" are bromi-
nated at the ortho positions of the biphenyl rings and are inducers of micro-
soraal cytochrome P-450 (phenobarbital-type). On the other hand, PBB congeners
which are cytochrome P-448 inducers (3-methylcholanthrene-type) and are
unsubstituted in the ortho positions of the biphenyl rings do not inhibit
"metabolic cooperations." The ability of other halogenated aromatic compounds
to inhibit "metabolic cooperation" has not been tested. However, all these
halogenated aromatics are generally believed to act by a common mechanism
because of the similarities of chemical structures and biological effects.
Like PBBs, other halogenated aromatic compounds such as PCBs (e.g., 50, 51),
PCTs (52), chlorinated naphthalenes (52, 53) as well as chlorinated benzenes
(54) are all known to be inducers of microsomal mixed-function oxidases. The
-------
structure-activity relationship of PCBs as inducers of cytochrome P-450
(phenobarbital-type) and cytochrome P-448 (3-methylcholanthrene-type) in liver
microsomes are closely similar to those of PBBs (51, see also Section
5.2.2.2.2.2). Several highly halogenated naphthalenes which contain chlorine
or bromine substitution in the lateral 2,3,6 and/or 7-positions of the mole-
cule are cytochrome P-448 inducers (53, 55). Hexachlorobenzene appears to
induce cytochrome P-450, but all other chlorinated benzenes are cytochrome
P-448 inducers (54).
While congeners of halogenated biphenyls, naphthalenes, and benzenes
which induce cytochrome P-450 may act via inhibition of "metabolic coopera-
tion," the cytochrome P-448 inducers of this chemical group may act by
mechanisms similar to those of 2,3,7,8-tetrachlorodibenzo-jv-dioxin (TCDD) (the
most potent cytochrome P-448 inducer). The expression of normally
"restricted" genes by TCDD has been suggested to lead to a pleiotropic
response of various toxicological effects probably including tumorigenesis
(see Section 5.2.2.3.2.2 and Section 5.2.2.3.4).
ENVIRONMENTAL SIGNIFICANCE
A large number of chlorinated compounds have been detected in the vicin-
ity of Love Canal, a chemical dump site in Niagara Falls, New York. These
include isomers of hexachlorocyclohexane, mirex, hexachlorocyclopentadiene,
aldrin, endrin, endosulfan, ODD and chlorinated benzenes (56). Mice exposed
to Love Canal soil (placed in animal cages as bedding) for 90 days resulted in
the production of significant hepatic lesions, indicating that the liver was
the primary target organ (57).
Studies conducted during the last few years indicate that hexachloro-
cyclopentadiene (hex) continues to pose a potential hazard in industry and the
-------
environment. In 1975 and 1977, hex was identified as a contaminant in the
discharge of pesticide production plants in Tennessee and Michigan, respec-
tively (cited in 58). Significant amounts of hexachlorocyclopentadiene deri-
vatives were detected in edible fish from the Mississippi River near Memphis
(cited in 58). In March 1977, a municipal wastewater treatment plant in
Kentucky was found heavily contaminated with hex. The range of airborne
concentrations of hex in the primary treatment areas was 270-970 ppb, which is
much higher than the recommended Time-Weighted Average Threshold Limit Value
of 10 ppm. As a result of the episode, a large number of workers immediately
experienced mucous membrane, skin and respiratory tract irritation in addition
to headache, nausea, abdominal cramps and other symptoms (59, 60). The long-
term effects of exposure of humans and animals to hex is still unknown.
In Scotland, dieldrin is still used as a wood preservative. In 1981, a
batch of wood shavings from dieldrin-treated timber was used in the nesting
boxes of a chicken farm in West Lothian. As a result, 350 birds out of 10,000
died in a six week period due to dieldrin poisoning. Workers in the farm had
an estimated intake of dieldrin near or above the non-toxic-effect dose (0.7-
3.5 mg/day) for about 3 months by inhalation, skin contact, and by eating
contaminated eggs. Besides the farm workers, it was suspected that dieldrin
might have entered the human food chain through consumption of the birds, the
eggs or egg products by the public (12).
According to data of recent monitoring studies conducted by the U.S. Fish
and Wildlife Service, levels of DDT and its metabolites have decreased signi-
ficantly nationwide; however, their concentrations in fish and wildlife
species in large areas of Arizona, New Mexico and Western Texas have been
rising since 1976, indicating possible post-ban use of DDT in the southwestern
United States (61). The use of dicofol, an increasingly popular pesticide
10
-------
which contains 7% of more DDT as a by-product, could be one of the sources of
DDT contamination.
Among several widely publicized PCB-contaminated areas in the United
States, the cumulative exposure of aquatic animals and humans to PCBs in and
around New Bedford, Massachusetts, is considered to be unique (62). A New
England PCB survey in 1976 revealed that two electronic capacitor manufactur-
ing plants were discharging wastewater containing significant amounts of
PCBs. As a result, the water column and sediment in the entire New Bedford
Harbor contains PCBs levels well in excess of the marine water quality stan-
dard of 0.03 ppb; large areas of the Harbor have been closed to harvesting of
shellfish, finfish and lobster. Moreover, waste oils containing PCBs were
used by New Bedford and neighboring areas in the oiling of local roadways. As
a consequence, contamination with PCBs was reported throughout the entire
community. The 51 residents who have been examined in the course of an epi-
demiology study all contained elevated levels of PCBs in the blood (62).
Although the production of PCBs in Japan was banned in 1972, high concen-
trations of PCBs were found in 1981 in the sediment, water and biological
samples collected near the shipyards of Nagasaki Bay. The PCB pollution from
shipbuilding is the result of the use of PCBs in ship paints and the discharge
from the scraping of stale paints in shipyards (63).
Research conducted in 1981 has also shown that low levels of PCBs, DDT
and DDE are still detectable in antarctic fish (64). Between 1978 and 1980,
subcutaneous abdominal adipose tissues of 51 deceased Danish cancer patients,
and of 63 persons of Denmark who died without cancer, were submitted to chemi-
cal analysis. The results of this analysis suggest a significant association
between the level of PCB and DDE in the subcutaneous fat and cancer (65).
11
-------
References for Section 5.2.2.2 Update
1. NTP: "NTP Technical Bulletin No. 9," U.S. National Toxicology Program,
Research Triangle Park, North Carolina, 1983.
2. Haworth, S., Lawlor, T., Mortelmans, K., Speck, W., and Zieger, E.:
Environ. Mutagen. Suppl. J_, 3 (1983).
3. Shimizu, M., Yasui, Y., and Matsumoto, N.: Mutation Res. 116, 217
(1983).
4. Loeser, E., and Litchfield, M.H.: Food Chem. Toxicol. 21, 825 (1983).
5. NTP: "NTP Technical Bulletin No. 8," U.S. National Toxicology Program,
Research Triangle Park, North Carolina, 1982.
6. Lakkad, B.C., Nigam, S.K., Karnik, A.B., Thakore, K.N., Babu, A., Bhatt,
D.K., and Kashyap, S.K.: Mutation Res. 101, 315 (1982).
7. Rogauska, J.F., and Pollack, G.A.: Toxicologist 4, 35 (1984).
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